CN117482302A - Heparin anticoagulation coating and preparation method and application thereof - Google Patents
Heparin anticoagulation coating and preparation method and application thereof Download PDFInfo
- Publication number
- CN117482302A CN117482302A CN202210887524.1A CN202210887524A CN117482302A CN 117482302 A CN117482302 A CN 117482302A CN 202210887524 A CN202210887524 A CN 202210887524A CN 117482302 A CN117482302 A CN 117482302A
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- China
- Prior art keywords
- heparin
- double bond
- modified
- substrate
- coating
- 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.)
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- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 title claims abstract description 341
- 229960002897 heparin Drugs 0.000 title claims abstract description 273
- 229920000669 heparin Polymers 0.000 title claims abstract description 273
- 238000000576 coating method Methods 0.000 title claims abstract description 168
- 239000011248 coating agent Substances 0.000 title claims abstract description 156
- 230000010100 anticoagulation Effects 0.000 title claims abstract description 117
- 238000002360 preparation method Methods 0.000 title claims abstract description 51
- 239000000758 substrate Substances 0.000 claims abstract description 140
- 239000003999 initiator Substances 0.000 claims abstract description 33
- 238000010526 radical polymerization reaction Methods 0.000 claims abstract description 8
- -1 amide compound Chemical class 0.000 claims description 137
- 239000000243 solution Substances 0.000 claims description 112
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 55
- 238000000034 method Methods 0.000 claims description 54
- 239000000126 substance Substances 0.000 claims description 54
- 150000001875 compounds Chemical class 0.000 claims description 48
- 239000004593 Epoxy Substances 0.000 claims description 45
- 239000000463 material Substances 0.000 claims description 43
- 229910052739 hydrogen Inorganic materials 0.000 claims description 29
- 239000001257 hydrogen Substances 0.000 claims description 29
- 229920002873 Polyethylenimine Polymers 0.000 claims description 27
- 150000001408 amides Chemical class 0.000 claims description 27
- 125000003277 amino group Chemical group 0.000 claims description 27
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 claims description 21
- 239000003054 catalyst Substances 0.000 claims description 21
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 15
- 125000000217 alkyl group Chemical group 0.000 claims description 14
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 14
- 150000008064 anhydrides Chemical class 0.000 claims description 13
- 239000003795 chemical substances by application Substances 0.000 claims description 13
- GJKGAPPUXSSCFI-UHFFFAOYSA-N 2-Hydroxy-4'-(2-hydroxyethoxy)-2-methylpropiophenone Chemical compound CC(C)(O)C(=O)C1=CC=C(OCCO)C=C1 GJKGAPPUXSSCFI-UHFFFAOYSA-N 0.000 claims description 11
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- 229910052736 halogen Chemical group 0.000 claims description 10
- 150000002367 halogens Chemical group 0.000 claims description 10
- SLJFKNONPLNAPF-UHFFFAOYSA-N 3-Vinyl-7-oxabicyclo[4.1.0]heptane Chemical compound C1C(C=C)CCC2OC21 SLJFKNONPLNAPF-UHFFFAOYSA-N 0.000 claims description 9
- 230000035484 reaction time Effects 0.000 claims description 9
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- AUNGANRZJHBGPY-SCRDCRAPSA-N Riboflavin Chemical compound OC[C@@H](O)[C@@H](O)[C@@H](O)CN1C=2C=C(C)C(C)=CC=2N=C2C1=NC(=O)NC2=O AUNGANRZJHBGPY-SCRDCRAPSA-N 0.000 claims description 8
- 230000003213 activating effect Effects 0.000 claims description 8
- 239000003146 anticoagulant agent Substances 0.000 claims description 8
- 229940127219 anticoagulant drug Drugs 0.000 claims description 8
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- 150000002431 hydrogen Chemical group 0.000 claims description 8
- STMDPCBYJCIZOD-UHFFFAOYSA-N 2-(2,4-dinitroanilino)-4-methylpentanoic acid Chemical compound CC(C)CC(C(O)=O)NC1=CC=C([N+]([O-])=O)C=C1[N+]([O-])=O STMDPCBYJCIZOD-UHFFFAOYSA-N 0.000 claims description 7
- ILSLNOWZSKKNJQ-UHFFFAOYSA-N 7-oxabicyclo[4.1.0]hept-4-ene Chemical compound C1=CCCC2OC21 ILSLNOWZSKKNJQ-UHFFFAOYSA-N 0.000 claims description 7
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- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 claims description 6
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 6
- 125000003172 aldehyde group Chemical group 0.000 claims description 6
- RWCCWEUUXYIKHB-UHFFFAOYSA-N benzophenone Chemical compound C=1C=CC=CC=1C(=O)C1=CC=CC=C1 RWCCWEUUXYIKHB-UHFFFAOYSA-N 0.000 claims description 6
- 239000012965 benzophenone Substances 0.000 claims description 6
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- ZHNUHDYFZUAESO-UHFFFAOYSA-N formamide Substances NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 claims description 6
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- XHIRWEVPYCTARV-UHFFFAOYSA-N n-(3-aminopropyl)-2-methylprop-2-enamide;hydrochloride Chemical compound Cl.CC(=C)C(=O)NCCCN XHIRWEVPYCTARV-UHFFFAOYSA-N 0.000 claims description 5
- 229920000729 poly(L-lysine) polymer Polymers 0.000 claims description 5
- AUNGANRZJHBGPY-UHFFFAOYSA-N D-Lyxoflavin Natural products OCC(O)C(O)C(O)CN1C=2C=C(C)C(C)=CC=2N=C2C1=NC(=O)NC2=O AUNGANRZJHBGPY-UHFFFAOYSA-N 0.000 claims description 4
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- VFHVQBAGLAREND-UHFFFAOYSA-N diphenylphosphoryl-(2,4,6-trimethylphenyl)methanone Chemical compound CC1=CC(C)=CC(C)=C1C(=O)P(=O)(C=1C=CC=CC=1)C1=CC=CC=C1 VFHVQBAGLAREND-UHFFFAOYSA-N 0.000 claims description 4
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- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 claims description 3
- VILCJCGEZXAXTO-UHFFFAOYSA-N 2,2,2-tetramine Chemical compound NCCNCCNCCN VILCJCGEZXAXTO-UHFFFAOYSA-N 0.000 claims description 3
- 238000007385 chemical modification Methods 0.000 claims description 3
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims description 3
- SEACYXSIPDVVMV-UHFFFAOYSA-L eosin Y Chemical compound [Na+].[Na+].[O-]C(=O)C1=CC=CC=C1C1=C2C=C(Br)C(=O)C(Br)=C2OC2=C(Br)C([O-])=C(Br)C=C21 SEACYXSIPDVVMV-UHFFFAOYSA-L 0.000 claims description 3
- 238000009832 plasma treatment Methods 0.000 claims description 3
- 125000001424 substituent group Chemical group 0.000 claims description 3
- FAGUFWYHJQFNRV-UHFFFAOYSA-N tetraethylenepentamine Chemical compound NCCNCCNCCNCCN FAGUFWYHJQFNRV-UHFFFAOYSA-N 0.000 claims description 3
- KLGDRWGOXDJNPH-UHFFFAOYSA-N P(=O)(O)(O)O.C1(=CC=CC=C1)C=1C(=C(C(=O)[Li])C(=CC1C)C)C Chemical compound P(=O)(O)(O)O.C1(=CC=CC=C1)C=1C(=C(C(=O)[Li])C(=CC1C)C)C KLGDRWGOXDJNPH-UHFFFAOYSA-N 0.000 claims description 2
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- 239000005020 polyethylene terephthalate Substances 0.000 description 2
- 239000004926 polymethyl methacrylate Substances 0.000 description 2
- 229920001343 polytetrafluoroethylene Polymers 0.000 description 2
- 239000004810 polytetrafluoroethylene Substances 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 229940047670 sodium acrylate Drugs 0.000 description 2
- 239000012279 sodium borohydride Substances 0.000 description 2
- 229910000033 sodium borohydride Inorganic materials 0.000 description 2
- BBOPQNDFZDQFMP-UHFFFAOYSA-M sodium pent-2-enoate Chemical compound [Na+].CCC=CC([O-])=O BBOPQNDFZDQFMP-UHFFFAOYSA-M 0.000 description 2
- SONHXMAHPHADTF-UHFFFAOYSA-M sodium;2-methylprop-2-enoate Chemical compound [Na+].CC(=C)C([O-])=O SONHXMAHPHADTF-UHFFFAOYSA-M 0.000 description 2
- GOCYQQKRJUGVRU-UHFFFAOYSA-M sodium;but-2-enoate Chemical compound [Na+].CC=CC([O-])=O GOCYQQKRJUGVRU-UHFFFAOYSA-M 0.000 description 2
- DKYPZNSPQXLRRQ-UHFFFAOYSA-M sodium;undec-10-enoate Chemical compound [Na+].[O-]C(=O)CCCCCCCCC=C DKYPZNSPQXLRRQ-UHFFFAOYSA-M 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- UIERETOOQGIECD-ONEGZZNKSA-N tiglic acid Chemical compound C\C=C(/C)C(O)=O UIERETOOQGIECD-ONEGZZNKSA-N 0.000 description 2
- YIYBQIKDCADOSF-ONEGZZNKSA-N trans-pent-2-enoic acid Chemical compound CC\C=C\C(O)=O YIYBQIKDCADOSF-ONEGZZNKSA-N 0.000 description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 2
- 229960002703 undecylenic acid Drugs 0.000 description 2
- DTCCTIQRPGSLPT-ONEGZZNKSA-N (E)-2-pentenal Chemical compound CC\C=C\C=O DTCCTIQRPGSLPT-ONEGZZNKSA-N 0.000 description 1
- IDEYZABHVQLHAF-GQCTYLIASA-N (e)-2-methylpent-2-enal Chemical compound CC\C=C(/C)C=O IDEYZABHVQLHAF-GQCTYLIASA-N 0.000 description 1
- IDEYZABHVQLHAF-UHFFFAOYSA-N 2-Methyl-2-pentenal Natural products CCC=C(C)C=O IDEYZABHVQLHAF-UHFFFAOYSA-N 0.000 description 1
- XUKUURHRXDUEBC-KAYWLYCHSA-N Atorvastatin Chemical compound C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CC[C@@H](O)C[C@@H](O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-KAYWLYCHSA-N 0.000 description 1
- XUKUURHRXDUEBC-UHFFFAOYSA-N Atorvastatin Natural products C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CCC(O)CC(O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-UHFFFAOYSA-N 0.000 description 1
- 239000005552 B01AC04 - Clopidogrel Substances 0.000 description 1
- 102000004506 Blood Proteins Human genes 0.000 description 1
- 108010017384 Blood Proteins Proteins 0.000 description 1
- 229910000531 Co alloy Inorganic materials 0.000 description 1
- 206010053567 Coagulopathies Diseases 0.000 description 1
- 239000007821 HATU Substances 0.000 description 1
- 239000007987 MES buffer Substances 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- IGAAQDGISNXKQL-UHFFFAOYSA-L P(=O)(OC(C1=C(C(=C(C=C1C)C)C1=CC=CC=C1)C)=O)([O-])[O-].[Li+].[Li+] Chemical compound P(=O)(OC(C1=C(C(=C(C=C1C)C)C1=CC=CC=C1)C)=O)([O-])[O-].[Li+].[Li+] IGAAQDGISNXKQL-UHFFFAOYSA-L 0.000 description 1
- 239000002262 Schiff base Substances 0.000 description 1
- 150000004753 Schiff bases Chemical class 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical group [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 229920004933 Terylene® Polymers 0.000 description 1
- 229910001069 Ti alloy Inorganic materials 0.000 description 1
- RTAQQCXQSZGOHL-UHFFFAOYSA-N Titanium Chemical compound [Ti] RTAQQCXQSZGOHL-UHFFFAOYSA-N 0.000 description 1
- 238000007112 amidation reaction Methods 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 229940127218 antiplatelet drug Drugs 0.000 description 1
- 229960005370 atorvastatin Drugs 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- DTCCTIQRPGSLPT-UHFFFAOYSA-N beta-Aethyl-acrolein Natural products CCC=CC=O DTCCTIQRPGSLPT-UHFFFAOYSA-N 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- GKTWGGQPFAXNFI-HNNXBMFYSA-N clopidogrel Chemical compound C1([C@H](N2CC=3C=CSC=3CC2)C(=O)OC)=CC=CC=C1Cl GKTWGGQPFAXNFI-HNNXBMFYSA-N 0.000 description 1
- 229960003009 clopidogrel Drugs 0.000 description 1
- 230000035602 clotting Effects 0.000 description 1
- 230000001276 controlling effect Effects 0.000 description 1
- 229920001577 copolymer Polymers 0.000 description 1
- MLUCVPSAIODCQM-NSCUHMNNSA-N crotonaldehyde Chemical compound C\C=C\C=O MLUCVPSAIODCQM-NSCUHMNNSA-N 0.000 description 1
- MLUCVPSAIODCQM-UHFFFAOYSA-N crotonaldehyde Natural products CC=CC=O MLUCVPSAIODCQM-UHFFFAOYSA-N 0.000 description 1
- 230000000593 degrading effect Effects 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 150000004676 glycans Chemical class 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- FPYJFEHAWHCUMM-UHFFFAOYSA-N maleic anhydride Chemical compound O=C1OC(=O)C=C1 FPYJFEHAWHCUMM-UHFFFAOYSA-N 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- WTNTZFRNCHEDOS-UHFFFAOYSA-N n-(2-hydroxyethyl)-2-methylpropanamide Chemical compound CC(C)C(=O)NCCO WTNTZFRNCHEDOS-UHFFFAOYSA-N 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 239000000106 platelet aggregation inhibitor Substances 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 239000004814 polyurethane Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- ARJOQCYCJMAIFR-UHFFFAOYSA-N prop-2-enoyl prop-2-enoate Chemical compound C=CC(=O)OC(=O)C=C ARJOQCYCJMAIFR-UHFFFAOYSA-N 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000009877 rendering Methods 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 229930195734 saturated hydrocarbon Natural products 0.000 description 1
- 229920002379 silicone rubber Polymers 0.000 description 1
- 239000004945 silicone rubber Substances 0.000 description 1
- 239000007974 sodium acetate buffer Substances 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- MNWBNISUBARLIT-UHFFFAOYSA-N sodium cyanide Chemical compound [Na+].N#[C-] MNWBNISUBARLIT-UHFFFAOYSA-N 0.000 description 1
- 125000000020 sulfo group Chemical group O=S(=O)([*])O[H] 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 239000010936 titanium Substances 0.000 description 1
- 229910052719 titanium Inorganic materials 0.000 description 1
Classifications
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- 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
- A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
- A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
- A61L31/16—Biologically active materials, e.g. therapeutic substances
-
- 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
- A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
- A61L31/08—Materials for coatings
- A61L31/10—Macromolecular materials
-
- 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
- A61L33/00—Antithrombogenic treatment of surgical articles, e.g. sutures, catheters, prostheses, or of articles for the manipulation or conditioning of blood; Materials for such treatment
- A61L33/0005—Use of materials characterised by their function or physical properties
- A61L33/0011—Anticoagulant, e.g. heparin, platelet aggregation inhibitor, fibrinolytic agent, other than enzymes, attached to the substrate
-
- 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
- A61L33/00—Antithrombogenic treatment of surgical articles, e.g. sutures, catheters, prostheses, or of articles for the manipulation or conditioning of blood; Materials for such treatment
- A61L33/06—Use of macromolecular materials
- A61L33/08—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
- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/20—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials
- A61L2300/23—Carbohydrates
- A61L2300/236—Glycosaminoglycans, e.g. heparin, hyaluronic acid, chondroitin
-
- 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
- A61L2300/42—Anti-thrombotic agents, anticoagulants, anti-platelet 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
- A61L2300/60—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a special physical form
- A61L2300/606—Coatings
Abstract
The invention relates to a heparin anticoagulation coating, a preparation method and application thereof. The preparation method of the heparin anticoagulation coating comprises the following steps: modifying the substrate to enable the substrate to carry double bonds so as to obtain a modified substrate; modifying heparin to make heparin carry double bond so as to obtain modified heparin; treating the modified substrate with a solution containing modified heparin and an initiator to enable double bonds carried by the modified heparin and double bonds carried by the modified substrate to undergo free radical polymerization, and forming a heparin anticoagulation coating on the surface of the modified substrate. The preparation method of the heparin anticoagulation coating can ensure that the heparin anticoagulation coating can be stably combined on the surface of the substrate while the bioactivity of heparin is maintained.
Description
Technical Field
The invention relates to the field of medical instruments, in particular to a heparin anticoagulation coating and a preparation method and application thereof.
Background
For blood-contacting medical devices, it is important to prevent thrombosis. This is because the biocompatibility of the materials used in such medical devices is often not ideal, and when in direct contact with blood, plasma proteins rapidly adsorb to the surface of the material and eventually cause thrombus formation. Although the risk of thrombosis can be reduced by injecting or taking anticoagulant antiplatelet drugs such as heparin, clopidogrel, atorvastatin, etc., this increases the risk of systemic bleeding and burden on the liver and kidney. Therefore, coating the surface of medical device materials with an anticoagulant coating to achieve a local anticoagulant effect has become a conventional means for improving the biocompatibility of blood contact medical devices in recent years.
One common form of coating the surface of the device with an anticoagulant coating is to coat the device with a coating containing anticoagulant drug, which has an obvious anticoagulant effect, can avoid bleeding risk caused by whole body anticoagulation, and is the current mainstream. Heparin is the most commonly used anticoagulant, and can effectively prevent and alleviate thrombosis.
Heparin is a polysaccharide molecule containing a plurality of active groups such as hydroxyl, carboxyl, sulfo, sulfate and the like, and can be fixed in a coating in an ionic bond, covalent bond and the like. Wherein, the covalent bond fixed heparin coating has stronger binding force, and heparin is not easy to fall off. The covalent bonding methods commonly used at present are those in which heparin is reacted with reactive groups previously grafted onto the surface of the material by amide/esterification reactions, e.gIs of (1) TM Heparin coating, however, this approach tends to result in too many binding sites between heparin and the surface of the material, rendering it biologically inactive. In addition, covalent bonds between heparin and the material surface formed in this way are mostly reversible amide or ester bonds, which can be broken during subsequent handling or use of the device. Or degrading heparin by end point fixation method to generate end aldehyde group, and reacting with active amino group on the surface of material Binding to form Schiff base, followed by reduction to a stable secondary amine bond by a specific reducing agent such as sodium borohydride, e.g.>A bioactive surface. However, the method can partially degrade heparin molecules, which can reduce biological activity, and active amino groups on the surface of the material can be preferentially combined with heparin ions, so that the covalent combination effect is affected.
Disclosure of Invention
Based on this, it is necessary to provide a preparation method capable of stably binding heparin anticoagulation coating to the surface of a substrate while maintaining heparin bioactivity.
In addition, it is also necessary to provide a heparin anticoagulation coating, its use.
A preparation method of heparin anticoagulation coating comprises the following steps:
modifying the substrate to enable the substrate to carry double bonds so as to obtain a modified substrate;
modifying heparin with a double bond-containing carboxylic acid, a double bond-containing anhydride, a double bond-containing epoxy compound or a double bond-containing amide compound to make the heparin carry double bonds, so as to obtain modified heparin; and
And treating the modified substrate by using a solution containing the modified heparin and an initiator to enable double bonds carried by the modified heparin and double bonds carried by the modified substrate to carry out free radical polymerization, so that a heparin anticoagulation coating is formed on the surface of the modified substrate.
In one embodiment, the step of modifying the substrate comprises:
firstly, carrying out surface activation on the base material, then grafting polyamino substances, and then, reacting the grafted base material with carboxylic acid containing double bonds, epoxy compound containing double bonds or aldehyde compound containing double bonds to form amide bonds or divalent amino groups.
In one embodiment, the grafted substrate and the carboxylic acid containing double bonds are reacted in an amide catalyst-containing solution, wherein the concentration of the carboxylic acid containing double bonds in the amide catalyst-containing solution is 1 mg/mL-5 mg/mL, the molar ratio of the carboxylic acid containing double bonds to the amide catalyst is 1 (0.01-0.2), and the reaction time is 3-10 h; or alternatively, the first and second heat exchangers may be,
reacting the grafted base material with the double bond-containing epoxy compound in a solution with the pH of 7.4-8.5, wherein the concentration of the double bond-containing epoxy compound in the solution with the pH of 7.4-8.5 is 1 mg/mL-5 mg/mL, and the reaction time is 3-12 h; or alternatively, the first and second heat exchangers may be,
the step of reacting the grafted substrate with the double bond-containing aldehyde compound comprises: firstly, reacting in a solution with the pH value of 3-5 for 3-8 hours, and then reducing by using a reducing agent; in the solution with the pH of 3-5, the concentration of the aldehyde compound containing double bonds is 1 mg/mL-5 mg/mL.
In one embodiment, the step of modifying the substrate comprises:
modifying polyamino substances by using carboxylic acid containing double bonds, epoxy compound containing double bonds or aldehyde compound containing double bonds to form amide bonds or divalent amino groups;
surface activating the substrate;
and (3) reacting the modified polyamino substance with the surface-activated base material.
In one embodiment, in the step of modifying a polyamino substance with a carboxylic acid containing double bonds, the polyamino substance and the carboxylic acid containing double bonds are reacted in a solution containing an amide catalyst for 0.5 to 5 hours, and the molar ratio of amino groups in the polyamino substance, carboxyl groups in the carboxylic acid containing double bonds and the amide catalyst is 1 (0.2 to 0.8): 0.02 to 0.4; or alternatively, the first and second heat exchangers may be,
in the step of modifying the polyamino substance with the double bond-containing epoxy compound, the polyamino substance and the double bond-containing epoxy compound are reacted in a solution with a pH of 7.4-8.5 for 0.5-10 hours, and the molar ratio of amino groups in the polyamino substance to epoxy groups in the double bond-containing epoxy compound is 1 (0.2-0.8); or alternatively, the first and second heat exchangers may be,
The step of modifying the polyamino substance by using the aldehyde compound containing double bonds comprises the following steps: firstly, reacting the polyamino substance with the aldehyde compound containing double bonds in a solution containing pH 3-5 for 1-5 h, and then reducing the reaction product by using a reducing agent, wherein the molar ratio of amino groups in the polyamino substance to aldehyde groups in the aldehyde compound containing double bonds is 1 (0.2-0.8).
In one embodiment, the polyamino substance is at least one selected from polyethylenimine, chitosan, polyallylamine hydrochloride, poly L-arginine hydrochloride, poly L-lysine hydrobromide, diethylenetriamine, triethylenetetramine and tetraethylenepentamine; and/or the number of the groups of groups,
the double bond-containing carboxylic acid has a general formula of CHX=CY- (L) n -COOZ wherein X is hydrogen or phenyl and Y is hydrogen, C 1～ C 6 C substituted by alkyl or halogen 1～ C 6 L is a divalent linking group, n is 0 or 1, Z is hydrogen or sodium; and/or the number of the groups of groups,
the aldehyde compound containing double bonds has a general formula CR 1 R 2 ＝CR 3 -CHO, wherein R 1 Is hydrogen or C 1～ C 6 Alkyl of R 2 Is hydrogen or C 2～ C 6 Alkenyl, R 3 Is hydrogen or C 1～ C 6 Alkyl of (a); and/or the number of the groups of groups,
the epoxy compound containing double bonds is at least one selected from glycidyl methacrylate, allyl glycidyl ether, epoxybutene and homologs thereof, 1, 2-epoxy-4-vinylcyclohexane and 3, 4-epoxy-1-cyclohexene; and/or the number of the groups of groups,
The base material is a metal-based biological material or a polymer-based biological material; and/or the number of the groups of groups,
the method for surface activation of the substrate comprises at least one of plasma treatment, ultraviolet irradiation, chemical modification and photochemical grafting.
In one embodiment, the amide catalyst is selected from at least one of 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride/N-hydroxysulfosuccinimide, genipin, 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride/1-hydroxybenzotriazole, O-benzotriazole-tetramethylurea hexafluorophosphate, 2- (7-azabenzotriazole) -N, N, N ', N' -tetramethylurea hexafluorophosphate, and 1H-benzotriazole-1-yloxytris (dimethylamino) hexafluorophosphate.
In one embodiment, in the step of modifying heparin with a double bond-containing carboxylic acid or a double bond-containing anhydride, the heparin and the double bond-containing carboxylic acid or the double bond-containing anhydride are reacted in an alkaline solution for 3 to 8 hours, and the mass ratio of the heparin to the double bond-containing carboxylic acid or the double bond-containing anhydride is 1 (0.05 to 0.5); or alternatively, the first and second heat exchangers may be,
in the step of modifying heparin by using double bond-containing epoxy compound, the heparin and the double bond-containing epoxy compound are reacted in a solution with pH of 7-8 for 3-8 days, and the mass ratio of the heparin to the double bond-containing epoxy compound is 1 (0.3-1); or alternatively, the first and second heat exchangers may be,
In the step of modifying heparin by using an amide compound containing double bonds, the heparin and the amide compound containing double bonds are stirred and reacted for 3 to 8 hours at the temperature of between 0 and 4 ℃ under the action of an activating agent and a condensing agent, wherein the mass ratio of the heparin to the amide compound containing double bonds, the activating agent to the condensing agent is (1 to 1.2): 0.8 to 1.
In one embodiment, the double bond containing carboxylic acid has the formula chx=cy-L-COOZ, wherein X is hydrogen or phenyl and Y is hydrogen, C 1～ C 6 C substituted by alkyl or halogen 1～ C 6 L is a divalent linking group and Z is hydrogen or sodium;
the general formula of the double bond-containing anhydride is R 4 -C(＝O)O-C(＝O)-R 5 ，R 4 And R is 5 At least one of which is C 2 ～C 6 Or, R 4 And R is 5 Forming a 5-7 membered monocyclic ring, wherein the 5-7 membered monocyclic ring contains a carbon-carbon double bond or has a substituent containing a carbon-carbon double bond;
the epoxy compound containing double bonds is at least one selected from glycidyl methacrylate, allyl glycidyl ether, epoxybutene and homologs thereof, 1, 2-epoxy-4-vinylcyclohexane and 3, 4-epoxy-1-cyclohexene;
the amide compound containing double bonds is N- (3-aminopropyl) methacrylamide hydrochloride.
In one embodiment, in the solution containing modified heparin and initiator, the concentration of the modified heparin is 2 mg/mL-5 mg/mL, and the mass ratio of the modified heparin to the initiator is 1: (0.005-0.05); and/or the number of the groups of groups,
the pH of the solution containing the modified heparin and the initiator is 6-6.8.
In one embodiment, the modified substrate is treated with a solution comprising modified heparin and an initiator by coating.
In one embodiment, the initiator is a photoinitiator, and in the step of treating the modified substrate with a solution containing modified heparin and the initiator, the modified substrate is coated once, and after the coating, the modified substrate is irradiated with ultraviolet light or visible light for 15min to 2h; or,
the initiator is a photoinitiator, in the step of treating the modified substrate by using a solution containing modified heparin and the initiator, the modified substrate is coated for a plurality of times, after each coating, the modified substrate is irradiated by ultraviolet light or visible light for 10 s-3 min, then the next coating is performed, and after the last coating, the modified substrate is irradiated by ultraviolet light or visible light for 15 min-2 h.
In one embodiment, the initiator is selected from at least one of 2-hydroxy-2-methyl-1- [4- (2-hydroxyethoxy) phenyl ] -1-propanone, benzophenone, diphenyl (2, 4, 6-trimethylbenzoyl) phosphine oxide, lithium phenyl (2, 4, 6-trimethylbenzoyl) phosphate, 2' -azo (2-methyl-N- (2-hydroxyethoxy) propionamide, riboflavin, and eosin Y, and/or,
the coating mode is dip coating, spray coating or spin coating.
The heparin anticoagulation coating is prepared by the preparation method of the heparin anticoagulation coating.
The heparin anticoagulation coating is applied in preparing blood contact medical equipment.
According to the preparation method of the heparin anticoagulation coating, the base material and the heparin are modified respectively, so that the base material carries double bonds, the heparin carries double bonds, then under the action of an initiator, the double bonds carried by the base material and the double bonds carried by the heparin undergo free radical polymerization to generate chemical crosslinking, so that the heparin anticoagulation coating with strong binding force is formed on the surface of the base material, and heparin molecules cannot fall off in the use process of medical instruments. In addition, in the step of modifying heparin, the reaction site of heparin is restricted by a modifying reagent (carboxylic acid containing double bond, anhydride containing double bond, epoxy compound containing double bond or amide compound containing double bond), thereby ensuring the bioactivity of heparin. Therefore, the preparation method of the heparin anticoagulation coating can ensure that the heparin anticoagulation coating is stably combined on the surface of the substrate while the bioactivity of the heparin anticoagulation coating is maintained.
Drawings
Fig. 1 is a process flow diagram of a method of preparing a heparin anticoagulant coating according to one embodiment.
Detailed Description
In order that the invention may be readily understood, a more complete description of the invention will be rendered by reference to specific embodiments that are now described. Preferred embodiments of the invention are given in the detailed description. This invention may, however, be embodied in many different forms and should not be construed as limited to the embodiments set forth herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The terminology used herein in the description of the invention is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. The term "and/or" as used herein includes any and all combinations of one or more of the associated listed items.
Herein, "ammoniaThe radical "means-NH 2 or-NH-.
"double bond" refers to a carbon-carbon double bond.
"carrying" means having, for example, by covalent bonding, and making the substrate carry double bonds means making the substrate have double bonds by covalent bonding.
The term "poly" in the term "polyamino substance" means 3 or more.
"alkyl" refers to a saturated hydrocarbon containing primary (normal) carbon atoms, or secondary carbon atoms, or tertiary carbon atoms, or quaternary carbon atoms, or a combination thereof. Phrases containing this term, e.g., "C 1 ～C 6 Alkyl "means an alkyl group containing 1 to 6 carbon atoms, which at each occurrence may be, independently of one another, C 1 Alkyl, C 2 Alkyl, C 3 Alkyl, C 4 Alkyl, C 5 Alkyl or C 6 An alkyl group. Suitable examples include, but are not limited to: methyl (Me, -CH) 3 ) Ethyl (Et, -CH) 2 CH 3 ) 1-propyl (n-Pr, n-propyl, -CH 2 CH 2 CH 3 ) 2-propyl (i-Pr, i-propyl, -CH (CH) 3 ) 2 ) Etc.
"alkylene" means a hydrocarbon group derived by removal of one hydrogen atom on an alkyl basis to form a center having two monovalent radicals, which may be a saturated branched alkyl group or a saturated straight chain alkyl group. Suitable examples include, but are not limited to: methylene (-CH) 2 (-), 1-ethyl (-CH (CH) 3 ) (-), 1, 2-ethyl (-CH) 2 CH 2 (-), 1-propyl (-CH (CH) 2 CH 3 ) (-), 1, 2-propyl (-CH) 2 CH(CH 3 ) (-), 1, 3-propyl (-CH) 2 CH 2 CH 2 (-) and 1, 4-butyl (-CH) 2 CH 2 CH 2 CH 2 (-), etc.
"homologs" means structurally similar and differing in molecular composition by several-CH' s 2 -an organic compound.
Aiming at the problems that heparin molecules fall off, heparin biological activity is affected and the like in the current heparin anticoagulation coating, the application provides an anticoagulation coating which is prepared by respectively carrying out double-bonding modification on the surfaces of heparin and materials and then carrying out free radical initiated polymerization to realize chemical crosslinking on the surfaces of the heparin and the materials, and provides a specific method for preparing the coating. The chemically crosslinked heparin anticoagulation coating prepared by the method can be stably and covalently bonded to the surface of the material while maintaining the bioactivity of heparin, and the preparation method is also easy to adjust the heparin density, so that the continuous anticoagulation effect of the medical instrument is realized.
Specifically, referring to fig. 1, a method for preparing a heparin anticoagulation coating according to an embodiment includes the following steps:
step S110: and modifying the substrate to enable the substrate to carry double bonds so as to obtain the modified substrate.
Wherein the base material is a metal-based biological material or a polymer-based biological material. Specifically, the metal-based biomaterial is stainless steel, cobalt-based alloy, titanium and titanium alloy or magnesium and magnesium alloy. The polymer-based biomaterial is terylene (PET), polymethyl methacrylate (PMMA), polyvinyl chloride (PVC), polyethylene (PE), polypropylene (PP), polytetrafluoroethylene (PTFE), polyether ether ketone (PEEK), polyurethane (PU), silicone rubber, polycaprolactone (PCL), polylactic acid (PLA), glycolide-lactide copolymer (PLGA) or polymethylpentene (PMP).
Further, in the process of modifying the substrate, the substrate carries double bonds and amino groups. Because the amino has electropositivity, more electronegative heparin can be adsorbed before polymerization when the modified heparin solution is coated later, thereby being beneficial to the improvement of the heparin density on the surface of the substrate.
Specifically, the present embodiment provides two approaches for modifying a substrate, and in some examples, the step of modifying the substrate includes:
Firstly, surface activation is carried out on a base material, then polyamino substances are grafted, and then the grafted base material reacts with carboxylic acid containing double bonds, epoxy compound containing double bonds or aldehyde compound containing double bonds to form amide bonds or divalent amino groups.
Specifically, the method for surface activation of a substrate comprises: plasma treatment, ultraviolet irradiation, chemical modification or photochemical grafting. For example, in one specific example, the substrate is treated with an oxygen plasma for 10 to 30 minutes. Alternatively, the substrate is placed in an aqueous acrylic solution at a concentration of 1.5mg/mL and irradiated with ultraviolet light for 30 minutes. Alternatively, the substrate is treated with concentrated sulfuric acid for 10 to 15 minutes. Alternatively, the substrate was placed in an ethanol solution having an acrylic acid concentration of 2.0mg/mL and a benzophenone concentration of 0.03mg/mL, and irradiated with ultraviolet light for 15 minutes. It will be appreciated that the above list just a few common methods of surface activation of a substrate, but is not limited thereto.
Specifically, the polyamino substance is at least one selected from polyethylenimine, chitosan, polyallylamine hydrochloride, poly L-arginine hydrochloride, poly L-lysine hydrobromide, diethylenetriamine, triethylenetetramine and tetraethylenepentamine. Further, the polyamino substance is at least one selected from the group consisting of polyethylenimine, chitosan, polyallylamine hydrochloride, poly L-arginine hydrochloride, poly L-lysine and poly L-lysine hydrobromide.
A layer of polyamino substances is grafted on the surface of the substrate, so that the density of double bonds on the surface of the substrate is effectively improved, electrostatic adsorption of amino groups on electronegative heparin is also utilized, more heparin can be adsorbed, and finally, the heparin density of the prepared heparin anticoagulation coating is jointly ensured.
In the step of grafting the polyamino substances on the substrate after surface activation, the substrate after surface activation is immersed into a first solution containing the polyamino substances for reaction for 0.5 to 5 hours, and then washed and dried. In one embodiment, the first solution is a pure water solution, a PBS buffer (phosphate buffer), or a Tris-HCl buffer (Tris-hydroxymethyl aminomethane-HCl buffer).
In one embodiment, the reaction of the grafted substrate with the carboxylic acid containing double bonds is carried out in a second solution containing an amide catalyst, the concentration of the carboxylic acid containing double bonds in the second solution containing the amide catalyst is 1 mg/mL-5 mg/mL, the molar ratio of the carboxylic acid containing double bonds to the amide catalyst is 1 (0.01-0.2), and the reaction time is 3-10 h. In a specific example, in the second solution comprising the amide catalyst, the concentration of the double bond-containing carboxylic acid is 1mg/mL, 2mg/mL, 3mg/mL, 4mg/mL, 5mg/mL, or a range of any two of these values. The molar ratio of the double bond containing carboxylic acid to the amide catalyst is in the range of 1:0.01, 1:0.02, 1:0.03, 1:0.05, 1:0.08, 1:0.1, 1:0.12, 1:0.15, 1:0.18, 1:0.2 or any two of these values.
Further, the double bond containing carboxylic acid has the general formula chx=cy- (L) n -COOZ wherein X is hydrogen or phenyl and Y is hydrogen, C 1～ C 6 C substituted by alkyl or halogen 1～ C 6 L is a divalent linking group, n is 0 or 1, Z is hydrogen or sodium. Further, Y is hydrogen, methyl or halogen substituted methyl. For example, the halogen substituted methyl group may be trifluoromethyl. Preferably, L is alkylene. The alkylene group may be straight or branched. For example, alkylene is methylene (-CH) 2 (-), 1-ethyl (-CH (CH) 3 ) (-), 1, 2-ethyl (-CH) 2 CH 2 (-), 1-propyl (-CH (CH) 2 CH 3 ) (-), 1, 2-propyl (-CH) 2 CH(CH 3 ) (-), 1, 3-propyl (-CH) 2 CH 2 CH 2 (-) and 1, 4-butyl (-CH) 2 CH 2 CH 2 CH 2 -)。
In one embodiment, the carboxylic acid containing a double bond is CH 2 ＝CH-(L) n -COOH、CH 2 ＝CH-(L) n -COONa、CH 2 ＝C(CH 3 )-(L) n -COOH、CH 2 ＝C(CH 3 )-(L) n -COONa、CH 2 ＝C(CF 3 ) -COOH or C 6 H 5 -ch=ch-COOH, n is 0 or 1, l is alkylene. In a specific example, the carboxylic acid containing a double bond may be acrylic acid, butenoic acid, pentenoic acid, undecylenic acid, oleic acid, methacrylic acid, methyl butenoic acid, sodium acrylate, sodium butenate, sodium pentenoate, sodium undecylenate, sodium oleate, sodium methacrylate, cinnamic acid, trifluoromethyl acrylic acid, or the like.
The amide catalyst is selected from at least one of EDC/NHS (1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride/N-hydroxysulfosuccinimide), genipin, EDC/HOBT (1-hydroxybenzotriazole), HBTU (O-benzotriazol-tetramethylurea hexafluorophosphate), HATU (2- (7-azabenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate) and BOP (1H-benzotriazol-1-yloxytris (dimethylamino) hexafluorophosphate). Herein, "/" means combination.
The second solution is a pure water solution, a PBS buffer solution, an MES buffer solution, a Tris-HCl buffer solution, a sodium acetate buffer solution, an organic solvent or a mixed solution prepared from an organic solvent and water. The organic solvent is methanol, ethanol, isopropanol, acetone or acetonitrile.
Amidation reaction is carried out by utilizing amino groups in the polyamino substances grafted on the grafted base material and carboxylic acid in carboxylic acid containing double bonds, so that the base material carries double bond groups. The polyamino substance contains a plurality of amino groups, can be combined with a plurality of carboxyl groups, and improves the density of double bonds on the surface of the substrate.
Further, the grafted substrate is reacted with carboxylic acid containing double bond, and then the substrate is washed with pure water and dried.
In another embodiment, the reaction of the grafted substrate with the double bond containing epoxy compound is carried out in a second solution having a pH of 7.4 to 8.5, and the double bond containing epoxy compound is present in the second solution having a pH of 7.4 to 8.5 at a concentration of 1mg/mL to 5mg/mL for a reaction time of 3 hours to 12 hours. In a specific example, the concentration of the double bond containing reducing compound is 1mg/mL, 2mg/mL, 3mg/mL, 4mg/mL, 5mg/mL, or a range of any two of these values.
Further, the epoxy compound having a double bond is at least one selected from the group consisting of glycidyl methacrylate, allyl glycidyl ether, epoxybutene and its homologs, 1, 2-epoxy-4-vinylcyclohexane and 3, 4-epoxy-1-cyclohexene. In a specific example, the homolog of epoxybutene may be epoxypentene, or the like.
Further, after the reaction of the grafted substrate with the double bond-containing epoxy compound, a step of washing with pure water and drying is also included.
In yet another embodiment, the step of reacting the grafted substrate with a double bond containing aldehyde compound comprises: firstly, reacting in a second solution with the pH value of 3-5 for 3-8 hours, and then reducing by using a reducing agent; in the second solution with the pH value of 3-5, the concentration of the aldehyde compound containing double bonds is 1 mg/mL-5 mg/mL. For example, the concentration of the double bond-containing aldehyde compound is 1mg/mL, 2mg/mL, 3mg/mL, 4mg/mL, 5mg/mL, or a range of any two of these values. In a specific example, the reducing agent is sodium cyanoborohydride.
Specifically, the aldehyde compound containing double bonds has a general formula CR 1 R 2 ＝CR 3 -CHO, wherein R 1 Is hydrogen or C 1～ C 6 Alkyl of R 2 Is hydrogen or C 2～ C 6 Alkenyl, R 3 Is hydrogen or C 1～ C 6 Is a hydrocarbon group. Further, the aldehyde compound containing double bond is at least one selected from citral, acrolein and homologs thereof, methacrolein and homologs thereof. In one embodiment, the homolog of acrolein may be crotonaldehyde, pentenal, and the like. The homologs of methacrolein may be 3-methyl-2-butenal, 2-methyl-2-pentenal, and the like.
Further, the method further comprises the steps of washing with pure water and drying after the grafted substrate is reacted with the aldehyde compound containing double bonds.
In other embodiments, the step of modifying the substrate comprises:
modifying polyamino substances by using carboxylic acid containing double bonds, epoxy compound containing double bonds or aldehyde compound containing double bonds to form amide bonds or divalent amino groups;
surface activating the substrate;
and (3) reacting the modified polyamino substance with the surface-activated base material.
Specifically, in the step of modifying the polyamino substance with the carboxylic acid containing a double bond, the polyamino substance and the carboxylic acid containing a double bond are reacted in a second solution containing an amide catalyst for 0.5 to 5 hours, and then dialyzed and freeze-dried. Wherein the molar ratio of the amino group in the polyamino substance to the carboxyl group in the carboxylic acid containing double bonds to the amide catalyst is 1 (0.2-0.8): 0.02-0.4.
In the step of modifying the polyamino substance by using the epoxy compound containing double bonds, the polyamino substance and the epoxy compound containing double bonds are reacted in a second solution containing pH 7.4-8.5 for 0.5-10 h, and then dialyzed and freeze-dried; the molar ratio of the amino groups in the polyamino substance to the epoxy groups in the double bond-containing epoxy compound is 1 (0.2-0.8). In a specific example, the molar ratio of amino groups in the polyamino substance to epoxy groups in the double bond containing epoxy compound is in the range of 1:0.2, 1:0.3, 1:0.4, 1:0.5, 1:0.6, 1:0.7, 1:0.8 or any two of these values.
In the step of modifying polyamino substances by using aldehyde compounds containing double bonds, the polyamino substances and the aldehyde compounds containing double bonds are reacted in a second solution containing pH 3-5 for 1-5 h, then reduced by using cyano sodium borohydride, dialyzed and freeze-dried; the molar ratio of the amino groups in the polyamino substance to the aldehyde groups in the aldehyde compound containing double bonds is 1 (0.2-0.8). In a specific example, the molar ratio of amino groups in the polyamino substance to aldehyde groups in the double bond containing aldehyde compound is 1:0.2, 1:0.3, 1:0.4, 1:0.5, 1:0.6, 1:0.7, 1:0.8 or a range of any two of these values.
Specifically, the polyamino substance, the carboxylic acid containing double bonds, the amide catalyst, the epoxy compound containing double bonds, and the aldehyde compound containing double bonds are the same as those described above, and will not be described again.
Further, in the step of reacting the modified polyamino substance with the surface-activated substrate, the surface-activated substrate is immersed in a first solution containing the modified polyamino substance, reacted for 0.5 to 3 hours, and then washed with pure water and dried.
The modification of the substrate is realized by utilizing the reaction of the active amino groups on the polyamino substances with other active groups, and a plurality of modification methods are provided, and different modification methods can be selected according to actual requirements, such as double bond density, solubility and reactivity of the polyamino substances, substrate types and the like.
Step S120: modifying heparin to make heparin carry double bond so as to obtain modified heparin.
Specifically, heparin is modified with a double bond-containing carboxylic acid, a double bond-containing acid anhydride, a double bond-containing epoxy compound, or a double bond-containing amide compound.
In some embodiments, the step of modifying the heparin with a double bond containing carboxylic acid or double bond containing anhydride comprises: reacting double bond-containing carboxylic acid or double bond-containing anhydride with heparin in alkaline solution for 3-8 h, dialyzing, and freeze drying.
Specifically, the mass ratio of heparin to the double bond-containing carboxylic acid or the double bond-containing anhydride is 1 (0.05-0.5). In a specific example, the mass ratio of heparin to the double bond containing carboxylic acid or double bond containing anhydride is 1:0.05, 1:0.1, 1:0.2, 1:0.3, 1:0.4, 1:0.5 or a range of any two of these values.
Specifically, the double bond containing carboxylic acid has the general formula chx=cy- (L) n -COOZ wherein X is hydrogen or phenyl and Y is hydrogen, C 1～ C 6 C substituted by alkyl or halogen 1～ C 6 L is a divalent linking group, n is 0 or 1, Z is hydrogen or sodium. Further, Y is hydrogen, methyl or halogen substituted methyl. For example, the halogen substituted methyl group may be trifluoromethyl. Preferably, L is alkylene. The alkylene group may be straight or branched. For example, alkylene is methylene (-CH) 2 (-), 1-ethyl (-CH (CH) 3 ) (-), 1, 2-ethyl (-CH) 2 CH 2 (-), 1-propyl (-CH (CH) 2 CH 3 ) (-), 1, 2-propyl (-CH) 2 CH(CH 3 ) (-), 1, 3-propyl (-CH) 2 CH 2 CH 2 (-) and 1, 4-butyl (-CH) 2 CH 2 CH 2 CH 2 -)。
In one embodiment, the carboxylic acid containing a double bond is CH 2 ＝CH-(L) n -COOH、CH 2 ＝CH-(L) n -COONa、CH 2 ＝C(CH 3 )-(L) n -COOH、CH 2 ＝C(CH 3 )-(L) n -COONa、CH 2 ＝C(CF 3 ) -COOH or C 6 H 5 -ch=ch-COOH, n is 0 or 1, l is alkylene. In a specific exampleThe carboxylic acid having a double bond may be acrylic acid, butenoic acid, pentenoic acid, undecylenic acid, oleic acid, methacrylic acid, methyl butenoic acid, sodium acrylate, sodium butenoate, sodium pentenoate, sodium undecylenate, sodium oleate, sodium methacrylate, cinnamic acid, trifluoromethyl acrylic acid, or the like.
Specifically, the double bond-containing anhydride has the general formula R 4 -C(＝O)O-C(＝O)-R 5 ，R 4 And R is 5 At least one of which is C 2 ～C 6 Or, R 4 And R is 5 Forming a 5-7 membered monocyclic ring, wherein the 5-7 membered monocyclic ring contains a carbon-carbon double bond or has a substituent containing a carbon-carbon double bond. Further, the double bond-containing acid anhydride is at least one selected from the group consisting of acrylic anhydride, methacrylic anhydride and maleic anhydride.
In one embodiment, the alkaline solution may have a pH of 8. The alkaline solution may be an aqueous sodium hydroxide solution.
In other embodiments, the step of modifying the heparin with an epoxy compound containing a double bond comprises: heparin and epoxy compound containing double bond are reacted in solution with pH of 7-8 for 3-8 days, and then dialyzed and freeze dried.
Specifically, the mass ratio of heparin to the double bond-containing epoxy compound is 1 (0.3-1). In a specific example, the mass ratio of heparin to double bond containing epoxy compound is 1:0.3, 1:0.4, 1:0.5, 1:0.6, 1:0.7, 1:0.8, 1:0.9, 1:1 or a range of any two of these values.
Further, the double bond-containing epoxy compound is at least one selected from the group consisting of glycidyl methacrylate, allyl glycidyl ether, 1, 2-epoxy-4-vinylcyclohexane, 3, 4-epoxy-1-cyclohexene, epoxybutene and homologs thereof.
In one embodiment, the solution having a pH of 7 to 8 may be a phosphate buffer.
In still other embodiments, the step of modifying the heparin with an amide compound containing a double bond comprises: heparin and an amide compound containing double bonds are stirred and reacted for 3 to 8 hours at the temperature of between 0 and 4 ℃ under the action of an activating agent and a condensing agent, and then the mixture is dialyzed and freeze-dried.
Further, the mass ratio of heparin to the double bond-containing amide compound to the activator to the condensing agent is (1-1.2): 0.8-1. Preferably, the mass ratio of heparin, the amide compound containing double bonds, the activator and the condensing agent is 1.2:1:1:1. In one embodiment, the activator is NHS (N-hydroxysulfosuccinimide) and the condensing agent is EDC (1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride).
In one embodiment, the double bond containing amide compound is N- (3-aminopropyl) methacrylamide hydrochloride.
In the process of modifying heparin, the reaction site of heparin is regulated and controlled by different modification methods, such as carboxylic acid/anhydride modification, epoxy modification, amide modification and the like, and the double-bonding amount of heparin can be effectively controlled by adjusting the proportion of heparin and a modifying reagent, so that the crosslinking density of heparin is controlled while the bioactivity of heparin is ensured.
Step S130: treating the modified substrate with a solution containing modified heparin and an initiator to enable double bonds carried by the modified heparin and double bonds carried by the modified substrate to undergo free radical polymerization, and forming a heparin anticoagulation coating on the surface of the modified substrate.
Wherein, in the solution containing modified heparin and initiator, the pH is 6-6.8, the concentration of modified heparin is 2 mg/mL-5 mg/mL, and the mass ratio of modified heparin to initiator is 1 (0.005-0.05). In a specific example, the modified heparin concentration is 2mg/mL, 3mg/mL, 4mg/mL, 5mg/mL, or a range of any two of these values in a solution containing the modified heparin and the initiator. The mass ratio of modified heparin to initiator is 1:0.005, 1:0.01, 1:0.02, 1:0.03, 1:0.04, 1:0.05 or a range of any two of these values. In one embodiment, the solution containing modified heparin and initiator is PBS buffer.
Specifically, the initiator is a photoinitiator. The photoinitiator is at least one selected from Irgacure 2959 (2-hydroxy-2-methyl-1- [4- (2-hydroxy ethoxy) phenyl ] -1-propanone), benzophenone, TPO (diphenyl (2, 4, 6-trimethylbenzoyl) phosphine oxide), LAP (phenyl (2, 4, 6-trimethylbenzoyl) lithium phosphate), VA-086 (2, 2' -azo (2-methyl-N- (2-hydroxy ethyl) propionamide), riboflavin and eosin Y.
Specifically, in the step of treating the modified substrate with a solution containing modified heparin and an initiator, a coating method is used. Further, the coating mode is dip coating, spray coating or spin coating. In one specific example, the coating time is 30s to 5min. For example, the coating time is 30s, 1min, 2min, 3min, 4min, 5min, or a range of any two of these values.
In one example, in the step of treating the modified substrate with a solution containing modified heparin and an initiator, a coating is performed once, and after the coating, the coated substrate is irradiated with ultraviolet light or visible light for 15min to 2h. For example, the substrate after coating with ultraviolet light or visible light is irradiated for 15min, 20min, 30min, 60min, 90min, 120min, or a range of any two of these values.
In another embodiment, in the step of treating the modified substrate with a solution containing modified heparin and an initiator, a plurality of coating is performed, after each coating, the coated substrate is irradiated with ultraviolet light or visible light for 10s to 3min, and then the next coating is performed, and after the last coating, the substrate is irradiated with ultraviolet light or visible light for 15min to 2h. Compared with the mode of carrying out one-time coating and multiple-time coating, the method forms a plurality of layers of three-dimensional networks overlapped layer by layer, and the multiple networks are mutually penetrated, so that the stability of the prepared heparin anticoagulation coating is obviously improved. Further, the time of each coating is independently 30s to 5min.
The chemical crosslinking of heparin and the surface of the substrate is realized by virtue of double bond free radical polymerization on the surface of the heparin and the substrate, and the selection of a plurality of photoinitiators is provided, and different photoinitiators can be selected according to practical requirements, such as illumination wavelength, illumination time, initiator solubility, concentration and the like.
Further, the method further comprises the steps of washing with pure water and drying.
The preparation method of the heparin anticoagulation coating has at least the following advantages:
(1) According to the preparation method of the heparin anticoagulation coating, the base material and the heparin are modified respectively, so that the base material and the heparin carry double bonds, then under the action of an initiator, the double bonds carried by the base material and the double bonds carried by the heparin are subjected to free radical polymerization, chemical crosslinking is generated between the base material and the heparin coating, a crosslinking network is formed, the heparin anticoagulation coating has very firm binding force, heparin molecules cannot fall off in the use process of medical instruments, and real local anticoagulation is realized. Meanwhile, a layer of polyamino substances is grafted on the surface of the substrate, so that the density of double bonds on the surface of the substrate is effectively improved, electrostatic adsorption of amino groups on electronegative heparin is also utilized, more electronegative heparin is adsorbed before polymerization when a solution containing modified heparin is coated, and finally, the heparin density of the anticoagulation coating is jointly ensured.
(2) On the one hand, the preparation method of the heparin anticoagulation coating provides a plurality of methods for modifying the substrate, and can effectively regulate and control the double bonding density of the surface of the substrate; on the other hand, the preparation method also provides a plurality of methods for modifying the heparin, and can effectively adjust the double-bonded reaction sites and the double bonds of the heparin, thereby controlling the biological activity of the heparin not to be greatly influenced.
(3) In the preparation method, the heparin and the surface of the substrate are chemically crosslinked through covalent bonds, so that the bonding force is strong, the thickness of the coating and the density of the heparin can be regulated and controlled through the double-bonding degree of the heparin and the surface of the substrate, and the coating times can be regulated and controlled.
(4) The preparation method adopts a photoinitiated polymerization mode to carry out free radical polymerization, and has higher efficiency, safety, environmental protection and economy compared with other polymerization modes.
The application also provides the heparin anticoagulation coating of an embodiment, which is prepared from the heparin anticoagulation coating of the embodiment.
The application also provides the application of the heparin anticoagulation coating in preparing the blood contact medical device.
In order to make the objects and advantages of the present invention more apparent, the following more particular description of the method for preparing heparin anticoagulation coating and the effect thereof will be given in connection with the specific examples, which are to be construed as merely illustrative and not limitative of the present invention.
Comparative example 1
Comparative example 1 provides a heparin anticoagulation coating prepared by electrostatic adsorption method, which is obtained by the following steps:
(1) Washing and drying the polyethylene film needing surface modification, treating the polyethylene film with oxygen plasma for 30 minutes, immersing the treated polyethylene film into PBS buffer solution with PEI concentration of 1.5mg/mL, reacting for 1 hour, taking out, and washing with purified water to obtain the PEI grafted polyethylene film.
(2) PBS buffer with heparin concentration of 1.5mg/mL and pH value of 6.4 was prepared.
(3) Immersing the PEI grafted polyethylene film prepared in the step (1) into the heparin solution prepared in the step (2), lifting the polyethylene film after 1 hour, washing the polyethylene film with purified water, and drying the polyethylene film to obtain a heparin anticoagulation coating prepared by an electrostatic adsorption method.
Comparative example 2
Comparative example 2 provides a heparin anticoagulant coating prepared by an amide covalent immobilization method, obtained by the steps of:
(1) Washing and drying the polyethylene film needing surface modification, treating the polyethylene film with oxygen plasma for 30 minutes, immersing the treated polyethylene film into PBS buffer solution with PEI concentration of 1.5mg/mL, reacting for 1 hour, taking out, and washing with purified water to obtain the PEI grafted polyethylene film.
(2) Heparin was dissolved in PBS buffer to a heparin concentration of 1.5mg/mL, activated with 0.02mg/mL EDC/NHS and adjusted to pH 6.4.
(3) Immersing the PEI grafted polyethylene film prepared in the step (1) into the heparin solution prepared in the step (2), stirring and reacting for 5 hours, lifting, washing with purified water, and drying to obtain a heparin anticoagulation coating prepared by an amide covalent fixation method.
Examples 1 to 2
Example 1 and example 2 both provide a method for preparing heparin anticoagulation coating, which specifically comprises the following steps:
(1) Modification of a substrate
The substrate was modified by the following two methods, wherein the heparin anticoagulation coating obtained by modifying the substrate by the method 1 and passing through the subsequent steps (2), step (3) and step (4) was the heparin anticoagulation coating prepared in example 1, and the heparin anticoagulation coating obtained by modifying the substrate by the method 2 and passing through the subsequent steps (2), step (3) and step (4) was the heparin anticoagulation coating prepared in example 2.
Specifically, the method 1 comprises the following steps:
washing and drying the polyethylene film, treating the polyethylene film with oxygen plasma for 30 minutes, then putting the polyethylene film into PBS buffer solution with PEI concentration of 1.5mg/mL, taking out the polyethylene film after reacting for 1 hour, washing the polyethylene film with purified water, and drying the polyethylene film to obtain the PEI grafted polyethylene film.
The PEI grafted polyethylene film is placed in an acrylic acid aqueous solution with the concentration of 1.5mg/mL for reaction, EDC/NHS is used for catalysis, the concentration of EDC/NHS is 0.02mg/mL, and the reaction time is 4 hours. And after the reaction is finished, washing with purified water and drying to obtain the modified polyethylene film.
The method 2 comprises the following steps:
preparing a PEI aqueous solution with the concentration of 1.5mg/mL, adding EDC/NHS with the concentration of 0.02mg/mL for activation, then adding an acrylic acid aqueous solution with the concentration of 1.5mg/mL, reacting for 2 hours, washing with purified water, and freeze-drying to obtain the modified PEI.
Washing and drying the polyethylene film, treating the polyethylene film with oxygen plasma for 30 minutes, then placing the polyethylene film into a PBS buffer solution containing the modified PEI, reacting the polyethylene film for 1 hour in the PBS buffer solution with the concentration of the modified PEI of 1.5mg/mL, taking out the polyethylene film, washing the polyethylene film with purified water, and drying the polyethylene film to obtain the modified polyethylene film.
(2) Modification of heparin
1.0g of heparin was reacted with 0.1g of methacrylic anhydride in an aqueous sodium hydroxide solution having a pH of 8 for 8 hours, followed by dialysis and freeze-drying to obtain a modified heparin.
(3) Preparation of heparin solution
And (3) preparing PBS buffer solution with pH value of 6.4 by using 0.8g of modified heparin obtained in the step (2) and 20mg Irgacure 2959, wherein the concentration of the modified heparin is 2.5mg/mL.
(4) Coating preparation
Immersing the modified polyethylene film prepared in the step (1) into the heparin solution prepared in the step (3), lifting after 5 minutes, and continuously irradiating with 275nm ultraviolet light for 1 hour. And then washing with purified water and drying to obtain a layer of chemically cross-linked heparin anticoagulation coating.
Examples 3 to 4
Example 3 to example 4 provide a preparation method of heparin anticoagulation coating, which specifically comprises the following steps:
(1) Modification of a substrate
Washing and drying the polyethylene film, treating the polyethylene film with oxygen plasma for 30 minutes, then putting the polyethylene film into PBS buffer solution with PEI concentration of 1.5mg/mL, taking out the polyethylene film after reacting for 1 hour, washing the polyethylene film with purified water, and drying the polyethylene film to obtain the PEI grafted polyethylene film.
The PEI grafted polyethylene film was reacted in an aqueous acrylic acid solution at a concentration of 1.5mg/mL, catalyzed with EDC/NHS at a concentration of 0.02mg/mL for 4 hours. And after the reaction is finished, washing with purified water and drying to obtain the modified polyethylene film.
(2) Modification of heparin
The heparin was modified by three methods, wherein the heparin anticoagulation coating obtained by modifying the heparin by the method a and passing through the subsequent steps (3) and (4) was the heparin anticoagulation coating prepared in the above-mentioned example 1, the heparin anticoagulation coating obtained by modifying the heparin by the method b and passing through the subsequent steps (3) and (4) was the heparin anticoagulation coating prepared in the example 3, and the heparin anticoagulation coating obtained by modifying the heparin by the method c and passing through the subsequent steps (3) and (4) was the heparin anticoagulation coating prepared in the example 4.
Specifically, the method a is as follows:
1.0g heparin and 0.1g methacrylic anhydride in aqueous sodium hydroxide solution with pH value of 8.0 are reacted for 8 hours, and then dialyzed and freeze-dried to obtain modified heparin.
The method b comprises the following steps:
1.0g heparin and 0.9g N- (3-amino propyl) methacrylamide hydrochloride are stirred and reacted for 6 hours at 0 ℃ under the action of 0.9g NHS and 1.2g EDC, and then dialyzed and freeze-dried to obtain the modified heparin.
The method c comprises the following steps:
1g of heparin and 0.5g of 1, 2-epoxy-4-vinylcyclohexane are reacted in a phosphate buffer with a pH value of 7.4 for 5 days, and then dialyzed and freeze-dried to obtain modified heparin.
(3) Preparation of heparin solution
And (3) preparing PBS buffer solution with pH value of 6.4 by using 0.8g of modified heparin obtained in the step (2) and 20mg Irgacure 2959, wherein the concentration of the modified heparin is 2.5mg/mL.
(4) Coating preparation
Immersing the modified polyethylene film prepared in the step (1) into the heparin solution prepared in the step (3), lifting after 5 minutes, and continuously irradiating with 275nm ultraviolet light for 1 hour. And then washing with purified water and drying to obtain a heparin anticoagulation coating.
Example 5
Embodiment 5 provides a preparation method of heparin anticoagulation coating, which specifically comprises the following steps:
(1) Modification of a substrate
The polyethylene film is washed, dried, treated by oxygen plasma for 30 minutes, then put into PBS buffer solution with the concentration of diethylenetriamine of 1.5mg/mL, taken out after reacting for 1 hour, washed by purified water and dried, and the diethylenetriamine grafted polyethylene film is obtained.
The diethylenetriamine grafted polyethylene film is placed in an acrylic acid aqueous solution with the concentration of 1.5mg/mL for reaction, EDC/NHS is used for catalysis, the concentration of EDC/NHS is 0.02mg/mL, and the reaction time is 4 hours. And after the reaction is finished, washing with purified water and drying to obtain the modified polyethylene film.
(2) Modification of heparin
1.0g of heparin was reacted with 0.1g of methacrylic anhydride in an aqueous sodium hydroxide solution having a pH of 8 for 8 hours, followed by dialysis and freeze-drying to obtain a modified heparin.
(3) Preparation of heparin solution
And (3) preparing PBS buffer solution with pH value of 6.4 by using 0.8g of modified heparin obtained in the step (2) and 20mg Irgacure 2959, wherein the concentration of the modified heparin is 2.5mg/mL.
(4) Coating preparation
Immersing the modified polyethylene film prepared in the step (1) into the heparin solution prepared in the step (3), lifting after 5 minutes, and continuously irradiating with 275nm ultraviolet light for 1 hour. And then washing with purified water and drying to obtain a layer of chemically cross-linked heparin anticoagulation coating.
Examples 6 to 8
Example 6 to example 8 provide a preparation method of heparin anticoagulation coating, which specifically comprises the following steps:
(1) Modification of a substrate
Washing and drying the polyethylene film, treating the polyethylene film with oxygen plasma for 30 minutes, then putting the polyethylene film into PBS buffer solution with PEI concentration of 1.5mg/mL, taking out the polyethylene film after reacting for 1 hour, washing the polyethylene film with purified water, and drying the polyethylene film to obtain the PEI grafted polyethylene film.
The PEI grafted polyethylene film was reacted in an aqueous acrylic acid solution at a concentration of 1.5mg/mL, catalyzed with EDC/NHS at a concentration of 0.02mg/mL for 4 hours. And after the reaction is finished, washing with purified water and drying to obtain the modified polyethylene film.
(2) Modification of heparin
1g of heparin was reacted with 0.1g of methacrylic anhydride in an aqueous sodium hydroxide solution having a pH of 8 for 8 hours, followed by dialysis and freeze-drying to obtain a modified heparin.
(3) Preparation of heparin solution
And (3) preparing PBS buffer solution with pH value of 6.4 by using 0.8g of modified heparin obtained in the step (2) and 20mg Irgacure 2959, wherein the concentration of the modified heparin is 2.5mg/mL.
(4) Coating preparation
Immersing the modified polyethylene film prepared in the step (1) into the heparin solution prepared in the step (3), lifting after 30 seconds, and continuously irradiating with 275nm ultraviolet light for 15 seconds. Immersing the solution into the heparin solution prepared in the step (3) for 30 seconds, lifting the solution, irradiating the solution for 15 seconds by ultraviolet light, and recording one dip-coating and one irradiation as one cycle, wherein 2 cycles, 4 cycles and 6 cycles are respectively carried out. Finally, continuously irradiating for 1 hour by using ultraviolet light, and then washing and drying by using purified water to obtain a heparin anticoagulation coating. Wherein, the heparin anticoagulation coating prepared by performing 2 cycles, 4 cycles and 6 cycles corresponds to the heparin anticoagulation coating of example 6, the heparin anticoagulation coating of example 7 and the heparin anticoagulation coating of example 8, respectively.
Example 9
The embodiment provides a preparation method of a heparin anticoagulation coating, which specifically comprises the following steps:
(1) Modification of a substrate
And (3) cleaning the polyether-ether-ketone base material, placing the cleaned polyether-ether-ketone base material into an acrylic acid aqueous solution with the concentration of 1.5mg/mL, irradiating the acrylic acid aqueous solution with ultraviolet light for 30 minutes, placing the PEI-ether-ketone base material into a PBS buffer solution with the PEI concentration of 1.5mg/mL, reacting the PEI-ether-ketone base material for 1 hour, taking out the PEI-ether-ketone base material, washing the PEI-ether-ketone base material with purified water, and drying the PEI-ether-ketone base material to obtain the PEI-ether-ketone base material.
The PEI grafted polyether-ether-ketone substrate is reacted in methacrylic acid aqueous solution with the concentration of 1.8mg/mL, and is catalyzed by genipin, the concentration of the genipin is 0.1mg/mL, and the reaction time is 5 hours. And after the reaction is finished, washing with purified water and drying to obtain the modified polyether-ether-ketone substrate.
(2) Modification of heparin
1g of heparin and 0.9g N- (3-aminopropyl) methacrylamide hydrochloride are stirred and reacted for 6 hours at 0 ℃ under the action of 0.9g of NHS and 1.2g of EDC, and then dialyzed and freeze-dried to obtain the modified heparin.
(3) Preparation of heparin solution
Preparing PBS buffer solution with pH value of 6.4 by using 0.8g modified heparin prepared in the step (2) and 20mg LAP, wherein the concentration of the modified heparin is 2mg/mL.
(4) Coating preparation
Spraying the heparin solution prepared in the step (3) (spraying amount is 0.05 mL/cm) 2 ) And (3) irradiating the modified polyether-ether-ketone substrate prepared in the step (1) with 405nm visible light for 2 minutes. Then spraying again, irradiating with 405nm visible light for 2 minutes and irradiating with visible light for 45 minutes. Finally, washing with purified water and drying to obtain a heparin anticoagulation coating.
Example 10
The embodiment provides a preparation method of a heparin anticoagulation coating, which specifically comprises the following steps:
(1) Modification of a substrate
And (3) cleaning and drying the polyvinyl chloride substrate, treating the polyvinyl chloride substrate with concentrated sulfuric acid for 15 minutes, washing the polyvinyl chloride substrate with purified water, then placing the polyvinyl chloride substrate in chitosan aqueous solution with the concentration of 1.5mg/mL, reacting the polyvinyl chloride substrate for 45 minutes, washing the polyvinyl chloride substrate with purified water, and drying the polyvinyl chloride substrate to obtain the chitosan grafted polyvinyl chloride substrate.
The polyvinyl chloride substrate grafted by the chitosan is reacted in PBS buffer solution (pH value is 7.4) with the concentration of glycidyl methacrylate of 2mg/mL for 6 hours, and then washed by purified water and dried to obtain the modified polyvinyl chloride substrate.
(2) Modification of heparin
1g of heparin was reacted with 0.1g of methacrylic anhydride in an aqueous sodium hydroxide solution having a pH of 8 for 8 hours, followed by dialysis and freeze-drying to obtain a modified heparin.
(3) Preparation of heparin solution
Preparing PBS buffer solution with pH value of 6.5 by using 0.8g modified heparin prepared in the step (2) and 25mg Irgacure2959, wherein the concentration of the modified heparin is 2.5mg/mL.
(4) Coating preparation
Immersing the modified polyvinyl chloride substrate prepared in the step (1) into the heparin solution prepared in the step (3) for 5 minutes, lifting, irradiating for 1 hour by ultraviolet light, washing by purified water, and drying to obtain a heparin anticoagulation coating.
Example 11
The embodiment provides a preparation method of a heparin anticoagulation coating, which specifically comprises the following steps:
(1) Modification of a substrate
And (3) reacting PEI, cinnamic acid and EDC/HOBT in an aqueous solution for 1.5 hours, wherein the molar ratio of amino groups of PEI to carboxyl groups of cinnamic acid to EDC/HOBT catalyst is 1:0.4:0.2, washing with purified water after the reaction is finished, and freeze-drying to obtain the modified PEI.
After the medical stainless steel 316L is washed and dried, the medical stainless steel is treated with concentrated sulfuric acid for 10 minutes and then washed with purified water. Then immersing the stainless steel into the modified PEI aqueous solution with the concentration of 3mg/mL for reaction for 30 minutes, washing the stainless steel with purified water and drying the stainless steel to obtain the modified stainless steel 316L.
(2) Modification of heparin
1g of heparin and 0.5g of 1, 2-epoxy-4-vinylcyclohexane are reacted in a phosphate buffer with a pH value of 7.4 for 5 days, and then dialyzed and freeze-dried to obtain modified heparin.
(3) Preparation of heparin solution
Preparing PBS buffer solution with pH value of 6.4 by using 0.8g modified heparin prepared in the step (2) and 20mg VA-086, wherein the concentration of the modified heparin is 2.5mg/mL.
(4) Coating preparation
Immersing the modified stainless steel 316L prepared in the step (1) into the heparin solution prepared in the step (3) for 5 minutes, lifting, irradiating with 405nm visible light for 1.5 minutes, immersing into the heparin solution prepared in the step (3) for 5 minutes, lifting, irradiating with 405nm for 1.5 minutes, recording one dip coating and one irradiation as one cycle, and continuously irradiating with ultraviolet light for 1 hour after three cycles. Finally, washing with purified water and drying to obtain a heparin anticoagulation coating.
Example 12
The embodiment provides a preparation method of a heparin anticoagulation coating, which specifically comprises the following steps:
(1) Modification of a substrate
After washing and drying the magnesium alloy stent, the stent is treated with oxygen plasma for 10 minutes and then washed with purified water. Then placing the stent in a polypropylene-based amine hydrochloride aqueous solution with the concentration of 1.5mg/mL, taking out the stent after reacting for 1.5 hours, washing the stent with purified water, and drying the stent to obtain the polypropylene-based amine grafted magnesium alloy stent.
And (3) reacting the polypropylene-based amine grafted magnesium alloy bracket in an ethanol solution with the concentration of 3, 4-epoxy-1-cyclohexene of 1.5mg/mL for 8 hours, and then washing with ethanol, washing with purified water and drying in sequence to obtain the modified magnesium alloy bracket.
(2) Modification of heparin
1g of heparin was reacted with 0.1g of methacrylic anhydride in an aqueous sodium hydroxide solution having a pH of 8 for 5 hours, followed by dialysis and freeze-drying to obtain a modified heparin.
(3) Preparation of heparin solution
Preparing PBS buffer solution with pH value of 6.8 by using 0.8g modified heparin prepared in the step (2) and 25mg Irgacure2959, wherein the concentration of the modified heparin is 2mg/mL.
(4) Coating preparation
Spraying the heparin solution prepared in the step (3) (spraying amount is 0.05 mL/cm) 2 ) And (3) irradiating the surface of the modified magnesium alloy bracket prepared in the step (1) with 275nm ultraviolet light for 20 seconds. Then spraying again, irradiating with ultraviolet light for 20 seconds, finally irradiating with ultraviolet light for 1.2 hours, washing with purified water, drying, and coating a heparin anticoagulation coating on the surface of the magnesium alloy bracket.
Example 13
The embodiment provides a preparation method of a heparin anticoagulation coating, which specifically comprises the following steps:
(1) Modification of a substrate
PEI and citral were reacted in a water-ethanol (2:8 v: v) mixed solution for 2 hours, wherein the molar ratio of amino groups of PEI to aldehyde groups of citral was 1.0:0.6. After the reaction is finished, adding sodium cyanoborohydride to make the molar ratio of the sodium cyanoborohydride to citral be 1:1, stirring and reacting for 2 hours, then washing with water-ethanol mixed solvent (2:8 v: v) and purified water in sequence, and freeze-drying to obtain the modified PEI.
After the polymethylpentene substrate was washed, it was put in an ethanol solution having an acrylic acid concentration of 2mg/mL and a benzophenone concentration of 0.03mg/mL, and irradiated with ultraviolet light for 15 minutes. And then washing with ethanol and purified water in turn, placing the washed product in a Tris-HCl solution with the concentration of 2mg/mL of the modified PEI, reacting for 1 hour, taking out the product, washing with purified water, and drying to obtain the modified polymethylpentene substrate.
(2) Modification of heparin
1g of heparin and 0.5g of 1, 2-epoxy-4-vinylcyclohexane are reacted in a phosphate buffer with a pH value of 7.4 for 5 days, and then dialyzed and freeze-dried to obtain modified heparin.
(3) Preparation of heparin solution
Preparing PBS buffer solution with pH value of 6.4 by using 0.8g modified heparin prepared in the step (2) and 40mg riboflavin, wherein the concentration of the modified heparin is 2mg/mL.
(4) Coating preparation
Spin-coating the heparin solution prepared in the step (3) with a layer of coating with a thickness of about 20 mu m on the surface of the modified polymethylpentene substrate prepared in the step (1), irradiating with 425nm visible light for 1 hour, washing with purified water, and drying to obtain a heparin anticoagulation coating.
Example 14
The embodiment provides a preparation method of a heparin anticoagulation coating, which specifically comprises the following steps:
(1) Modification of a substrate
And cleaning and drying the polylactic acid substrate, treating the polylactic acid substrate with oxygen plasma for 20 minutes, placing the polylactic acid substrate in chitosan solution with the concentration of 3mg/mL, reacting for 30 minutes, and washing and drying the polylactic acid substrate with purified water to obtain the chitosan grafted polylactic acid substrate.
And (3) reacting the chitosan grafted polylactic acid substrate in an aqueous solution with the allyl glycidyl ether concentration of 3mg/mL for 8 hours, washing with purified water, and drying to obtain the modified polylactic acid substrate.
(2) Modification of heparin
1g of heparin was reacted with 0.1g of methacrylic anhydride in an aqueous sodium hydroxide solution having a pH of 8 for 6 hours, followed by dialysis and freeze-drying to obtain a modified heparin.
(3) Preparation of heparin solution
Preparing PBS buffer solution with pH value of 6.4 by using 0.8g modified heparin prepared in the step (2), 25mg Irgacure2959 and 15mg benzophenone, wherein the concentration of the modified heparin is 2.5mg/mL.
(4) Coating preparation
Immersing the modified polylactic acid substrate prepared in the step (1) into the heparin solution prepared in the step (3) for 1 minute, lifting, and then irradiating with 275nm ultraviolet light for 2 minutes. Immersing the solution into the heparin solution prepared in the step (3) for 1 minute, lifting the solution, irradiating the solution for 2 minutes by using 275nm ultraviolet light, recording one dip coating and one irradiation as one cycle, and carrying out three cycles in an accumulated way. Finally, after continuously irradiating for 1 hour by ultraviolet light, washing by purified water and drying to obtain a heparin anticoagulation coating.
The following are specific test parts:
(1) Heparin content determination
The heparin contents in the heparin anticoagulation coatings prepared in examples 1 to 13 and comparative examples 1 to 2 were measured by toluidine blue colorimetry, respectively, and the results are shown in Table 1.
Table 1 heparin content in heparin anticoagulation coating of each example
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As shown in table 1, the heparin anticoagulation coatings prepared by the above examples 1 to 13 all showed higher heparin content than the heparin anticoagulation coatings prepared by comparative examples 1 and 2. The modification process of the different substrates and the different heparin modification processes have no significant effect on the heparin content of the final coating. However, the heparin content in the obtained heparin anticoagulation coating prepared after the substrate is modified by the macromolecular polyamino compound is obviously higher than that of the heparin modified by the small polyamino compound, such as example 1 modified by PEI and example 5 modified by diethylenetriamine. Furthermore, as can be seen from a comparison of examples 6 to 8, the heparin content significantly increased as the number of coating applications of the coating increased.
(2) Coagulation time experiment
Collecting fresh venous blood of rabbits, uniformly mixing the fresh venous blood with a sodium citrate solution with the mass percentage concentration of 3.8% according to the volume ratio of 9:1, centrifuging for 10 minutes at the rotating speed of 3000r/min, and separating to obtain platelet-poor plasma. The uncoated polyethylene films used in the examples (designated as control), comparative example 1, comparative example 2, and polyethylene films coated with heparin anticoagulation coating prepared in examples 1 to 8 were cut into 5mm×5mm pieces and placed in 24-well culture plates. Subsequently, 700. Mu.L of platelet-poor plasma was added to each sample well, incubated in a constant temperature water bath at 37℃for 2 hours, and the incubated plasma was extracted and assayed by a coagulation analyzer. The results are shown in Table 2.
Table 2 clotting time for each example
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As shown in table 2, the coated polyethylene films all showed superior anticoagulation effect compared to the uncoated polyethylene films, and the heparin anticoagulation coatings prepared in examples 1 to 8 were significantly better in anticoagulation ability than the heparin anticoagulation coatings prepared in comparative examples 1 to 2 by the electrostatic adsorption method and the amide covalent fixation method. Meanwhile, as can be seen from comparison of different embodiments, modification of the substrate by different modification methods and modification of heparin by different methods have no obvious influence on the anticoagulation effect of the finally prepared heparin anticoagulation coating, but the anticoagulation effect is remarkably improved by using macromolecular polyamino compounds and increasing the coating times.
(3) Stability test
The polyethylene films coated with heparin anticoagulation coating prepared in comparative example 1, comparative example 2, example 1, example 6, example 8 were cut into 5mm×5mm pieces, respectively immersed in hydrochloric acid solution of pH 1, sodium hydroxide solution of pH 12 and physiological saline for 1 hour, 2 hours, 6 hours and 24 hours, taken out, washed with purified water, and the heparin content was measured by toluidine blue colorimetry. The results are shown in Table 3.
TABLE 3 coating stability test results
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As shown in Table 3, the heparin anticoagulation coating prepared by the electrostatic adsorption method in comparative example 1 was rapidly destroyed in acidic, alkaline and neutral environments, especially in acidic and alkaline conditions. The heparin anticoagulation coating prepared by adopting the amide method in the comparative example 2 has better binding force, but more obvious heparin molecules can be dropped off, and the heparin anticoagulation coating is more obvious in acidic and alkaline environments. The heparin anticoagulation coating obtained by the preparation methods provided in the examples 1, 6 and 8 has strong binding force, high heparin content in various environments and stable binding of heparin molecules after 24 hours of treatment.
The stability test was performed only by taking the heparin anticoagulation coatings prepared in examples 1, 6 and 8 as examples, but the heparin anticoagulation coatings prepared in other examples also have stability comparable to that of the heparin anticoagulation coatings prepared in examples 1, 6 and 8.
(4) Long term stability test
The polyethylene films with heparin anticoagulation coating prepared in example 1 and example 6 were placed in PBS buffer (pH 7.4) for 7 days, then washed with purified water, and the heparin contents were 1.32.+ -. 0.01. Mu.g/cm, respectively, as determined by toluidine blue colorimetry 2 And 1.39.+ -. 0.01. Mu.g/cm 2 . This shows that the heparin anticoagulation coating prepared in example 1 and example 6 has better long-term stability.
The long-term stability test was performed only by taking the heparin anticoagulation coatings prepared in example 1 and example 6 as examples, but the heparin anticoagulation coatings prepared in other examples also have long-term stability comparable to the heparin anticoagulation coatings prepared in example 1 and example 6.
The technical features of the above-described embodiments may be arbitrarily combined, and all possible combinations of the technical features in the above-described embodiments are not described for brevity of description, however, as long as there is no contradiction between the combinations of the technical features, they should be considered as the scope of the description.
The above examples merely represent a few embodiments of the present invention, which facilitate a specific and detailed understanding of the technical solutions of the present invention, but are not to be construed as limiting the scope of the invention. It should be noted that it will be apparent to those skilled in the art that several variations and modifications can be made without departing from the spirit of the invention, which are all within the scope of the invention. It should be understood that, based on the technical solutions provided by the present invention, those skilled in the art can obtain technical solutions through logical analysis, reasoning or limited experiments, which are all within the protection scope of the appended claims. The scope of the patent is therefore intended to be covered by the appended claims, and the description and drawings may be interpreted as illustrative of the contents of the claims.
Claims (14)
1. The preparation method of the heparin anticoagulation coating is characterized by comprising the following steps of:
modifying the substrate to enable the substrate to carry double bonds so as to obtain a modified substrate;
modifying heparin with a double bond-containing carboxylic acid, a double bond-containing anhydride, a double bond-containing epoxy compound or a double bond-containing amide compound to make the heparin carry double bonds, so as to obtain modified heparin; and
And treating the modified substrate by using a solution containing the modified heparin and an initiator to enable double bonds carried by the modified heparin and double bonds carried by the modified substrate to carry out free radical polymerization, so that a heparin anticoagulation coating is formed on the surface of the modified substrate.
2. The method for preparing a heparin anticoagulation coating according to claim 1, wherein the step of modifying the substrate comprises:
firstly, carrying out surface activation on the base material, then grafting polyamino substances, and then, reacting the grafted base material with carboxylic acid containing double bonds, epoxy compound containing double bonds or aldehyde compound containing double bonds to form amide bonds or divalent amino groups.
3. The method for producing heparin anticoagulation coating according to claim 2, wherein the grafted substrate is reacted with the double bond-containing carboxylic acid in an amide catalyst-containing solution in which the concentration of the double bond-containing carboxylic acid is 1mg/mL to 5mg/mL, the molar ratio of the double bond-containing carboxylic acid to the amide catalyst is 1 (0.01 to 0.2), and the reaction time is 3h to 10h; or alternatively, the first and second heat exchangers may be,
Reacting the grafted base material with the double bond-containing epoxy compound in a solution with the pH of 7.4-8.5, wherein the concentration of the double bond-containing epoxy compound in the solution with the pH of 7.4-8.5 is 1 mg/mL-5 mg/mL, and the reaction time is 3-12 h; or alternatively, the first and second heat exchangers may be,
the step of reacting the grafted substrate with the double bond-containing aldehyde compound comprises: firstly, reacting in a solution with the pH value of 3-5 for 3-8 hours, and then reducing by using a reducing agent; in the solution with the pH of 3-5, the concentration of the aldehyde compound containing double bonds is 1 mg/mL-5 mg/mL.
4. The method for preparing a heparin anticoagulation coating according to claim 1, wherein the step of modifying the substrate comprises:
modifying polyamino substances by using carboxylic acid containing double bonds, epoxy compound containing double bonds or aldehyde compound containing double bonds to form amide bonds or divalent amino groups;
surface activating the substrate;
and (3) reacting the modified polyamino substance with the surface-activated base material.
5. The method for producing heparin anticoagulation coating according to claim 4, wherein in the step of modifying polyamino substance with double bond-containing carboxylic acid, the polyamino substance is reacted with double bond-containing carboxylic acid in a solution of amide-containing catalyst for 0.5 to 5 hours, and the molar ratio of amino group in polyamino substance, carboxyl group in double bond-containing carboxylic acid and amide catalyst is 1 (0.2 to 0.8): 0.02 to 0.4; or alternatively, the first and second heat exchangers may be,
In the step of modifying the polyamino substance with the double bond-containing epoxy compound, the polyamino substance and the double bond-containing epoxy compound are reacted in a solution with a pH of 7.4-8.5 for 0.5-10 hours, and the molar ratio of amino groups in the polyamino substance to epoxy groups in the double bond-containing epoxy compound is 1 (0.2-0.8); or alternatively, the first and second heat exchangers may be,
the step of modifying the polyamino substance by using the aldehyde compound containing double bonds comprises the following steps: firstly, reacting the polyamino substance with the aldehyde compound containing double bonds in a solution containing pH 3-5 for 1-5 h, and then reducing the reaction product by using a reducing agent, wherein the molar ratio of amino groups in the polyamino substance to aldehyde groups in the aldehyde compound containing double bonds is 1 (0.2-0.8).
6. The method for preparing a heparin anticoagulation coating according to any one of claims 2-5, wherein the polyamino substance is at least one selected from the group consisting of polyethylenimine, chitosan, polyallylamine hydrochloride, poly-L-arginine hydrochloride, poly-L-lysine hydrobromide, diethylenetriamine, triethylenetetramine and tetraethylenepentamine; and/or the number of the groups of groups,
The double bond-containing carboxylic acid has a general formula of CHX=CY- (L) n -COOZ wherein X is hydrogen or phenyl and Y is hydrogen, C 1～ C 6 C substituted by alkyl or halogen 1～ C 6 L is a divalent linking group, n is 0 or 1, Z is hydrogen or sodium; and/or the number of the groups of groups,
the aldehyde compound containing double bonds has a general formula CR 1 R 2 ＝CR 3 -CHO, wherein R 1 Is hydrogen or C 1～ C 6 Alkyl of R 2 Is hydrogen or C 2～ C 6 Alkenyl, R 3 Is hydrogen or C 1～ C 6 Alkyl of (a); and/or the number of the groups of groups,
the epoxy compound containing double bonds is at least one selected from glycidyl methacrylate, allyl glycidyl ether, epoxybutene and homologs thereof, 1, 2-epoxy-4-vinylcyclohexane and 3, 4-epoxy-1-cyclohexene; and/or the number of the groups of groups,
the base material is a metal-based biological material or a polymer-based biological material; and/or the number of the groups of groups,
the method for surface activation of the substrate comprises at least one of plasma treatment, ultraviolet irradiation, chemical modification and photochemical grafting.
7. The method for preparing heparin anticoagulation coating according to claim 3 or 5, wherein the amide catalyst is at least one selected from the group consisting of 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride/N-hydroxysuccinimide, genipin, 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride/1-hydroxybenzotriazole, O-benzotriazol-tetramethylurea hexafluorophosphate, 2- (7-azabenzotriazol) -N, N' -tetramethylurea hexafluorophosphate and 1H-benzotriazol-1-yloxy tris (dimethylamino) hexafluorophosphate.
8. The method for producing a heparin anticoagulation coating according to claim 1, wherein in the step of modifying heparin with a double bond-containing carboxylic acid or a double bond-containing acid anhydride, the heparin is reacted with the double bond-containing carboxylic acid or the double bond-containing acid anhydride in an alkaline solution for 3 to 8 hours, and the mass ratio of the heparin to the double bond-containing carboxylic acid or the double bond-containing acid anhydride is 1 (0.05 to 0.5); or alternatively, the first and second heat exchangers may be,
in the step of modifying heparin by using double bond-containing epoxy compound, the heparin and the double bond-containing epoxy compound are reacted in a solution with pH of 7-8 for 3-8 days, and the mass ratio of the heparin to the double bond-containing epoxy compound is 1 (0.3-1); or alternatively, the first and second heat exchangers may be,
in the step of modifying heparin by using an amide compound containing double bonds, the heparin and the amide compound containing double bonds are stirred and reacted for 3 to 8 hours at the temperature of between 0 and 4 ℃ under the action of an activating agent and a condensing agent, wherein the mass ratio of the heparin to the amide compound containing double bonds, the activating agent to the condensing agent is (1 to 1.2): 0.8 to 1.
9. The method for preparing heparin anticoagulation coating according to claim 8, wherein the double bond-containing carboxylic acid has the general formula chx=cy-L-COOZ, wherein X is hydrogen or phenyl, Y is hydrogen, C 1～ C 6 C substituted by alkyl or halogen 1～ C 6 L is a divalent linking group and Z is hydrogen or sodium;
the general formula of the double bond-containing anhydride is R 4 -C(＝O)O-C(＝O)-R 5 ，R 4 And R is 5 At least one of which is C 2 ～C 6 Or, R 4 And R is 5 Forming a 5-7 membered monocyclic ring, wherein the 5-7 membered monocyclic ring contains a carbon-carbon double bond or has a substituent containing a carbon-carbon double bond;
the epoxy compound containing double bonds is at least one selected from glycidyl methacrylate, allyl glycidyl ether, epoxybutene and homologs thereof, 1, 2-epoxy-4-vinylcyclohexane and 3, 4-epoxy-1-cyclohexene;
the amide compound containing double bonds is N- (3-aminopropyl) methacrylamide hydrochloride.
10. The method for preparing the heparin anticoagulation coating according to claim 1, wherein in the modified heparin and initiator-containing solution, the concentration of the modified heparin is 2mg/mL to 5mg/mL, and the mass ratio of the modified heparin to the initiator is 1: (0.005-0.05); and/or the number of the groups of groups,
the pH of the solution containing the modified heparin and the initiator is 6-6.8.
11. The method for preparing a heparin anticoagulation coating according to claim 1 or 10, characterized in that the initiator is a photoinitiator, in the step of treating the modified substrate with a solution containing modified heparin and initiator, one-time coating is performed, and the modified substrate is irradiated with ultraviolet light or visible light for 15 min-2 h after coating; or,
The initiator is a photoinitiator, in the step of treating the modified substrate by using a solution containing modified heparin and the initiator, the modified substrate is coated for a plurality of times, after each coating, the modified substrate is irradiated by ultraviolet light or visible light for 10 s-3 min, then the next coating is performed, and after the last coating, the modified substrate is irradiated by ultraviolet light or visible light for 15 min-2 h.
12. The method for preparing heparin anticoagulation coating according to claim 11, wherein the initiator is at least one selected from the group consisting of 2-hydroxy-2-methyl-1- [4- (2-hydroxyethoxy) phenyl ] -1-propanone, benzophenone, diphenyl (2, 4, 6-trimethylbenzoyl) phosphine oxide, phenyl (2, 4, 6-trimethylbenzoyl) lithium phosphate, 2' -azo (2-methyl-N- (2-hydroxyethoxy) propionamide, riboflavin and eosin Y, and/or,
the coating mode is dip coating, spray coating or spin coating.
13. A heparin anticoagulation coating, characterized in that it is prepared by the preparation method of heparin anticoagulation coating according to any one of claims 1-12.
14. Use of the heparin anticoagulant coating of claim 13 for the preparation of blood contact medical devices.
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| CN202210887524.1A CN117482302A (en) | 2022-07-26 | 2022-07-26 | Heparin anticoagulation coating and preparation method and application thereof |
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