CN117547641A - Tissue viscosity absorbable material and preparation method and application thereof - Google Patents
Tissue viscosity absorbable material and preparation method and application thereof Download PDFInfo
- Publication number
- CN117547641A CN117547641A CN202311516439.5A CN202311516439A CN117547641A CN 117547641 A CN117547641 A CN 117547641A CN 202311516439 A CN202311516439 A CN 202311516439A CN 117547641 A CN117547641 A CN 117547641A
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- product
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- absorbable material
- lactide
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- 239000000463 material Substances 0.000 title claims abstract description 71
- 238000002360 preparation method Methods 0.000 title claims abstract description 7
- JJTUDXZGHPGLLC-UHFFFAOYSA-N lactide Chemical compound CC1OC(=O)C(C)OC1=O JJTUDXZGHPGLLC-UHFFFAOYSA-N 0.000 claims abstract description 17
- PAPBSGBWRJIAAV-UHFFFAOYSA-N ε-Caprolactone Chemical compound O=C1CCCCCO1 PAPBSGBWRJIAAV-UHFFFAOYSA-N 0.000 claims abstract description 16
- IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 claims abstract description 13
- 239000000178 monomer Substances 0.000 claims abstract description 13
- GOOHAUXETOMSMM-UHFFFAOYSA-N Propylene oxide Chemical compound CC1CO1 GOOHAUXETOMSMM-UHFFFAOYSA-N 0.000 claims abstract description 11
- 238000000034 method Methods 0.000 claims abstract description 11
- RKDVKSZUMVYZHH-UHFFFAOYSA-N 1,4-dioxane-2,5-dione Chemical compound O=C1COC(=O)CO1 RKDVKSZUMVYZHH-UHFFFAOYSA-N 0.000 claims abstract description 9
- VEZXCJBBBCKRPI-UHFFFAOYSA-N beta-propiolactone Chemical compound O=C1CCO1 VEZXCJBBBCKRPI-UHFFFAOYSA-N 0.000 claims abstract description 8
- 229960000380 propiolactone Drugs 0.000 claims abstract description 8
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 128
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 72
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 64
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 54
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 36
- 238000003756 stirring Methods 0.000 claims description 35
- 238000005406 washing Methods 0.000 claims description 30
- 239000003999 initiator Substances 0.000 claims description 29
- 239000002904 solvent Substances 0.000 claims description 29
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 27
- 239000003106 tissue adhesive Substances 0.000 claims description 27
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 18
- 239000000203 mixture Substances 0.000 claims description 18
- 238000002156 mixing Methods 0.000 claims description 16
- 238000001291 vacuum drying Methods 0.000 claims description 16
- 229920000642 polymer Polymers 0.000 claims description 14
- KSBAEPSJVUENNK-UHFFFAOYSA-L tin(ii) 2-ethylhexanoate Chemical compound [Sn+2].CCCCC(CC)C([O-])=O.CCCCC(CC)C([O-])=O KSBAEPSJVUENNK-UHFFFAOYSA-L 0.000 claims description 14
- BDNKZNFMNDZQMI-UHFFFAOYSA-N 1,3-diisopropylcarbodiimide Chemical compound CC(C)N=C=NC(C)C BDNKZNFMNDZQMI-UHFFFAOYSA-N 0.000 claims description 13
- YCLSOMLVSHPPFV-UHFFFAOYSA-N 3-(2-carboxyethyldisulfanyl)propanoic acid Chemical compound OC(=O)CCSSCCC(O)=O YCLSOMLVSHPPFV-UHFFFAOYSA-N 0.000 claims description 12
- GOUHYARYYWKXHS-UHFFFAOYSA-N 4-formylbenzoic acid Chemical compound OC(=O)C1=CC=C(C=O)C=C1 GOUHYARYYWKXHS-UHFFFAOYSA-N 0.000 claims description 12
- 239000000843 powder Substances 0.000 claims description 12
- 239000000376 reactant Substances 0.000 claims description 12
- 239000007787 solid Substances 0.000 claims description 12
- NQTADLQHYWFPDB-UHFFFAOYSA-N N-Hydroxysuccinimide Chemical compound ON1C(=O)CCC1=O NQTADLQHYWFPDB-UHFFFAOYSA-N 0.000 claims description 11
- FALRKNHUBBKYCC-UHFFFAOYSA-N 2-(chloromethyl)pyridine-3-carbonitrile Chemical compound ClCC1=NC=CC=C1C#N FALRKNHUBBKYCC-UHFFFAOYSA-N 0.000 claims description 10
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 10
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 10
- WXZMFSXDPGVJKK-UHFFFAOYSA-N pentaerythritol Chemical compound OCC(CO)(CO)CO WXZMFSXDPGVJKK-UHFFFAOYSA-N 0.000 claims description 10
- 229940014800 succinic anhydride Drugs 0.000 claims description 10
- TXBCBTDQIULDIA-UHFFFAOYSA-N 2-[[3-hydroxy-2,2-bis(hydroxymethyl)propoxy]methyl]-2-(hydroxymethyl)propane-1,3-diol Chemical compound OCC(CO)(CO)COCC(CO)(CO)CO TXBCBTDQIULDIA-UHFFFAOYSA-N 0.000 claims description 9
- 239000005977 Ethylene Substances 0.000 claims description 9
- 239000005057 Hexamethylene diisocyanate Substances 0.000 claims description 9
- 238000001035 drying Methods 0.000 claims description 9
- RRAMGCGOFNQTLD-UHFFFAOYSA-N hexamethylene diisocyanate Chemical compound O=C=NCCCCCCN=C=O RRAMGCGOFNQTLD-UHFFFAOYSA-N 0.000 claims description 9
- PTJWCLYPVFJWMP-UHFFFAOYSA-N 2-[[3-hydroxy-2-[[3-hydroxy-2,2-bis(hydroxymethyl)propoxy]methyl]-2-(hydroxymethyl)propoxy]methyl]-2-(hydroxymethyl)propane-1,3-diol Chemical compound OCC(CO)(CO)COCC(CO)(CO)COCC(CO)(CO)CO PTJWCLYPVFJWMP-UHFFFAOYSA-N 0.000 claims description 8
- 239000004386 Erythritol Substances 0.000 claims description 7
- UNXHWFMMPAWVPI-UHFFFAOYSA-N Erythritol Natural products OCC(O)C(O)CO UNXHWFMMPAWVPI-UHFFFAOYSA-N 0.000 claims description 7
- UNXHWFMMPAWVPI-ZXZARUISSA-N erythritol Chemical compound OC[C@H](O)[C@H](O)CO UNXHWFMMPAWVPI-ZXZARUISSA-N 0.000 claims description 7
- 229940009714 erythritol Drugs 0.000 claims description 7
- 235000019414 erythritol Nutrition 0.000 claims description 7
- 229920001306 poly(lactide-co-caprolactone) Polymers 0.000 claims description 7
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 claims description 6
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 claims description 6
- VHJLVAABSRFDPM-QWWZWVQMSA-N dithiothreitol Chemical compound SC[C@@H](O)[C@H](O)CS VHJLVAABSRFDPM-QWWZWVQMSA-N 0.000 claims description 6
- 150000001299 aldehydes Chemical group 0.000 claims description 5
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 5
- 238000001704 evaporation Methods 0.000 claims description 5
- NTTOTNSKUYCDAV-UHFFFAOYSA-N potassium hydride Chemical compound [KH] NTTOTNSKUYCDAV-UHFFFAOYSA-N 0.000 claims description 5
- 229910000105 potassium hydride Inorganic materials 0.000 claims description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 5
- 125000003827 glycol group Chemical group 0.000 claims description 4
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 claims description 4
- 229920001606 poly(lactic acid-co-glycolic acid) Polymers 0.000 claims description 3
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Polymers OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 claims description 2
- 239000002202 Polyethylene glycol Substances 0.000 claims description 2
- 230000000977 initiatory effect Effects 0.000 claims description 2
- 229920000747 poly(lactic acid) Polymers 0.000 claims description 2
- 229920001610 polycaprolactone Polymers 0.000 claims description 2
- 239000004632 polycaprolactone Substances 0.000 claims description 2
- 229920001223 polyethylene glycol Polymers 0.000 claims description 2
- 239000003795 chemical substances by application Substances 0.000 claims 1
- 238000007334 copolymerization reaction Methods 0.000 claims 1
- 231100000956 nontoxicity Toxicity 0.000 abstract description 4
- 230000035876 healing Effects 0.000 abstract description 2
- 210000000936 intestine Anatomy 0.000 abstract description 2
- 210000004072 lung Anatomy 0.000 abstract description 2
- 210000000496 pancreas Anatomy 0.000 abstract description 2
- 210000003491 skin Anatomy 0.000 abstract description 2
- 210000002784 stomach Anatomy 0.000 abstract description 2
- 239000000243 solution Substances 0.000 description 23
- 238000010586 diagram Methods 0.000 description 13
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 12
- 229910052739 hydrogen Inorganic materials 0.000 description 12
- 239000001257 hydrogen Substances 0.000 description 12
- 206010052428 Wound Diseases 0.000 description 10
- 208000027418 Wounds and injury Diseases 0.000 description 10
- 238000012360 testing method Methods 0.000 description 9
- 238000007151 ring opening polymerisation reaction Methods 0.000 description 7
- 238000005481 NMR spectroscopy Methods 0.000 description 6
- 230000015556 catabolic process Effects 0.000 description 6
- 238000007385 chemical modification Methods 0.000 description 6
- 238000006731 degradation reaction Methods 0.000 description 6
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 6
- 210000000813 small intestine Anatomy 0.000 description 5
- 210000004027 cell Anatomy 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 4
- 210000002889 endothelial cell Anatomy 0.000 description 4
- 239000002953 phosphate buffered saline Substances 0.000 description 4
- 125000003277 amino group Chemical group 0.000 description 3
- 102000004169 proteins and genes Human genes 0.000 description 3
- 108090000623 proteins and genes Proteins 0.000 description 3
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- 239000004743 Polypropylene Substances 0.000 description 2
- 125000003172 aldehyde group Chemical group 0.000 description 2
- 239000012620 biological material Substances 0.000 description 2
- 230000003833 cell viability Effects 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 150000002596 lactones Chemical group 0.000 description 2
- 230000014759 maintenance of location Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 239000002861 polymer material Substances 0.000 description 2
- -1 polypropylene Polymers 0.000 description 2
- 229920001155 polypropylene Polymers 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 125000003396 thiol group Chemical group [H]S* 0.000 description 2
- 206010056340 Diabetic ulcer Diseases 0.000 description 1
- 102000009123 Fibrin Human genes 0.000 description 1
- 108010073385 Fibrin Proteins 0.000 description 1
- BWGVNKXGVNDBDI-UHFFFAOYSA-N Fibrin monomer Chemical compound CNC(=O)CNC(=O)CN BWGVNKXGVNDBDI-UHFFFAOYSA-N 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 206010070834 Sensitisation Diseases 0.000 description 1
- 108010087230 Sincalide Proteins 0.000 description 1
- 239000004830 Super Glue Substances 0.000 description 1
- 208000002847 Surgical Wound Diseases 0.000 description 1
- 239000000853 adhesive Substances 0.000 description 1
- 230000001070 adhesive effect Effects 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000000560 biocompatible material Substances 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000010839 body fluid Substances 0.000 description 1
- 210000001124 body fluid Anatomy 0.000 description 1
- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 238000010609 cell counting kit-8 assay Methods 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 125000003700 epoxy group Chemical group 0.000 description 1
- 229950003499 fibrin Drugs 0.000 description 1
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 1
- 230000023597 hemostasis Effects 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- 239000012948 isocyanate Substances 0.000 description 1
- 150000002513 isocyanates Chemical class 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 229920006210 poly(glycolide-co-caprolactone) Polymers 0.000 description 1
- 238000006116 polymerization reaction Methods 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 230000008313 sensitization Effects 0.000 description 1
- 239000012679 serum free medium Substances 0.000 description 1
- IZTQOLKUZKXIRV-YRVFCXMDSA-N sincalide Chemical compound C([C@@H](C(=O)N[C@@H](CCSC)C(=O)NCC(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(N)=O)NC(=O)[C@@H](N)CC(O)=O)C1=CC=C(OS(O)(=O)=O)C=C1 IZTQOLKUZKXIRV-YRVFCXMDSA-N 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000007655 standard test method Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000003894 surgical glue Substances 0.000 description 1
- 238000011477 surgical intervention Methods 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
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-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
- A61L24/046—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
- A61L24/001—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
- A61L24/0042—Materials resorbable by the body
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G63/00—Macromolecular compounds obtained by reactions forming a carboxylic ester link in the main chain of the macromolecule
- C08G63/02—Polyesters derived from hydroxycarboxylic acids or from polycarboxylic acids and polyhydroxy compounds
- C08G63/06—Polyesters derived from hydroxycarboxylic acids or from polycarboxylic acids and polyhydroxy compounds derived from hydroxycarboxylic acids
- C08G63/08—Lactones or lactides
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G63/00—Macromolecular compounds obtained by reactions forming a carboxylic ester link in the main chain of the macromolecule
- C08G63/66—Polyesters containing oxygen in the form of ether groups
- C08G63/664—Polyesters containing oxygen in the form of ether groups derived from hydroxy carboxylic acids
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G63/00—Macromolecular compounds obtained by reactions forming a carboxylic ester link in the main chain of the macromolecule
- C08G63/91—Polymers modified by chemical after-treatment
- C08G63/912—Polymers modified by chemical after-treatment derived from hydroxycarboxylic acids
Abstract
The invention provides a tissue viscosity absorbable material, the molecular structure of which is a multi-arm molecular chain structure, and the structural unit of which is polymerized by one or more monomers of glycolide, lactide, caprolactone, beta-propiolactone, ethylene oxide or propylene oxide; the molecular chain is blocked by a reactive group, and the reactive group is one of N-hydroxysuccinimide-NHS, aldehyde-CHO, isocyanate-NCO or mercapto-SH. The invention also provides a preparation method and application of the tissue viscosity absorbable material. The tissue viscosity absorbable material provided by the invention has biocompatibility, biodegradability, no toxicity, good tissue viscosity, and can be used for directly adhering wound tissues without an additional curing process, and can be widely applied to adhesion of wound surfaces of tissues, such as adhesion and healing of wound surfaces of skin, lung, stomach, intestine, pancreas and the like.
Description
Technical Field
The invention relates to a tissue viscosity absorbable material, in particular to a tissue viscosity absorbable material, a preparation method and application thereof.
Background
Tens of millions of people each year suffer from a wide variety of tissue wounds, including skin cuts, chronic wounds (such as diabetic ulcers), surgical incisions, and the like. Suturing and stapling are traditional surgical approaches to dealing with wounds, but can cause additional tissue damage and are not effective in preventing leakage of body fluids and gases. The tissue adhesive material can seal the wound site, provide mechanical support and hemostasis while preventing leakage, and provide an effective solution for surgical intervention in the wound.
Currently, existing tissue adhesive materials have significant chemical property drawbacks and are still limited in clinical application. Although considered as gold standard, fibrin adhesives have low viscosity and are prone to leakage at the stoma; cyanoacrylate adhesives have strong stability but are considered toxic, cause significant inflammatory reactions, and require an additional curing process, which is inconvenient for clinical use. The ideal tissue-adhesive material should be biocompatible, biodegradable, non-toxic and capable of producing a strong adhesion to tissue.
Disclosure of Invention
The invention aims to solve the technical problem of providing a tissue viscosity absorbable material and a preparation method thereof, wherein the tissue viscosity absorbable material has biocompatibility, biodegradability, no toxicity, good tissue viscosity, and can directly adhere wound tissues without an additional curing process, and can be widely applied to the adhesion of wound surfaces of tissues, such as the adhesion and healing of wound surfaces of skin, lung, stomach, intestines, pancreas and the like.
In order to solve the technical problems, the technical scheme of the invention is as follows:
the structural unit of the tissue viscosity absorbable material is polymerized by one or more monomers of glycolide, lactide, caprolactone, beta-propiolactone, ethylene oxide or propylene oxide.
Further, the molecular chain of the tissue viscosity absorbable material is blocked by a reactive group, and the reactive group is one of N-hydroxysuccinimide-NHS, aldehyde-CHO, isocyanate-NCO or mercapto-SH.
Further, the multi-arm molecular chain structure of the tissue viscosity absorbable material is formed by initiating polymerization by an initiator, wherein the initiator is one of ethylene glycol, glycerol, pentaerythritol, erythritol, dipentaerythritol or tripentaerythritol.
Further, the single-arm molecular structure chain segment in the multi-arm molecular chain structure of the tissue adhesive absorbable material is a polylactide chain segment, a polyglycolide chain segment, a polycaprolactone chain segment, a polyethylene glycol chain segment, a poly (lactide-co-glycolide) chain segment, a poly (lactide-co-caprolactone) chain segment, a poly (lactide-co-ethylene glycol) chain segment, a poly (glycolide-co-caprolactone) chain segment, a poly (glycolide-co-ethylene glycol) chain segment, a poly (ethylene glycol-co-caprolactone) chain segment, a poly (lactide-co-glycolide) chain segment, a poly (lactide-co-caprolactone-co-glycolide) chain segment, a poly (glycolide-co-caprolactone-co-glycolide) chain segment, a poly (lactide-co-glycolide-co-caprolactone-co-glycolide) chain segment, one of the poly (glycolide-co-caprolactone-co-propanediol) chain segment or the poly (lactide-co-beta-propiolactone-co-propanediol) chain segment is formed by copolymerizing any two or more monomers of glycolide, lactide, caprolactone, beta-propiolactone, ethylene oxide and propylene oxide.
Further, the tissue viscosity absorbable material of the present invention has a number average molecular weight of 1000 to 200000g/mol, and further, a number average molecular weight of 2000 to 100000g/mol.
The preparation method of the tissue viscosity absorbable material comprises the following steps:
s1, when the initiator is glycerol, dipentaerythritol and tripentaerythritol, adding a monomer into the initiator according to the molar ratio of 1 (36.5-59.02), and blending for 10-20 minutes at the room temperature to 160 ℃ to obtain a blend;
when the initiator is glycol, pentaerythritol and erythritol, dissolving the initiator and potassium hydride in tetrahydrofuran according to the proportion of 1mmol (1-8) mmol (60-120) mL, stirring and reacting for 4 hours at room temperature to obtain an initiator solution, adding ethylene oxide or propylene oxide into the initiator solution, stirring and reacting for 24 hours at room temperature, adding other monomers, evaporating the solvent at 80 ℃ and then blending for 10-20 minutes to obtain a blend, wherein the molar ratio of the initiator to the monomers is 1 (28.6-95.49);
s2, adding stannous octoate into the blend obtained in the step S1 according to the weight ratio of 0.0045:1, and reacting for 20-24 hours at the temperature of 100-140 ℃ to obtain a crude pre-product;
s3, dissolving the crude pre-product obtained in the step S2 in methylene dichloride according to the proportion of 1g (1-2) mL, washing and purifying the crude pre-product for 3-5 times at the temperature of 0-5 ℃ by using diethyl ether, and drying the crude pre-product in vacuum at room temperature for 12-24 hours to remove the solvent to obtain a pre-product I, wherein the pre-product I is a polymer of which the end group of a molecular chain segment is hydroxyl;
s4, dissolving the first pre-product obtained in the step S3 in dichloromethane, adding succinic anhydride and 4-dimethylaminopyridine at the temperature of 0-5 ℃, and stirring and reacting for 20-30 hours at the temperature of 15-30 ℃ to obtain a second pre-product, wherein the ratio of the first pre-product to the dichloromethane to the succinic anhydride to the 4-dimethylaminopyridine is (0.2-0.5) g, 1mL, (4-35) mmol and (1.2-12) mmol;
s5, washing and purifying the pre-product obtained in the step S4 with diethyl ether at 0-5 ℃ for 3-5 times, and vacuum drying at room temperature for 12-24 hours to remove the solvent to obtain a pre-product III, wherein the pre-product III is a polymer with a carboxyl end group of a molecular chain segment;
s6, dissolving the pre-product III obtained in the step S5 in dichloromethane, adding N-hydroxysuccinimide, 4-dimethylaminopyridine and N, N '-diisopropylcarbodiimide at 0-5 ℃, and stirring at 15-30 ℃ for reacting for 20-30 hours to obtain a pre-product IV, wherein the ratio of the pre-product III to the dichloromethane to the N-hydroxysuccinimide to the 4-dimethylaminopyridine to the N, N' -diisopropylcarbodiimide is (0.2-0.5) g to 1mL (4-35) mmol (1.2-12) mmol (4-35) mmol;
s7, washing and purifying the pre-product obtained in the step S6 with diethyl ether at 0-5 ℃ for 3-5 times, and vacuum drying at room temperature for 12-24 hours to remove the solvent to obtain the tissue adhesive absorbable material with the molecular chain segment end group of N-hydroxysuccinimide-NHS;
s8, dissolving the first pre-product obtained in the step S3 in dichloromethane, adding 4-formylbenzoic acid and 4-dimethylaminopyridine, uniformly mixing, adding dicyclohexylcarbodiimide at 0-5 ℃, and stirring for reacting for 24 hours to obtain a fifth pre-product, wherein the ratio of the first pre-product to the dichloromethane to the 4-formylbenzoic acid to the 4-dimethylaminopyridine to the dicyclohexylcarbodiimide is (0.2-0.5) g, 1mL, (4-35) mmol, (1.2-12) mmol and (4-35) mmol; washing and purifying the pre-product with diethyl ether at 0-5deg.C for 3-5 times, vacuum drying at room temperature for 12-24 hr, and removing solvent to obtain the tissue viscosity absorbable material with aldehyde group-CHO terminal group as molecular chain segment;
s9, dissolving the first pre-product obtained in the step S3 in toluene to obtain a toluene pre-product solution with the concentration of 0.2-0.5g/mL, adding the toluene pre-product solution into a toluene solution of hexamethylene diisocyanate with the concentration of 0.2-0.5g/mL, wherein the molar ratio of the first pre-product to the hexamethylene diisocyanate is 1 (4-30), stirring uniformly, adding stannous octoate, wherein the weight of the stannous octoate is 0.45% of the sum of the weights of the toluene pre-product solution and the toluene solution of hexamethylene diisocyanate, and stirring at 60 ℃ for 2 hours to obtain a sixth pre-product; washing and purifying the pre-product six with diethyl ether at 0-5 ℃ for 3-5 times, and vacuum drying at room temperature for 12-24 hours to remove the solvent to obtain the tissue adhesive absorbable material with the molecular chain segment end group of isocyanate-NCO;
s10, dissolving the pre-product I, dithiodipropionic acid and 4-dimethylaminopyridine obtained in the step S3 in methylene dichloride, adding N, N '-diisopropylcarbodiimide at 0-5 ℃ after uniform mixing, stirring and reacting for 8 hours to obtain a reactant I, washing the reactant with methanol at 0-5 ℃ for three times to obtain solid powder, wherein the ratio of the pre-product I, methylene dichloride, 4-dimethylaminopyridine, N' -diisopropylcarbodiimide and methanol is (0.2-0.5) g to 1mL to 1.2-12 mmol to (4-35) mmol to (10-15) mL, and the molar ratio of the pre-product I to the dithiodipropionic acid is (1 to 4-30);
s11, dissolving the solid powder obtained in the step S10 and dithiothreitol in dichloromethane, stirring and reacting for 8 hours to obtain a reactant II, washing the reactant II with methanol at 0-5 ℃ for three times to obtain the tissue adhesive absorbable material with the end group of a molecular chain segment being mercapto-SH, wherein the ratio of the solid powder to the dichloromethane to the methanol is (0.5-1) g to 1mL (10-15), and the molar ratio of the solid powder to the dithiothreitol is (1) (2-10).
Further, in the step S1 of the present invention, the monomer is one or more of glycolide, lactide, caprolactone, β -propiolactone, ethylene oxide or propylene oxide.
The invention also provides application of the tissue adhesive absorbable material in preparing a tissue adhesive material.
Compared with the prior art, the invention has the following beneficial effects:
(1) The invention initiates ring-opening polymerization of epoxy groups by an initiator with multi-arm hydroxyl groups to obtain polymer materials, the polymer materials are chemically modified to obtain active group end-capped, N-hydroxysuccinimide and aldehyde groups in the active groups can react with amino groups and sulfhydryl groups of proteins in human tissues to generate bonding, isocyanate can react with amino groups and hydroxyl groups of proteins in human tissues to generate bonding, sulfhydryl groups can react with amino groups of proteins in human tissues to generate bonding, so that the tissue adhesive absorbable material prepared by the invention has better tissue adhesiveness and convenient clinical use, and can be directly smeared on wound surfaces of tissues and bonded after being pressed.
(2) The raw materials used in the invention are all biocompatible materials, the raw materials are easy to obtain, the cost is low, the invention is suitable for industrial production, and the prepared tissue viscosity absorbable material has biocompatibility, biodegradability and nontoxicity.
Drawings
The accompanying drawings, which are included to provide a further understanding of the invention and constitute a part of this specification, are incorporated in and constitute a part of this specification and do not limit the invention in any way, and in which:
FIG. 1 is a schematic molecular structure diagram of a tissue viscosity absorbable material prepared in example 1 of the present invention and a hydrogen nuclear magnetic resonance spectrum;
FIG. 2 is a schematic molecular structure diagram of a tissue viscosity absorbable material prepared in example 2 of the present invention and a hydrogen nuclear magnetic resonance spectrum;
FIG. 3 is a schematic molecular structure diagram of a tissue viscosity absorbable material prepared in example 3 of the present invention and a hydrogen nuclear magnetic resonance spectrum;
FIG. 4 is a schematic molecular structure diagram of a tissue viscosity absorbable material prepared in example 4 of the present invention and a hydrogen nuclear magnetic resonance spectrum;
FIG. 5 is a schematic molecular structure diagram of a tissue viscosity absorbable material prepared in example 5 of the present invention and a hydrogen nuclear magnetic resonance spectrum;
FIG. 6 is a schematic molecular structure diagram of a tissue viscosity absorbable material prepared in example 6 of the present invention and a hydrogen nuclear magnetic resonance spectrum;
FIG. 7 is a graph showing the burst pressure test of experimental example 1 of the present invention;
FIG. 8 is a photomicrograph of endothelial cells of Experimental example 1 of the present invention after 24 hours of culture in a petri dish containing the viscous absorbable material of the tissue of example 2;
FIG. 9 is an in vitro degradation test chart of experimental example 3 of the present invention.
Detailed Description
The present invention will be described in detail with reference to specific examples, wherein the exemplary embodiments of the present invention and the descriptions thereof are provided for the purpose of illustrating the present invention, but are not to be construed as limiting the present invention.
Example 1
The method is characterized in that dipentaerythritol is used as an initiator to initiate lactide, glycolide and caprolactone to carry out ring-opening polymerization, and the tissue viscosity absorbable material with the end group of N-hydroxysuccinimide-NHS and the number average molecular weight of 6000g/mol is obtained through chemical modification, and the steps are as follows:
s1, adding 13.79mmol of lactide, 13.79mmol of glycolide and 13.79mmol of caprolactone into 1mmol of dipentaerythritol, and blending for 10 minutes at 160 ℃ to obtain a blend;
s2, adding stannous octoate into the blend obtained in the step S1 according to the weight ratio of 0.0045:1, and reacting at 130 ℃ for 20 hours to obtain a crude pre-product;
s3, dissolving the crude pre-product obtained in the step S2 in 10mL of dichloromethane, washing and purifying the crude pre-product with diethyl ether at 0 ℃ for 3 times, and drying the crude pre-product in vacuum at room temperature for 12 hours to remove the solvent to obtain a pre-product I, wherein the pre-product I is a polymer with hydroxyl groups as end groups, wherein the polymer comprises a dipentaerythritol segment and a poly (lactide-co-glycolide-co-caprolactone) chain;
s4, dissolving the first pre-product obtained in the step S3 in methylene dichloride, adding succinic anhydride and 4-dimethylaminopyridine at the temperature of 0 ℃, and stirring and reacting for 24 hours at the temperature of 25 ℃ to obtain a second pre-product, wherein the ratio of the first pre-product to the methylene dichloride to the succinic anhydride to the 4-dimethylaminopyridine is 0.2g to 1mL to 8mmol to 2.7mmol;
s5, washing and purifying the pre-product obtained in the step S4 with diethyl ether at 0 ℃ for 3 times, and vacuum drying at room temperature for 12 hours to remove the solvent to obtain a pre-product III, wherein the pre-product III is a polymer with carboxyl groups as the end groups of a dipentaerythritol segment and a poly (lactide-co-glycolide-co-caprolactone) chain;
s6, dissolving the pre-product III obtained in the step S5 in dichloromethane, adding N-hydroxysuccinimide, 4-dimethylaminopyridine and N, N '-diisopropylcarbodiimide at 0 ℃, and stirring at 25 ℃ for reacting for 24 hours to obtain a pre-product IV, wherein the ratio of the pre-product III to the dichloromethane to the N-hydroxysuccinimide to the 4-dimethylaminopyridine to the N, N' -diisopropylcarbodiimide is 0.2g:1mL:9mmol:2.7mmol:9mmol;
s7, washing and purifying the pre-product obtained in the step S6 with diethyl ether at 0 ℃ for 3 times, and vacuum drying at room temperature for 12 hours to remove the solvent to obtain the tissue viscosity absorbable material with the number average molecular weight of 6000g/mol and including dipentaerythritol sections and N-hydroxysuccinimide-NHS as the end group of poly (lactide-co-glycolide-co-caprolactone) chains, wherein the molecular structure schematic diagram and the nuclear magnetic resonance hydrogen spectrogram of the tissue viscosity absorbable material are shown in the figure 1.
Example 2
The lactide and caprolactone ring-opening polymerization is initiated by using glycerol as an initiator, and the tissue viscosity absorbable material with the end group of N-hydroxysuccinimide-NHS and the number average molecular weight of 8000g/mol is obtained through chemical modification, and the method comprises the following steps:
s1, adding 29.51mmol of lactide and 29.51mmol of caprolactone into 1mmol of glycerol, and blending for 20 minutes at 110 ℃ to obtain a blend;
s2, adding stannous octoate into the blend obtained in the step S1 according to the weight ratio of 0.0045:1, and reacting for 20 hours at 110 ℃ to obtain a crude pre-product;
s3, dissolving the crude pre-product obtained in the step S2 in 10mL of dichloromethane, washing and purifying the crude pre-product with diethyl ether at 0 ℃ for 4 times, and drying the crude pre-product in vacuum at room temperature for 24 hours to remove the solvent to obtain a pre-product I, wherein the pre-product I is a polymer with a glycerol segment and a poly (lactide-co-caprolactone) chain end group as a hydroxyl group;
s4, dissolving the first pre-product obtained in the step S3 in dichloromethane, adding succinic anhydride and 4-dimethylaminopyridine at the temperature of 0 ℃, and stirring and reacting for 24 hours at the temperature of 25 ℃ to obtain a second pre-product, wherein the ratio of the first pre-product to the dichloromethane to the succinic anhydride to the 4-dimethylaminopyridine is 0.5g to 1mL to 4mmol to 1.4mmol;
s5, washing and purifying the pre-product obtained in the step S4 with diethyl ether at 0 ℃ for 4 times, and vacuum drying at room temperature for 24 hours to remove the solvent to obtain a pre-product III, wherein the pre-product III is a polymer with a carboxyl end group comprising a glycerol segment and a poly (lactide-co-caprolactone) chain;
s6, dissolving the pre-product III obtained in the step S5 in dichloromethane, adding N-hydroxysuccinimide, 4-dimethylaminopyridine and N, N '-diisopropylcarbodiimide at 0 ℃, and stirring at 25 ℃ for reacting for 24 hours to obtain a pre-product IV, wherein the ratio of the pre-product III to the dichloromethane to the N-hydroxysuccinimide to the 4-dimethylaminopyridine to the N, N' -diisopropylcarbodiimide is 0.2g to 1mL to 4.5mmol to 1.4mmol to 4.5mmol;
s7, washing and purifying the pre-product obtained in the step S6 with diethyl ether at 0 ℃ for 3 times, and vacuum drying at room temperature for 24 hours to remove the solvent to obtain the tissue viscosity absorbable material with the number average molecular weight of 8000g/mol and comprising glycerol segments and poly (lactide-co-caprolactone) chains and N-hydroxysuccinimide-NHS as the end groups, wherein the molecular structure schematic diagram and the nuclear magnetic resonance hydrogen spectrogram are shown in figure 2.
Example 3
The method is characterized in that pentaerythritol is used as an initiator to initiate ring-opening polymerization of lactide, caprolactone and ethylene oxide, and the tissue viscosity absorbable material with the end group of N-hydroxysuccinimide-NHS and the number average molecular weight of 10000g/mol is obtained through chemical modification, and the steps are as follows:
s1, dissolving 1mmol of pentaerythritol and 3.6mmol of potassium hydride in 120mL of tetrahydrofuran, stirring at room temperature for reaction for 4 hours to obtain an initiator solution, adding 31.83mmol of ethylene oxide into the initiator solution, stirring at room temperature for reaction for 24 hours, then adding 31.83mmol of lactide and 31.83mmol of caprolactone, evaporating the solvent at 80 ℃ and blending for 20 minutes to obtain a blend;
s2, adding stannous octoate into the blend obtained in the step S1 according to the weight ratio of 0.0045:1, and reacting at 100 ℃ for 22 hours to obtain a crude pre-product;
s3, dissolving the crude pre-product obtained in the step S2 in 10mL of dichloromethane, washing and purifying the crude pre-product with diethyl ether at 0 ℃ for 5 times, and drying at room temperature in vacuum for 24 hours to remove the solvent to obtain a pre-product I, wherein the pre-product I is a polymer with hydroxyl groups as end groups, including pentaerythritol sections and poly (lactide-co-ethylene glycol-co-caprolactone) chains;
s4, dissolving the first pre-product obtained in the step S3 in dichloromethane, adding succinic anhydride and 4-dimethylaminopyridine at the temperature of 0 ℃, and stirring and reacting for 24 hours at the temperature of 25 ℃ to obtain a second pre-product, wherein the ratio of the first pre-product to the dichloromethane to the succinic anhydride to the 4-dimethylaminopyridine is 0.3g to 1mL to 5.3mmol to 1.8mmol;
s5, washing and purifying the pre-product obtained in the step S4 with diethyl ether at 0 ℃ for 5 times, and vacuum drying at room temperature for 24 hours to remove the solvent to obtain a pre-product III, wherein the pre-product III is a polymer with a carboxyl end group comprising a pentaerythritol segment and a poly (lactide-co-ethylene glycol-co-caprolactone) chain;
s6, dissolving the pre-product III obtained in the step S5 in dichloromethane, adding N-hydroxysuccinimide, 4-dimethylaminopyridine and N, N '-diisopropylcarbodiimide at 0 ℃, and stirring at 25 ℃ for reacting for 24 hours to obtain a pre-product IV, wherein the ratio of the pre-product III to the dichloromethane to the N-hydroxysuccinimide to the 4-dimethylaminopyridine to the N, N' -diisopropylcarbodiimide is 0.3 g/1 mL/6 mmol/1.8 mmol/6 mmol;
s7, washing and purifying the pre-product obtained in the step S6 with diethyl ether at 5 ℃ for 5 times, and vacuum drying at room temperature for 24 hours to remove the solvent to obtain the tissue viscosity absorbable material with the number average molecular weight of 10000g/mol and including pentaerythritol sections and poly (lactide-co-ethylene glycol-co-caprolactone) chains and N-hydroxysuccinimide-NHS as the end groups, wherein the molecular structure schematic diagram and the nuclear magnetic resonance hydrogen spectrogram of the tissue viscosity absorbable material are shown in figure 3.
Example 4
Using erythritol as an initiator to initiate ring-opening polymerization of ethylene oxide, lactide and caprolactone, and obtaining the tissue viscosity absorbable material with end groups of isocyanate-NCO and number average molecular weight of 40000g/mol through chemical modification, wherein the method comprises the following steps:
s1, dissolving 0.5mmol of pentaerythritol and 1.8mmol of potassium hydride in 120mL of tetrahydrofuran, stirring at room temperature for 4 hours to obtain an initiator solution, adding 9mmol of ethylene oxide into the initiator solution, stirring at room temperature for 24 hours, adding 14mmol of lactide and 14mmol of caprolactone, evaporating the solvent at 80 ℃ and blending for 20 minutes to obtain a blend;
s2, adding stannous octoate into the blend obtained in the step S1 according to the weight ratio of 0.0045:1, and reacting at 120 ℃ for 21 hours to obtain a crude pre-product;
s3, dissolving the crude pre-product obtained in the step S2 in 10mL of dichloromethane, washing and purifying the crude pre-product with diethyl ether at 0 ℃ for 3 times, and drying at room temperature in vacuum for 24 hours to remove the solvent to obtain a pre-product I, wherein the pre-product I is a polymer with hydroxyl groups as end groups, including erythritol segments and poly (ethylene glycol-co-lactide-co-caprolactone) chains;
s4, dissolving the first pre-product obtained in the step S3 in toluene to obtain a toluene pre-product solution with the concentration of 0.5g/mL, adding the toluene pre-product solution into a toluene solution of hexamethylene diisocyanate with the concentration of 0.5g/mL, wherein the molar ratio of the first pre-product to the hexamethylene diisocyanate is 1:30, stirring uniformly, adding stannous octoate, wherein the weight of the stannous octoate is 0.45% of the sum of the weights of the toluene pre-product solution and the toluene solution of hexamethylene diisocyanate, and stirring at 60 ℃ for 2 hours to obtain a pre-product six;
s5, washing and purifying the pre-product obtained in the step S4 with diethyl ether at 5 ℃ for 3 times, and vacuum drying at room temperature for 18 hours to remove the solvent to obtain the tissue viscosity absorbable material with the number average molecular weight of 40000g/mol and comprising erythritol segments and poly (ethylene glycol-co-lactide-co-caprolactone) chains, wherein the end groups of the poly (ethylene glycol-co-lactide-co-caprolactone) chains are isocyanate-NCO, and the molecular structure schematic diagram and the nuclear magnetic resonance hydrogen spectrogram of the tissue viscosity absorbable material are shown in figure 4.
Example 5
The method is characterized in that ethylene glycol is used as an initiator to initiate ring-opening polymerization of propylene oxide, lactide and caprolactone, and the tissue viscosity absorbable material with aldehyde group-CHO terminal group and number average molecular weight of 2000g/mol is obtained through chemical modification, and the steps are as follows:
s1, dissolving 1mmol of ethylene glycol and 2mmol of potassium hydride in 60mL of tetrahydrofuran, stirring at room temperature for reaction for 4 hours to obtain an initiator solution, adding 21mmol of propylene oxide into the initiator solution, stirring at room temperature for reaction for 24 hours, then adding 3.8mmol of lactide and 3.8mmol of caprolactone, evaporating the solvent at 80 ℃ and then blending for 15 minutes to obtain a blend;
s2, adding stannous octoate into the blend obtained in the step S1 according to the weight ratio of 0.0045:1, and reacting for 20 hours at 110 ℃ to obtain a crude pre-product;
s3, dissolving the crude pre-product obtained in the step S2 in 10mL of dichloromethane, washing and purifying the crude pre-product with diethyl ether at 0 ℃ for 3 times, and drying the crude pre-product in vacuum at room temperature for 12 hours to remove the solvent to obtain a pre-product I, wherein the pre-product I is a polymer with hydroxyl groups as end groups, including ethylene glycol segments and poly (ethylene glycol-co-lactide-co-caprolactone) chains;
s4, dissolving the first pre-product obtained in the step S3 in dichloromethane, adding 4-formylbenzoic acid and 4-dimethylaminopyridine, uniformly mixing, adding dicyclohexylcarbodiimide at 5 ℃, and stirring for reacting for 24 hours to obtain a fifth pre-product, wherein the ratio of the first pre-product to the dichloromethane to the 4-formylbenzoic acid to the 4-dimethylaminopyridine to the dicyclohexylcarbodiimide is 0.5g to 1mL to 10mmol to 2mmol to 20mmol;
s5, washing and purifying the pre-product obtained in the step S4 with diethyl ether for 3 times at the temperature of 5 ℃, and vacuum drying at room temperature for 24 hours to remove the solvent to obtain the tissue viscosity absorbable material with the number average molecular weight of 2000g/mol and comprising glycol segments and poly (lactide-co-caprolactone) chains, wherein the end groups of the poly (lactide-co-caprolactone) chains are aldehyde groups-CHO, and the molecular structure schematic diagram and the nuclear magnetic resonance hydrogen spectrogram of the tissue viscosity absorbable material are shown in figure 5.
Example 6
The tripentaerythritol is used as an initiator to initiate the ring-opening polymerization of beta-propiolactone, and the tissue viscosity absorbable material with the end group of mercapto-SH and the number average molecular weight of 3000g/mol is obtained through chemical modification, and the steps are as follows:
s1, adding 36.5mmol of beta-propiolactone into 1mmol of tripentaerythritol, and blending for 20 minutes at 120 ℃ to obtain a blend;
s2, adding stannous octoate into the blend obtained in the step S1 according to the weight ratio of 0.0045:1, and reacting at 130 ℃ for 24 hours to obtain a crude pre-product;
s3, dissolving the crude pre-product obtained in the step S2 in 10mL of dichloromethane, washing and purifying the crude pre-product with diethyl ether at 0 ℃ for 3 times, and drying the crude pre-product in vacuum at room temperature for 12 hours to remove the solvent to obtain a pre-product I, wherein the pre-product I is a polymer with a tripentaerythritol segment and a polypropylene lactone chain end group as a hydroxyl group;
s4, dissolving the pre-product I, dithiodipropionic acid and 4-dimethylaminopyridine obtained in the step S3 in methylene dichloride, uniformly mixing, adding N, N '-diisopropylcarbodiimide at the temperature of 2 ℃, stirring and reacting for 8 hours to obtain a reactant I, washing the reactant with methanol at the temperature of 2 ℃ for three times to obtain solid powder, wherein the molar ratio of the pre-product I, methylene dichloride, 4-dimethylaminopyridine, N' -diisopropylcarbodiimide and methanol is 0.2g:1mL:1.2mmol:4mmol:10mL, and the molar ratio of the pre-product I to the dithiodipropionic acid is 1:10;
s5, dissolving the solid powder obtained in the step S4 and dithiothreitol in dichloromethane, stirring and reacting for 8 hours to obtain a reactant II, washing the reactant II with methanol at 0 ℃ for three times to obtain the tissue viscosity absorbable material with the number average molecular weight of 3000g/mol, wherein the tissue viscosity absorbable material comprises tripentaerythritol sections and the end groups of polypropylene lactone chains, the end groups of the aldehyde groups-CHO are aldehyde groups, the molecular structure schematic diagram and the nuclear magnetic resonance hydrogen spectrum diagram of the tissue viscosity absorbable material are shown in figure 6, the ratio of the solid powder to the dichloromethane to the methanol is 0.5g to 1mL to 10mL, and the mole ratio of the solid powder to the dithiothreitol is 1 to 10.
Experimental example 1:
burst pressure test: the tissue viscosity absorbable materials prepared in examples 1-6 were applied to pig small intestine weeping blocking experiments. The above examples were subjected to burst pressure testing according to the standard test method for surgical sealants (ASTM F2392-04): a 25G needle was used to puncture a hole in the pig's small intestine and 100 μl of the examples were smeared to seal the hole, as shown in fig. 1. The small intestine was clamped at both ends, and distilled water was injected into the upper part of the small intestine at a constant rate of 1mL/min to apply pressure. The pressure in the membrane was monitored throughout the experiment, and burst pressure was defined as the pressure at which the material broke and the small intestine began to leak, and the burst pressure data for examples 1-6 are shown in Table 1. As can be seen from the experimental data in Table 1, the tissue adhesive biomaterial provided by the invention can effectively adhere to a tissue wound site, thereby effectively preventing gas leakage and blood leakage at the injured tissue site.
| Examples | Fracture pressure (mmHg) | Endothelial cell viability (%) |
| Example 1 | 163±21 | 120±13 |
| Example 2 | 174±16 | 135±19 |
| Example 3 | 190±18 | 120±16 |
| Example 4 | 224±27 | 125±9 |
| Example 5 | 113±19 | 130±14 |
| Example 6 | 136±26 | 128±11 |
| Control group | - | 125±8 |
TABLE 1
Cell compatibility test: the tissue adhesive absorbable material prepared in examples 1-6 was placed in a 48-well plate, 100. Mu.L of endothelial cells (density 5000 cells/mL) was added, 100. Mu.L of fresh serum-free medium containing 8% CCK-8 reagent, and cultured in 5% carbon dioxide, 95% air and 95% humidity atmosphere at 37℃for 24 hours, with the cells in the 48-well plate without examples as positive control. The endothelial cell viability of examples 1-6 after 24 hours of incubation is shown in Table 1. From the experimental data in Table 1, it can be seen that all examples do not negatively affect cell proliferation, indicating that examples 1-6 have good cell compatibility.
Experimental example 2:
biocompatibility testing: the tissue viscosity absorbable materials prepared in examples 1 to 6 were subjected to a biocompatibility test according to the relevant national standards, and the results of the biocompatibility tests of examples 1 to 6 are shown in table 2. As can be seen from Table 2, the tissue adhesive biomaterial provided by the invention has good biological non-toxicity, non-sensitization and non-irritation.
TABLE 2
Experimental example 3:
in vitro degradation test: 20mg of the films formed of the tissue-adhesive absorbable materials prepared in examples 1 to 4, respectively, were immersed in a Phosphate Buffered Saline (PBS) solution, the pH of the solution was set to 7.4, the temperature was 37℃and the solution was shaken at 150rpm using a table-type orbital shaker, the films were periodically taken out, the film mass was weighed after drying, and the mass retention rate was calculated. Examples 1-4 the mass retention of the samples over time is shown in figure 9. As can be seen from fig. 9, the tissue viscosity absorbable material prepared by the present invention has good degradation performance in Phosphate Buffered Saline (PBS) solution, and the degradation period thereof varies according to the variation of the designed molecular weight: the high molecular weight examples have long degradation cycles whereas the low molecular weight examples have short degradation cycles.
The above embodiments are merely illustrative of the principles of the present invention and its effectiveness, and are not intended to limit the invention. Modifications and variations may be made to the above-described embodiments by those skilled in the art without departing from the spirit and scope of the invention. Accordingly, it is intended that all equivalent modifications and variations of the invention be covered by the claims, which are within the ordinary skill of the art, be within the spirit and scope of the present disclosure.
Claims (9)
1. A tissue adhesive absorbable material characterized by: the molecular structure is a multi-arm molecular chain structure, and the structural unit is polymerized by one or more monomers of glycolide, lactide, caprolactone, beta-propiolactone, ethylene oxide or propylene oxide.
2. A tissue adhesive absorbable material, according to claim 1, characterized in that: the molecular chain is blocked by a reactive group, and the reactive group is one of N-hydroxysuccinimide-NHS, aldehyde-CHO, isocyanate-NCO or mercapto-SH.
3. A tissue adhesive absorbable material, according to claim 1, characterized in that: the multi-arm molecular chain structure is polymerized by initiating agent, which is one of glycol, glycerol, pentaerythritol, erythritol, dipentaerythritol or tripentaerythritol.
4. A tissue adhesive absorbable material, according to claim 1, characterized in that: the single-arm molecular structure chain segment in the multi-arm molecular chain structure is a polylactide chain segment, a polyglycolide chain segment, a polycaprolactone chain segment, a polyethylene glycol chain segment, a poly (lactide-co-glycolide) chain segment, a poly (lactide-co-caprolactone) chain segment, a poly (lactide-co-ethylene glycol) chain segment, a poly (glycolide-co-ethylene glycol) chain segment, a poly (ethylene glycol-co-caprolactone) chain segment, a poly (lactide-co-glycolide-co-ethylene glycol) chain segment, a poly (lactide-co-caprolactone-co-ethylene glycol) chain segment, a poly (lactide-co-glycolide-co-caprolactone-co-ethylene glycol) chain segment, a poly (glycolide-co-caprolactone-co-propylene glycol) chain segment or a poly (lactide-co-beta-propylene glycol) chain segment, which is formed by copolymerization of lactide, glycolide, ethylene oxide and propylene oxide and any one of the monomers.
5. A tissue adhesive absorbable material, according to claim 1, characterized in that: the number average molecular weight is 1000-200000g/mol.
6. A tissue adhesive absorbable material, as set forth in claim 5, wherein: the number average molecular weight is 2000-100000g/mol.
7. A method of preparing a tissue adhesive absorbable material, as set forth in any one of claims 1-6, characterized in that: the method comprises the following steps:
s1, when the initiator is glycerol, dipentaerythritol and tripentaerythritol, adding a monomer into the initiator according to the molar ratio of 1 (36.5-59.02), and blending for 10-20 minutes at the room temperature to 160 ℃ to obtain a blend;
when the initiator is glycol, pentaerythritol and erythritol, dissolving the initiator and potassium hydride in tetrahydrofuran according to the proportion of 1mmol (1-8) mmol (60-120) mL, stirring and reacting for 4 hours at room temperature to obtain an initiator solution, adding ethylene oxide or propylene oxide into the initiator solution, stirring and reacting for 24 hours at room temperature, adding other monomers, evaporating the solvent at 80 ℃ and then blending for 10-20 minutes to obtain a blend, wherein the molar ratio of the initiator to the monomers is 1 (28.6-95.49);
s2, adding stannous octoate into the blend obtained in the step S1 according to the weight ratio of 0.0045:1, and reacting for 20-24 hours at the temperature of 100-140 ℃ to obtain a crude pre-product;
s3, dissolving the crude pre-product obtained in the step S2 in methylene dichloride according to the proportion of 1g (1-2) mL, washing and purifying the crude pre-product for 3-5 times at the temperature of 0-5 ℃ by using diethyl ether, and drying the crude pre-product in vacuum at room temperature for 12-24 hours to remove the solvent to obtain a pre-product I, wherein the pre-product I is a polymer of which the end group of a molecular chain segment is hydroxyl;
s4, dissolving the first pre-product obtained in the step S3 in dichloromethane, adding succinic anhydride and 4-dimethylaminopyridine at the temperature of 0-5 ℃, and stirring and reacting for 20-30 hours at the temperature of 15-30 ℃ to obtain a second pre-product, wherein the ratio of the first pre-product to the dichloromethane to the succinic anhydride to the 4-dimethylaminopyridine is (0.2-0.5) g, 1mL, (4-35) mmol and (1.2-12) mmol;
s5, washing and purifying the pre-product obtained in the step S4 with diethyl ether at 0-5 ℃ for 3-5 times, and vacuum drying at room temperature for 12-24 hours to remove the solvent to obtain a pre-product III, wherein the pre-product III is a polymer with a carboxyl end group of a molecular chain segment;
s6, dissolving the pre-product III obtained in the step S5 in dichloromethane, adding N-hydroxysuccinimide, 4-dimethylaminopyridine and N, N '-diisopropylcarbodiimide at 0-5 ℃, and stirring at 15-30 ℃ for reacting for 20-30 hours to obtain a pre-product IV, wherein the ratio of the pre-product III to the dichloromethane to the N-hydroxysuccinimide to the 4-dimethylaminopyridine to the N, N' -diisopropylcarbodiimide is (0.2-0.5) g to 1mL (4-35) mmol (1.2-12) mmol (4-35) mmol;
s7, washing and purifying the pre-product obtained in the step S6 with diethyl ether at 0-5 ℃ for 3-5 times, and vacuum drying at room temperature for 12-24 hours to remove the solvent to obtain the tissue adhesive absorbable material with the molecular chain segment end group of N-hydroxysuccinimide-NHS;
s8, dissolving the first pre-product obtained in the step S3 in dichloromethane, adding 4-formylbenzoic acid and 4-dimethylaminopyridine, uniformly mixing, adding dicyclohexylcarbodiimide at 0-5 ℃, and stirring for reacting for 24 hours to obtain a fifth pre-product, wherein the ratio of the first pre-product to the dichloromethane to the 4-formylbenzoic acid to the 4-dimethylaminopyridine to the dicyclohexylcarbodiimide is (0.2-0.5) g, 1mL, (4-35) mmol, (1.2-12) mmol and (4-35) mmol; washing and purifying the pre-product with diethyl ether at 0-5deg.C for 3-5 times, vacuum drying at room temperature for 12-24 hr, and removing solvent to obtain the tissue viscosity absorbable material with aldehyde group-CHO terminal group as molecular chain segment;
s9, dissolving the first pre-product obtained in the step S3 in toluene to obtain a toluene pre-product solution with the concentration of 0.2-0.5g/mL, adding the toluene pre-product solution into a toluene solution of hexamethylene diisocyanate with the concentration of 0.2-0.5g/mL, wherein the molar ratio of the first pre-product to the hexamethylene diisocyanate is 1 (4-30), stirring uniformly, adding stannous octoate, wherein the weight of the stannous octoate is 0.45% of the sum of the weights of the toluene pre-product solution and the toluene solution of hexamethylene diisocyanate, and stirring at 60 ℃ for 2 hours to obtain a sixth pre-product; washing and purifying the pre-product six with diethyl ether at 0-5 ℃ for 3-5 times, and vacuum drying at room temperature for 12-24 hours to remove the solvent to obtain the tissue adhesive absorbable material with the molecular chain segment end group of isocyanate-NCO;
s10, dissolving the pre-product I, dithiodipropionic acid and 4-dimethylaminopyridine obtained in the step S3 in methylene dichloride, adding N, N '-diisopropylcarbodiimide at 0-5 ℃ after uniform mixing, stirring and reacting for 8 hours to obtain a reactant I, washing the reactant with methanol at 0-5 ℃ for three times to obtain solid powder, wherein the ratio of the pre-product I, methylene dichloride, 4-dimethylaminopyridine, N' -diisopropylcarbodiimide and methanol is (0.2-0.5) g to 1mL to 1.2-12 mmol to (4-35) mmol to (10-15) mL, and the molar ratio of the pre-product I to the dithiodipropionic acid is (1 to 4-30);
s11, dissolving the solid powder obtained in the step S10 and dithiothreitol in dichloromethane, stirring and reacting for 8 hours to obtain a reactant II, washing the reactant II with methanol at 0-5 ℃ for three times to obtain the tissue adhesive absorbable material with the end group of a molecular chain segment being mercapto-SH, wherein the ratio of the solid powder to the dichloromethane to the methanol is (0.5-1) g to 1mL (10-15), and the molar ratio of the solid powder to the dithiothreitol is (1) (2-10).
8. A method of preparing a tissue adhesive absorbable material, as set forth in claim 7, wherein: in the step S1, the monomer is one or more of glycolide, lactide, caprolactone, beta-propiolactone, ethylene oxide or propylene oxide.
9. Use of a tissue adhesive absorbable material as defined in any one of claims 1 to 6 for the preparation of a tissue adhesive material.
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