WO2022135453A1 - Enzyme-modified anticoagulant valve and manufacturing method therefor - Google Patents
Enzyme-modified anticoagulant valve and manufacturing method therefor Download PDFInfo
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- WO2022135453A1 WO2022135453A1 PCT/CN2021/140377 CN2021140377W WO2022135453A1 WO 2022135453 A1 WO2022135453 A1 WO 2022135453A1 CN 2021140377 W CN2021140377 W CN 2021140377W WO 2022135453 A1 WO2022135453 A1 WO 2022135453A1
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- Prior art keywords
- valve
- preparing
- anticoagulant
- enzyme
- valve according
- Prior art date
Links
- 239000003146 anticoagulant agent Substances 0.000 title claims abstract description 28
- 229940127219 anticoagulant drug Drugs 0.000 title claims abstract description 28
- 238000004519 manufacturing process Methods 0.000 title abstract 3
- 239000000463 material Substances 0.000 claims abstract description 39
- 238000006243 chemical reaction Methods 0.000 claims abstract description 29
- 229910052751 metal Inorganic materials 0.000 claims abstract description 20
- 239000002184 metal Substances 0.000 claims abstract description 20
- 235000013824 polyphenols Nutrition 0.000 claims abstract description 20
- SXRSQZLOMIGNAQ-UHFFFAOYSA-N Glutaraldehyde Chemical compound O=CCCCC=O SXRSQZLOMIGNAQ-UHFFFAOYSA-N 0.000 claims abstract description 18
- 102000004190 Enzymes Human genes 0.000 claims abstract description 17
- 108090000790 Enzymes Proteins 0.000 claims abstract description 17
- 229940088598 enzyme Drugs 0.000 claims abstract description 17
- 108010015776 Glucose oxidase Proteins 0.000 claims abstract description 15
- 239000004366 Glucose oxidase Substances 0.000 claims abstract description 15
- 229940116332 glucose oxidase Drugs 0.000 claims abstract description 15
- 235000019420 glucose oxidase Nutrition 0.000 claims abstract description 15
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims abstract description 14
- -1 polyphenol compound Chemical class 0.000 claims abstract description 14
- 150000003839 salts Chemical class 0.000 claims abstract description 10
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims abstract description 6
- 238000004132 cross linking Methods 0.000 claims abstract description 6
- 239000008103 glucose Substances 0.000 claims abstract description 6
- 239000000243 solution Substances 0.000 claims description 24
- 238000000034 method Methods 0.000 claims description 13
- VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 claims description 10
- 150000008442 polyphenolic compounds Chemical class 0.000 claims description 10
- 239000002105 nanoparticle Substances 0.000 claims description 8
- WMBWREPUVVBILR-UHFFFAOYSA-N GCG Natural products C=1C(O)=C(O)C(O)=CC=1C1OC2=CC(O)=CC(O)=C2CC1OC(=O)C1=CC(O)=C(O)C(O)=C1 WMBWREPUVVBILR-UHFFFAOYSA-N 0.000 claims description 7
- 229910021607 Silver chloride Inorganic materials 0.000 claims description 7
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 claims description 7
- 239000010931 gold Substances 0.000 claims description 7
- HKZLPVFGJNLROG-UHFFFAOYSA-M silver monochloride Chemical compound [Cl-].[Ag+] HKZLPVFGJNLROG-UHFFFAOYSA-M 0.000 claims description 7
- XMOCLSLCDHWDHP-IUODEOHRSA-N epi-Gallocatechin Chemical compound C1([C@H]2OC3=CC(O)=CC(O)=C3C[C@H]2O)=CC(O)=C(O)C(O)=C1 XMOCLSLCDHWDHP-IUODEOHRSA-N 0.000 claims description 6
- WMBWREPUVVBILR-WIYYLYMNSA-N (-)-Epigallocatechin-3-o-gallate Chemical compound O([C@@H]1CC2=C(O)C=C(C=C2O[C@@H]1C=1C=C(O)C(O)=C(O)C=1)O)C(=O)C1=CC(O)=C(O)C(O)=C1 WMBWREPUVVBILR-WIYYLYMNSA-N 0.000 claims description 5
- TUSDEZXZIZRFGC-UHFFFAOYSA-N 1-O-galloyl-3,6-(R)-HHDP-beta-D-glucose Natural products OC1C(O2)COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC1C(O)C2OC(=O)C1=CC(O)=C(O)C(O)=C1 TUSDEZXZIZRFGC-UHFFFAOYSA-N 0.000 claims description 5
- 239000001263 FEMA 3042 Substances 0.000 claims description 5
- 229910021578 Iron(III) chloride Inorganic materials 0.000 claims description 5
- LRBQNJMCXXYXIU-PPKXGCFTSA-N Penta-digallate-beta-D-glucose Natural products OC1=C(O)C(O)=CC(C(=O)OC=2C(=C(O)C=C(C=2)C(=O)OC[C@@H]2[C@H]([C@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)[C@@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)[C@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)O2)OC(=O)C=2C=C(OC(=O)C=3C=C(O)C(O)=C(O)C=3)C(O)=C(O)C=2)O)=C1 LRBQNJMCXXYXIU-PPKXGCFTSA-N 0.000 claims description 5
- 229960003638 dopamine Drugs 0.000 claims description 5
- 229910052737 gold Inorganic materials 0.000 claims description 5
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical group Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 claims description 5
- LRBQNJMCXXYXIU-NRMVVENXSA-N tannic acid Chemical compound OC1=C(O)C(O)=CC(C(=O)OC=2C(=C(O)C=C(C=2)C(=O)OC[C@@H]2[C@H]([C@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)[C@@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)[C@@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)O2)OC(=O)C=2C=C(OC(=O)C=3C=C(O)C(O)=C(O)C=3)C(O)=C(O)C=2)O)=C1 LRBQNJMCXXYXIU-NRMVVENXSA-N 0.000 claims description 5
- 229940033123 tannic acid Drugs 0.000 claims description 5
- 235000015523 tannic acid Nutrition 0.000 claims description 5
- 229920002258 tannic acid Polymers 0.000 claims description 5
- XMOCLSLCDHWDHP-UHFFFAOYSA-N L-Epigallocatechin Natural products OC1CC2=C(O)C=C(O)C=C2OC1C1=CC(O)=C(O)C(O)=C1 XMOCLSLCDHWDHP-UHFFFAOYSA-N 0.000 claims description 4
- YCIMNLLNPGFGHC-UHFFFAOYSA-N catechol Chemical compound OC1=CC=CC=C1O YCIMNLLNPGFGHC-UHFFFAOYSA-N 0.000 claims description 4
- ORTQZVOHEJQUHG-UHFFFAOYSA-L copper(II) chloride Chemical compound Cl[Cu]Cl ORTQZVOHEJQUHG-UHFFFAOYSA-L 0.000 claims description 4
- WQGWDDDVZFFDIG-UHFFFAOYSA-N pyrogallol Chemical compound OC1=CC=CC(O)=C1O WQGWDDDVZFFDIG-UHFFFAOYSA-N 0.000 claims description 4
- 239000011259 mixed solution Substances 0.000 claims description 3
- PFTAWBLQPZVEMU-ZFWWWQNUSA-N (+)-epicatechin Natural products C1([C@@H]2OC3=CC(O)=CC(O)=C3C[C@@H]2O)=CC=C(O)C(O)=C1 PFTAWBLQPZVEMU-ZFWWWQNUSA-N 0.000 claims description 2
- PFTAWBLQPZVEMU-UKRRQHHQSA-N (-)-epicatechin Chemical compound C1([C@H]2OC3=CC(O)=CC(O)=C3C[C@H]2O)=CC=C(O)C(O)=C1 PFTAWBLQPZVEMU-UKRRQHHQSA-N 0.000 claims description 2
- LSHVYAFMTMFKBA-TZIWHRDSSA-N (-)-epicatechin-3-O-gallate Chemical compound O([C@@H]1CC2=C(O)C=C(C=C2O[C@@H]1C=1C=C(O)C(O)=CC=1)O)C(=O)C1=CC(O)=C(O)C(O)=C1 LSHVYAFMTMFKBA-TZIWHRDSSA-N 0.000 claims description 2
- LSHVYAFMTMFKBA-UHFFFAOYSA-N ECG Natural products C=1C=C(O)C(O)=CC=1C1OC2=CC(O)=CC(O)=C2CC1OC(=O)C1=CC(O)=C(O)C(O)=C1 LSHVYAFMTMFKBA-UHFFFAOYSA-N 0.000 claims description 2
- 229910021380 Manganese Chloride Inorganic materials 0.000 claims description 2
- GLFNIEUTAYBVOC-UHFFFAOYSA-L Manganese chloride Chemical compound Cl[Mn]Cl GLFNIEUTAYBVOC-UHFFFAOYSA-L 0.000 claims description 2
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 claims description 2
- 210000001765 aortic valve Anatomy 0.000 claims description 2
- LPTRNLNOHUVQMS-UHFFFAOYSA-N epicatechin Natural products Cc1cc(O)cc2OC(C(O)Cc12)c1ccc(O)c(O)c1 LPTRNLNOHUVQMS-UHFFFAOYSA-N 0.000 claims description 2
- 235000012734 epicatechin Nutrition 0.000 claims description 2
- DZYNKLUGCOSVKS-UHFFFAOYSA-N epigallocatechin Natural products OC1Cc2cc(O)cc(O)c2OC1c3cc(O)c(O)c(O)c3 DZYNKLUGCOSVKS-UHFFFAOYSA-N 0.000 claims description 2
- 229940030275 epigallocatechin gallate Drugs 0.000 claims description 2
- 150000002343 gold Chemical class 0.000 claims description 2
- 229910001922 gold oxide Inorganic materials 0.000 claims description 2
- 229940099607 manganese chloride Drugs 0.000 claims description 2
- 235000002867 manganese chloride Nutrition 0.000 claims description 2
- 239000011565 manganese chloride Substances 0.000 claims description 2
- 210000004115 mitral valve Anatomy 0.000 claims description 2
- TWNQGVIAIRXVLR-UHFFFAOYSA-N oxo(oxoalumanyloxy)alumane Chemical compound O=[Al]O[Al]=O TWNQGVIAIRXVLR-UHFFFAOYSA-N 0.000 claims description 2
- 210000003102 pulmonary valve Anatomy 0.000 claims description 2
- 229940079877 pyrogallol Drugs 0.000 claims description 2
- OGIDPMRJRNCKJF-UHFFFAOYSA-N titanium oxide Inorganic materials [Ti]=O OGIDPMRJRNCKJF-UHFFFAOYSA-N 0.000 claims description 2
- 210000000591 tricuspid valve Anatomy 0.000 claims description 2
- 210000002073 venous valve Anatomy 0.000 claims description 2
- 150000004697 chelate complex Chemical class 0.000 claims 1
- 230000010100 anticoagulation Effects 0.000 abstract description 5
- 238000004140 cleaning Methods 0.000 abstract description 3
- 238000001727 in vivo Methods 0.000 abstract 1
- 239000000203 mixture Substances 0.000 abstract 1
- MWUXSHHQAYIFBG-UHFFFAOYSA-N Nitric oxide Chemical compound O=[N] MWUXSHHQAYIFBG-UHFFFAOYSA-N 0.000 description 26
- 238000002360 preparation method Methods 0.000 description 12
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 8
- 239000007864 aqueous solution Substances 0.000 description 7
- 239000013522 chelant Substances 0.000 description 7
- 239000013077 target material Substances 0.000 description 7
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 6
- 102000008299 Nitric Oxide Synthase Human genes 0.000 description 5
- 108010021487 Nitric Oxide Synthase Proteins 0.000 description 5
- ODKSFYDXXFIFQN-BYPYZUCNSA-N L-arginine Chemical compound OC(=O)[C@@H](N)CCCN=C(N)N ODKSFYDXXFIFQN-BYPYZUCNSA-N 0.000 description 4
- 229930064664 L-arginine Natural products 0.000 description 4
- 235000014852 L-arginine Nutrition 0.000 description 4
- 125000004151 quinonyl group Chemical group 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 230000004913 activation Effects 0.000 description 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 3
- 230000015271 coagulation Effects 0.000 description 3
- 238000005345 coagulation Methods 0.000 description 3
- 239000001257 hydrogen Substances 0.000 description 3
- 229910052739 hydrogen Inorganic materials 0.000 description 3
- 229910021645 metal ion Inorganic materials 0.000 description 3
- AZQWKYJCGOJGHM-UHFFFAOYSA-N 1,4-benzoquinone Chemical compound O=C1C=CC(=O)C=C1 AZQWKYJCGOJGHM-UHFFFAOYSA-N 0.000 description 2
- 230000002776 aggregation Effects 0.000 description 2
- 238000004220 aggregation Methods 0.000 description 2
- 125000003172 aldehyde group Chemical group 0.000 description 2
- 230000002429 anti-coagulating effect Effects 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
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- 238000006555 catalytic reaction Methods 0.000 description 2
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- 230000000694 effects Effects 0.000 description 2
- 239000000835 fiber Substances 0.000 description 2
- 230000007774 longterm Effects 0.000 description 2
- ODUCDPQEXGNKDN-UHFFFAOYSA-N nitroxyl Chemical compound O=N ODUCDPQEXGNKDN-UHFFFAOYSA-N 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 230000000087 stabilizing effect Effects 0.000 description 2
- 238000003860 storage Methods 0.000 description 2
- 102000015081 Blood Coagulation Factors Human genes 0.000 description 1
- 108010039209 Blood Coagulation Factors Proteins 0.000 description 1
- 102000008946 Fibrinogen Human genes 0.000 description 1
- 108010049003 Fibrinogen Proteins 0.000 description 1
- 206010067171 Regurgitation Diseases 0.000 description 1
- 208000007536 Thrombosis Diseases 0.000 description 1
- XJLXINKUBYWONI-DQQFMEOOSA-N [[(2r,3r,4r,5r)-5-(6-aminopurin-9-yl)-3-hydroxy-4-phosphonooxyoxolan-2-yl]methoxy-hydroxyphosphoryl] [(2s,3r,4s,5s)-5-(3-carbamoylpyridin-1-ium-1-yl)-3,4-dihydroxyoxolan-2-yl]methyl phosphate Chemical compound NC(=O)C1=CC=C[N+]([C@@H]2[C@H]([C@@H](O)[C@H](COP([O-])(=O)OP(O)(=O)OC[C@@H]3[C@H]([C@@H](OP(O)(O)=O)[C@@H](O3)N3C4=NC=NC(N)=C4N=C3)O)O2)O)=C1 XJLXINKUBYWONI-DQQFMEOOSA-N 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 239000000853 adhesive Substances 0.000 description 1
- 230000001070 adhesive effect Effects 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- 239000003114 blood coagulation factor Substances 0.000 description 1
- 239000003130 blood coagulation factor inhibitor Substances 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- 230000000711 cancerogenic effect Effects 0.000 description 1
- 231100000315 carcinogenic Toxicity 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 229960003280 cupric chloride Drugs 0.000 description 1
- 230000009849 deactivation Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 230000007850 degeneration Effects 0.000 description 1
- 230000008021 deposition Effects 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 210000002889 endothelial cell Anatomy 0.000 description 1
- 230000003511 endothelial effect Effects 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 229940012952 fibrinogen Drugs 0.000 description 1
- 239000008204 material by function Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 229930027945 nicotinamide-adenine dinucleotide Natural products 0.000 description 1
- 239000002840 nitric oxide donor Substances 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- 230000035790 physiological processes and functions Effects 0.000 description 1
- 230000010118 platelet activation Effects 0.000 description 1
- 231100000614 poison Toxicity 0.000 description 1
- 231100000683 possible toxicity Toxicity 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 150000003141 primary amines Chemical group 0.000 description 1
- 235000018102 proteins Nutrition 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 230000002040 relaxant effect Effects 0.000 description 1
- 238000001179 sorption measurement Methods 0.000 description 1
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 239000003440 toxic substance Substances 0.000 description 1
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- 230000001988 toxicity Effects 0.000 description 1
- 230000001960 triggered effect Effects 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/36—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix
- A61L27/3604—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix characterised by the human or animal origin of the biological material, e.g. hair, fascia, fish scales, silk, shellac, pericardium, pleura, renal tissue, amniotic membrane, parenchymal tissue, fetal tissue, muscle tissue, fat tissue, enamel
- A61L27/3625—Vascular tissue, e.g. heart valves
-
- 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
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/36—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix
- A61L27/3683—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix subjected to a specific treatment prior to implantation, e.g. decellularising, demineralising, grinding, cellular disruption/non-collagenous protein removal, anti-calcification, crosslinking, supercritical fluid extraction, enzyme treatment
- A61L27/3687—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix subjected to a specific treatment prior to implantation, e.g. decellularising, demineralising, grinding, cellular disruption/non-collagenous protein removal, anti-calcification, crosslinking, supercritical fluid extraction, enzyme treatment characterised by the use of chemical agents in the treatment, e.g. specific enzymes, detergents, capping agents, crosslinkers, anticalcification 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
- 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
- A61L33/0047—Enzymes, e.g. urokinase, streptokinase
-
- 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
- A61L33/0076—Chemical modification of 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
- A61L33/02—Use of inorganic 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
- A61L33/04—Use of organic materials, e.g. acetylsalicylic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2400/00—Materials characterised by their function or physical properties
- A61L2400/18—Modification of implant surfaces in order to improve biocompatibility, cell growth, fixation of biomolecules, e.g. plasma treatment
-
- 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
- A61L2430/00—Materials or treatment for tissue regeneration
- A61L2430/20—Materials or treatment for tissue regeneration for reconstruction of the heart, e.g. heart valves
Definitions
- the invention belongs to the technical field of biomedical engineering functional materials, and in particular relates to an enzyme-modified anticoagulation valve and a preparation method thereof.
- valve insufficiency or failure In view of the clinical status of valve insufficiency or failure, the development of prosthetic valves that can be used to treat valve regurgitation disease is of great market value.
- the valve in a physiological state is thin and easily affected by the blood flow pressure around the valve leaflet.
- the main cause of valve failure is thrombosis.
- a series of coagulation reactions will be triggered, such as deposition of coagulation factors and adhesive proteins, adsorption and degeneration of fibrinogen, and platelet aggregation and activation.
- Endothelial-derived relaxing factor nitric oxide is an important anticoagulant factor secreted by endothelial cells, which can maintain vascular blood pressure and inhibit platelet activation and aggregation.
- NO anticoagulant materials There are usually two types of NO anticoagulant materials, namely NO donors and NO catalysis. Although the effective release of NO can inhibit the coagulation reaction after the material is implanted into the body, such materials also face many limitations, especially the NO donor itself. Unstable, exogenous donor precursor substances are carcinogenic, and endogenous NO donors have low concentrations and large changes in the body, and toxic substances are also produced during the reaction.
- NO is produced by the catalysis of L-arginine by nitric oxide synthase in the presence of NADPH and O 2 (or hydrogen peroxide), in addition, when the concentration of L-arginine or hydrogen peroxide is limited Nitric oxide synthase catalyzes the generation of the one-electron reduced form of NO, nitroxyl (HNO), which has the same anticoagulant effect as NO.
- the source of HNO is L-arginine, which is stable and abundant in the body, and its reaction toxicity and stability are better than NO.
- nitric oxide synthase is highly specific and efficient, but its high price and difficulty in long-term storage limit its industrial application.
- the present invention provides an enzyme-modified anticoagulant valve and a preparation method thereof.
- the polyphenol-metal chelate provides a nitric oxide synthase-like function, which is compatible with stable cross-linking.
- the glucose oxidase linked in the valve forms an enzyme series system to efficiently catalyze the generation of anticoagulant substance nitroxyl, and has the characteristics of simple preparation process, low cost and ideal anticoagulation effect.
- a preparation method of an enzyme-modified anticoagulant valve comprising the following steps:
- step (2) Taking the product obtained in step (1) as the base, repeating step (1) for 1 to 20 times, taking it out for cleaning and drying at room temperature;
- step (3) After the product obtained in step (2) is placed in a glutaraldehyde solution with a concentration of 0.1 to 2.5% for 2 to 10 hours, and then placed in an enzyme solution with a concentration of 0.01 to 10 mg/mL, which can utilize glucose to generate hydrogen peroxide After activating at 1 ⁇ 15°C for 4 ⁇ 12h, take it out and wash it.
- the mass ratio of the polyphenol compound to the soluble metal salt is 1:0.1 ⁇ 1.
- the mass ratio of the polyphenol compound to the soluble metal salt is 1:0.1.
- step (1) the reaction temperature was 30° C., and the reaction time was 10 min.
- the polyphenol compound is a polyphenol compound having an ortho-phenol structure.
- polyphenolic compound with ortho-phenol structure is dopamine, tannic acid, epigallocatechin gallate EGCG, epicatechin gallate ECG, epicatechin EC, epigallocatechin EGC, At least one of catechol and pyrogallol.
- the soluble metal salt is ferric chloride, cupric chloride, silver chloride, manganese chloride or silver chloride.
- the enzyme is one of glucose oxidase, citric acid-modified gold nanoparticles, gold/aluminum oxide nanoparticles, gold/titanium oxide particles, and gold-containing bimetallic/trimetallic nanoparticles.
- step (3) the activation temperature is 4°C, and the activation time is 4h.
- the biological valve material is aortic valve, pulmonary valve, venous valve, mitral valve or tricuspid valve.
- Natural enzymes can catalyze reactions efficiently under mild conditions and have high specificity for substrates, but the problems of high price, easy deactivation and difficult long-term storage limit its application in the industrial field.
- the polyphenol-metal chelate prepared in the present application not only has the catalytic ability similar to nitric oxide synthase, but also is more stable than nitric oxide synthase, easy to prepare and lower cost.
- the polyphenol metal chelate is more stable, easy to prepare, suitable for industrialization, and does not cause the problem of single-molecule aggregation and loss of activity.
- the phenolic hydroxyl groups in polyphenolic compounds can be oxidized to quinone functional groups in the presence of high-valent metal ions or in the presence of oxygen.
- Polyphenols and soluble metal salts can be mixed to prepare phenol-metal complexes.
- the phenolic hydroxyl groups and partially oxidized quinone groups in such compounds can interact with groups (hydroxyl groups, aldehyde groups, carboxyl groups, etc.) on the valve material. Hydrogen bonding, thereby stabilizing the fibrous structure of the glutaraldehyde valve.
- Polyphenol-metal chelate combined with glucose oxidase can form an enzymatic tandem pathway.
- Glucose oxidase which is stabilized and abundantly present in the valve through glutaraldehyde cross-linking, can utilize glucose in the blood to generate local high concentrations of hydrogen peroxide , which is then utilized by polyphenol metal chelate and catalyzes L-arginine to produce the anticoagulant substance HNO, which can avoid the potential toxicity and unstable donor source defects of traditional NO coating, so as to maintain the valve resistance efficiently and lastingly.
- coagulation properties The invention utilizes the characteristics of the valve itself, modifies the polyphenol-metal chelate and the glucose oxidase, simply and efficiently realizes the requirement of long-acting anticoagulation in the valve body and reduces the valve failure rate.
- Fig. 1 is the hemibody hemocompatibility test result of traditional glutaraldehyde valve
- FIG. 2 is the test result of hemibody blood compatibility of the valve material prepared in Example 2 of the present application.
- the invention discloses a preparation method of an anticoagulation valve, comprising the following steps:
- the biological valve material is placed in a mixed solution of polyphenolic compounds and soluble metal salts for reaction, and the biological valve material is cleaned after the reaction is completed;
- Polyphenol compounds contain a large number of phenolic hydroxyl functional groups, which can form hydrogen bonds with the compounds of amino, hydroxyl and carboxyl groups in the valve; in addition, the phenolic hydroxyl groups in polyphenol compounds can chelate metal ions to form phenol-metal complexes
- the phenolic hydroxyl group and the partially oxidized quinone group in the polyphenol compound can hydrogen bond with the groups (hydroxyl group, aldehyde group, carboxyl group, etc.) on the valve material, thereby stabilizing the fiber structure of the glutaraldehyde valve.
- the cross-linked biological valve material is treated with an enzyme solution, wherein the enzyme in the enzyme solution can utilize glucose to generate hydrogen peroxide.
- step (1) can be repeated for several times, for example, preferably 1 to 20 times.
- a preparation method of an enzyme-modified anticoagulant valve comprising the following steps:
- valve into a mixed aqueous solution of dopamine with a concentration of 1 mg/ml and ferric chloride with a concentration of 0.5 mg/ml, react at 25°C for 20 minutes, take out the valve and clean it 3 times to complete a reaction cycle;
- step (3) soak the material treated in step (2) in a glutaraldehyde solution with a concentration of 0.5% for 4 hours and then wash it;
- step (3) The material obtained in step (3) was placed in a PBS solution of glucose oxidase with a concentration of 0.15 mg/ml, activated at 4°C for 4 hours, and washed to obtain the target material.
- a preparation method of an enzyme-modified anticoagulant valve comprising the following steps:
- valve into a mixed aqueous solution of tannic acid with a concentration of 1 mg/ml and ferric chloride with a concentration of 0.1 mg/ml, react at 30°C for 10 minutes, take out the valve and clean it 3 times to complete a reaction cycle;
- step (3) soak the material treated in step (2) in a glutaraldehyde solution with a concentration of 0.15% for 2 hours and then wash it;
- step (3) The material obtained in step (3) was placed in a PBS solution of glucose oxidase with a concentration of 0.2 mg/ml, activated at 4°C for 4 h, and washed to obtain the target material.
- a preparation method of an enzyme-modified anticoagulant valve comprising the following steps:
- valve into a mixed aqueous solution of tannic acid with a concentration of 1 mg/ml and copper chloride with a concentration of 0.1 mg/ml, react at 30°C for 20 minutes, take out the valve and clean it 3 times to complete a reaction cycle;
- step (3) soak the material treated in step (2) in a glutaraldehyde solution with a concentration of 0.2% for 2 hours and then wash it;
- step (3) The material obtained in step (3) was placed in a PBS solution of glucose oxidase with a concentration of 0.2 mg/ml, activated at 4°C for 4 h, and washed to obtain the target material.
- a preparation method of an enzyme-modified anticoagulant valve comprising the following steps:
- valve into a mixed aqueous solution of EGCG with a concentration of 1 mg/ml and ferric chloride with a concentration of 0.1 mg/ml, react at 30°C for 10 minutes, take out the valve and wash it three times to complete a reaction cycle;
- step (3) soak the material treated in step (2) in a glutaraldehyde solution with a concentration of 0.1% for 2 hours and then wash it;
- step (3) The material obtained in step (3) was placed in a PBS solution of glucose oxidase with a concentration of 0.5 mg/ml, activated at 4°C for 4 h, and washed to obtain the target material.
- a preparation method of an enzyme-modified anticoagulant valve comprising the following steps:
- valve into a mixed aqueous solution of tannic acid with a concentration of 0.8 mg/ml and silver chloride with a concentration of 0.1 mg/ml, react at 25°C for 60 minutes, take out the valve and clean it 3 times to complete a reaction cycle;
- step (3) soak the material treated in step (2) in a glutaraldehyde solution with a concentration of 0.15% for 2 hours and then wash it;
- step (3) The material obtained in step (3) was placed in a PBS solution of glucose oxidase with a concentration of 0.15 mg/ml, activated at 4°C for 4 hours, and washed to obtain the target material.
- a preparation method of an enzyme-modified anticoagulant valve comprising the following steps:
- valve into a mixed aqueous solution of dopamine with a concentration of 1 mg/ml and silver chloride with a concentration of 0.1 mg/ml, react at 30°C for 20 minutes, take out the valve and clean it 3 times to complete a reaction cycle;
- step (3) soak the material treated in step (2) in a glutaraldehyde solution with a concentration of 1% for 2 hours and then wash it;
- step (3) The material obtained in step (3) was placed in a PBS solution of glucose oxidase with a concentration of 0.2 mg/ml, activated at 4°C for 4 h, and washed to obtain the target material.
- a preparation method of an enzyme-modified anticoagulant valve comprising the following steps:
- valve into a mixed aqueous solution of dopamine with a concentration of 1 mg/ml and silver chloride with a concentration of 0.1 mg/ml, react at 30°C for 20 minutes, take out the valve and clean it 3 times to complete a reaction cycle;
- step (3) soak the material treated in step (2) in a glutaraldehyde solution with a concentration of 1% for 2 hours and then wash it;
- step (3) The material obtained in step (3) was placed in a PBS solution of glucose oxidase with a concentration of 0.2 mg/ml, activated at 4°C for 4 h, and washed to obtain the target material.
- the glutaraldehyde valve was used as the control group, and the anticoagulant valve prepared in Example 2 was used as the experimental group, and their hemibody hemocompatibility was tested respectively. The results are shown in Figures 1 and 2, respectively.
- valve material prepared in this application has excellent biocompatibility and anticoagulant properties.
Abstract
Provided are an enzyme-modified anticoagulant valve and a manufacturing method therefor. The manufacturing method is: (1) placing a bioprosthetic valve material in a mixture of a polyphenol compound and a soluble metal salt for a reaction, and cleaning the bioprosthetic valve material when the reaction is completed; (2) crosslinking the bioprosthetic valve material using glutaraldehyde; and (3) utilizing an enzyme solution to treat the crosslinked bioprosthetic valve material, where the enzyme in the enzyme solution is capable of utilizing glucose to produce hydrogen peroxide. The inherent characteristics of the valve are utilized to modify a polyphenol-metal conjugate and glucose oxidase, the requirement on the valve for in vivo long-acting anticoagulation is implemented simply and efficiently, and the failure rate of the valve is reduced.
Description
本发明属于生物医学工程功能材料技术领域,具体涉及一种酶改性的抗凝血瓣膜及其制备方法。The invention belongs to the technical field of biomedical engineering functional materials, and in particular relates to an enzyme-modified anticoagulation valve and a preparation method thereof.
针对瓣膜功能不全或失效的临床现状,开发可用于治疗瓣膜反流性疾病的人工瓣膜极具市场价值。生理状态下的瓣膜较薄,且容易受到瓣叶周围血流压力的影响,目前导致瓣膜失效的主要原因是血栓问题。瓣膜植入体内后会立刻引发一系列凝血反应,如凝血因子与黏着蛋白沉积,纤维蛋白原吸附变性,血小板聚集与激活等,因此对瓣膜进行抗凝修饰对维持瓣膜长期服役能力至关重要。In view of the clinical status of valve insufficiency or failure, the development of prosthetic valves that can be used to treat valve regurgitation disease is of great market value. The valve in a physiological state is thin and easily affected by the blood flow pressure around the valve leaflet. Currently, the main cause of valve failure is thrombosis. Immediately after the valve is implanted into the body, a series of coagulation reactions will be triggered, such as deposition of coagulation factors and adhesive proteins, adsorption and degeneration of fibrinogen, and platelet aggregation and activation.
内皮衍生舒张因子一氧化氮(NO)是内皮细胞分泌的重要的抗凝因子,可维持血管血压、抑制血小板激活与聚集。NO抗凝材料常有两类,即NO供体类与NO催化类,虽然NO的有效释放能抑制材料植入体内后的凝血反应,但此类材料也面临诸多限制,尤其是NO供体本身不稳定,外源性供体前体物质致癌,内源性NO供体在体内浓度低且变化大,反应过程中也会产生毒性物质。生理条件下,NO是由一氧化氮合酶在NADPH和O
2(或过氧化氢)存在下催化L-精氨酸产生的,此外当L-精氨酸或过氧化氢浓度受限的情况下,一氧化氮合酶会催化生成NO的单电子还原形式硝酰(HNO),与NO一样具有抗凝血作用。HNO的来源是体内稳定且含量丰富的L-精氨酸,其反应毒性、稳定性均优于NO。然而一氧化氮合酶作为天然酶,虽然高度专一且高效,但价格高,难以长期储存的问题限制了其产业应用。
Endothelial-derived relaxing factor nitric oxide (NO) is an important anticoagulant factor secreted by endothelial cells, which can maintain vascular blood pressure and inhibit platelet activation and aggregation. There are usually two types of NO anticoagulant materials, namely NO donors and NO catalysis. Although the effective release of NO can inhibit the coagulation reaction after the material is implanted into the body, such materials also face many limitations, especially the NO donor itself. Unstable, exogenous donor precursor substances are carcinogenic, and endogenous NO donors have low concentrations and large changes in the body, and toxic substances are also produced during the reaction. Under physiological conditions, NO is produced by the catalysis of L-arginine by nitric oxide synthase in the presence of NADPH and O 2 (or hydrogen peroxide), in addition, when the concentration of L-arginine or hydrogen peroxide is limited Nitric oxide synthase catalyzes the generation of the one-electron reduced form of NO, nitroxyl (HNO), which has the same anticoagulant effect as NO. The source of HNO is L-arginine, which is stable and abundant in the body, and its reaction toxicity and stability are better than NO. However, as a natural enzyme, nitric oxide synthase is highly specific and efficient, but its high price and difficulty in long-term storage limit its industrial application.
针对现有技术中的上述不足,本发明提供一种酶改性的抗凝血瓣膜及其制备方法,本申请中多酚-金属螯合物提供类一氧化氮合酶的功能,与稳定交联在瓣膜中的葡萄糖氧化酶组成酶串联系统高效催化生成抗凝血物质硝酰,具有制备工艺简单,成本较低且抗凝效果理想的特点。In view of the above deficiencies in the prior art, the present invention provides an enzyme-modified anticoagulant valve and a preparation method thereof. In the present application, the polyphenol-metal chelate provides a nitric oxide synthase-like function, which is compatible with stable cross-linking. The glucose oxidase linked in the valve forms an enzyme series system to efficiently catalyze the generation of anticoagulant substance nitroxyl, and has the characteristics of simple preparation process, low cost and ideal anticoagulation effect.
为实现上述目的,本发明解决其技术问题所采用的技术方案是:For realizing the above-mentioned purpose, the technical scheme that the present invention solves its technical problem adopts is:
一种酶改性的抗凝血瓣膜的制备方法,包括以下步骤:A preparation method of an enzyme-modified anticoagulant valve, comprising the following steps:
(1)将生物瓣膜材料置于多酚化合物与可溶性金属盐的混合溶液中,于20~40℃反应5~60min,取出清洗;(1) Put the biological valve material in the mixed solution of polyphenol compound and soluble metal salt, react at 20~40℃ for 5~60min, take it out for cleaning;
(2)以步骤(1)所得产物为基底,重复步骤(1)1~20次后,取出清洗并在室温下干燥;(2) Taking the product obtained in step (1) as the base, repeating step (1) for 1 to 20 times, taking it out for cleaning and drying at room temperature;
(3)将步骤(2)所得产物置于浓度为0.1~2.5%的戊二醛溶液中活化2~10h后,置于浓度为0.01~10mg/mL,能利用葡萄糖产生过氧化氢的酶溶液中,于1~15℃活化4~12h后,取出洗净即可。(3) After the product obtained in step (2) is placed in a glutaraldehyde solution with a concentration of 0.1 to 2.5% for 2 to 10 hours, and then placed in an enzyme solution with a concentration of 0.01 to 10 mg/mL, which can utilize glucose to generate hydrogen peroxide After activating at 1~15℃ for 4~12h, take it out and wash it.
进一步地,多酚化合物与可溶性金属盐的质量比为1:0.1~1。Further, the mass ratio of the polyphenol compound to the soluble metal salt is 1:0.1~1.
进一步地,多酚化合物与可溶性金属盐的质量比为1:0.1。Further, the mass ratio of the polyphenol compound to the soluble metal salt is 1:0.1.
进一步地,步骤(1)中反应温度为30℃,反应时间为10min。Further, in step (1), the reaction temperature was 30° C., and the reaction time was 10 min.
进一步地,进一步地,多酚化合物为具有邻酚结构的多酚化合物。Further, further, the polyphenol compound is a polyphenol compound having an ortho-phenol structure.
进一步地,具有邻酚结构的多酚化合物为多巴胺、单宁酸、表没食子儿茶素没食子酸酯EGCG、表儿茶素没食子酸酯ECG、表儿茶素EC、表没食子儿茶素EGC、邻苯二酚及邻苯三酚中的至少一种。Further, the polyphenolic compound with ortho-phenol structure is dopamine, tannic acid, epigallocatechin gallate EGCG, epicatechin gallate ECG, epicatechin EC, epigallocatechin EGC, At least one of catechol and pyrogallol.
进一步地,可溶性金属盐为氯化铁、氯化铜、氯化银、氯化锰或氯化银。Further, the soluble metal salt is ferric chloride, cupric chloride, silver chloride, manganese chloride or silver chloride.
进一步地,酶为葡萄糖氧化酶、柠檬酸修饰的金纳米颗粒、金/三氧化二铝纳米颗粒、金/氧化钛颗粒、含金的双金属/三金属纳米颗粒中的一种。Further, the enzyme is one of glucose oxidase, citric acid-modified gold nanoparticles, gold/aluminum oxide nanoparticles, gold/titanium oxide particles, and gold-containing bimetallic/trimetallic nanoparticles.
进一步地,步骤(3)中活化温度为4℃,活化时间为4h。Further, in step (3), the activation temperature is 4°C, and the activation time is 4h.
进一步地,生物瓣膜材料为主动脉瓣、肺动脉瓣、静脉瓣、二尖瓣或三尖瓣。Further, the biological valve material is aortic valve, pulmonary valve, venous valve, mitral valve or tricuspid valve.
本发明的有益效果为:The beneficial effects of the present invention are:
1、天然酶可催化反应在温和条件下高效进行,且对底物有高度专一性,但价格高,易失活不易长期储存的问题限制了它在工业领域的应用。本申请中制备的多酚-金属螯合物既具有类似一氧化氮合酶的催化能力,又相比一氧化氮合酶更稳定,易制备且成本更低。此外,多酚金属螯合物更加稳定,易于制备,适合工业化推广且不会产生单分子易聚集失去活性的问题。多酚化合物中的酚羟基可以在高价金属离子存在条件或氧气存在下氧化为醌基官能团。多酚和可溶性金属盐混合,可以制备出酚-金属配位化合物,这类化合物中的酚羟基及部分氧化出的醌基可以与瓣膜材料上的基团(羟基、醛基、羧基等)发生氢键作用,从而稳定在戊二醛瓣膜的纤维结构上。1. Natural enzymes can catalyze reactions efficiently under mild conditions and have high specificity for substrates, but the problems of high price, easy deactivation and difficult long-term storage limit its application in the industrial field. The polyphenol-metal chelate prepared in the present application not only has the catalytic ability similar to nitric oxide synthase, but also is more stable than nitric oxide synthase, easy to prepare and lower cost. In addition, the polyphenol metal chelate is more stable, easy to prepare, suitable for industrialization, and does not cause the problem of single-molecule aggregation and loss of activity. The phenolic hydroxyl groups in polyphenolic compounds can be oxidized to quinone functional groups in the presence of high-valent metal ions or in the presence of oxygen. Polyphenols and soluble metal salts can be mixed to prepare phenol-metal complexes. The phenolic hydroxyl groups and partially oxidized quinone groups in such compounds can interact with groups (hydroxyl groups, aldehyde groups, carboxyl groups, etc.) on the valve material. Hydrogen bonding, thereby stabilizing the fibrous structure of the glutaraldehyde valve.
2、将葡萄糖氧化酶以交联的方式与瓣膜结合相比于表面修饰更加稳定及持久地发挥作用。2. Combining glucose oxidase with the valve in a cross-linked manner is more stable and durable than surface modification.
3、多酚-金属螯合物联合葡萄糖氧化酶可形成酶串联通路,瓣膜中通过戊二醛交联而稳定且大量存在的葡萄糖氧化酶可利用血液中的葡萄糖产生局部高浓度的过氧化氢,随后被多酚金属螯合物利用并催化L-精氨酸产生抗凝血物质HNO,可避免传统NO涂层具有潜在毒性及供体来源不稳定的缺陷,从而高效持久地维持瓣膜的抗凝血性能。本发明利用瓣膜自身特点,修饰多酚-金属螯合物与葡萄糖氧化酶,简便高效地实现瓣膜体内长效抗凝血的要求,降低瓣膜失效率。3. Polyphenol-metal chelate combined with glucose oxidase can form an enzymatic tandem pathway. Glucose oxidase, which is stabilized and abundantly present in the valve through glutaraldehyde cross-linking, can utilize glucose in the blood to generate local high concentrations of hydrogen peroxide , which is then utilized by polyphenol metal chelate and catalyzes L-arginine to produce the anticoagulant substance HNO, which can avoid the potential toxicity and unstable donor source defects of traditional NO coating, so as to maintain the valve resistance efficiently and lastingly. coagulation properties. The invention utilizes the characteristics of the valve itself, modifies the polyphenol-metal chelate and the glucose oxidase, simply and efficiently realizes the requirement of long-acting anticoagulation in the valve body and reduces the valve failure rate.
图1为传统戊二醛瓣膜的半体血液相容性测试结果;Fig. 1 is the hemibody hemocompatibility test result of traditional glutaraldehyde valve;
图2为本申请实施例2制备得到的瓣膜材料的半体血液相容性测试结果。FIG. 2 is the test result of hemibody blood compatibility of the valve material prepared in Example 2 of the present application.
下面对本发明的具体实施方式进行描述,以便于本技术领域的技术人员理解本发明,但应该清楚,本发明不限于具体实施方式的范围,对本技术领域的普通技术人员来讲,只要各种变化在所附的权利要求限定和确定的本发明的精神和范围内,这些变化是显而易见的,一切利用本发明构思的发明创造均在保护之列。The specific embodiments of the present invention are described below to facilitate those skilled in the art to understand the present invention, but it should be clear that the present invention is not limited to the scope of the specific embodiments. For those skilled in the art, as long as various changes Such changes are obvious within the spirit and scope of the present invention as defined and determined by the appended claims, and all inventions and creations utilizing the inventive concept are within the scope of protection.
本发明公开了一种抗凝血瓣膜的制备方法,包括以下步骤:The invention discloses a preparation method of an anticoagulation valve, comprising the following steps:
(1)将生物瓣膜材料置于多酚化合物与可溶性金属盐的混合溶液中进行反应,反应结束后对生物瓣膜材料进行清洗;(1) The biological valve material is placed in a mixed solution of polyphenolic compounds and soluble metal salts for reaction, and the biological valve material is cleaned after the reaction is completed;
多酚化合物中含有大量酚羟基官能团,其可以与瓣膜中的氨基、羟基、羧基的化合物形成氢键作用;此外,多酚化合物中的酚羟基可以螯合金属离子,形成酚-金属配位化合物;多酚化合物中的酚羟基也可以在高价金属离子存在条件或氧气存在下氧化为醌基官能团,醌可以与带有伯胺基的物质发生西弗碱反应生成C=N共价键。Polyphenol compounds contain a large number of phenolic hydroxyl functional groups, which can form hydrogen bonds with the compounds of amino, hydroxyl and carboxyl groups in the valve; in addition, the phenolic hydroxyl groups in polyphenol compounds can chelate metal ions to form phenol-metal complexes The phenolic hydroxyl group in the polyphenol compound can also be oxidized to a quinone functional group in the presence of high-valent metal ions or in the presence of oxygen, and the quinone can react with a substance with a primary amine group to form a C=N covalent bond.
多酚化合物中的酚羟基及部分氧化出的醌基可以与瓣膜材料上的基团(羟基、醛基、羧基等)发生氢键作用,从而稳定在戊二醛瓣膜的纤维结构上。The phenolic hydroxyl group and the partially oxidized quinone group in the polyphenol compound can hydrogen bond with the groups (hydroxyl group, aldehyde group, carboxyl group, etc.) on the valve material, thereby stabilizing the fiber structure of the glutaraldehyde valve.
(2)用戊二醛对生物瓣膜材料进行交联处理;(2) Cross-linking the biological valve material with glutaraldehyde;
(3)利用酶溶液对交联处理后的生物瓣膜材料进行处理,其中所述酶溶液中的酶能够利用葡萄糖产生过氧化氢。(3) The cross-linked biological valve material is treated with an enzyme solution, wherein the enzyme in the enzyme solution can utilize glucose to generate hydrogen peroxide.
为了增加瓣膜纤维上修饰的酶的含量,可重复步骤(1)多次,例如优选1~20次。In order to increase the content of the modified enzyme on the valve fiber, step (1) can be repeated for several times, for example, preferably 1 to 20 times.
实施例1 Example 1
一种酶改性的抗凝血瓣膜的制备方法,包括以下步骤:A preparation method of an enzyme-modified anticoagulant valve, comprising the following steps:
(1)将瓣膜放入浓度为1mg/ml的多巴胺与浓度为0.5mg/ml的氯化铁的混合水溶液中,25℃反应20min,取出瓣膜清洗3次,完成一个反应周期;(1) Put the valve into a mixed aqueous solution of dopamine with a concentration of 1 mg/ml and ferric chloride with a concentration of 0.5 mg/ml, react at 25°C for 20 minutes, take out the valve and clean it 3 times to complete a reaction cycle;
(2)重复反应周期10次,干燥;(2) Repeat the reaction cycle 10 times and dry;
(3)将经步骤(2)处理的材料浸泡在浓度为0.5%的戊二醛溶液中活化4h后洗净;(3) soak the material treated in step (2) in a glutaraldehyde solution with a concentration of 0.5% for 4 hours and then wash it;
(4)将步骤(3)所得材料放入浓度为0.15mg/ml的葡萄糖氧化酶的PBS溶液中,4℃条件下活化4h,洗净即得目标材料。(4) The material obtained in step (3) was placed in a PBS solution of glucose oxidase with a concentration of 0.15 mg/ml, activated at 4°C for 4 hours, and washed to obtain the target material.
实施例2 Example 2
一种酶改性的抗凝血瓣膜的制备方法,包括以下步骤:A preparation method of an enzyme-modified anticoagulant valve, comprising the following steps:
(1)将瓣膜放入浓度为1mg/ml的单宁酸与浓度为0.1mg/ml的氯化铁的混合水溶液中,30℃反应10min,取出瓣膜清洗3次,完成一个反应周期;(1) Put the valve into a mixed aqueous solution of tannic acid with a concentration of 1 mg/ml and ferric chloride with a concentration of 0.1 mg/ml, react at 30°C for 10 minutes, take out the valve and clean it 3 times to complete a reaction cycle;
(2)重复反应周期5次,干燥;(2) Repeat the reaction cycle 5 times and dry;
(3)将经步骤(2)处理的材料浸泡在浓度为0.15%的戊二醛溶液中活化2h后洗净;(3) soak the material treated in step (2) in a glutaraldehyde solution with a concentration of 0.15% for 2 hours and then wash it;
(4)将步骤(3)所得材料放入浓度为0.2mg/ml的葡萄糖氧化酶的PBS溶液中,4℃条件下活化4h,洗净即得目标材料。(4) The material obtained in step (3) was placed in a PBS solution of glucose oxidase with a concentration of 0.2 mg/ml, activated at 4°C for 4 h, and washed to obtain the target material.
实施例3 Example 3
一种酶改性的抗凝血瓣膜的制备方法,包括以下步骤:A preparation method of an enzyme-modified anticoagulant valve, comprising the following steps:
(1)将瓣膜放入浓度为1mg/ml的单宁酸与浓度为0.1mg/ml的氯化铜的混合水溶液中,30℃反应20min,取出瓣膜清洗3次,完成一个反应周期;(1) Put the valve into a mixed aqueous solution of tannic acid with a concentration of 1 mg/ml and copper chloride with a concentration of 0.1 mg/ml, react at 30°C for 20 minutes, take out the valve and clean it 3 times to complete a reaction cycle;
(2)重复反应周期5次,干燥;(2) Repeat the reaction cycle 5 times and dry;
(3)将经步骤(2)处理的材料浸泡在浓度为0.2%的戊二醛溶液中活化2h后洗净;(3) soak the material treated in step (2) in a glutaraldehyde solution with a concentration of 0.2% for 2 hours and then wash it;
(4)将步骤(3)所得材料放入浓度为0.2mg/ml的葡萄糖氧化酶的PBS溶液中,4℃条件下活化4h,洗净即得目标材料。(4) The material obtained in step (3) was placed in a PBS solution of glucose oxidase with a concentration of 0.2 mg/ml, activated at 4°C for 4 h, and washed to obtain the target material.
实施例4 Example 4
一种酶改性的抗凝血瓣膜的制备方法,包括以下步骤:A preparation method of an enzyme-modified anticoagulant valve, comprising the following steps:
(1)将瓣膜放入浓度为1mg/ml的EGCG与浓度为0.1mg/ml的氯化铁的混合水溶液中,30℃反应10min,取出瓣膜清洗3次,完成一个反应周期;(1) Put the valve into a mixed aqueous solution of EGCG with a concentration of 1 mg/ml and ferric chloride with a concentration of 0.1 mg/ml, react at 30°C for 10 minutes, take out the valve and wash it three times to complete a reaction cycle;
(2)重复反应周期5次,干燥;(2) Repeat the reaction cycle 5 times and dry;
(3)将经步骤(2)处理的材料浸泡在浓度为0.1%的戊二醛溶液中活化2h后洗净;(3) soak the material treated in step (2) in a glutaraldehyde solution with a concentration of 0.1% for 2 hours and then wash it;
(4)将步骤(3)所得材料放入浓度为0.5mg/ml的葡萄糖氧化酶的PBS溶液中,4℃条件下活化4h,洗净即得目标材料。(4) The material obtained in step (3) was placed in a PBS solution of glucose oxidase with a concentration of 0.5 mg/ml, activated at 4°C for 4 h, and washed to obtain the target material.
实施例5 Example 5
一种酶改性的抗凝血瓣膜的制备方法,包括以下步骤:A preparation method of an enzyme-modified anticoagulant valve, comprising the following steps:
(1)将瓣膜放入浓度为0.8mg/ml的单宁酸与浓度为0.1mg/ml的氯化银的混合水溶液中,25℃反应60min,取出瓣膜清洗3次,完成一个反应周期;(1) Put the valve into a mixed aqueous solution of tannic acid with a concentration of 0.8 mg/ml and silver chloride with a concentration of 0.1 mg/ml, react at 25°C for 60 minutes, take out the valve and clean it 3 times to complete a reaction cycle;
(2)重复反应周期5次,干燥;(2) Repeat the reaction cycle 5 times and dry;
(3)将经步骤(2)处理的材料浸泡在浓度为0.15%的戊二醛溶液中活化2h后洗净;(3) soak the material treated in step (2) in a glutaraldehyde solution with a concentration of 0.15% for 2 hours and then wash it;
(4)将步骤(3)所得材料放入浓度为0.15mg/ml的葡萄糖氧化酶的PBS溶液中,4℃条件下活化4h,洗净即得目标材料。(4) The material obtained in step (3) was placed in a PBS solution of glucose oxidase with a concentration of 0.15 mg/ml, activated at 4°C for 4 hours, and washed to obtain the target material.
实施例6Example 6
一种酶改性的抗凝血瓣膜的制备方法,包括以下步骤:A preparation method of an enzyme-modified anticoagulant valve, comprising the following steps:
(1)将瓣膜放入浓度为1mg/ml的多巴胺与浓度为0.1mg/ml的氯化银的混合水溶液中,30℃反应20min,取出瓣膜清洗3次,完成一个反应周期;(1) Put the valve into a mixed aqueous solution of dopamine with a concentration of 1 mg/ml and silver chloride with a concentration of 0.1 mg/ml, react at 30°C for 20 minutes, take out the valve and clean it 3 times to complete a reaction cycle;
(2)重复反应周期5次,干燥;(2) Repeat the reaction cycle 5 times and dry;
(3)将经步骤(2)处理的材料浸泡在浓度为1%的戊二醛溶液中活化2h后洗净;(3) soak the material treated in step (2) in a glutaraldehyde solution with a concentration of 1% for 2 hours and then wash it;
(4)将步骤(3)所得材料放入浓度为0.2mg/ml的葡萄糖氧化酶的PBS溶液中,4℃条件下活化4h,洗净即得目标材料。(4) The material obtained in step (3) was placed in a PBS solution of glucose oxidase with a concentration of 0.2 mg/ml, activated at 4°C for 4 h, and washed to obtain the target material.
实施例7Example 7
一种酶改性的抗凝血瓣膜的制备方法,包括以下步骤:A preparation method of an enzyme-modified anticoagulant valve, comprising the following steps:
(1)将瓣膜放入浓度为1mg/ml的多巴胺与浓度为0.1mg/ml的氯化银的混合水溶液中,30℃反应20min,取出瓣膜清洗3次,完成一个反应周期;(1) Put the valve into a mixed aqueous solution of dopamine with a concentration of 1 mg/ml and silver chloride with a concentration of 0.1 mg/ml, react at 30°C for 20 minutes, take out the valve and clean it 3 times to complete a reaction cycle;
(2)重复反应周期10次;(2) Repeat the reaction cycle 10 times;
(3)将经步骤(2)处理的材料浸泡在浓度为1%的戊二醛溶液中活化2h后洗净;(3) soak the material treated in step (2) in a glutaraldehyde solution with a concentration of 1% for 2 hours and then wash it;
(4)将步骤(3)所得材料放入浓度为0.2mg/ml的葡萄糖氧化酶的PBS溶液中,4℃条件下活化4h,洗净即得目标材料。(4) The material obtained in step (3) was placed in a PBS solution of glucose oxidase with a concentration of 0.2 mg/ml, activated at 4°C for 4 h, and washed to obtain the target material.
实验例Experimental example
以戊二醛瓣膜为对照组,实施例2制备得到的抗凝血瓣膜为实验组,分别检测其半体血液相容性,其结果分别见图1和图2。The glutaraldehyde valve was used as the control group, and the anticoagulant valve prepared in Example 2 was used as the experimental group, and their hemibody hemocompatibility was tested respectively. The results are shown in Figures 1 and 2, respectively.
在图1中,可明显看到有与瓣膜不相容的血细胞,而图2中则未见与瓣膜不相容的血细胞,可以看出本申请制备得到的瓣膜材料具有优异的生物相容性和抗凝血性能。In Figure 1, it can be clearly seen that there are blood cells that are incompatible with the valve, while in Figure 2, there are no blood cells that are incompatible with the valve. It can be seen that the valve material prepared in this application has excellent biocompatibility and anticoagulant properties.
Claims (13)
- 一种抗凝血瓣膜的制备方法,其特征在于,包括以下步骤: A method for preparing an anticoagulant valve, comprising the following steps:(1)将生物瓣膜材料置于多酚化合物与可溶性金属盐的混合溶液中进行反应,反应结束后对生物瓣膜材料进行清洗;(1) The biological valve material is placed in a mixed solution of polyphenolic compounds and soluble metal salts for reaction, and the biological valve material is cleaned after the reaction is completed;(2)用戊二醛对生物瓣膜材料进行交联处理;(2) Cross-linking the biological valve material with glutaraldehyde;(3)利用酶溶液对交联处理后的生物瓣膜材料进行处理,其中所述酶溶液中的酶能够利用葡萄糖产生过氧化氢。(3) The cross-linked biological valve material is treated with an enzyme solution, wherein the enzyme in the enzyme solution can utilize glucose to generate hydrogen peroxide.
- 根据权利要求1所述抗凝血瓣膜的制备方法,其特征在于,在戊二醛对生物瓣膜材料进行交联处理前,重复步骤(1)1~20次,对生物瓣膜进行干燥处理。 The method for preparing an anticoagulant valve according to claim 1, characterized in that before the glutaraldehyde crosslinks the biological valve material, repeating step (1) 1 to 20 times to dry the biological valve.
- 根据权利要求2所述抗凝血瓣膜的制备方法,其特征在于,所述多酚化合物与可溶性金属盐的质量比为1:0.1~1。 The method for preparing an anticoagulant valve according to claim 2, wherein the mass ratio of the polyphenol compound to the soluble metal salt is 1:0.1~1.
- 根据权利要求1或2所述的酶改性的抗凝血瓣膜的制备方法,其特征在于,所述多酚化合物为具有邻酚结构的多酚化合物。 The method for preparing an enzyme-modified anticoagulant valve according to claim 1 or 2, wherein the polyphenolic compound is a polyphenolic compound having an ortho-phenolic structure.
- 根据权利要求4所述的酶改性的抗凝血瓣膜的制备方法,其特征在于,所述具有邻酚结构的多酚化合物为多巴胺、单宁酸、表没食子儿茶素没食子酸酯EGCG、表儿茶素没食子酸酯ECG、表儿茶素EC、表没食子儿茶素EGC、邻苯二酚及邻苯三酚中的至少一种。 The method for preparing an enzyme-modified anticoagulant valve according to claim 4, wherein the polyphenolic compound having an ortho-phenol structure is dopamine, tannic acid, epigallocatechin gallate EGCG, At least one of epicatechin gallate ECG, epicatechin EC, epigallocatechin EGC, catechol and pyrogallol.
- 根据权利要求1或2所述的酶改性的抗凝血瓣膜的制备方法,其特征在于,所述可溶性金属盐为氯化铁、氯化铜、氯化银、氯化锰或氯化银。 The method for preparing an enzyme-modified anticoagulant valve according to claim 1 or 2, wherein the soluble metal salt is ferric chloride, copper chloride, silver chloride, manganese chloride or silver chloride .
- 根据权利要求1或2所述抗凝血瓣膜的制备方法,其特征在于,步骤(2)中采用浓度0.1~2.5%戊二醛溶液交联生物瓣膜,交联时间为2~10h。 The method for preparing an anticoagulant valve according to claim 1 or 2, wherein in step (2), a glutaraldehyde solution with a concentration of 0.1-2.5% is used to cross-link the biological valve, and the cross-linking time is 2-10 h.
- 根据权利要求1或2所述抗凝血瓣膜的制备方法,其特征在于,步骤(3)中采用浓度为0.01~10mg/mL的葡萄糖酶溶液。 The method for preparing an anticoagulant valve according to claim 1 or 2, wherein in step (3), a glucose enzyme solution with a concentration of 0.01-10 mg/mL is used.
- 根据权利要求8所述抗凝血瓣膜的制备方法,其特征在于,所述酶溶液还包括柠檬酸修饰的金纳米颗粒、金和三氧化二铝的纳米颗粒、金和氧化钛的纳米颗粒、含金的双金属纳米颗粒或含金的三金属纳米颗粒。 The method for preparing an anticoagulant valve according to claim 8, wherein the enzyme solution further comprises citric acid-modified gold nanoparticles, gold and aluminum oxide nanoparticles, gold and titanium oxide nanoparticles, Gold-containing bimetallic nanoparticles or gold-containing trimetallic nanoparticles.
- 根据权利要求2所述抗凝血瓣膜的制备方法,其特征在于,步骤(1)中反应条件为:20~40℃,反应5~60min。 The method for preparing an anticoagulant valve according to claim 2, wherein the reaction conditions in step (1) are: 20-40° C. for 5-60 minutes.
- 根据权利要求1所述抗凝血瓣膜的制备方法,其特征在于,步骤(3)的反应条件为:1~15℃反应4~12h。 The method for preparing an anticoagulant valve according to claim 1, wherein the reaction conditions of step (3) are: 1-15°C for 4-12 hours.
- 根据权利要求1或2所述抗凝血瓣膜的制备方法,其特征在于,所述生物瓣膜材料为主动脉瓣、肺动脉瓣、静脉瓣、二尖瓣或三尖瓣。 The method for preparing an anticoagulant valve according to claim 1 or 2, wherein the biological valve material is an aortic valve, a pulmonary valve, a venous valve, a mitral valve or a tricuspid valve.
- 一种抗凝血瓣膜,其特征在于,包括交联后的生物瓣膜材料,所述生物瓣膜材料修饰有葡萄糖氧化酶串联多酚-金属螯合物的反应系统。 An anticoagulant valve is characterized in that it comprises a cross-linked biological valve material, and the biological valve material is modified with a reaction system of glucose oxidase in series with a polyphenol-metal chelate complex.
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