CN117940174A - Modified polymer membrane material with surface compositely grafted with phosphorylcholine and heparin anticoagulation coating and preparation method thereof - Google Patents
Modified polymer membrane material with surface compositely grafted with phosphorylcholine and heparin anticoagulation coating and preparation method thereof Download PDFInfo
- Publication number
- CN117940174A CN117940174A CN202280058209.6A CN202280058209A CN117940174A CN 117940174 A CN117940174 A CN 117940174A CN 202280058209 A CN202280058209 A CN 202280058209A CN 117940174 A CN117940174 A CN 117940174A
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- CN
- China
- Prior art keywords
- membrane material
- heparin
- solution
- cerium
- grafted
- Prior art date
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- Pending
Links
- 239000000463 material Substances 0.000 title claims abstract description 124
- 229920000669 heparin Polymers 0.000 title claims abstract description 91
- 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 84
- 229960002897 heparin Drugs 0.000 title claims abstract description 84
- 229920005597 polymer membrane Polymers 0.000 title claims abstract description 45
- YHHSONZFOIEMCP-UHFFFAOYSA-O phosphocholine Chemical compound C[N+](C)(C)CCOP(O)(O)=O YHHSONZFOIEMCP-UHFFFAOYSA-O 0.000 title claims abstract description 30
- 229950004354 phosphorylcholine Drugs 0.000 title claims abstract description 30
- 230000010100 anticoagulation Effects 0.000 title claims abstract description 28
- 239000011248 coating agent Substances 0.000 title claims abstract description 25
- 238000000576 coating method Methods 0.000 title claims abstract description 25
- 238000002360 preparation method Methods 0.000 title abstract description 31
- 239000012528 membrane Substances 0.000 claims abstract description 92
- 238000004140 cleaning Methods 0.000 claims abstract description 39
- 238000000034 method Methods 0.000 claims abstract description 34
- GUAQVFRUPZBRJQ-UHFFFAOYSA-N n-(3-aminopropyl)-2-methylprop-2-enamide Chemical compound CC(=C)C(=O)NCCCN GUAQVFRUPZBRJQ-UHFFFAOYSA-N 0.000 claims abstract description 20
- 239000000126 substance Substances 0.000 claims abstract description 10
- NJNWCIAPVGRBHO-UHFFFAOYSA-N 2-hydroxyethyl-dimethyl-[(oxo-$l^{5}-phosphanylidyne)methyl]azanium Chemical class OCC[N+](C)(C)C#P=O NJNWCIAPVGRBHO-UHFFFAOYSA-N 0.000 claims abstract description 8
- 229920000578 graft copolymer Polymers 0.000 claims abstract description 8
- 150000001718 carbodiimides Chemical class 0.000 claims abstract description 4
- 239000000243 solution Substances 0.000 claims description 114
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 50
- 239000004814 polyurethane Substances 0.000 claims description 48
- 229920002635 polyurethane Polymers 0.000 claims description 47
- -1 polyethylene terephthalate Polymers 0.000 claims description 42
- 238000001035 drying Methods 0.000 claims description 40
- 239000008213 purified water Substances 0.000 claims description 37
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 29
- 238000006243 chemical reaction Methods 0.000 claims description 27
- 229910052684 Cerium Inorganic materials 0.000 claims description 24
- 238000005406 washing Methods 0.000 claims description 22
- 229920006254 polymer film Polymers 0.000 claims description 21
- GWXLDORMOJMVQZ-UHFFFAOYSA-N cerium Chemical compound [Ce] GWXLDORMOJMVQZ-UHFFFAOYSA-N 0.000 claims description 20
- 150000001875 compounds Chemical class 0.000 claims description 20
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 claims description 18
- SXGZJKUKBWWHRA-UHFFFAOYSA-N 2-(N-morpholiniumyl)ethanesulfonate Chemical compound [O-]S(=O)(=O)CC[NH+]1CCOCC1 SXGZJKUKBWWHRA-UHFFFAOYSA-N 0.000 claims description 18
- 238000001291 vacuum drying Methods 0.000 claims description 18
- NQTADLQHYWFPDB-UHFFFAOYSA-N N-Hydroxysuccinimide Chemical compound ON1C(=O)CCC1=O NQTADLQHYWFPDB-UHFFFAOYSA-N 0.000 claims description 17
- 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 15
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 14
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 12
- HSJPMRKMPBAUAU-UHFFFAOYSA-N cerium(3+);trinitrate Chemical compound [Ce+3].[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O HSJPMRKMPBAUAU-UHFFFAOYSA-N 0.000 claims description 12
- 239000001301 oxygen Substances 0.000 claims description 12
- 229910052760 oxygen Inorganic materials 0.000 claims description 12
- 229960001231 choline Drugs 0.000 claims description 11
- OEYIOHPDSNJKLS-UHFFFAOYSA-N choline Chemical compound C[N+](C)(C)CCO OEYIOHPDSNJKLS-UHFFFAOYSA-N 0.000 claims description 11
- 238000002791 soaking Methods 0.000 claims description 10
- 229920001343 polytetrafluoroethylene Polymers 0.000 claims description 8
- 239000004810 polytetrafluoroethylene Substances 0.000 claims description 8
- 230000008569 process Effects 0.000 claims description 8
- 125000003277 amino group Chemical group 0.000 claims description 7
- 239000007853 buffer solution Substances 0.000 claims description 7
- ZFGMDIBRIDKWMY-PASTXAENSA-N heparin Chemical compound CC(O)=N[C@@H]1[C@@H](O)[C@H](O)[C@@H](COS(O)(=O)=O)O[C@@H]1O[C@@H]1[C@@H](C(O)=O)O[C@@H](O[C@H]2[C@@H]([C@@H](OS(O)(=O)=O)[C@@H](O[C@@H]3[C@@H](OC(O)[C@H](OS(O)(=O)=O)[C@H]3O)C(O)=O)O[C@@H]2O)CS(O)(=O)=O)[C@H](O)[C@H]1O ZFGMDIBRIDKWMY-PASTXAENSA-N 0.000 claims description 7
- 229960001008 heparin sodium Drugs 0.000 claims description 7
- 230000000977 initiatory effect Effects 0.000 claims description 7
- 239000008363 phosphate buffer Substances 0.000 claims description 6
- 238000005345 coagulation Methods 0.000 claims description 5
- 230000015271 coagulation Effects 0.000 claims description 5
- 239000002904 solvent Substances 0.000 claims description 5
- 239000004696 Poly ether ether ketone Substances 0.000 claims description 4
- 239000004952 Polyamide Substances 0.000 claims description 4
- 239000004642 Polyimide Substances 0.000 claims description 4
- 229920004890 Triton X-100 Polymers 0.000 claims description 4
- 239000013504 Triton X-100 Substances 0.000 claims description 4
- HKVFISRIUUGTIB-UHFFFAOYSA-O azanium;cerium;nitrate Chemical compound [NH4+].[Ce].[O-][N+]([O-])=O HKVFISRIUUGTIB-UHFFFAOYSA-O 0.000 claims description 4
- 238000009954 braiding Methods 0.000 claims description 4
- 229910000420 cerium oxide Inorganic materials 0.000 claims description 4
- VYLVYHXQOHJDJL-UHFFFAOYSA-K cerium trichloride Chemical compound Cl[Ce](Cl)Cl VYLVYHXQOHJDJL-UHFFFAOYSA-K 0.000 claims description 4
- TYAVIWGEVOBWDZ-UHFFFAOYSA-K cerium(3+);phosphate Chemical compound [Ce+3].[O-]P([O-])([O-])=O TYAVIWGEVOBWDZ-UHFFFAOYSA-K 0.000 claims description 4
- GHLITDDQOMIBFS-UHFFFAOYSA-H cerium(3+);tricarbonate Chemical compound [Ce+3].[Ce+3].[O-]C([O-])=O.[O-]C([O-])=O.[O-]C([O-])=O GHLITDDQOMIBFS-UHFFFAOYSA-H 0.000 claims description 4
- QCCDYNYSHILRDG-UHFFFAOYSA-K cerium(3+);trifluoride Chemical compound [F-].[F-].[F-].[Ce+3] QCCDYNYSHILRDG-UHFFFAOYSA-K 0.000 claims description 4
- 238000002386 leaching Methods 0.000 claims description 4
- BMMGVYCKOGBVEV-UHFFFAOYSA-N oxo(oxoceriooxy)cerium Chemical compound [Ce]=O.O=[Ce]=O BMMGVYCKOGBVEV-UHFFFAOYSA-N 0.000 claims description 4
- 229920002647 polyamide Polymers 0.000 claims description 4
- 229920002530 polyetherether ketone Polymers 0.000 claims description 4
- 229920000139 polyethylene terephthalate Polymers 0.000 claims description 4
- 239000005020 polyethylene terephthalate Substances 0.000 claims description 4
- 229920001721 polyimide Polymers 0.000 claims description 4
- 230000035484 reaction time Effects 0.000 claims description 4
- 238000005507 spraying Methods 0.000 claims description 4
- 239000004698 Polyethylene Substances 0.000 claims description 3
- 239000004793 Polystyrene Substances 0.000 claims description 3
- 229920001971 elastomer Polymers 0.000 claims description 3
- 239000000806 elastomer Substances 0.000 claims description 3
- 238000001523 electrospinning Methods 0.000 claims description 3
- 239000007788 liquid Substances 0.000 claims description 3
- 229920000573 polyethylene Polymers 0.000 claims description 3
- 229920002223 polystyrene Polymers 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims 9
- 229920006264 polyurethane film Polymers 0.000 description 46
- 238000012360 testing method Methods 0.000 description 21
- 210000001772 blood platelet Anatomy 0.000 description 20
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 16
- 239000004721 Polyphenylene oxide Substances 0.000 description 8
- 229910052786 argon Inorganic materials 0.000 description 8
- 229920000570 polyether Polymers 0.000 description 8
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 239000003146 anticoagulant agent Substances 0.000 description 4
- 229940127219 anticoagulant drug Drugs 0.000 description 4
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 4
- 239000002131 composite material Substances 0.000 description 4
- VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 description 4
- 229920002946 poly[2-(methacryloxy)ethyl phosphorylcholine] polymer Polymers 0.000 description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 3
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
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- 238000003892 spreading Methods 0.000 description 3
- 230000007480 spreading Effects 0.000 description 3
- 230000002429 anti-coagulating effect Effects 0.000 description 2
- 239000012620 biological material Substances 0.000 description 2
- 210000001124 body fluid Anatomy 0.000 description 2
- 239000010839 body fluid Substances 0.000 description 2
- 210000000170 cell membrane Anatomy 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 229960003638 dopamine Drugs 0.000 description 2
- 229920000642 polymer Polymers 0.000 description 2
- 239000002861 polymer material Substances 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- PGOHTUIFYSHAQG-LJSDBVFPSA-N (2S)-6-amino-2-[[(2S)-5-amino-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-4-amino-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-5-amino-2-[[(2S)-5-amino-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S,3R)-2-[[(2S)-5-amino-2-[[(2S)-2-[[(2S)-2-[[(2S,3R)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-5-amino-2-[[(2S)-1-[(2S,3R)-2-[[(2S)-2-[[(2S)-2-[[(2R)-2-[[(2S)-2-[[(2S)-2-[[2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-1-[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-amino-4-methylsulfanylbutanoyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-5-carbamimidamidopentanoyl]amino]propanoyl]pyrrolidine-2-carbonyl]amino]-3-methylbutanoyl]amino]-4-methylpentanoyl]amino]-4-methylpentanoyl]amino]acetyl]amino]-3-hydroxypropanoyl]amino]-4-methylpentanoyl]amino]-3-sulfanylpropanoyl]amino]-4-methylsulfanylbutanoyl]amino]-5-carbamimidamidopentanoyl]amino]-3-hydroxybutanoyl]pyrrolidine-2-carbonyl]amino]-5-oxopentanoyl]amino]-3-hydroxypropanoyl]amino]-3-hydroxypropanoyl]amino]-3-(1H-imidazol-5-yl)propanoyl]amino]-4-methylpentanoyl]amino]-3-hydroxybutanoyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-5-carbamimidamidopentanoyl]amino]-5-oxopentanoyl]amino]-3-hydroxybutanoyl]amino]-3-hydroxypropanoyl]amino]-3-carboxypropanoyl]amino]-3-hydroxypropanoyl]amino]-5-oxopentanoyl]amino]-5-oxopentanoyl]amino]-3-phenylpropanoyl]amino]-5-carbamimidamidopentanoyl]amino]-3-methylbutanoyl]amino]-4-methylpentanoyl]amino]-4-oxobutanoyl]amino]-5-carbamimidamidopentanoyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-4-carboxybutanoyl]amino]-5-oxopentanoyl]amino]hexanoic acid Chemical compound CSCC[C@H](N)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@@H](Cc1cnc[nH]1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCCN)C(O)=O PGOHTUIFYSHAQG-LJSDBVFPSA-N 0.000 description 1
- 102000009123 Fibrin Human genes 0.000 description 1
- 108010073385 Fibrin Proteins 0.000 description 1
- BWGVNKXGVNDBDI-UHFFFAOYSA-N Fibrin monomer Chemical compound CNC(=O)CNC(=O)CN BWGVNKXGVNDBDI-UHFFFAOYSA-N 0.000 description 1
- 108010049003 Fibrinogen Proteins 0.000 description 1
- 102000008946 Fibrinogen Human genes 0.000 description 1
- 206010018910 Haemolysis Diseases 0.000 description 1
- 108010094028 Prothrombin Proteins 0.000 description 1
- 102100027378 Prothrombin Human genes 0.000 description 1
- 108090000190 Thrombin Proteins 0.000 description 1
- 108010000499 Thromboplastin Proteins 0.000 description 1
- 102000002262 Thromboplastin Human genes 0.000 description 1
- 208000007536 Thrombosis Diseases 0.000 description 1
- 238000005299 abrasion Methods 0.000 description 1
- 238000004220 aggregation Methods 0.000 description 1
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- 239000002473 artificial blood Substances 0.000 description 1
- 239000003012 bilayer membrane Substances 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- XMPZTFVPEKAKFH-UHFFFAOYSA-P ceric ammonium nitrate Chemical compound [NH4+].[NH4+].[Ce+4].[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O XMPZTFVPEKAKFH-UHFFFAOYSA-P 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
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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
- 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
- A61L33/068—Use of macromolecular materials obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
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- A—HUMAN NECESSITIES
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- 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
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- 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
- A61L33/0041—Anticoagulant, e.g. heparin, platelet aggregation inhibitor, fibrinolytic agent, other than enzymes, attached to the substrate characterised by the choice of an antithrombatic agent other than heparin
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
- C08J5/00—Manufacture of articles or shaped materials containing macromolecular substances
- C08J5/18—Manufacture of films or sheets
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
- C08J7/00—Chemical treatment or coating of shaped articles made of macromolecular substances
- C08J7/12—Chemical modification
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
- C08J7/00—Chemical treatment or coating of shaped articles made of macromolecular substances
- C08J7/12—Chemical modification
- C08J7/16—Chemical modification with polymerisable compounds
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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
- 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
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Abstract
The application relates to a modified polymer membrane material with a surface compositely grafted phosphorylcholine and heparin anticoagulation coating, and the preparation method of the modified polymer membrane material comprises the following steps: s1, preparing a polymer membrane material; s2, chemically grafting unsaturated phosphorylcholine and N- (3-aminopropyl) methacrylamide on the surface of the high polymer membrane material; s3, cleaning the grafted polymer membrane material obtained in the step S2; s4, grafting heparin on the cleaned grafted polymer membrane material obtained in the step S3 by adopting a carbodiimide chemical method.
Description
RELATED APPLICATIONS
The application claims priority from China patent application No. 202111123851.1, entitled "modified Polymer film Material and method for preparing same", filed 24, 9, 2021, which is incorporated herein by reference in its entirety.
The application relates to the field of biomedical high polymer materials, in particular to a polyurethane film with a surface grafted with a heparin coating and a preparation method thereof.
The polymer material is widely used for materials contacting body fluids or blood because of its good mechanical properties, abrasion resistance and processability. Polyurethane is used as one of important medical materials, and has very wide application in artificial heart and artificial blood vessel. Polyurethane biological materials can be used for medical instruments such as catheters for interventional operations, ureteral catheters, wound dressings, artificial hearts, artificial heart valves, intravenous ports and the like.
The medical polyurethane material can be polyester polyurethane, polyether polyurethane, polycarbonate polyurethane and the like according to chemical components. Polyester polyurethane is a polyurethane material synthesized based on polyester polyol, but ester bonds are also easily influenced by water to undergo degradation reaction, so that the application of the polyester polyurethane in the aspect of long-term implantation materials is limited; polyether polyurethane is a polyurethane material synthesized based on polyether polyol, and polyether chains of the polyether polyurethane are easy to decompose, so that the application of the polyether polyurethane in the aspect of implantation materials is limited; in addition, due to the flexibility of the polyether chain, the polyether polyurethane material has high transmittance to water and water vapor, and has great threat to metal parts of equipment when being used as a medical equipment material; the polycarbonate Polyurethane (PCU) has better biocompatibility than other polyurethane materials, and meanwhile, the chemical structure determines that the polycarbonate Polyurethane (PCU) is more stable in organisms, so that the requirements of long-term implantation type application on the materials can be met.
Although polyurethane materials have good biocompatibility, coagulation and hemolysis occur when they are in direct contact with blood, thereby causing thrombus. To solve this problem, researchers have conducted anticoagulation studies on materials by surface modification. Among them, heparin and Phosphorylcholine (PC) are hot spots of research. Heparin can inhibit the activity of thromboplastin, thereby inhibiting the conversion of prothrombin into thrombin, so that the heparin cannot play a role in promoting the conversion of fibrinogen into fibrin, and the aggregation of tissue platelets, thereby having anticoagulation performance. Phosphorylcholine is a hydrophilic end group of a basic unit constituting a cell membrane, plays an important role in an outer cell membrane, and directly affects living cells to act with the outside. The phosphorylcholine group contains quaternary ammonium groups and phosphoryl groups, has positive and negative charges, is of a zwitterionic structure, and has strong water binding capacity. By simulating the structure of extracellular phospholipid bilayer membrane, the phosphorylcholine group-rich material is modified into natural components in organisms, so that the material has excellent biocompatibility, the surface is not easy to adsorb platelets, and the anticoagulation performance of the material is improved.
Patent CN104629058a discloses a preparation method of heparinized polyurethane film, which uses polyurethane film with carboxyl as substrate, activates carboxyl on polyurethane surface by 1-ethyl-3- (dimethylpropylamine) carbodiimide (WSC), then grafts heparin, and prepares heparinized polyurethane film. However, the polyurethane film has a limited amount of carboxyl groups on the surface, and has fewer active groups, so that the grafting efficiency of heparin is low.
Patent CN101967235A discloses a phosphorylcholine modified polyurethane biological material and a preparation method thereof, wherein a plasma surface modification method is adopted to introduce functional molecules or groups on the surface of the material, so that the contact angle is reduced, and the anticoagulation performance is improved. However, the grafting of the surface of the film subjected to the plasma treatment is not firm, and the long-term requirement of surface modification cannot be met.
Patent CN112316218a discloses a zwitterionic polymer and heparin composite coating and a preparation method and application, wherein a dopamine solution is used to form a mediating layer, and then an amide bond grafted heparin is formed by immersing in the zwitterionic polymer solution. However, the membrane formed by the method has limited amino or carboxyl content on the surface, which results in lower heparin grafting efficiency; at the same time, the mechanical properties of the membrane may be affected by this method of dopamine adhesion.
Disclosure of Invention
According to various embodiments of the application, a modified polymer membrane material with a surface compositely grafted with phosphorylcholine and heparin anticoagulation coating and a preparation method thereof are provided.
The technical scheme adopted by the application is as follows:
The application provides a modified polymer membrane material with a surface compositely grafted with phosphorylcholine and heparin anticoagulation coating, and the preparation method of the modified polymer membrane material comprises the following steps:
s1, preparing a polymer membrane material;
S2, chemically grafting unsaturated phosphorylcholine and N- (3-aminopropyl) methacrylamide on the surface of the high polymer membrane material;
s3, cleaning the grafted polymer membrane material obtained in the step S2;
S4, grafting heparin on the cleaned grafted polymer membrane material obtained in the step S3 by adopting a carbodiimide chemical method.
In some embodiments, the surface of the modified polymer film material is the coating with anticoagulant substances, which is chemically grafted with the phosphorylcholine and the heparin.
In some embodiments, the unsaturated phosphorylcholine comprises dimethyl acryloxyethyl phosphorylcholine (MPC).
In some embodiments, the modified polymeric film material has a thickness of 0.01 to 2mm.
In some embodiments, the polymeric membrane material comprises one or more of a polyurethane membrane, a polyethylene terephthalate membrane, a polytetrafluoroethylene membrane, a polyetheretherketone membrane, a polyimide, a polyamide, a super polyurethane polyethylene membrane, and a polystyrene elastomer membrane.
In some embodiments, the method for preparing the modified polymer film material comprises the following steps:
Washing the polymer membrane material in isopropanol solution, washing with purified water, drying, placing in pretreatment solution containing N- (3-aminopropyl) methacrylamide hydrochloride and dimethyl acryloyloxyethyl phosphorylcholine, and under the initiation of cerium-containing compound, obtaining the polymer membrane material containing polyphosphoryl choline zwitterion and a plurality of heparin binding sites, wherein the heparin binding sites are amino groups of the poly N- (3-aminopropyl) methacrylamide hydrochloride;
placing the polymer membrane material grafted with polyphosphoryl choline zwitterion and N- (3-aminopropyl) methacrylamide into a cleaning solution for cleaning, soaking and drying;
And (3) placing the dried polymer membrane material grafted with polyphosphoryl choline zwitterion and N- (3-aminopropyl) methacrylamide in a heparin solution containing 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide and N-hydroxysuccinimide, reacting, cleaning and drying to obtain the polymer membrane material with the surface compositely grafted zwitterion and the heparin coating.
The application also provides a preparation method of the modified polymer membrane material with the surface compositely grafted phosphorylcholine and heparin anticoagulation coating, which comprises the following steps:
(1) Washing the polymer membrane material in isopropanol solution, washing with purified water, drying, placing in a pretreatment solution containing N- (3-aminopropyl) methacrylamide hydrochloride and dimethyl acryloyloxyethyl phosphorylcholine, and under the initiation of a cerium-containing compound, obtaining a membrane material containing polyphosphoryl choline zwitterion and amino groups of a plurality of heparin binding sites (poly N- (3-aminopropyl) methacrylamide hydrochloride);
(2) Placing the membrane material in the step (1) into a cleaning solution for cleaning, soaking and drying;
(3) And (3) placing the membrane material dried in the step (2) into a heparin solution containing 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide and N-hydroxysuccinimide for reaction, cleaning, and drying to obtain the modified polymer membrane material with the surface compositely grafted with phosphorylcholine and the heparin anticoagulation coating.
In some embodiments, the polymeric film material in step (1) is prepared by one or more of a braiding process, an electrospinning process, a solution coagulation process, a leaching process, and a spraying process.
In some embodiments, the concentration of the isopropyl alcohol solution in step (1) is 2.5-25%; the cleaning time of the isopropanol solution and the purified water is 10-30 min.
In some embodiments, the concentration of said N- (3-aminopropyl) methacrylamide hydrochloride in step (1) is 5 to 25% w/v; the concentration of the dimethyl acryloyloxyethyl phosphorylcholine is 5-25% w/v.
In some embodiments, the pretreatment solution in step (1) requires removal of oxygen from the solution prior to addition of the cerium-containing compound; the concentration of cerium ions in the cerium-containing compound is 0.01-0.1M.
In some embodiments, the reaction temperature in step (1) is 40-60 ℃ and the reaction time is 12-24 hours, and no oxygen can participate in the reaction in the whole process.
In some embodiments, the cerium-containing compound includes one or more of cerium oxide, cerium chloride, cerium fluoride, cerium carbonate, cerium phosphate, cerium nitrate, and cerium ammonium nitrate.
In some embodiments, the wash solution in step (2) is one of purified water, phosphate buffer, triton X-100 solution; the soaking time is 12-24 hours; the drying mode is room temperature drying or vacuum drying.
In some embodiments, the solvent of the heparin solution in step (3) is 2-morpholinoethanesulfonic acid buffer having a ph=5-6, the 2-morpholinoethanesulfonic acid buffer being present in an amount of 0.05 to 0.5M.
In some embodiments, the heparin solution in step (3) may be prepared from heparin or heparin sodium; the concentration of the heparin solution is 0.5-5 mg/ml.
In some embodiments, the molar ratio of said 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide to said N-hydroxysuccinimide in step (3) is from 0.5 to 10; the concentration of N-hydroxysuccinimide is 0.02-0.04M.
In some embodiments, the reaction in step (3) is carried out at 37℃in the absence of light for 12-24 hours.
In some embodiments, the washing in step (3) is performed with purified water, phosphate buffer, purified water, 30-95% ethanol; the drying is room temperature drying or vacuum drying.
The details of one or more embodiments of the application are set forth in the accompanying drawings and the description below. Other features, objects, and advantages of the application will be apparent from the description and drawings, and from the claims.
In order to more clearly illustrate the technical solutions of the embodiments or the conventional techniques of the present application, the drawings required for the descriptions of the embodiments or the conventional techniques will be briefly described below, and it is apparent that the drawings in the following description are only embodiments of the present application, and other drawings may be obtained from the disclosed drawings without inventive effort to those skilled in the art.
FIG. 1 is a schematic reaction flow diagram of a method for preparing a modified polymer film material according to various embodiments of the present application.
FIG. 2 is a water contact angle of an unmodified polyurethane film in example 1 of the present application.
Fig. 3 is the water contact angle of the modified polyurethane film with the surface composite grafted phosphorylcholine and heparin anticoagulation coating in example 1 of the present application.
FIG. 4 is a scanning electron microscope image of the platelet adhesion of the unmodified polyurethane film in example 1 of the present application.
FIG. 5 is a drawing of a modified polyurethane membrane platelet adhesion Scanning Electron Microscope (SEM) with a surface composite grafted phosphorylcholine and heparin anticoagulant coating in example 1 of the present application.
FIG. 6 is a graph of a platelet adhesion Scanning Electron Microscope (SEM) of the modified polyurethane film of example 1 of the present application with a surface composite grafted phosphorylcholine and heparin anticoagulation coating after 30 days of PBS solution cleaning.
The following description of the embodiments of the present application will be made clearly and completely with reference to the accompanying drawings, in which it is apparent that the embodiments described are only some embodiments of the present application, but not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the application without making any inventive effort, are intended to be within the scope of the application.
Some of the specific details set forth in the following description and the accompanying drawings illustrate various embodiments under the teachings of the application, and those skilled in the relevant art can, in the absence of one or more details described herein, practice other embodiments under the teachings of the application. Therefore, it is not the intention of the applicant to restrict or in any way limit the scope of the appended claims to such detail. Although the steps and sequence of steps are described in detail below in order with reference to the drawings, the steps and the terminology used should not be considered as necessary to practice all embodiments of the teachings of the present application.
Also, it is to be understood that the phraseology and terminology used herein is for the purpose of description and should not be regarded as limiting. The use of "including," "comprising," or "having" and variations thereof herein is meant to encompass the items listed thereafter and equivalents thereof as well as additional items.
In order to solve one of the technical problems mentioned in the background art, an embodiment of the present application provides a modified polymer membrane material with a surface compositely grafted with phosphorylcholine and heparin anticoagulation coating, and a preparation method of the modified polymer membrane material includes the following steps:
s1, preparing a polymer membrane material;
S2, chemically grafting unsaturated phosphorylcholine and N- (3-aminopropyl) methacrylamide (APMA) on the surface of a high molecular film material;
s3, cleaning the grafted polymer membrane material obtained in the step S2;
S4, grafting heparin on the cleaned grafted polymer membrane material obtained in the step S3 by adopting a carbodiimide (EDC) chemical method.
In some embodiments, the surface of the modified polymer membrane material is a coating of two anticoagulant substances, namely chemical grafting phosphorylcholine and heparin.
In some embodiments, the unsaturated phosphorylcholine comprises dimethyl acryloxyethyl phosphorylcholine (MPC).
In some embodiments, the modified polymeric film material has a thickness of 0.01 to 2mm.
In some embodiments, the polymeric membrane material comprises one or more of a Polyurethane (PU) membrane, a polyethylene terephthalate (PET) membrane, a Polytetrafluoroethylene (PTFE) membrane, a Polyetheretherketone (PEEK) membrane, a Polyimide (PI), a Polyamide (PA), a superpolyurethane polyethylene (UMWPE) membrane, a polystyrene elastomer (SIBS) membrane.
In some embodiments, the method for preparing the modified polymeric membrane material comprises the steps of:
S100, cleaning a polymer membrane material in isopropanol solution, then cleaning with purified water, drying, and placing in a pretreatment solution containing N- (3-aminopropyl) methacrylamide hydrochloride (APMA) and dimethyl acryloyloxyethyl phosphorylcholine (MPC), under the initiation of a cerium-containing compound, obtaining the polymer membrane material containing polyphosphoryl choline zwitterionic (PMPC) and a plurality of heparin binding sites, wherein the heparin binding sites are amino groups of poly N- (3-aminopropyl) methacrylamide hydrochloride (PAPMA);
S200, placing a polymer membrane material grafted with polyphosphoryl choline zwitterion (PMPC) and N- (3-aminopropyl) methacrylamide (APMA) into a cleaning solution for cleaning, soaking and drying;
S300, placing the dried polymer membrane material grafted with polyphosphoryl choline zwitterion (PMPC) and N- (3-aminopropyl) methacrylamide (APMA) in a heparin solution containing 1- (3-dimethylaminopropyl) -3-Ethylcarbodiimide (EDC) and N-hydroxysuccinimide (NHS), reacting, cleaning and drying to obtain the polymer membrane material with the surface grafted with the zwitterion and the heparin coating.
In some embodiments, the polymer film material in the step S100 of the preparation method of the modified polymer film material is prepared by one or more of a braiding method, an electrostatic spinning method, a solution coagulation method, a leaching method and a spraying method.
In some embodiments, the concentration of the isopropanol solution in the step S100 of the preparation method of the modified polymer film material is 2.5-25%; the cleaning time of the isopropanol solution and the purified water is 10-30 min.
In some embodiments, the concentration of N- (3-aminopropyl) methacrylamide hydrochloride (APMA) in the step S100 of the preparation method of the modified polymer film material is 5-25%w/v; the concentration of the dimethyl acryloyloxyethyl phosphorylcholine is 5-25% w/v.
In some embodiments, the pretreatment solution in step S100 of the preparation method of the modified polymer film material needs to remove oxygen in the solution before adding the cerium-containing compound; the concentration of cerium ions in the cerium-containing compound is 0.01 to 0.1M.
In some embodiments, the reaction temperature in the step S100 of the preparation method of the modified polymer film material is 40-60 ℃, the reaction time is 12-24 h, and no oxygen can participate in the reaction in the whole process.
In some embodiments, the cerium-containing compound in the step S100 of the preparation method of the modified polymer film material includes one or more of cerium oxide, cerium chloride, cerium fluoride, cerium carbonate, cerium phosphate, cerium nitrate, and ammonium cerium nitrate.
In some embodiments, the cleaning solution in step S200 of the preparation method of the modified polymer film material is one of purified water, phosphate buffer solution, triton X-100 solution; the soaking time is 12-24 hours; the drying mode is room temperature drying or vacuum drying.
In some embodiments, the solvent of the heparin solution in the step S300 of the preparation method of the modified polymer film material is 2-morpholinoethanesulfonic acid buffer solution with ph=5-6, and the content of the 2-morpholinoethanesulfonic acid buffer solution is 0.05-0.5M.
In some embodiments, the heparin solution in step S300 of the preparation method of the modified polymer film material may be prepared from heparin or heparin sodium; the concentration of heparin solution is 0.5-5 mg/ml.
In some embodiments, the molar ratio of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide to N-hydroxysuccinimide in the step S300 of the preparation method of the modified polymer film material is 0.5-10; the concentration of N-hydroxysuccinimide is 0.02-0.04M.
In some embodiments, the reaction in the step S300 of the preparation method of the modified polymer film material is carried out at 37 ℃ for 12-24 hours in a dark place.
In some embodiments, the step S300 of the preparation method of the modified polymer film material is performed by cleaning with purified water, phosphate buffer, purified water, and 30-95% ethanol; the drying is room temperature drying or vacuum drying.
The application also provides a preparation method of the modified polymer membrane material with the surface compositely grafted with phosphorylcholine and heparin anticoagulation coating, which comprises the following steps:
(1) Cleaning a high molecular membrane material in isopropanol solution, then cleaning with purified water, drying, placing in a pretreatment solution containing N- (3-aminopropyl) methacrylamide hydrochloride (APMA) and dimethyl acryloyloxyethyl phosphorylcholine (MPC), and under the initiation of a cerium-containing compound, obtaining a membrane material containing polyphosphorylcholine zwitterion (PMPC) and a plurality of heparin binding sites (amino groups of poly N- (3-aminopropyl) methacrylamide hydrochloride (PAPMA);
(2) Placing the membrane material in the step (1) into a cleaning solution for cleaning, soaking and drying;
(3) And (3) placing the membrane material in the step (2) into a heparin solution containing 1- (3-dimethylaminopropyl) -3-Ethylcarbodiimide (EDC) and N-hydroxysuccinimide (NHS) for reaction, cleaning, and drying to obtain the modified polymer membrane material with the surface compositely grafted phosphorylcholine and the heparin anticoagulation coating.
In the preparation method of the modified polymer membrane material with the surface compositely grafted with phosphorylcholine and heparin anticoagulation coating, the phosphorylcholine and the heparin anticoagulation coating are only combined on the surface of the polymer membrane material.
In some embodiments, the polymeric film material in step (1) is prepared by one or more of braiding, electrospinning, solution coagulation, leaching, spraying.
In some embodiments, the concentration of the isopropanol solution in step (1) is 2.5 to 25%; the cleaning time of the isopropanol solution and the purified water is 10-30 min.
In some embodiments, the concentration of N- (3-aminopropyl) methacrylamide (APMA) in step (1) is 5 to 25% w/v; the concentration of the dimethyl acryloyloxyethyl phosphorylcholine (MPC) is 5-25% w/v.
In some embodiments, the pretreatment solution in step (1) requires removal of oxygen from the solution prior to addition of the cerium-containing compound; the concentration of cerium ions in the cerium-containing compound is 0.01 to 0.1M.
In some embodiments, the cerium-containing compound includes one or more combinations of cerium oxide, cerium chloride, cerium fluoride, cerium carbonate, cerium phosphate, cerium nitrate, and ammonium cerium nitrate.
In some embodiments, the reaction temperature in step (1) is 40-60 ℃, the reaction time is 12-24 hours, no oxygen can participate in the reaction in the whole course, and the reaction is under the protection of argon.
In some embodiments, the wash solution in step (2) is one of purified water, phosphate buffer (PBS solution), triton X-100 solution; the soaking time is 12-24 hours; the drying mode is room temperature drying or vacuum drying.
In some embodiments, the solvent of the heparin solution in step (3) is a 2-morpholinoethanesulfonic acid buffer (MES) solution having a ph=5-6, the content of MES being 0.05 to 0.5M.
In some embodiments, the heparin solution in step (3) may be prepared from heparin or heparin sodium; the concentration of heparin solution is 0.5-5 mg/ml.
In some embodiments, the molar ratio of EDC to NHS in step (3) is 0.5 to 10; the concentration of NHS is 0.02-0.04M.
In some embodiments, step (3) is reacted at 37℃in the absence of light for 12-24 hours.
In some embodiments, the washing in step (3) is performed with purified water, PBS solution, purified water, 30-95% ethanol; the drying is room temperature drying or vacuum drying.
In a preferred embodiment, the polymeric membrane material is a polyurethane membrane.
In some embodiments, preparing a pretreatment liquid in the step (1), introducing argon, and removing oxygen in the solution; and (3) adding a cerium-containing compound when the temperature of the pretreatment liquid reaches a specified temperature, adding a film, and reacting.
In some embodiments, the method of preparing a polyurethane film includes the steps of: dissolving polyurethane granules in one or more mixed solutions of dimethylacetamide (DMAc), dimethylformamide (DMF), tetrahydrofuran and dioxane to prepare polyurethane solution with the mass concentration of 10-15%, pouring the polyurethane solution into a polytetrafluoroethylene mould, and completely evaporating the solvent through vacuum drying to obtain a polyurethane film; after the polyurethane film is cleaned, the polyurethane film is dried at room temperature or in vacuum for standby.
The modified polymer membrane material prepared by the preparation method is characterized in that phosphorylcholine is chemically grafted on the surface of the polymer membrane material, phosphorylcholine zwitterion and N- (3-aminopropyl) methacrylamide are introduced, a large number of heparin grafting sites (amino groups) are provided while the anticoagulation effect is achieved, and then 1- (3-dimethylaminopropyl) -3-Ethylcarbodiimide (EDC) is used for chemically grafting heparin, so that the anticoagulation effect of the modified polymer membrane material is more efficient and durable through the combination of the phosphorylcholine zwitterion and the biological activity heparin.
Compared with the prior art, the application has the advantages that:
1. in some embodiments of the application, APMA and MPC are grafted onto the polyurethane membrane surface by initiation of a cerium-containing compound, and anticoagulant phosphorylcholine is introduced to create a plurality of amino binding sites for heparin grafting at the same time, thereby improving the grafting amount of heparin and the anticoagulant property of the polyurethane membrane.
2. Unlike the conventional art, in some embodiments of the present application, by grafting phosphorylcholine zwitterion and heparin to the surface of the polyurethane film, platelet adhesion can be effectively reduced and anticoagulant properties can be improved.
3. In some embodiments of the application, phosphorylcholine zwitterion and heparin are fixed on the surface of the polyurethane film by a chemical grafting method, so that the firmness of heparin can be ensured, and the prepared material can meet the in-vivo anticoagulation requirement and realize long-acting anticoagulation.
4. Compared with the prior art, the preparation method of the modified polyurethane film in some embodiments of the application is simple, the preparation condition is mild and environment-friendly, and the modified polyurethane film has good market application prospect; in addition, other materials in contact with blood and body fluids, other than polyurethane films, may be modified using this technique.
The application will be described in more detail below with reference to different embodiments and examples of several aspects of the application.
Example 1:
In this embodiment, the polymer film material is a polyurethane film.
Dissolving polyurethane granules in dimethylacetamide to prepare polyurethane solution with the mass concentration of 12%, pouring the polyurethane solution into a polytetrafluoroethylene mould, uniformly spreading, putting into a vacuum drying oven, vacuum drying at 50 ℃ for 24 hours, taking out the mould, cooling to room temperature, adding purified water, taking out the membrane, cleaning, and carrying out room temperature or vacuum drying for standby, thus obtaining a flat polyurethane membrane, and dividing the polyurethane membrane into two groups, namely a control group and a test group, wherein each group comprises 3 pieces; wherein,
Control group: washing the flattened polyurethane film in PBS solution, cutting the polyurethane film into a sheet with the thickness of 10mm or 10mm, and carrying out contact angle and platelet adhesion test;
test group: firstly, preparing 100ml of pretreatment solution containing 10% w/vAPMA and 10% w/v MPC, pouring the solution into a three-neck flask, introducing argon at a speed of 1L/min for 10min, and removing oxygen in the solution; secondly, adding 0.02M ammonium cerium nitrate when the temperature of the solution reaches 50 ℃, uniformly stirring, adding a film, and reacting for 18 hours under the protection of argon; thirdly, washing the pretreated membrane with purified water, preparing a PBS solution with pH of 7.4+/-0.2, immersing the membrane in the PBS solution at room temperature for 24 hours, washing the membrane with purified water, and drying in air; fourthly, preparing MES solution with pH=5.5+/-0.5, wherein the molar concentration of MES is 0.05M, adding 1.25mg/ml heparin sodium into the MES solution, adding 0.03M EDC and NHS, stirring uniformly, immersing the membrane, and carrying out light-shielding reaction for 24 hours at 37 ℃; fifthly, taking out the membrane after the reaction, cleaning the membrane with purified water, PBS solution, purified water and 70% ethanol in sequence, and drying the membrane in air, wherein the preparation reaction flow of the modified polyurethane membrane is shown in a figure 1; the test group modified polyurethane film was cut into 10mm x 10mm plaques for contact angle, heparin graft density, platelet adhesion testing.
In this example, the modified polyurethane film of the test group was washed with 1 XPBS solution at 37℃for 30 days at a rotational speed of 500 revolutions, and after removal, washed with deionized water to perform a platelet adhesion test.
Analysis of results: as shown in fig. 2 and 4, after the polyurethane films are treated differently, the water contact angle alpha of the polyurethane film of the control group is 96 degrees, and the adhesion of platelets is extremely high; as shown in fig. 3 and 5, the water contact angle β of the test group modified polyurethane film was 40 °, the platelet adhesion was almost zero, the heparin graft density was 6.3 μg/cm 2, with significant differences; as shown in fig. 6, the platelet adhesion remained minimal after 30 days of PBS solution washing of the test group modified polyurethane film.
Conclusion: the method of the embodiment 1 of the application can effectively graft heparin on the surface of the polyurethane film and effectively reduce the contact angle, thereby greatly improving the anticoagulation performance of the polyurethane film.
Example 2:
the difference from example 1 is that:
Dissolving polyurethane granules in dioxane to prepare polyurethane solution with the mass concentration of 15%, pouring the polyurethane solution into a polytetrafluoroethylene mould, uniformly spreading, putting into a vacuum drying oven, vacuum drying at 50 ℃ for 24 hours, taking out the mould, cooling to room temperature, adding purified water, taking out the membrane, cleaning, and carrying out room temperature or vacuum drying for later use to obtain a flat polyurethane membrane, and dividing the polyurethane membrane into two groups, namely a control group and a test group, wherein each group comprises 3 pieces; wherein,
Control group: washing the flattened polyurethane film in PBS solution, cutting the polyurethane film into a sheet with the thickness of 10mm or 10mm, and carrying out contact angle and platelet adhesion test;
Test group: firstly, preparing 100ml of pretreatment solution containing 15% w/vAPMA and 15% w/v MPC, pouring the solution into a three-neck flask, introducing argon at a speed of 1.5L/min for 20min, and removing oxygen in the solution; secondly, adding 0.03M cerium nitrate when the temperature of the solution reaches 50 ℃, stirring uniformly, adding a film, and reacting for 18 hours under the protection of argon; thirdly, washing the pretreated membrane with purified water, preparing a PBS solution with pH of 7.4+/-0.2, immersing the membrane in the PBS solution at room temperature for 12 hours, washing the membrane with purified water, and drying in air; fourthly, preparing MES solution with pH=5.5+/-0.5, wherein the molar concentration of MES is 0.1M, adding 2mg/ml heparin sodium into the MES solution, adding 0.06M EDC and 0.03M NHS, stirring uniformly, immersing the membrane, and carrying out light-shielding reaction for 18h at 37 ℃; fifthly, taking out the membrane after the reaction, cleaning the membrane with purified water, PBS solution, purified water and 75% ethanol in sequence, and drying the membrane in air, wherein the preparation reaction flow of the modified polyurethane membrane is shown in a figure 1; the modified polyurethane films of the test group were cut into 10mm x 10mm plaques for contact angle, heparin graft density, platelet adhesion testing.
Analysis of results: after the unmodified polyurethane film is treated differently, the water contact angle of the polyurethane film of the control group is 102 DEG, and the adhesion of blood platelets is extremely high; the water contact angle of the modified polyurethane film of the test group is 50 degrees, the adhesion of platelets is almost zero, the grafting density of heparin is 4.3 mug/cm 2, and the difference is obvious.
Conclusion: the method of the embodiment 2 of the application can effectively graft heparin on the surface of the polyurethane film and effectively reduce the contact angle, thereby greatly improving the anticoagulation performance of the polyurethane film.
Example 3:
the difference from example 1 is that:
In this example, the unmodified polyurethane film was prepared by dissolving polyurethane pellets in tetrahydrofuran/dioxane = 1:1, pouring polyurethane solution with the mass concentration of 15% into a polytetrafluoroethylene mould, uniformly spreading, putting into a vacuum drying oven, vacuum drying at 50 ℃ for 24 hours, taking out the mould, cooling to room temperature, adding purified water, taking out the membrane, washing, and performing room temperature or vacuum drying for later use to obtain a flat polyurethane membrane, and dividing the polyurethane membrane into two groups, namely a control group and a test group, wherein each group comprises 3 pieces; wherein,
Control group: washing the flattened polyurethane film in PBS solution, cutting the polyurethane film into a sheet with the thickness of 10mm or 10mm, and carrying out contact angle and platelet adhesion test;
Test group: firstly, preparing 100ml of pretreatment solution containing 20% w/vAPMA and 20% w/v MPC, pouring the solution into a three-neck flask, introducing argon at a speed of 1.5L/min for 20min, and removing oxygen in the solution; secondly, adding 0.1M cerium nitrate when the temperature of the solution reaches 50 ℃, uniformly stirring, adding a film, and reacting for 24 hours under the protection of argon; thirdly, washing the pretreated membrane with purified water, preparing a PBS solution with pH of 7.4+/-0.2, immersing the membrane in the PBS solution at room temperature for 24 hours, washing the membrane with purified water, and drying in air; fourthly, preparing an MES solution with the pH of=5.5+/-0.5, wherein the molar concentration of MES is 0.5M, adding 2mg/ml heparin sodium into the MES solution, adding 0.3M EDC and 0.03M NHS, uniformly stirring, immersing the membrane, and carrying out light-shielding reaction for 24 hours at 37 ℃; fifthly, taking out the membrane after the reaction, cleaning the membrane with purified water, PBS solution, purified water and 75% ethanol in sequence, and drying the membrane in air, wherein the preparation reaction flow of the modified polyurethane membrane is shown in a figure 1; the membranes of the test groups were cut into 10mm x10 mm plaques for contact angle, heparin graft density, platelet adhesion testing.
Analysis of results: after the unmodified polyurethane film is treated differently, the water contact angle of the polyurethane film of the control group is 98 degrees, and the adhesion of blood platelets is extremely high; the water contact angle of the modified polyurethane film of the test group is 45 degrees, the adhesion of platelets is almost zero, the grafting density of heparin is 5.8 mug/cm 2, and the modified polyurethane film has obvious difference.
Conclusion: the method of the embodiment 3 of the application can effectively graft heparin on the surface of the polyurethane film and effectively reduce the contact angle, thereby greatly improving the anticoagulation performance of the polyurethane film.
The technical features of the above embodiments may be arbitrarily combined, and all possible combinations of the technical features in the above 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 foregoing examples illustrate only a few embodiments of the application, which are described in detail and are not to be construed as limiting the scope of the claims. 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 application, which are all within the scope of the application. Accordingly, the scope of protection of the present application is to be determined by the appended claims.
Claims (14)
- The modified polymer membrane material with the surface compositely grafted with phosphorylcholine and heparin anticoagulation coating is characterized by comprising the following steps of:s1, preparing a polymer membrane material;S2, chemically grafting unsaturated phosphorylcholine and N- (3-aminopropyl) methacrylamide on the surface of the high polymer membrane material;s3, cleaning the grafted polymer membrane material obtained in the step S2;S4, grafting heparin on the cleaned grafted polymer membrane material obtained in the step S3 by adopting a carbodiimide chemical method.
- The modified polymeric membrane material according to claim 1, wherein the modified polymeric membrane material has a thickness of 0.01 to 2mm.
- The modified polymeric membrane material of any one of claims 1 to 2, wherein the polymeric membrane material comprises one or more of a polyurethane membrane, a polyethylene terephthalate membrane, a polytetrafluoroethylene membrane, a polyetheretherketone membrane, a polyimide, a polyamide, a superpolyurethane polyethylene membrane, and a polystyrene elastomer membrane.
- A modified polymeric membrane material according to any one of claims 1 to 3, wherein the method for producing the modified polymeric membrane material comprises the steps of:Washing the polymer membrane material in isopropanol solution, washing with purified water, drying, placing in pretreatment solution containing N- (3-aminopropyl) methacrylamide hydrochloride and dimethyl acryloyloxyethyl phosphorylcholine, and under the initiation of cerium-containing compound, obtaining the polymer membrane material containing polyphosphoryl choline zwitterion and a plurality of heparin binding sites, wherein the heparin binding sites are amino groups of the poly N- (3-aminopropyl) methacrylamide hydrochloride;placing the polymer membrane material grafted with polyphosphoryl choline zwitterion and N- (3-aminopropyl) methacrylamide into a cleaning solution for cleaning, soaking and drying;And (3) placing the dried polymer membrane material grafted with polyphosphoryl choline zwitterion and N- (3-aminopropyl) methacrylamide in a heparin solution containing 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide and N-hydroxysuccinimide, reacting, cleaning and drying to obtain the polymer membrane material with the surface compositely grafted zwitterion and the heparin coating.
- The method for preparing a modified polymer film material with a surface compositely grafted with phosphorylcholine and heparin anticoagulation coating as claimed in any one of claims 1 to 4, which is characterized by comprising the following steps:(1) Washing the polymer membrane material in isopropanol solution, washing with purified water, drying, placing in a pretreatment solution containing N- (3-aminopropyl) methacrylamide hydrochloride and dimethyl acryloyloxyethyl phosphorylcholine, and under the initiation of a cerium-containing compound, obtaining a membrane material containing polyphosphoryl choline zwitterion and amino groups of a plurality of heparin binding sites (poly N- (3-aminopropyl) methacrylamide hydrochloride);(2) Placing the membrane material in the step (1) into a cleaning solution for cleaning, soaking and drying;(3) And (3) placing the membrane material dried in the step (2) into a heparin solution containing 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide and N-hydroxysuccinimide for reaction, cleaning, and drying to obtain the modified polymer membrane material with the surface compositely grafted with phosphorylcholine and the heparin anticoagulation coating.
- The method for producing a modified polymer film material according to claim 5, wherein the polymer film material in the step (1) is produced by one or more of a braiding method, an electrospinning method, a solution coagulation method, a leaching method and a spraying method.
- The method for producing a modified polymeric membrane material according to any one of claims 5 to 6, wherein step (1) satisfies at least one of the following conditions:1) The concentration of the isopropanol solution in the step (1) is 2.5-25%; the cleaning time of the isopropanol solution and the purified water is 10-30 min;2) The concentration of the N- (3-aminopropyl) methacrylamide hydrochloride in the step (1) is 5-25%w/v; the concentration of the dimethyl acryloyloxyethyl phosphorylcholine is 5-25% w/v;3) The pretreatment solution in step (1) requires removal of oxygen from the solution prior to addition of the cerium-containing compound; the concentration of cerium ions in the cerium-containing compound is 0.01-0.1M;4) The reaction temperature in the step (1) is 40-60 ℃, the reaction time is 12-24 h, and no oxygen can participate in the reaction in the whole process.
- The method for producing a modified polymeric film material according to any one of claims 5 to 7, wherein the cerium-containing compound comprises one or more of cerium oxide, cerium chloride, cerium fluoride, cerium carbonate, cerium phosphate, cerium nitrate and ammonium cerium nitrate.
- The method for producing a modified polymeric membrane material according to any one of claims 5 to 8, wherein the cleaning liquid in the step (2) is one of purified water, phosphate buffer, triton X-100 solution; the soaking time is 12-24 hours; the drying mode is room temperature drying or vacuum drying.
- The method according to any one of claims 5 to 9, wherein the solvent of the heparin solution in the step (3) is 2-morpholinoethanesulfonic acid buffer solution having ph=5-6, and the content of the 2-morpholinoethanesulfonic acid buffer solution is 0.05 to 0.5M.
- The method for producing a modified polymeric membrane material according to any one of claims 5 to 10, wherein the heparin solution in step (3) is prepared from heparin or heparin sodium; the concentration of the heparin solution is 0.5-5 mg/ml.
- The method for producing a modified polymeric membrane material according to any one of claims 5 to 11, wherein the molar ratio of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide to N-hydroxysuccinimide in step (3) is 0.5 to 10; the concentration of N-hydroxysuccinimide is 0.02-0.04M.
- The method for producing a modified polymeric membrane material according to any one of claims 5 to 12, wherein the reaction in step (3) is carried out at 37 ℃ for 12 to 24 hours in the absence of light.
- The method for producing a modified polymeric membrane material according to any one of claims 5 to 13, wherein the washing in step (3) is performed with purified water, phosphate buffer, purified water, 30 to 95% ethanol; the drying is room temperature drying or vacuum drying.
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