CN112473636A - Blood perfusion adsorbent coated and covalently fixed with heparin and preparation method thereof - Google Patents
Blood perfusion adsorbent coated and covalently fixed with heparin and preparation method thereof Download PDFInfo
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- CN112473636A CN112473636A CN201910859292.7A CN201910859292A CN112473636A CN 112473636 A CN112473636 A CN 112473636A CN 201910859292 A CN201910859292 A CN 201910859292A CN 112473636 A CN112473636 A CN 112473636A
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- adsorbent
- heparin
- hemoperfusion
- coated
- covalently
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- 239000003463 adsorbent Substances 0.000 title claims abstract description 142
- 229920000669 heparin Polymers 0.000 title claims abstract description 96
- 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 86
- 229960002897 heparin Drugs 0.000 title claims abstract description 80
- 230000008081 blood perfusion Effects 0.000 title claims abstract description 27
- 238000002360 preparation method Methods 0.000 title abstract description 12
- 230000001951 hemoperfusion Effects 0.000 claims abstract description 34
- 229920000768 polyamine Chemical class 0.000 claims abstract description 19
- 235000013824 polyphenols Nutrition 0.000 claims abstract description 18
- 150000001875 compounds Chemical class 0.000 claims abstract description 17
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 12
- 150000008442 polyphenolic compounds Chemical class 0.000 claims abstract description 11
- 239000012528 membrane Substances 0.000 claims abstract description 8
- 239000000243 solution Substances 0.000 claims description 34
- NQTADLQHYWFPDB-UHFFFAOYSA-N N-Hydroxysuccinimide Chemical compound ON1C(=O)CCC1=O NQTADLQHYWFPDB-UHFFFAOYSA-N 0.000 claims description 28
- 238000003756 stirring Methods 0.000 claims description 23
- 238000005406 washing Methods 0.000 claims description 23
- VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 claims description 22
- 239000008213 purified water Substances 0.000 claims description 22
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 22
- 239000007864 aqueous solution Substances 0.000 claims description 21
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 15
- 239000007853 buffer solution Substances 0.000 claims description 15
- 238000000034 method Methods 0.000 claims description 13
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 12
- 229960003638 dopamine Drugs 0.000 claims description 11
- -1 polyphenol compounds Chemical class 0.000 claims description 11
- 239000011347 resin Substances 0.000 claims description 11
- 229920005989 resin Polymers 0.000 claims description 11
- 230000002378 acidificating effect Effects 0.000 claims description 10
- 239000011248 coating agent Substances 0.000 claims description 10
- 238000000576 coating method Methods 0.000 claims description 10
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 9
- VILCJCGEZXAXTO-UHFFFAOYSA-N 2,2,2-tetramine Chemical compound NCCNCCNCCN VILCJCGEZXAXTO-UHFFFAOYSA-N 0.000 claims description 8
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 claims description 8
- RPNUMPOLZDHAAY-UHFFFAOYSA-N Diethylenetriamine Chemical compound NCCNCCN RPNUMPOLZDHAAY-UHFFFAOYSA-N 0.000 claims description 8
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 claims description 8
- 239000007987 MES buffer Substances 0.000 claims description 8
- LSHROXHEILXKHM-UHFFFAOYSA-N n'-[2-[2-[2-(2-aminoethylamino)ethylamino]ethylamino]ethyl]ethane-1,2-diamine Chemical compound NCCNCCNCCNCCNCCN LSHROXHEILXKHM-UHFFFAOYSA-N 0.000 claims description 8
- 239000000126 substance Substances 0.000 claims description 8
- FAGUFWYHJQFNRV-UHFFFAOYSA-N tetraethylenepentamine Chemical compound NCCNCCNCCNCCN FAGUFWYHJQFNRV-UHFFFAOYSA-N 0.000 claims description 8
- 239000007983 Tris buffer Substances 0.000 claims description 6
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 4
- 238000002791 soaking Methods 0.000 claims description 4
- 238000000151 deposition Methods 0.000 claims description 3
- 229920001864 tannin Polymers 0.000 claims description 3
- 235000018553 tannin Nutrition 0.000 claims description 3
- 239000001648 tannin Substances 0.000 claims description 3
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims description 2
- 229910019142 PO4 Inorganic materials 0.000 claims description 2
- 229910021529 ammonia Inorganic materials 0.000 claims description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 2
- 239000010452 phosphate Substances 0.000 claims description 2
- 239000002594 sorbent Substances 0.000 claims 2
- 238000004519 manufacturing process Methods 0.000 claims 1
- 210000004369 blood Anatomy 0.000 abstract description 17
- 239000008280 blood Substances 0.000 abstract description 17
- 230000015271 coagulation Effects 0.000 abstract description 6
- 238000005345 coagulation Methods 0.000 abstract description 6
- 239000003146 anticoagulant agent Substances 0.000 abstract description 5
- 229940127219 anticoagulant drug Drugs 0.000 abstract description 5
- 230000009286 beneficial effect Effects 0.000 abstract description 4
- 239000011148 porous material Substances 0.000 abstract description 4
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 abstract description 3
- 230000000694 effects Effects 0.000 abstract description 2
- 230000005661 hydrophobic surface Effects 0.000 abstract description 2
- 230000003100 immobilizing effect Effects 0.000 abstract description 2
- 238000000746 purification Methods 0.000 abstract description 2
- 239000002253 acid Substances 0.000 abstract 1
- 125000003277 amino group Chemical group 0.000 description 18
- 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 description 16
- 229960001008 heparin sodium Drugs 0.000 description 16
- 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 description 13
- 239000001263 FEMA 3042 Substances 0.000 description 13
- 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 description 13
- 229940033123 tannic acid Drugs 0.000 description 13
- 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 description 13
- 235000015523 tannic acid Nutrition 0.000 description 13
- 229920002258 tannic acid Polymers 0.000 description 13
- BPYKTIZUTYGOLE-IFADSCNNSA-N Bilirubin Chemical compound N1C(=O)C(C)=C(C=C)\C1=C\C1=C(C)C(CCC(O)=O)=C(CC2=C(C(C)=C(\C=C/3C(=C(C=C)C(=O)N\3)C)N2)CCC(O)=O)N1 BPYKTIZUTYGOLE-IFADSCNNSA-N 0.000 description 10
- 238000001035 drying Methods 0.000 description 10
- 238000001914 filtration Methods 0.000 description 10
- 238000001179 sorption measurement Methods 0.000 description 10
- 239000003053 toxin Substances 0.000 description 10
- 231100000765 toxin Toxicity 0.000 description 10
- 108700012359 toxins Proteins 0.000 description 10
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 10
- 230000023555 blood coagulation Effects 0.000 description 9
- 239000000463 material Substances 0.000 description 8
- 239000000203 mixture Substances 0.000 description 8
- 230000000052 comparative effect Effects 0.000 description 7
- 239000002504 physiological saline solution Substances 0.000 description 6
- CTENFNNZBMHDDG-UHFFFAOYSA-N Dopamine hydrochloride Chemical compound Cl.NCCC1=CC=C(O)C(O)=C1 CTENFNNZBMHDDG-UHFFFAOYSA-N 0.000 description 5
- 229960001149 dopamine hydrochloride Drugs 0.000 description 5
- 238000012986 modification Methods 0.000 description 5
- 230000004048 modification Effects 0.000 description 5
- 239000002245 particle Substances 0.000 description 5
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- 230000010100 anticoagulation Effects 0.000 description 4
- 230000010412 perfusion Effects 0.000 description 4
- 239000002953 phosphate buffered saline Substances 0.000 description 4
- 230000008569 process Effects 0.000 description 4
- 108090000623 proteins and genes Proteins 0.000 description 3
- 102000004169 proteins and genes Human genes 0.000 description 3
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 2
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 2
- 241000237536 Mytilus edulis Species 0.000 description 2
- 235000011114 ammonium hydroxide Nutrition 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 229940095529 heparin calcium Drugs 0.000 description 2
- 230000006872 improvement Effects 0.000 description 2
- 229910052744 lithium Inorganic materials 0.000 description 2
- 235000020638 mussel Nutrition 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- 229920000747 poly(lactic acid) Polymers 0.000 description 2
- 229920001690 polydopamine Polymers 0.000 description 2
- 239000004626 polylactic acid Substances 0.000 description 2
- 230000002035 prolonged effect Effects 0.000 description 2
- 238000005086 pumping Methods 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- 239000001488 sodium phosphate Substances 0.000 description 2
- 229910000162 sodium phosphate Inorganic materials 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 2
- 206010067484 Adverse reaction Diseases 0.000 description 1
- 206010053567 Coagulopathies Diseases 0.000 description 1
- 208000005189 Embolism Diseases 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 239000002250 absorbent Substances 0.000 description 1
- 230000002745 absorbent Effects 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- 230000007815 allergy Effects 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 230000002429 anti-coagulating effect Effects 0.000 description 1
- 230000000740 bleeding effect Effects 0.000 description 1
- 210000000601 blood cell Anatomy 0.000 description 1
- 210000001772 blood platelet Anatomy 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 230000035602 clotting Effects 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 238000000502 dialysis Methods 0.000 description 1
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 208000019423 liver disease Diseases 0.000 description 1
- 230000008383 multiple organ dysfunction Effects 0.000 description 1
- 230000001717 pathogenic effect Effects 0.000 description 1
- 238000011056 performance test Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 239000013535 sea water Substances 0.000 description 1
- 230000003248 secreting effect Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
Classifications
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
- B01J20/30—Processes for preparing, regenerating, or reactivating
- B01J20/32—Impregnating or coating ; Solid sorbent compositions obtained from processes involving impregnating or coating
- B01J20/3214—Impregnating or coating ; Solid sorbent compositions obtained from processes involving impregnating or coating characterised by the method for obtaining this coating or impregnating
- B01J20/3217—Resulting in a chemical bond between the coating or impregnating layer and the carrier, support or substrate, e.g. a covalent bond
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M1/00—Suction or pumping devices for medical purposes; Devices for carrying-off, for treatment of, or for carrying-over, body-liquids; Drainage systems
- A61M1/36—Other treatment of blood in a by-pass of the natural circulatory system, e.g. temperature adaptation, irradiation ; Extra-corporeal blood circuits
- A61M1/3672—Means preventing coagulation
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M1/00—Suction or pumping devices for medical purposes; Devices for carrying-off, for treatment of, or for carrying-over, body-liquids; Drainage systems
- A61M1/36—Other treatment of blood in a by-pass of the natural circulatory system, e.g. temperature adaptation, irradiation ; Extra-corporeal blood circuits
- A61M1/3679—Other treatment of blood in a by-pass of the natural circulatory system, e.g. temperature adaptation, irradiation ; Extra-corporeal blood circuits by absorption
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
- B01J20/02—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof comprising inorganic material
- B01J20/20—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof comprising inorganic material comprising free carbon; comprising carbon obtained by carbonising processes
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
- B01J20/30—Processes for preparing, regenerating, or reactivating
- B01J20/32—Impregnating or coating ; Solid sorbent compositions obtained from processes involving impregnating or coating
- B01J20/3231—Impregnating or coating ; Solid sorbent compositions obtained from processes involving impregnating or coating characterised by the coating or impregnating layer
- B01J20/3242—Layers with a functional group, e.g. an affinity material, a ligand, a reactant or a complexing group
- B01J20/3268—Macromolecular compounds
- B01J20/3272—Polymers obtained by reactions otherwise than involving only carbon to carbon unsaturated bonds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M2202/00—Special media to be introduced, removed or treated
- A61M2202/04—Liquids
- A61M2202/0413—Blood
Abstract
The invention relates to the technical field of blood purification, and discloses a blood perfusion adsorbent coated with a membrane and covalently fixing heparin and a preparation method thereof. Through the codeposition effect of polyphenol and polyamine compounds, the surfaces and the inner parts of pores of the hemoperfusion adsorbent are coated, a polyamino hydrophilic interface is generated at the same time, and finally, the reaction with carboxyl of heparin molecules is carried out under the weak acid condition and the existence of EDC and NHS, heparin is fixed on the hemoperfusion adsorbent in a covalent mode, so that the anticoagulant performance of the hemoperfusion adsorbent is improved. The invention improves the hydrophobic surface of the hemoperfusion adsorbent, introduces amino to improve the hydrophilicity of the hemoperfusion adsorbent, and is beneficial to improving the blood compatibility of the hemoperfusion adsorbent; in particular, by covalently immobilizing heparin on the surface of the hemoperfusion adsorbent, the coagulation phenomenon occurring when blood comes into contact with the adsorbent can be reduced. The hemoperfusion adsorbent of the invention has firm envelope, the fixed heparin is not easy to fall off, and the hemoperfusion adsorbent is suitable for various hemoperfusion products used clinically at present, and improves the safety of clinical application.
Description
Technical Field
The invention relates to the technical field of blood purification, in particular to a blood perfusion adsorbent which is coated and covalently fixes heparin and a preparation method thereof.
Background
The hemoperfusion adsorbent is a porous medical consumable with high specific surface area, and is mainly used for adsorption of small and medium molecular toxins, adsorption of bilirubin in liver diseases and adsorption of pathogenic factors in the immune field. The main application modes at present are a separate blood perfusion mode, a blood dialysis and blood perfusion combined mode and a plasma separation and adsorption mode.
The blood perfusion adsorbent is generally spherical resin or spherical activated carbon, and blood cells (such as blood platelets) in blood can adhere and aggregate on the surface of the adsorbent in the clinical use process to cause blood coagulation. In addition, if the adsorbent is broken, the particles can fall off, and adverse reactions such as particle embolism, allergy and the like are caused. Therefore, it is usually necessary to coat the surface of the adsorbent with a film of material to improve the blood compatibility of the adsorbent. Although the coating can improve the blood compatibility of the adsorbent, the improvement of the anticoagulant capacity of the adsorbent is very limited, and the adsorbent still easily generates blood coagulation when being in contact with blood. Therefore, in blood perfusion, it is usually necessary to inject a certain amount of heparin into the vein of a patient to perform systemic anticoagulation so as to ensure smooth perfusion treatment. If the amount of heparin is too large, uncontrolled bleeding may occur in the body and even multiple organ dysfunction may result. At present, the blood perfusion adsorbent used in the market is coated by collodion, heparin cannot be immobilized on the adsorbent, and the blood coagulation phenomenon often occurs during clinical perfusion. Therefore, the development of the adsorbent with the anticoagulant capability on the surface has important significance for reducing the dosage of heparin and improving the treatment safety in the blood perfusion treatment process.
The marine organism mussel can be firmly adhered to the surfaces of the reefs and the ship body in seawater by secreting protein with strong adhesiveness. Inspired by this adhesion protein, scientists found that polyphenolic compounds have properties similar to mussel adhesion proteins. For example, polydopamine and tannic acid can form a film on the surface of a material under weak alkaline conditions. In the Chinese patent with publication No. CN105064040A, the surface of a porous hydrophobic material is adhered with polyphenol compounds (dopamine and tannic acid) to carry out hydrophilic modification. However, the adhesion of such polyphenolic compounds on the surface of materials has two disadvantages: (1) the adhesion is not strong. Research shows that the compound containing both polyphenol and polyamine groups has stronger adhesion on the surface of materials, such as: one dopamine molecule contains two phenolic groups and one amino group, the tannin molecule only contains a plurality of phenolic groups and no amino group, and the adhesion of dopamine on the surface of the material is stronger than that of tannin. (2) The material to which the surface active groups are attached is insufficient to covalently immobilize sufficient heparin. In the Chinese patent with publication No. CN102614783A, the modification of the surface of the nanometer material by the adhesion of dopamine is carried out. In the Chinese invention patent with the publication number of CN103316600A, dopamine is adopted to adhere to the surface of a polylactic acid blood permeable membrane and then fix heparin, in the scheme, the coating and the heparin immobilization are carried out in two steps, the heparin needs to be activated before the heparin immobilization, the heparin immobilization rate is low, and the process is complex. More importantly, in this scheme, the process of heparin sodium activation is not clear, and as will be understood by those skilled in the art, heparin sodium, after being activated under only acidic conditions, cannot be covalently immobilized on the surface of polydopamine-coated polylactic acid membrane, and must undergo other modifications and catalytic actions.
Disclosure of Invention
In view of the above, in order to overcome at least one of the deficiencies of the prior art, the invention adopts a method of co-depositing a coating on the surface of the hemoperfusion adsorbent by using a polyphenol compound and a polyamine compound to further covalently fix heparin, thereby solving the problems of poor blood compatibility and particle shedding of the adsorbent and simultaneously improving the anticoagulant performance of the adsorbent.
In order to solve the technical problems, the invention adopts the following technical scheme:
a blood perfusion adsorbent for coating and covalently fixing heparin is prepared by immersing adsorbent in the aqueous solution of polyphenol compounds and polyamine compounds, co-depositing and coating, and covalently fixing heparin.
According to the invention, the polyphenol compound and the polyamine compound are subjected to codeposition coating on the surface of the adsorbent by soaking, so that the surface which is firm in coating and provided with polyamino is obtained, and the covalent fixation of heparin molecules in the next step is facilitated; and then the carboxyl on the heparin molecule reacts with the amino on the surface of the membrane to covalently fix the heparin, so that the coated heparin-immobilized hemoperfusion adsorbent is prepared, the blood compatibility of the adsorbent can be improved, the falling of particles of the adsorbent is reduced, the coagulation phenomenon when the blood contacts with the adsorbent can be reduced, and the anticoagulation performance of the adsorbent is improved.
The membrane on the surface of the blood perfusion adsorbent for enveloping and covalently fixing heparin has the following chemical structure:
wherein the content of the first and second substances,
polyphenol adhered to the surface of the adsorbent; n is 1-5, and the corresponding polyamine compounds are ethylenediamine, diethylenetriamine, triethylenetetramine, tetraethylenepentamine and pentaethylenehexamine; heparin is Heparin.
The adsorbent is spherical resin or spherical active carbon.
The invention also provides a preparation method of the blood perfusion adsorbent coated and covalently fixed with heparin, which comprises the following steps: soaking the adsorbent in an aqueous solution of a polyphenol compound and a polyamine compound, and adjusting the pH value to be alkalescent to prepare an coated adsorbent containing amino; and then reacted with heparin under acidic conditions in the presence of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDC) and N-hydroxysuccinimide (NHS) to covalently immobilize the heparin on the surface of the adsorbent.
The method coats the surfaces and the inner parts of pores of the hemoperfusion adsorbent by codeposition of polyphenol and polyamine compounds, generates a polyamino hydrophilic interface at the same time, and finally reacts with carboxyl of heparin molecules under the conditions of weak acidity and EDC and NHS existence to covalently fix heparin on the hemoperfusion adsorbent, thereby improving the anticoagulation performance of the hemoperfusion adsorbent. According to the invention, the hydrophobic surface of the blood perfusion adsorbent is improved, the hydrophilicity of the adsorbent is improved by introducing amino, and a polyphenol/polyamine film is formed on the surface of the adsorbent, so that the blood compatibility of the adsorbent is improved, and the falling of particles of the adsorbent is reduced; in particular, by covalently immobilizing heparin having excellent anticoagulation properties on the surface of a hemoperfusion adsorbent, the coagulation phenomenon occurring when blood comes into contact with the adsorbent can be reduced. The preparation method is simple and effective, the blood perfusion absorbent prepared by the preparation method has firm coating, the fixed heparin is not easy to fall off, and the preparation method is suitable for various blood perfusion products clinically used at present and improves the safety of clinical application.
The preparation method of the blood perfusion adsorbent for enveloping and covalently fixing heparin comprises the following steps:
s1, soaking an adsorbent in an aqueous solution containing a polyphenol compound and a polyamine compound, adding a proper amount of alkalescent substances, adjusting the pH to 8.0-10, and stirring at room temperature for 2-24 hours to obtain an amino-containing coated adsorbent;
s2, fully washing with normal saline, draining, adding into an acidic buffer solution containing heparin salt, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDC) and N-hydroxysuccinimide (NHS), and stirring at room temperature for 2-24 hours to enable heparin to be covalently immobilized on the adsorbent;
and S3, washing with normal saline and purified water in sequence to obtain the blood perfusion adsorbent with the envelope and covalently fixing the heparin.
In step S1, the polyphenolic compound comprises dopamine or tannic acid; the polyamine compound includes any one of ethylenediamine, diethylenetriamine, triethylenetetramine, tetraethylenepentamine, and pentaethylenehexamine. The polyamine compound and the polyphenol compound in the invention are small molecules, are beneficial to entering the inside of the pores of the adsorbent, and are suitable for the hemoperfusion adsorbent with smaller pore diameter (generally less than 10nm), thereby further improving the biocompatibility and the anticoagulant property of the hemoperfusion adsorbent.
In step S1, the concentration of the polyphenol compound is 0.5-5g/L, and the concentration of the polyamine compound is 0.5-5 g/L.
In step S1, the weakly basic substance includes one or more of ammonia, phosphate, carbonate and Tris (hydroxymethyl) aminomethane (Tris).
In step S2, the heparin salt is heparin sodium, heparin calcium or heparin lithium, the concentration of the heparin salt is 0.1-1g/L, the concentration of EDC is 0.05-0.1mol/L, and the concentration of NHS is 0.05-0.1 mol/L.
In step S2, the acidic buffer solution is a PBS buffer solution (phosphate buffered saline), a MES buffer solution, or a citric acid buffer solution.
In step S2, the pH of the acidic buffer solution is 4-6.
Compared with the prior art, the invention has the following beneficial effects: the implementation of the preparation method has the advantage of improving the clinical treatment effect and safety in blood perfusion. Anticoagulant experiments show that after the hemoperfusion adsorbent is treated by the preparation method disclosed by the invention, the blood coagulation time is prolonged from 20 minutes to 50-140 minutes, so that the blood coagulation phenomenon during clinical perfusion is avoided, and the preparation method is beneficial to clinical application of hemoperfusion products.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention will be further described below. The technical solutions in the embodiments of the present invention are part of the embodiments of the present invention, and not all of the embodiments of the present invention. The following examples are illustrative and are intended to be illustrative of the invention and are not to be construed as limiting the invention. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
Example 1
Adding 0.075g of dopamine hydrochloride and 0.075g of ethylenediamine into 150mL of purified water to prepare 150mL of aqueous solution containing 0.5g/L of dopamine and 0.5g/L of ethylenediamine, putting 100mL of blood perfusion adsorbent (spherical resin used for adsorbing small and medium molecular toxins) into the aqueous solution, adding a proper amount of ammonia water to enable the pH value of the solution to be 10, slowly stirring for 24 hours, then fully washing with normal saline, and draining to prepare the coated adsorbent with amino groups;
dissolving 15mg of heparin sodium in 0.05M PBS buffer solution (pH 6) to prepare 150ml of heparin solution with the concentration of 0.1g/L, adding 1.438g of EDC and 0.863g of NHS, stirring to dissolve the heparin solution so that the concentration of EDC and NHS is 0.05mol/L, adding 100ml of adsorbent with amino, and slowly stirring for 24 hours to obtain the adsorbent with the envelope and covalently fixing heparin. And finally, filtering and collecting the adsorbent, washing with purified water, and drying to obtain the finished adsorbent.
Example 2
Adding 0.3g of dopamine hydrochloride and 0.3g of diethylenetriamine into 150mL of purified water to prepare 150mL of aqueous solution containing 2g/L of dopamine and 2g/L of diethylenetriamine, putting 100mL of blood perfusion adsorbent (spherical resin for adsorbing medium and small molecular toxins) into the solution, adding a proper amount of Tris (hydroxymethyl) aminomethane (Tris) to adjust the pH value of the solution to 8.5, slowly stirring for 24h, fully washing with normal saline, and pumping to dry to prepare the coated adsorbent with amino;
75mg of heparin sodium was dissolved in 0.05M MES buffer (pH 5.5) to prepare 150ml of a heparin solution having a concentration of 0.5g/L, 2.157g of EDC and 1.295g of NHS were added thereto and dissolved by stirring so that the concentration of EDC and NHS became 0.075mol/L, 100ml of an amino group-containing adsorbent was added thereto, and the mixture was stirred slowly for 24 hours to obtain a coated and covalently immobilized heparin adsorbent. And finally, filtering and collecting the adsorbent, washing with purified water, and drying to obtain the finished adsorbent.
Example 3
Adding 0.75g of dopamine hydrochloride and 0.75g of triethylenetetramine into 150mL of purified water to prepare 150mL of aqueous solution containing 5g/L of dopamine and 5g/L of triethylenetetramine, putting 100mL of blood perfusion adsorbent (spherical resin for adsorbing medium and small molecular toxins) into the aqueous solution, adding a proper amount of sodium carbonate to enable the pH value of the aqueous solution to be 8.0, slowly stirring for 24h, then fully washing with normal saline, and draining to prepare the coated adsorbent with amino groups;
150mg of heparin sodium was dissolved in 0.05M citric acid buffer solution (pH 4) to prepare 150ml of heparin solution with a concentration of 1g/L, 2.876g of EDC and 1.726g of NHS were added and stirred to dissolve the heparin solution so that the concentration of EDC and NHS were 0.1mol/L, 100ml of an adsorbent having an amino group was added thereto, and the mixture was slowly stirred for 24 hours to obtain an adsorbent coated with a membrane and covalently immobilized with heparin. And finally, filtering and collecting the adsorbent, washing with purified water, and drying to obtain the finished adsorbent.
Example 4
Adding 0.075g of dopamine hydrochloride and 0.075g of tetraethylenepentamine into 150mL of purified water to prepare 150mL of an aqueous solution containing 0.5g/L of dopamine and 0.5g/L of tetraethylenepentamine, putting 100mL of a hemoperfusion adsorbent (spherical activated carbon for adsorbing small and medium molecular toxins) into the solution, adding a proper amount of sodium phosphate to enable the pH value of the solution to be 9.0, slowly stirring for 24 hours, fully washing with physiological saline, and draining to prepare the coated adsorbent with amino groups.
75mg of heparin sodium was dissolved in 0.05M MES buffer (pH 5.5) to prepare 150ml of a heparin solution having a concentration of 0.5g/L, 2.157g of EDC and 1.295g of NHS were added thereto and dissolved by stirring so that the concentration of EDC and NHS became 0.075mol/L, 100ml of an amino group-containing adsorbent was added thereto, and the mixture was stirred slowly for 24 hours to obtain a coated and covalently immobilized heparin adsorbent. And finally, filtering and collecting the adsorbent, washing with purified water, and drying to obtain the finished adsorbent.
Example 5
Adding 0.075g of dopamine hydrochloride and 0.075g of pentaethylenehexamine into 150mL of purified water to prepare 150mL of an aqueous solution containing 0.5g/L of dobby amine and 0.5g/L of pentaethylenehexamine, putting 100mL of a hemoperfusion adsorbent (spherical activated carbon for adsorbing small and medium molecular toxins) into the solution, adding a proper amount of Tris (hydroxymethyl) aminomethane (Tris) to adjust the pH value of the solution to 8.5, slowly stirring for 24h, then fully washing with normal saline, and draining to prepare the coated amino-bearing adsorbent.
75mg of heparin sodium was dissolved in 0.05M MES buffer (pH 5.5) to prepare 150ml of a heparin solution having a concentration of 0.5g/L, 2.157g of EDC and 1.295g of NHS were added thereto and dissolved by stirring so that the concentration of EDC and NHS became 0.075mol/L, 100ml of an amino group-containing adsorbent was added thereto, and the mixture was stirred slowly for 24 hours to obtain a coated and covalently immobilized heparin adsorbent. And finally, filtering and collecting the adsorbent, washing with purified water, and drying to obtain the finished adsorbent.
Example 6
Adding 0.075g tannic acid and 0.075g ethylenediamine into 150mL of purified water to prepare 150mL of an aqueous solution containing 0.5g/L tannic acid and 0.5g/L ethylenediamine, adding 100mL of a blood perfusion adsorbent (spherical resin for bilirubin adsorption) into the solution, adding a proper amount of ammonia water to adjust the pH value of the solution to 10, slowly stirring for 24h, then fully washing with physiological saline, and draining to prepare the coated amino-group-containing adsorbent.
Dissolving 15mg of heparin sodium in 0.05M PBS buffer solution (pH 6) to prepare 150ml of heparin solution with the concentration of 0.1g/L, adding 1.438g of EDC and 0.863g of NHS, stirring to dissolve the heparin solution so that the concentration of EDC and NHS is 0.05mol/L, adding 100ml of adsorbent with amino, and slowly stirring for 24 hours to obtain the adsorbent with the envelope and covalently fixing heparin. And finally, filtering and collecting the adsorbent, washing with purified water, and drying to obtain the finished adsorbent.
Example 7
0.3g tannic acid and 0.3g diethylenetriamine were added to 150mL purified water to prepare 150mL aqueous solution containing 2g/L tannic acid and 2g/L diethylenetriamine, 100mL blood perfusion adsorbent (spherical resin for bilirubin adsorption) was put into the solution, and appropriate amount of Tris (hydroxymethyl) aminomethane (Tris) was added to adjust the pH of the solution to 8.5, and the solution was stirred slowly for 24 hours, then washed thoroughly with physiological saline, and dried by suction to prepare an adsorbent coated with an amino group.
75mg of heparin sodium was dissolved in 0.05M MES buffer (pH 5.5) to prepare 150ml of a heparin solution having a concentration of 0.5g/L, 2.157g of EDC and 1.295g of NHS were added thereto and dissolved by stirring so that the concentration of EDC and NHS became 0.075mol/L, 100ml of an amino group-containing adsorbent was added thereto, and the mixture was stirred slowly for 24 hours to obtain a coated and covalently immobilized heparin adsorbent. And finally, filtering and collecting the adsorbent, washing with purified water, and drying to obtain the finished adsorbent.
Example 8
Adding 0.75g of tannic acid and 0.75g of triethylenetetramine into 150mL of purified water to prepare 150mL of an aqueous solution containing 5g/L of tannic acid and 5g/L of triethylenetetramine, adding 100mL of a hemoperfusion adsorbent (spherical resin for bilirubin adsorption) into the aqueous solution, adding a proper amount of sodium carbonate to adjust the pH value of the aqueous solution to 8.0, slowly stirring for 24h, sufficiently washing with physiological saline, and draining to prepare the coated amino-bearing adsorbent.
150mg of heparin sodium was dissolved in 0.05M citric acid buffer solution (pH 4) to prepare 150ml of heparin solution with a concentration of 1g/L, 2.876g of EDC and 1.726g of NHS were added and stirred to dissolve the heparin solution so that the concentration of EDC and NHS were 0.1mol/L, 100ml of an adsorbent having an amino group was added thereto, and the mixture was slowly stirred for 24 hours to obtain an adsorbent coated with a membrane and covalently immobilized with heparin. And finally, filtering and collecting the adsorbent, washing with purified water, and drying to obtain the finished adsorbent.
Example 9
Adding 0.075g of tannic acid and 0.075g of tetraethylenepentamine into 150mL of purified water to prepare 150mL of an aqueous solution containing 0.5g/L of tannic acid and 0.5g/L of tetraethylenepentamine, putting 100mL of a hemoperfusion adsorbent (spherical activated carbon for adsorbing small and medium molecular toxins) into the solution, adding a proper amount of sodium phosphate to enable the pH value of the solution to be 9.0, slowly stirring for 24h, fully washing with physiological saline, and draining to prepare the coated amino-group-containing adsorbent.
75mg of heparin sodium was dissolved in 0.05M MES buffer (pH 5.5) to prepare 150ml of a heparin solution having a concentration of 0.5g/L, 2.157g of EDC and 1.295g of NHS were added thereto and dissolved by stirring so that the concentration of EDC and NHS became 0.075mol/L, 100ml of an amino group-containing adsorbent was added thereto, and the mixture was stirred slowly for 24 hours to obtain a coated and covalently immobilized heparin adsorbent. And finally, filtering and collecting the adsorbent, washing with purified water, and drying to obtain the finished adsorbent.
Example 10
Adding 0.075g of tannic acid and 0.075g of pentaethylenehexamine into 150mL of purified water to prepare 150mL of an aqueous solution containing 0.5g/L of tannic acid and 0.5g/L of pentaethylenehexamine, putting 100mL of a hemoperfusion adsorbent (spherical activated carbon for adsorbing small and medium molecular toxins) into the solution, adding a proper amount of Tris (hydroxymethyl) aminomethane (Tris) to adjust the pH value of the solution to 8.5, slowly stirring for 24h, then fully washing with physiological saline, and pumping to dry to prepare the coated amino-group-bearing adsorbent.
75mg of heparin sodium was dissolved in 0.05M MES buffer (pH 5.5) to prepare 150ml of a heparin solution having a concentration of 0.5g/L, 2.157g of EDC and 1.295g of NHS were added thereto and dissolved by stirring so that the concentration of EDC and NHS became 0.075mol/L, 100ml of an amino group-containing adsorbent was added thereto, and the mixture was stirred slowly for 24 hours to obtain a coated and covalently immobilized heparin adsorbent. And finally, filtering and collecting the adsorbent, washing with purified water, and drying to obtain the finished adsorbent.
Comparative example 1
Spherical resin without any treatment (used for small and medium molecular toxin adsorption).
Comparative example 2
Spherical activated carbon without any treatment (for small and medium molecular toxin adsorption).
Comparative example 3
Spherical resin without any treatment (for bilirubin adsorption).
The test method comprises the following steps:
blood coagulation test: adding 1ml of sample to be tested into a glass test tube, rinsing with normal saline for 3 times, and then adding 2ml of fresh rabbit blood along the tube wall. After 5min, the tube was tilted every 1min until the blood in the tube did not flow, and the time at this time was recorded as the clotting time.
The results of the finished coagulation performance tests for each example and comparative example are shown in the following table:
| sample (I) | Blood coagulation time (min) | Sample (I) | Blood coagulation time (min) | Sample (I) | Blood coagulation time (min) |
| Comparative example 1 | 26 | Comparative example 2 | 20 | Comparative example 3 | 35 |
| Example 1 | 55 | Example 6 | 48 | Example 4 | 125 |
| Example 2 | 108 | Example 7 | 104 | Example 5 | 127 |
| Example 3 | 136 | Example 8 | 129 | Example 9 | 114 |
| — | — | — | — | Example 10 | 118 |
The data in the above table show that: after heparin is coated and covalently fixed, the coagulation time of the three hemoperfusion adsorbents is obviously prolonged, and the coagulation performance is obviously improved, so that the safety of clinical perfusion is improved.
In the above examples, heparin sodium is used as an example, and in addition to heparin sodium, an acidic buffer solution containing another heparin salt (e.g., heparin lithium or heparin calcium), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDC), and N-hydroxysuccinimide (NHS) may be added to the coated adsorbent containing an amino group to covalently immobilize heparin on the adsorbent, and the specific procedure is basically the same as that of the heparin sodium example.
It should be understood that the above-described embodiments of the present invention are merely examples for clearly illustrating the present invention, and are not intended to limit the embodiments of the present invention. Other variations and modifications will be apparent to persons skilled in the art in light of the above description. And are neither required nor exhaustive of all embodiments. Any modification, equivalent replacement, and improvement made within the spirit and principle of the present invention should be included in the protection scope of the claims of the present invention.
Claims (10)
1. A blood perfusion adsorbent for coating and covalently fixing heparin is prepared by immersing adsorbent in the aqueous solution of polyphenol compounds and polyamine compounds, co-depositing, coating and covalently fixing heparin.
2. The coated and covalently immobilized heparin hemoperfusion sorbent according to claim 1, wherein the membrane on the surface of the hemoperfusion sorbent has the following chemical structure:
wherein the content of the first and second substances,
polyphenol adhered to the surface of the adsorbent; n is 1 to 5, and the corresponding polyamine compound is ethylenediamine, diethylenetriamine, triethylenetetramine, tetraethylenepentamine, pentaethylenehexamine; heparin is Heparin.
3. The coated and covalently immobilized heparin hemoperfusion adsorbent of claim 1 or 2 wherein the adsorbent is spherical resin or spherical activated carbon.
4. A process for preparing the coated and covalently immobilized heparin hemoperfusion adsorbent as claimed in claim 1 or 2, which comprises immersing the adsorbent in an aqueous solution of polyphenols and polyamines, adjusting pH to weak alkaline to obtain coated and amino adsorbent; then reacting with heparin under the acidic condition and in the presence of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride and N-hydroxysuccinimide to prepare the blood perfusion adsorbent with the envelope and covalently fixing the heparin.
5. The method for preparing the coated and covalently immobilized heparin hemoperfusion adsorbent according to claim 4, comprising the steps of:
s1, soaking an adsorbent in an aqueous solution containing a polyphenol compound and a polyamine compound, adding a proper amount of alkalescent substances, adjusting the pH to 8.0-10, and stirring at room temperature for 2-24 hours to obtain an amino-containing coated adsorbent;
s2, fully washing with normal saline, draining, adding into an acidic buffer solution containing heparin salt, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride and N-hydroxysuccinimide, and stirring at room temperature for 2-24 hours to enable heparin to be covalently fixed on an adsorbent;
and S3, washing with normal saline and purified water in sequence to obtain the blood perfusion adsorbent with the envelope and covalently fixing the heparin.
6. The method of claim 5, wherein in step S1, the polyphenolic compound comprises dopamine or tannin; the polyamine compound includes any one of ethylenediamine, diethylenetriamine, triethylenetetramine, tetraethylenepentamine, and pentaethylenehexamine.
7. The method for preparing coated and covalently immobilized heparin as claimed in claim 5, wherein in step S1, the concentration of the polyphenol compound is 0.5-5g/L and the concentration of the polyamine compound is 0.5-5 g/L.
8. The method of claim 5, wherein in step S1, the weakly basic substance comprises one or more of ammonia, phosphate, carbonate and tris.
9. The method for preparing coated and covalently immobilized heparin hemoperfusion adsorbent according to claim 5, wherein in step S2, the concentration of heparin salt is 0.1-1g/L, the concentration of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride is 0.05-0.1mol/L, and the concentration of N-hydroxysuccinimide is 0.05-0.1 mol/L.
10. The method for preparing coated and covalently immobilized heparin hemoperfusion adsorbent according to claim 5, wherein in step S2, the acidic buffer solution is PBS buffer solution, MES buffer solution or citric acid buffer solution, and the pH value of the acidic buffer solution is 4-6.
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| CN114702700A (en) * | 2022-05-09 | 2022-07-05 | 江苏恰瑞生物科技有限公司 | Preparation method of anticoagulant filler for blood perfusion apparatus |
| CN114042441B (en) * | 2021-12-09 | 2024-05-03 | 云南师范大学 | Method for modifying and immobilizing heparin on surface of hemoperfusion resin microsphere and adsorbent prepared by method |
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