CN116510703A - Adsorbent for improving anticoagulation effect and preparation method and application thereof - Google Patents
Adsorbent for improving anticoagulation effect and preparation method and application thereof Download PDFInfo
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- CN116510703A CN116510703A CN202310364735.1A CN202310364735A CN116510703A CN 116510703 A CN116510703 A CN 116510703A CN 202310364735 A CN202310364735 A CN 202310364735A CN 116510703 A CN116510703 A CN 116510703A
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- adsorbent
- carrier
- improving
- porous polymer
- styrene
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- 239000003463 adsorbent Substances 0.000 title claims abstract description 51
- 230000010100 anticoagulation Effects 0.000 title claims abstract description 27
- 230000000694 effects Effects 0.000 title claims abstract description 27
- 238000002360 preparation method Methods 0.000 title description 9
- 229920000642 polymer Polymers 0.000 claims abstract description 36
- 239000000463 material Substances 0.000 claims abstract description 34
- 239000011664 nicotinic acid Substances 0.000 claims abstract description 15
- 230000002429 anti-coagulating effect Effects 0.000 claims abstract description 13
- CHRJZRDFSQHIFI-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;styrene Chemical group C=CC1=CC=CC=C1.C=CC1=CC=CC=C1C=C CHRJZRDFSQHIFI-UHFFFAOYSA-N 0.000 claims abstract description 11
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims abstract description 6
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims abstract description 5
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 3
- 150000001875 compounds Chemical class 0.000 claims description 24
- 102000004169 proteins and genes Human genes 0.000 claims description 22
- 108090000623 proteins and genes Proteins 0.000 claims description 22
- 230000003592 biomimetic effect Effects 0.000 claims description 17
- 239000003053 toxin Substances 0.000 claims description 14
- 231100000765 toxin Toxicity 0.000 claims description 14
- 108700012359 toxins Proteins 0.000 claims description 14
- SLXKOJJOQWFEFD-UHFFFAOYSA-N 6-aminohexanoic acid Chemical compound NCCCCCC(O)=O SLXKOJJOQWFEFD-UHFFFAOYSA-N 0.000 claims description 9
- 229960002684 aminocaproic acid Drugs 0.000 claims description 9
- 229960001123 epoprostenol Drugs 0.000 claims description 9
- KAQKFAOMNZTLHT-VVUHWYTRSA-N epoprostenol Chemical compound O1C(=CCCCC(O)=O)C[C@@H]2[C@@H](/C=C/[C@@H](O)CCCCC)[C@H](O)C[C@@H]21 KAQKFAOMNZTLHT-VVUHWYTRSA-N 0.000 claims description 9
- 239000003146 anticoagulant agent Substances 0.000 claims description 8
- 235000014113 dietary fatty acids Nutrition 0.000 claims description 8
- 239000000194 fatty acid Substances 0.000 claims description 8
- 229930195729 fatty acid Natural products 0.000 claims description 8
- 229940127219 anticoagulant drug Drugs 0.000 claims description 7
- BTCSSZJGUNDROE-UHFFFAOYSA-N gamma-aminobutyric acid Chemical compound NCCCC(O)=O BTCSSZJGUNDROE-UHFFFAOYSA-N 0.000 claims description 6
- 239000011148 porous material Substances 0.000 claims description 6
- 230000008081 blood perfusion Effects 0.000 claims description 4
- OGNSCSPNOLGXSM-UHFFFAOYSA-N (+/-)-DABA Natural products NCCC(N)C(O)=O OGNSCSPNOLGXSM-UHFFFAOYSA-N 0.000 claims description 3
- 229960003692 gamma aminobutyric acid Drugs 0.000 claims description 3
- 239000002245 particle Substances 0.000 claims description 3
- 125000005313 fatty acid group Chemical group 0.000 claims description 2
- 150000004665 fatty acids Chemical class 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 239000002977 biomimetic material Substances 0.000 claims 2
- 230000002708 enhancing effect Effects 0.000 claims 2
- 239000002594 sorbent Substances 0.000 claims 1
- 210000004369 blood Anatomy 0.000 abstract description 23
- 239000008280 blood Substances 0.000 abstract description 23
- 238000000746 purification Methods 0.000 abstract description 13
- 238000000576 coating method Methods 0.000 abstract description 4
- 239000011248 coating agent Substances 0.000 abstract description 3
- 230000002349 favourable effect Effects 0.000 abstract description 3
- 208000010110 spontaneous platelet aggregation Diseases 0.000 abstract description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 53
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 40
- 239000000243 solution Substances 0.000 description 33
- 238000005406 washing Methods 0.000 description 30
- 238000010438 heat treatment Methods 0.000 description 24
- 235000018102 proteins Nutrition 0.000 description 21
- 238000001035 drying Methods 0.000 description 20
- 239000000203 mixture Substances 0.000 description 19
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 16
- 238000009835 boiling Methods 0.000 description 16
- 239000000047 product Substances 0.000 description 16
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 14
- BXFFHSIDQOFMLE-UHFFFAOYSA-N indoxyl sulfate Chemical compound C1=CC=C2C(OS(=O)(=O)O)=CNC2=C1 BXFFHSIDQOFMLE-UHFFFAOYSA-N 0.000 description 14
- 238000003756 stirring Methods 0.000 description 14
- MYRTYDVEIRVNKP-UHFFFAOYSA-N 1,2-Divinylbenzene Chemical compound C=CC1=CC=CC=C1C=C MYRTYDVEIRVNKP-UHFFFAOYSA-N 0.000 description 12
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 12
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 12
- 108010017384 Blood Proteins Proteins 0.000 description 12
- 102000004506 Blood Proteins Human genes 0.000 description 12
- 108010010803 Gelatin Proteins 0.000 description 12
- PPBRXRYQALVLMV-UHFFFAOYSA-N Styrene Chemical compound C=CC1=CC=CC=C1 PPBRXRYQALVLMV-UHFFFAOYSA-N 0.000 description 12
- 239000012043 crude product Substances 0.000 description 12
- 229920000159 gelatin Polymers 0.000 description 12
- 239000008273 gelatin Substances 0.000 description 12
- 235000019322 gelatine Nutrition 0.000 description 12
- 235000011852 gelatine desserts Nutrition 0.000 description 12
- 238000010907 mechanical stirring Methods 0.000 description 12
- 238000009423 ventilation Methods 0.000 description 12
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 12
- 238000001914 filtration Methods 0.000 description 10
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 7
- 239000004342 Benzoyl peroxide Substances 0.000 description 6
- OMPJBNCRMGITSC-UHFFFAOYSA-N Benzoylperoxide Chemical compound C=1C=CC=CC=1C(=O)OOC(=O)C1=CC=CC=C1 OMPJBNCRMGITSC-UHFFFAOYSA-N 0.000 description 6
- 239000005947 Dimethoate Substances 0.000 description 6
- 208000032843 Hemorrhage Diseases 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- 208000007536 Thrombosis Diseases 0.000 description 6
- 235000019400 benzoyl peroxide Nutrition 0.000 description 6
- 230000000052 comparative effect Effects 0.000 description 6
- 238000001816 cooling Methods 0.000 description 6
- MCWXGJITAZMZEV-UHFFFAOYSA-N dimethoate Chemical compound CNC(=O)CSP(=S)(OC)OC MCWXGJITAZMZEV-UHFFFAOYSA-N 0.000 description 6
- NKDDWNXOKDWJAK-UHFFFAOYSA-N dimethoxymethane Chemical compound COCOC NKDDWNXOKDWJAK-UHFFFAOYSA-N 0.000 description 6
- 229910052757 nitrogen Inorganic materials 0.000 description 6
- 239000012074 organic phase Substances 0.000 description 6
- 231100000614 poison Toxicity 0.000 description 6
- 239000002574 poison Substances 0.000 description 6
- 239000013557 residual solvent Substances 0.000 description 6
- 238000002390 rotary evaporation Methods 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- 239000012798 spherical particle Substances 0.000 description 6
- 239000011592 zinc chloride Substances 0.000 description 6
- 235000005074 zinc chloride Nutrition 0.000 description 6
- 102000009123 Fibrin Human genes 0.000 description 5
- 108010073385 Fibrin Proteins 0.000 description 5
- BWGVNKXGVNDBDI-UHFFFAOYSA-N Fibrin monomer Chemical compound CNC(=O)CNC(=O)CN BWGVNKXGVNDBDI-UHFFFAOYSA-N 0.000 description 5
- 229950003499 fibrin Drugs 0.000 description 5
- 229920000669 heparin Polymers 0.000 description 5
- 238000000034 method Methods 0.000 description 5
- 230000004048 modification Effects 0.000 description 5
- 238000012986 modification Methods 0.000 description 5
- DDBREPKUVSBGFI-UHFFFAOYSA-N phenobarbital Chemical compound C=1C=CC=CC=1C1(CC)C(=O)NC(=O)NC1=O DDBREPKUVSBGFI-UHFFFAOYSA-N 0.000 description 5
- 229960002695 phenobarbital Drugs 0.000 description 5
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 4
- 239000004471 Glycine Substances 0.000 description 4
- 230000002776 aggregation Effects 0.000 description 4
- 238000004220 aggregation Methods 0.000 description 4
- 230000009286 beneficial effect Effects 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 230000000740 bleeding effect Effects 0.000 description 4
- 239000007853 buffer solution Substances 0.000 description 4
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 4
- 230000015271 coagulation Effects 0.000 description 4
- 238000005345 coagulation Methods 0.000 description 4
- 239000005457 ice water Substances 0.000 description 4
- -1 modified amino-substituted fatty acids Chemical class 0.000 description 4
- 238000002791 soaking Methods 0.000 description 4
- 238000001179 sorption measurement Methods 0.000 description 4
- 108010049003 Fibrinogen Proteins 0.000 description 3
- 102000008946 Fibrinogen Human genes 0.000 description 3
- 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 description 3
- 239000004793 Polystyrene Substances 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 210000004204 blood vessel Anatomy 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 229940012952 fibrinogen Drugs 0.000 description 3
- 229960002897 heparin Drugs 0.000 description 3
- 229920002223 polystyrene Polymers 0.000 description 3
- 230000001954 sterilising effect Effects 0.000 description 3
- 238000004659 sterilization and disinfection Methods 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- 101000783577 Dendroaspis angusticeps Thrombostatin Proteins 0.000 description 2
- 101000783578 Dendroaspis jamesoni kaimosae Dendroaspin Proteins 0.000 description 2
- 108090000190 Thrombin Proteins 0.000 description 2
- 229940127218 antiplatelet drug Drugs 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- 210000003169 central nervous system Anatomy 0.000 description 2
- 230000020764 fibrinolysis Effects 0.000 description 2
- 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 2
- 229960001008 heparin sodium Drugs 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- 230000007935 neutral effect Effects 0.000 description 2
- 210000000056 organ Anatomy 0.000 description 2
- 239000000106 platelet aggregation inhibitor Substances 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 229920005989 resin Polymers 0.000 description 2
- 239000011347 resin Substances 0.000 description 2
- 230000002000 scavenging effect Effects 0.000 description 2
- 239000001509 sodium citrate Substances 0.000 description 2
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 2
- 239000012086 standard solution Substances 0.000 description 2
- 230000002195 synergetic effect Effects 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 229960004072 thrombin Drugs 0.000 description 2
- 239000002441 uremic toxin Substances 0.000 description 2
- 208000037157 Azotemia Diseases 0.000 description 1
- 108010039209 Blood Coagulation Factors Proteins 0.000 description 1
- 102000015081 Blood Coagulation Factors Human genes 0.000 description 1
- 206010053567 Coagulopathies Diseases 0.000 description 1
- 208000005189 Embolism Diseases 0.000 description 1
- 206010062713 Haemorrhagic diathesis Diseases 0.000 description 1
- 102000003839 Human Proteins Human genes 0.000 description 1
- 108090000144 Human Proteins Proteins 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 230000000702 anti-platelet effect Effects 0.000 description 1
- 239000004019 antithrombin Substances 0.000 description 1
- 239000012620 biological material Substances 0.000 description 1
- 239000012496 blank sample Substances 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- 230000023555 blood coagulation Effects 0.000 description 1
- 239000003114 blood coagulation factor Substances 0.000 description 1
- 239000012928 buffer substance Substances 0.000 description 1
- 231100000060 cardiovascular toxicity Toxicity 0.000 description 1
- 230000007681 cardiovascular toxicity Effects 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 208000020832 chronic kidney disease Diseases 0.000 description 1
- 230000035602 clotting Effects 0.000 description 1
- 230000024203 complement activation Effects 0.000 description 1
- 238000000151 deposition Methods 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 238000000502 dialysis Methods 0.000 description 1
- 208000028208 end stage renal disease Diseases 0.000 description 1
- 201000000523 end stage renal failure Diseases 0.000 description 1
- 210000003743 erythrocyte Anatomy 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 238000001631 haemodialysis Methods 0.000 description 1
- 230000000322 hemodialysis Effects 0.000 description 1
- 230000001951 hemoperfusion Effects 0.000 description 1
- 208000031169 hemorrhagic disease Diseases 0.000 description 1
- 230000002363 herbicidal effect Effects 0.000 description 1
- 239000004009 herbicide Substances 0.000 description 1
- 238000000099 in vitro assay Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 210000000265 leukocyte Anatomy 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 231100000417 nephrotoxicity Toxicity 0.000 description 1
- 210000005036 nerve Anatomy 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- BSCHIACBONPEOB-UHFFFAOYSA-N oxolane;hydrate Chemical compound O.C1CCOC1 BSCHIACBONPEOB-UHFFFAOYSA-N 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 231100000572 poisoning Toxicity 0.000 description 1
- 230000000607 poisoning effect Effects 0.000 description 1
- 235000004252 protein component Nutrition 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 229920003002 synthetic resin Polymers 0.000 description 1
- 239000000057 synthetic resin Substances 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 239000013076 target substance Substances 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 230000001732 thrombotic effect Effects 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 208000009852 uremia Diseases 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
- B01J20/22—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof comprising organic material
- B01J20/26—Synthetic macromolecular compounds
- B01J20/265—Synthetic macromolecular compounds modified or post-treated polymers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L33/00—Antithrombogenic treatment of surgical articles, e.g. sutures, catheters, prostheses, or of articles for the manipulation or conditioning of blood; Materials for such treatment
- A61L33/0005—Use of materials characterised by their function or physical properties
- A61L33/0011—Anticoagulant, e.g. heparin, platelet aggregation inhibitor, fibrinolytic agent, other than enzymes, attached to the substrate
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L33/00—Antithrombogenic treatment of surgical articles, e.g. sutures, catheters, prostheses, or of articles for the manipulation or conditioning of blood; Materials for such treatment
- A61L33/04—Use of organic materials, e.g. acetylsalicylic acid
-
- 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
- A61M1/3687—Chemical treatment
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01D—SEPARATION
- B01D15/00—Separating processes involving the treatment of liquids with solid sorbents; Apparatus therefor
- B01D15/08—Selective adsorption, e.g. chromatography
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Vascular Medicine (AREA)
- Heart & Thoracic Surgery (AREA)
- Engineering & Computer Science (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Hematology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Cardiology (AREA)
- Biomedical Technology (AREA)
- Anesthesiology (AREA)
- Analytical Chemistry (AREA)
- Materials Engineering (AREA)
- Surgery (AREA)
- Epidemiology (AREA)
- Organic Chemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Solid-Sorbent Or Filter-Aiding Compositions (AREA)
Abstract
The invention relates to an adsorbent for improving anticoagulant effect, which comprises a carrier and a bionic material modified on the carrier, wherein the carrier is a styrene-divinylbenzene crosslinked porous polymer, and the bionic material is a derivative of 3-hydroxy bicyclo [3, 0] heptane containing hydroxyl and/or carboxyl. The invention adopts a way different from the prior conventional anticoagulation, and groups favorable for reducing platelet aggregation are chemically modified on the surface of a polymer carrier without coating treatment on the surface of the carrier, so that the adsorbent with good anticoagulation effect for the blood purification field is obtained.
Description
Technical Field
The invention relates to the technical field of blood purification, in particular to an adsorbent for improving an anticoagulant effect, and a preparation method and application thereof.
Background
The blood perfusion is an effective blood purification therapy, can be used for acute drug or poison poisoning, end-stage kidney disease (uremia) and the like, and can be used for clinical treatment of the patient by the maintenance hemodialysis, especially for clinical manifestations caused by retention of protein-binding toxins.
Adsorbent materials for blood perfusion include activated carbon, synthetic resin materials, and the like. When the porous polystyrene polymer is used in the field of blood purification, physical coating is generally needed to improve the blood compatibility of the polymer, the blood compatibility of the material is improved, and when the porous polystyrene polymer is used as an adsorbent in the field of blood purification, heparinization is performed on the porous polystyrene polymer, and the surface of the adsorbent is heparinized by adding an anticoagulant.
The physical coating method improves the blood compatibility of the adsorbent, but has two disadvantages:
firstly, the coated layer can prevent target toxin to be removed from entering the inner pore canal of the adsorbent, and the speed of the adsorbent to adsorb target substances is just determined by the speed of the removed target toxin entering the pore canal, so that the removed target toxin cannot enter the pore canal or can enter the pore canal more fully, and the removal effect of the adsorbent on the target toxin is reduced within a certain treatment time.
Secondly, a new organic solvent is introduced in a physical coating mode, and the membrane layer is easy to fall off and enter blood to cause the particle index to exceed a limit or to cause embolism. The surface of the material is heparinized by adding an anticoagulant, and the anticoagulant added not only acts on the local area where the adsorbent of the hemoperfusion apparatus is positioned, but also enters into the whole body blood vessel and the organs along with the blood circulation, so that the risk of blood coagulation caused by biological materials is inhibited, and meanwhile, the risk of whole body hemorrhage is increased, and especially for people who have bleeding tendency and receive blood purification treatment.
To solve the above problems, the prior art also discloses that heparin is physically or chemically modified on a carrier to improve its blood compatibility, thereby improving the safety of blood purification materials, for example: the patent number CN201510482480.4 is a method for improving the anticoagulation performance of the adsorbent, and the anticoagulant heparin sodium is physically immobilized in a carrier in a network manner, so that the adsorbent with the anticoagulation effect is realized, but the combination of heparin and antithrombin AT-III reduces the overturning activity of anticoagulation, and the anticoagulation performance also reduces.
The invention provides a novel method for improving the blood compatibility and anticoagulation effect of an adsorbent based on the following coagulation and thrombosis mechanisms. The surface of the carrier is not required to be coated, so that the adsorbent with good anticoagulation effect for the blood purification field is obtained.
Disclosure of Invention
The invention aims to provide an adsorbent for improving the anticoagulation effect, solve the problem of systemic hemorrhage caused by adding an anticoagulant, and provide a preparation method and application of the adsorbent for improving the anticoagulation effect.
In order to achieve the above purpose, the present invention adopts the following technical scheme:
the adsorbent for improving the anticoagulation effect comprises a carrier and a bionic material modified on the carrier, wherein the carrier is a styrene-divinylbenzene crosslinked porous polymer, the bionic material is a derivative of 3-hydroxy bicyclo [3, 0] heptane containing hydroxyl and/or carboxyl, the particle size of the styrene-divinylbenzene crosslinked porous polymer is 0.6-1.4mm, and the pore diameter is 4-100nm.
The mass ratio of the bionic material to the carrier of the adsorbent for improving the anticoagulation effect is preferably (0.2-1): 1.
Preferably, the bionic material is prostacyclin.
Preferably, the amino substituent on the styrene-divinylbenzene crosslinked porous polymer is a fatty acid, and the fatty acid is 6-aminocaproic acid or gamma-aminobutyric acid.
The amount of the biomimetic compound modified per gram of the adsorbent surface is preferably (0.1-0.8) mg.
A preparation method of an adsorbent for improving anticoagulant effect comprises the following steps:
preparing a styrene-divinylbenzene crosslinked porous polymer;
the styrene-divinylbenzene crosslinked porous polymer-bonded biomimetic compounds.
An application of an adsorbent for improving anticoagulant effect is provided, which is applied to a blood perfusion device.
The application of an adsorbent for improving anticoagulant effect is applied to removing protein-bound toxins.
Due to the adoption of the technical scheme, the invention has the following advantages:
1. the bonded bionic compound has the function of reducing platelet aggregation, and the 6-aminocaproic acid modified on the porous polymer has the function of stopping bleeding and resisting fibrinolysis, and the synergistic effect of the bionic compound and the 6-aminocaproic acid can improve the anticoagulation effect and avoid the bleeding probability caused by excessive anticoagulation.
2. The method is different from the conventional anticoagulation mode, and groups favorable for reducing platelet aggregation are chemically modified on the surface of a polymer carrier, so that the surface of the carrier is not required to be coated, and an adsorbent with good anticoagulation effect and used in the field of blood purification is obtained.
3. Prostacyclin is an effective platelet aggregation inhibitor, can inhibit platelets from adhering to damaged blood vessel walls, has the characteristic of resisting formation of blood sieves, and forms a buffer layer between an adsorbent and plasma proteins by bonding the prostacyclin on the surface of a carrier, thereby being beneficial to reducing the adhesion of the surface of a porous polymer to the plasma proteins through electrostatic repulsion, indirectly reducing the adhesion of the platelets to the plasma proteins on the surface of the porous polymer, and achieving an anticoagulation effect. The rigid skeleton of the adsorbent bonded with the bionic compound is beneficial to batch purification treatment and high-pressure steam sterilization and industrial application.
4. The anticoagulant effect is improved, and simultaneously, the anticoagulant composition has good removal effects on endogenous protein-bound toxins and exogenous protein-bound toxins.
5. The rigid skeleton of the adsorbent is beneficial to batch purification treatment and high-pressure steam sterilization and industrial application.
Detailed Description
The following description of the present invention will be made in detail for the purpose of making the objects, technical solutions and advantages of the present invention more apparent. It will be apparent that the described embodiments are some, but not all, embodiments of the invention. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
1. Design of comparative experiment
1. Examples 1, 2, 3, 4, control 1 and 2 were designed, wherein examples 1-4 are adsorbents in which biomimetic compounds were grafted onto a carrier through a flexible modification, and control 1 and 2 are adsorbents in which biomimetic compounds were bonded without modification.
Example 1:
preparation of porous polymers of modified amino-substituted fatty acids:
a1000 mL three-necked flask was charged with a 0.4% aqueous gelatin solution, and the mixture was dissolved for use. Taking a 500mL three-neck flask, respectively adding 71.31g of styrene, 5.69g of divinylbenzene, 0.687g of benzoyl peroxide and 56.135g of solvent gasoline, introducing nitrogen for 20min, pouring an organic phase into a gelatin water solution, starting mechanical stirring to uniformly mix the materials, heating to 85 ℃ for reacting for 20h to obtain a crude product, removing residual solvent by rotary evaporation, extracting with acetone for 8h, washing with water, filtering, and carrying out ventilation drying to obtain white spherical particles. Taking 40g of white balls, putting the white balls into a 500mL three-neck flask, adding 200mL of dilute hydrochloric acid solution of 8g of anhydrous zinc chloride and methylal, starting mechanical stirring to mix the materials, heating to 60 ℃ for reacting for 18h to obtain a crude product, extracting with ethanol for 12h, boiling with boiling water, and washing with water to be neutral. And (3) taking 20g of the product after ventilation drying, adding 50mL of dichloroethane, stirring at normal temperature for 1h, slowly heating to 80 ℃ and preserving heat for 4h, continuously heating to 90 ℃ and preserving heat for 2h, cooling to below 40 ℃ and distilling to recover the dichloroethane until no smell exists, extracting with ethanol for 48h, and washing with water until no turbidity exists.
10g of the product is placed in an ice-water bath, 30mL of dichloroethane is added and stirred for 2h, then 20mL of 0.5% m-chloroperoxybenzoic acid is added in portions and stirred for 12h, ethanol is extracted for 8h, and the mixture is washed with water and then dried by ventilation. Adding 25mL of 6-aminocaproic acid solution with mass fraction of 5%, stirring at 50 ℃ for 16h, washing with water, extracting with ethanol for 8h, washing with water, and drying.
Porous polymer-bonded biomimetic compounds: and (3) adding 40mL of tetrahydrofuran solution of N, N-carbonyl diimidazole into 10g of the modified porous polymer obtained in the step (I), adding 20mL of glycine buffer solution of prostacyclin, stirring at room temperature for 24h, filtering to obtain a product, soaking in an aqueous solution of tetrahydrofuran for 48h, washing with water, boiling with water, and drying to obtain the modified porous polymer. The amount of surface-modified biomimetic compound was 0.8mg/g.
Example 2:
preparation of porous polymers of modified amino-substituted fatty acids:
a1000 mL three-necked flask was charged with a 0.5% aqueous gelatin solution, and the mixture was dissolved for use.
Taking a 500mL three-neck flask, respectively adding 60g of styrene, 5.184g of divinylbenzene, 0.587g of benzoyl peroxide and 47.454g of solvent gasoline, introducing nitrogen for 20min, pouring an organic phase into a gelatin water solution, starting mechanical stirring to uniformly mix the materials, heating to 90 ℃ for reaction for 18h to obtain a crude product, removing residual solvent by rotary evaporation, extracting with acetone for 8h, washing with water, filtering, and carrying out ventilation drying to obtain white spherical particles.
Adding 50g of white balls into a 500mL three-neck flask, adding 200mL of dilute hydrochloric acid solution of 10g of anhydrous zinc chloride and methylal, starting mechanical stirring to mix materials, heating to 60 ℃ to react for 18h to obtain a crude product, extracting with ethanol for 12h, boiling with boiling water, washing with water to neutrality, taking 20g of the product after ventilated drying, adding 50mL of dichloroethane, stirring for 1h at normal temperature, slowly heating to 85 ℃ to preserve heat for 4h, continuously heating to 90 ℃ to preserve heat for 2h, cooling to below 40 ℃ to distill and recover dichloroethane until no smell exists, extracting with ethanol for 48h, washing with water until no turbidity exists.
10g of the product is placed in an ice-water bath, 30mL of dichloroethane is added and stirred for 2h, 25mL of 0.5% m-chloroperoxybenzoic acid is added in portions and stirred for 12h, ethanol is extracted for 8h, and the mixture is washed with water and then dried by ventilation. Adding 25mL of 6-aminocaproic acid solution with the mass fraction of 4%, stirring at 50 ℃ for 16h, washing with water, extracting with ethanol for 8h, washing with water, and drying.
Porous polymer-bonded biomimetic compounds: and (3) adding 30mL of a tetrahydrofuran solution of N, N-carbonyl diimidazole into 10g of the modified porous polymer obtained in the step (I), then adding 15mL of a glycine buffer solution of prostacyclin, stirring at room temperature for 24h, filtering to obtain a product, soaking in an aqueous solution of tetrahydrofuran for 48h, washing with water, boiling with water, and drying to obtain the modified porous polymer. The amount of surface-modified biomimetic compound was 0.6mg/g.
Example 3:
preparation of porous polymers of modified amino-substituted fatty acids:
a1000 mL three-necked flask was charged with a 0.4% aqueous gelatin solution, and the mixture was dissolved for use.
Taking a 500mL three-neck flask, respectively adding 70.28g of styrene, 6.114g of divinylbenzene, 0.687g of benzoyl peroxide and 56.135g of solvent gasoline, introducing nitrogen for 20min, pouring an organic phase into a gelatin water solution, starting mechanical stirring to uniformly mix the materials, heating to 85 ℃ to react for 20h to obtain a crude product, removing residual solvent by rotary evaporation, extracting with acetone for 8h, washing with water, filtering, and carrying out ventilation drying to obtain white spherical particles.
Adding 40g of white balls into a 500mL three-neck flask, adding 200mL of dilute hydrochloric acid solution of 6g of anhydrous zinc chloride and methylal, starting mechanical stirring to mix materials, heating to 60 ℃ to react for 18h to obtain a crude product, extracting with ethanol for 12h, boiling with boiling water, washing with water to neutrality, taking 20g of the product after ventilated drying, adding 50mL of dichloroethane, stirring for 1h at normal temperature, slowly heating to 80 ℃ to preserve heat for 4h, continuously heating to 90 ℃ to preserve heat for 2h, cooling to below 40 ℃ to distill and recover dichloroethane until no smell exists, extracting with ethanol for 48h, washing with water until no turbidity exists.
10g of the product is placed in an ice-water bath, 30mL of dichloroethane is added and stirred for 2h, then 20mL of 0.5% m-chloroperoxybenzoic acid is added in portions and stirred for 12h, ethanol is extracted for 8h, and the mixture is washed with water and then dried by ventilation. Adding 20mL of 5% 6-aminocaproic acid solution into the dried product, stirring for 24h at 50 ℃, washing with water, extracting with ethanol for 8h, washing with water, and drying.
Porous polymer-bonded biomimetic compounds: and (3) adding 30mL of a tetrahydrofuran solution of N, N-carbonyl diimidazole into 10g of the modified porous polymer obtained in the step (I), then adding 15mL of a glycine buffer solution of prostacyclin, stirring at room temperature for 24h, filtering to obtain a product, soaking in an aqueous solution of tetrahydrofuran for 48h, washing with water, boiling with water, and drying to obtain the modified porous polymer. The amount of surface-modified biomimetic compound was 0.5mg/g.
Example 4:
preparation of porous polymers of modified amino-substituted fatty acids:
a1000 mL three-necked flask was charged with a 0.4% aqueous gelatin solution, and the mixture was dissolved for use.
Taking a 500mL three-neck flask, respectively adding 71.31g of styrene, 6.132g of divinylbenzene, 0.687g of benzoyl peroxide and 56.192g of solvent gasoline, introducing nitrogen for 20min, pouring an organic phase into a gelatin water solution, starting mechanical stirring to uniformly mix the materials, heating to 85 ℃ to react for 20h to obtain a crude product, removing residual solvent by rotary evaporation, extracting with acetone for 8h, washing with water, filtering, and carrying out ventilation drying to obtain white spherical particles.
Adding 40g of white balls into a 500mL three-neck flask, adding 200mL of dilute hydrochloric acid solution of 8g of anhydrous zinc chloride and methylal, starting mechanical stirring to mix materials, heating to 60 ℃ to react for 18h to obtain a crude product, extracting with ethanol for 12h, boiling with boiling water, washing with water to neutrality, taking 20g of the product after ventilated drying, adding 50mL of dichloroethane, stirring for 1h at normal temperature, slowly heating to 80 ℃ to preserve heat for 4h, continuously heating to 90 ℃ to preserve heat for 2h, cooling to below 40 ℃ to distill and recover dichloroethane until no smell exists, extracting with ethanol for 48h, washing with water until no turbidity exists.
10g of the product is placed in an ice-water bath, 30mL of dichloroethane is added and stirred for 2h, then 20mL of 0.5% m-chloroperoxybenzoic acid is added in portions and stirred for 12h, ethanol is extracted for 8h, and the mixture is washed with water and then dried by ventilation. Adding 20mL of gamma-aminobutyric acid solution with the mass fraction of 10%, stirring at 50 ℃ for 24h, washing with water, extracting with ethanol for 8h, washing with water, and drying.
Porous polymer-bonded biomimetic compounds: 10g of modified porous polymer obtained in the first step is added
N, N-carbonyl diimidazole in tetrahydrofuran 30mL, then adding 15mL glycine buffer solution of prostacyclin, stirring at room temperature for 24h, filtering to obtain a product, soaking in tetrahydrofuran water solution for 48h, washing with water, boiling with water, and drying. The amount of surface-modified biomimetic compound was 0.4mg/g.
Comparative example 1:
a1000 mL three-necked flask was charged with a 0.4% aqueous gelatin solution, and the mixture was dissolved for use.
Taking a 500mL three-neck flask, respectively adding 71.31g of styrene, 5.69g of divinylbenzene, 0.687g of benzoyl peroxide and 56.135g of solvent gasoline, introducing nitrogen for 20min, pouring an organic phase into a gelatin water solution, starting mechanical stirring to uniformly mix the materials, heating to 85 ℃ for reacting for 20h to obtain a crude product, removing residual solvent by rotary evaporation, extracting with acetone for 8h, washing with water, filtering, and carrying out ventilation drying to obtain white spherical particles.
Taking 40g of white balls, putting the white balls into a 500mL three-neck flask, adding 200mL of dilute hydrochloric acid solution of 8g of anhydrous zinc chloride and methylal, starting mechanical stirring to mix the materials, heating to 60 ℃ for reacting for 18h to obtain a crude product, extracting with ethanol for 12h, boiling with boiling water, and washing with water to be neutral. And (3) taking 20g of the product after ventilation drying, adding 50mL of dichloroethane, stirring at normal temperature for 1h, slowly heating to 80 ℃ and preserving heat for 4h, continuously heating to 90 ℃ and preserving heat for 2h, cooling to below 40 ℃ and distilling to recover the dichloroethane until no smell exists, extracting with ethanol for 48h, and washing with water until no turbidity exists.
Comparative example 2:
a1000 mL three-necked flask was charged with a 0.5% aqueous gelatin solution, and the mixture was dissolved for use.
Taking a 500mL three-neck flask, respectively adding 60g of styrene, 5.184g of divinylbenzene, 0.587g of benzoyl peroxide and 47.454g of solvent gasoline, introducing nitrogen for 20min, pouring an organic phase into a gelatin water solution, starting mechanical stirring to uniformly mix the materials, heating to 90 ℃ for reaction for 18h to obtain a crude product, removing residual solvent by rotary evaporation, extracting with acetone for 8h, washing with water, filtering, and carrying out ventilation drying to obtain white spherical particles.
Adding 50g of white balls into a 500mL three-neck flask, adding 200mL of dilute hydrochloric acid solution of 10g of anhydrous zinc chloride and methylal, starting mechanical stirring to mix materials, heating to 60 ℃ to react for 18h to obtain a crude product, extracting with ethanol for 12h, boiling with boiling water, washing with water to neutrality, taking 20g of the product after ventilated drying, adding 50mL of dichloroethane, stirring for 1h at normal temperature, slowly heating to 85 ℃ to preserve heat for 4h, continuously heating to 90 ℃ to preserve heat for 2h, cooling to below 40 ℃ to distill and recover dichloroethane until no smell exists, extracting with ethanol for 48h, washing with water until no turbidity exists.
2. Evaluation of anticoagulation Effect
1. Platelet adhesion aggregation assay
Upon coagulation of the surface of the material, the coagulation factors activate, resulting in platelet adhesion and aggregation with the surface of the material, and thus, the anticoagulant effect of the material can be assessed by assessing the platelet count.
The specific method comprises the following steps:
blood of healthy volunteers was collected in 5mL, anticoagulated with 3.8% sodium citrate, and centrifuged at 3000r/min for 10min. The adsorbent was added in a proportion of 0.1g/mL of anticoagulated plasma, a blank was prepared in the same manner, the test and blank samples were placed in a 37℃water bath for incubation for 30min, the number of platelets was measured with a fully automatic cell analyzer, and the platelet adhesion rate was calculated, with the results shown in Table 1.
TABLE 1 platelet adhesion Rate
| Examples | Platelet count (10) 9 /L) | Platelet adhesion Rate (%) |
| Example 1 | 195.2 | 4.1 |
| Example 2 | 192.7 | 5.3 |
| Example 3 | 192.1 | 5.6 |
| Example 4 | 191.5 | 5.9 |
| Comparative example 1 | 152.4 | 25.1 |
| Comparative example 2 | 155.7 | 23.5 |
Remarks: platelet count value of the blank group was 203.5X10 9 /L
It can be seen that the platelet adhesion rate of the adsorbent grafted with the biomimetic compound onto the carrier through the flexible modification is within 6%, which is far smaller than that of the adsorbent bonded with the biomimetic compound without modification.
2. In vitro thrombotic test
When the surface of the material is coagulated, the adhesion of the platelet adhesion and aggregation induces the adhesion of the surface of the material to fibrin, so that thrombus is formed, and the anticoagulation effect of the material can be evaluated by evaluating the adhesion of the material to plasma fibrin, so as to evaluate the difficulty of in-vitro thrombus formation.
The specific method comprises the following steps: 10mL of healthy human blood is taken, 0.4mL of 3.8% sodium citrate solution is added for partial anticoagulation, and then the mixture is injected into a siliconized glass tube containing a proper amount of adsorbent. A blank was prepared in the same way, and 6250U/mL heparin sodium solution was added to the blank tube. The blood was then centrifuged at 2000r/min for 10min at 6deg.C and the upper plasma was taken and assayed for residual fibrinogen content as shown in Table 2.
TABLE 2 fibrinogen content
It can be seen that, compared with the blank group added with heparin, the fibrinogen content of the carrier modified by the bionic compound has no obvious difference, and the thrombus is not easy to form on the surface of the material.
3. In vitro assay for removal of endogenous protein-bound toxins
1g of the adsorbent was weighed into a conical flask, 10mL of plasma with a protein-bound indoxyl sulfate concentration of 25mg/L was added, the mixture was placed at 37℃and oscillated in a constant temperature water bath oscillator at a rate of 60 times/min for 2 hours, the concentration of the protein-bound indoxyl sulfate before and after adsorption was detected by liquid chromatography from the supernatant, and the decrease rate was calculated, and the results were shown in Table 3.
TABLE 3 Industive protein binding toxin indoxyl sulfate scavenging Effect
| Examples | Protein-bound toxin indoxyl sulfate reduction rate (%) |
| Example 1 | 28.7 |
| Example 2 | 30.3 |
| Example 3 | 26.2 |
| Example 4 | 27.6 |
| Comparative example 1 | 9.8 |
At present, uremic toxin protein binding indoxyl sulfate cannot be removed by high-flux dialysis treatment. It can be seen that the clearance rate of the modified biomimetic compound adsorbent to uremic toxin protein binding indoxyl sulfate is more than 25% compared with the unmodified adsorbent, and is more than 2 times of the clearance effect of the unmodified adsorbent.
4. Exogenous protein binding poison clearance assay:
respectively preparing standard solutions of phenobarbital drugs with the concentration of 80 mug/mL, oscillating for 2 hours in a water area constant-temperature oscillator for 60 times/min at 37 ℃ according to the ratio of resin to solution=1:20 (W: V), detecting the concentration of the drugs before and after adsorption, and calculating the reduction rate of the phenobarbital.
The Dimethoate (purity 97%) was prepared into 80. Mu.g/mL standard solution, and the Dimethoate was subjected to shaking in a water area constant temperature shaker at 37℃for 60 times/min for 2 hours in a ratio of resin: solution=1:30 (W: V), and the concentration of Dimethoate before and after adsorption was detected, and the rate of decrease in Dimethoate was calculated.
The results of the comparison are shown in Table 4.
TABLE 4 exogenous poison scavenging effect
Phenobarbital is an exogenous poison with wide inhibition effect on the central nervous system, and the binding rate of the phenobarbital and protein reaches more than 80%. Dimethoate is a herbicide that is extremely harmful to central nerves and tissues and organs and is toxic by binding with human proteins. As shown in Table 4, the clearance rate of the exogenous protein binding poison phenobarbital for inhibiting toxicity to the central nervous system of the adsorbent prepared by the invention is more than 80%, the clearance rate of the adsorbent for dimethoate is more than 90%, and the adsorbent has good clearance effect on the exogenous protein binding poison.
Has good effect of removing protein-binding toxins, especially protein-binding indoxyl sulfate with renal toxicity and cardiovascular toxicity, and also has good effect of removing exogenous protein-binding toxins.
During the surface contact of the circulating blood and the artificial device, which is led out of the body during the blood purification process, plasma proteins first interact with the device/material surface, some protein components are first adsorbed to the surface, and then platelets in the circulating blood are attracted to proteins attached to the device surface, which adhere and undergo a series of changes, releasing a large amount of highly reactive products, the adsorbed plasma proteins and the attached platelets may activate the coagulation and complement pathways, leading to thrombin generation and fibrin formation. The production of platelet-released substances and local thrombin may upgrade the reaction, depositing a large number of platelets encapsulated in the fibrin network, leading to the development of clotting, and red and white blood cells trapped in the fibrin network, thus forming a thrombus at the blood-instrument interface.
According to the coagulation and thrombosis mechanism, a buffer substance is designed between a carrier and contacted plasma proteins, and a bionic compound with the same or similar characteristics (groups) as protein is bonded on the surface of a porous polymer, so that the substance is equivalent to a substance which introduces the protein before the porous polymer contacts blood, and the electrostatic repulsive interaction generated by the carboxyl groups is used for reducing the adhesion of the surface of the porous polymer to the plasma proteins due to the carboxyl groups which are the same or similar to the plasma proteins, thereby reducing the possibility that platelets are attracted and adhered to the surface of the plasma proteins, reducing the aggregation and adhesion of the platelets and improving the anticoagulation effect of the porous polymer.
Prostacyclin itself is a platelet aggregation inhibitor that inhibits platelet adhesion to damaged blood vessel walls and has anti-platelet formation properties. The adsorption agent and the plasma protein are bonded on the surface of the carrier to form a buffer layer, which is favorable for reducing the adhesion of the porous polymer surface to the plasma protein through electrostatic repulsion, thereby indirectly reducing the adhesion of platelets on the plasma protein on the porous polymer surface and achieving the anticoagulation effect. The rigid skeleton of the adsorbent bonded with the bionic compound is beneficial to batch purification treatment and high-pressure steam sterilization and industrial application.
The 6-aminocaproic acid modified on the porous polymer has the functions of stopping bleeding and resisting fibrinolysis, and the synergistic effect of the bionic compound and the 6-aminocaproic acid can improve the anticoagulation effect and avoid the bleeding probability caused by excessive anticoagulation.
Finally, it should be noted that: the above embodiments are only for illustrating the technical solution of the present invention, and are not limiting; although the invention has been described in detail with reference to the foregoing embodiments, it will be understood by those of ordinary skill in the art that: the technical scheme described in the foregoing embodiments can be modified or some technical features thereof can be replaced by equivalents; such modifications and substitutions do not depart from the spirit and scope of the technical solutions of the embodiments of the present invention.
Claims (8)
1. The adsorbent for improving the anticoagulation effect is characterized by comprising a carrier and a bionic material modified on the carrier, wherein the carrier is a styrene-divinylbenzene crosslinked porous polymer, and the bionic material is a derivative of 3-hydroxy bicyclo [3, 0] heptane containing hydroxyl and/or carboxyl; the particle size of the styrene-divinylbenzene crosslinked porous polymer is 0.6-1.4mm, and the pore diameter is 4-100nm.
2. The adsorbent for improving anticoagulant effect according to claim 1, wherein a mass ratio of the biomimetic material to the carrier is (0.2-1): 1.
3. The sorbent for improving anticoagulant effect of claim 1, wherein the biomimetic material is prostacyclin.
4. The anticoagulant effect enhancing adsorbent of claim 1, wherein the amino substituent on the styrene-divinylbenzene crosslinked porous polymer is a fatty acid, and the fatty acid is 6-aminocaproic acid or gamma-aminobutyric acid.
5. The adsorbent for improving anticoagulant effect according to claim 1, wherein the amount of the surface-modified biomimetic compound per gram of the adsorbent is (0.1 to 0.8) mg.
6. A method for producing the anticoagulant effect-improving adsorbent according to any one of claims 1 to 5, comprising the steps of:
preparing a styrene-divinylbenzene crosslinked porous polymer;
the styrene-divinylbenzene crosslinked porous polymer-bonded biomimetic compounds.
7. Use of an adsorbent for enhancing anticoagulant effect according to any one of claims 1 to 5 in a blood perfusion device.
8. Use of an adsorbent according to any one of claims 1 to 5 for increasing the anticoagulant effect for the removal of protein-bound toxins.
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