CN1563157A - Method for covalent grafting heparin on surface of polymer film - Google Patents
Method for covalent grafting heparin on surface of polymer film Download PDFInfo
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- CN1563157A CN1563157A CN 200410009002 CN200410009002A CN1563157A CN 1563157 A CN1563157 A CN 1563157A CN 200410009002 CN200410009002 CN 200410009002 CN 200410009002 A CN200410009002 A CN 200410009002A CN 1563157 A CN1563157 A CN 1563157A
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- film
- heparin
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- polymeric film
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Links
- 229920000669 heparin Polymers 0.000 title claims abstract description 57
- 238000000034 method Methods 0.000 title claims abstract description 55
- 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 54
- 229960002897 heparin Drugs 0.000 title claims abstract description 54
- 229920006254 polymer film Polymers 0.000 title abstract 3
- 239000007864 aqueous solution Substances 0.000 claims abstract description 51
- ROOXNKNUYICQNP-UHFFFAOYSA-N ammonium peroxydisulfate Substances [NH4+].[NH4+].[O-]S(=O)(=O)OOS([O-])(=O)=O ROOXNKNUYICQNP-UHFFFAOYSA-N 0.000 claims abstract description 30
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims abstract description 29
- 229910001870 ammonium persulfate Inorganic materials 0.000 claims abstract description 21
- 230000004913 activation Effects 0.000 claims abstract description 20
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 15
- 239000000178 monomer Substances 0.000 claims abstract description 13
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims abstract description 12
- 229920002554 vinyl polymer Polymers 0.000 claims abstract description 12
- 239000000243 solution Substances 0.000 claims description 59
- 238000006243 chemical reaction Methods 0.000 claims description 52
- 238000004506 ultrasonic cleaning Methods 0.000 claims description 29
- 235000019395 ammonium persulphate Nutrition 0.000 claims description 21
- -1 polyoxyethylene Polymers 0.000 claims description 19
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 18
- 239000008367 deionised water Substances 0.000 claims description 17
- 229910021641 deionized water Inorganic materials 0.000 claims description 17
- 239000004743 Polypropylene Substances 0.000 claims description 15
- 229920001155 polypropylene Polymers 0.000 claims description 15
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 14
- 238000003756 stirring Methods 0.000 claims description 14
- 238000010926 purge Methods 0.000 claims description 13
- NIXOWILDQLNWCW-UHFFFAOYSA-N Acrylic acid Chemical compound OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 claims description 12
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 11
- 239000004698 Polyethylene Substances 0.000 claims description 10
- 229960000935 dehydrated alcohol Drugs 0.000 claims description 10
- 229920000573 polyethylene Polymers 0.000 claims description 10
- 229920000139 polyethylene terephthalate Polymers 0.000 claims description 9
- 239000005020 polyethylene terephthalate Substances 0.000 claims description 9
- CERQOIWHTDAKMF-UHFFFAOYSA-N Methacrylic acid Chemical compound CC(=C)C(O)=O CERQOIWHTDAKMF-UHFFFAOYSA-N 0.000 claims description 7
- 229920003171 Poly (ethylene oxide) Polymers 0.000 claims description 7
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 claims description 7
- 235000019394 potassium persulphate Nutrition 0.000 claims description 7
- IMBKASBLAKCLEM-UHFFFAOYSA-L ferrous ammonium sulfate (anhydrous) Chemical compound [NH4+].[NH4+].[Fe+2].[O-]S([O-])(=O)=O.[O-]S([O-])(=O)=O IMBKASBLAKCLEM-UHFFFAOYSA-L 0.000 claims description 6
- 239000004160 Ammonium persulphate Substances 0.000 claims description 5
- 239000002253 acid Substances 0.000 claims description 5
- 150000001718 carbodiimides Chemical class 0.000 claims description 5
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims description 5
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 5
- 239000004159 Potassium persulphate Substances 0.000 claims description 4
- 238000010559 graft polymerization reaction Methods 0.000 claims description 4
- 238000005502 peroxidation Methods 0.000 claims description 4
- USHAGKDGDHPEEY-UHFFFAOYSA-L potassium persulfate Chemical compound [K+].[K+].[O-]S(=O)(=O)OOS([O-])(=O)=O USHAGKDGDHPEEY-UHFFFAOYSA-L 0.000 claims description 4
- 230000033228 biological regulation Effects 0.000 claims description 3
- 230000015572 biosynthetic process Effects 0.000 claims description 3
- 238000006482 condensation reaction Methods 0.000 claims description 3
- 239000007822 coupling agent Substances 0.000 claims description 3
- ZFGMDIBRIDKWMY-PASTXAENSA-N heparin Chemical compound CC(O)=N[C@@H]1[C@@H](O)[C@H](O)[C@@H](COS(O)(=O)=O)O[C@@H]1O[C@@H]1[C@@H](C(O)=O)O[C@@H](O[C@H]2[C@@H]([C@@H](OS(O)(=O)=O)[C@@H](O[C@@H]3[C@@H](OC(O)[C@H](OS(O)(=O)=O)[C@H]3O)C(O)=O)O[C@@H]2O)CS(O)(=O)=O)[C@H](O)[C@H]1O ZFGMDIBRIDKWMY-PASTXAENSA-N 0.000 claims description 3
- 229960001008 heparin sodium Drugs 0.000 claims description 3
- ORRXNPKJTGGJNV-UHFFFAOYSA-N n-ethyl-n'-(3-methylbutyl)methanediimine Chemical compound CCN=C=NCCC(C)C ORRXNPKJTGGJNV-UHFFFAOYSA-N 0.000 claims description 3
- 238000002203 pretreatment Methods 0.000 claims description 3
- 230000037452 priming Effects 0.000 claims description 3
- 238000001291 vacuum drying Methods 0.000 claims description 3
- 229910019931 (NH4)2Fe(SO4)2 Inorganic materials 0.000 claims description 2
- 229960004756 ethanol Drugs 0.000 claims description 2
- 238000012545 processing Methods 0.000 claims description 2
- 238000006116 polymerization reaction Methods 0.000 abstract description 4
- 230000000977 initiatory effect Effects 0.000 abstract description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 abstract 1
- VAZSKTXWXKYQJF-UHFFFAOYSA-N ammonium persulfate Chemical compound [NH4+].[NH4+].[O-]S(=O)OOS([O-])=O VAZSKTXWXKYQJF-UHFFFAOYSA-N 0.000 abstract 1
- 230000005494 condensation Effects 0.000 abstract 1
- 238000009833 condensation Methods 0.000 abstract 1
- 239000003431 cross linking reagent Substances 0.000 abstract 1
- 150000002978 peroxides Chemical class 0.000 abstract 1
- 229920000151 polyglycol Polymers 0.000 abstract 1
- 239000010695 polyglycol Substances 0.000 abstract 1
- 238000005406 washing Methods 0.000 abstract 1
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 24
- GPRLSGONYQIRFK-MNYXATJNSA-N triton Chemical compound [3H+] GPRLSGONYQIRFK-MNYXATJNSA-N 0.000 description 9
- 238000010521 absorption reaction Methods 0.000 description 8
- 229920001519 homopolymer Polymers 0.000 description 8
- 238000004519 manufacturing process Methods 0.000 description 8
- 239000000463 material Substances 0.000 description 8
- SMZOUWXMTYCWNB-UHFFFAOYSA-N 2-(2-methoxy-5-methylphenyl)ethanamine Chemical compound COC1=CC=C(C)C=C1CCN SMZOUWXMTYCWNB-UHFFFAOYSA-N 0.000 description 7
- 230000015556 catabolic process Effects 0.000 description 7
- 238000006731 degradation reaction Methods 0.000 description 7
- 150000003839 salts Chemical class 0.000 description 7
- 238000001179 sorption measurement Methods 0.000 description 7
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 6
- 229920002125 Sokalan® Polymers 0.000 description 6
- 239000008280 blood Substances 0.000 description 6
- 210000004369 blood Anatomy 0.000 description 6
- 239000004584 polyacrylic acid Substances 0.000 description 6
- 125000000524 functional group Chemical group 0.000 description 5
- 229920000642 polymer Polymers 0.000 description 5
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Substances [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 5
- 230000010100 anticoagulation Effects 0.000 description 4
- 230000004044 response Effects 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- HRPVXLWXLXDGHG-UHFFFAOYSA-N Acrylamide Chemical compound NC(=O)C=C HRPVXLWXLXDGHG-UHFFFAOYSA-N 0.000 description 3
- 230000008021 deposition Effects 0.000 description 3
- 239000003999 initiator Substances 0.000 description 3
- 239000012528 membrane Substances 0.000 description 3
- 230000033116 oxidation-reduction process Effects 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- 150000003254 radicals Chemical class 0.000 description 3
- 108010049003 Fibrinogen Proteins 0.000 description 2
- 102000008946 Fibrinogen Human genes 0.000 description 2
- CBENFWSGALASAD-UHFFFAOYSA-N Ozone Chemical compound [O-][O+]=O CBENFWSGALASAD-UHFFFAOYSA-N 0.000 description 2
- 108090000190 Thrombin Proteins 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- XMPZTFVPEKAKFH-UHFFFAOYSA-P ceric ammonium nitrate Chemical compound [NH4+].[NH4+].[Ce+4].[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O XMPZTFVPEKAKFH-UHFFFAOYSA-P 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000000835 fiber Substances 0.000 description 2
- 229940012952 fibrinogen Drugs 0.000 description 2
- 238000001631 haemodialysis Methods 0.000 description 2
- 230000000322 hemodialysis Effects 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- VLCAYQIMSMPEBW-UHFFFAOYSA-N methyl 3-hydroxy-2-methylidenebutanoate Chemical compound COC(=O)C(=C)C(C)O VLCAYQIMSMPEBW-UHFFFAOYSA-N 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 230000007420 reactivation Effects 0.000 description 2
- PODWXQQNRWNDGD-UHFFFAOYSA-L sodium thiosulfate pentahydrate Chemical compound O.O.O.O.O.[Na+].[Na+].[O-]S([S-])(=O)=O PODWXQQNRWNDGD-UHFFFAOYSA-L 0.000 description 2
- 238000010186 staining Methods 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 229960004072 thrombin Drugs 0.000 description 2
- 229950003937 tolonium Drugs 0.000 description 2
- HNONEKILPDHFOL-UHFFFAOYSA-M tolonium chloride Chemical compound [Cl-].C1=C(C)C(N)=CC2=[S+]C3=CC(N(C)C)=CC=C3N=C21 HNONEKILPDHFOL-UHFFFAOYSA-M 0.000 description 2
- 102000004411 Antithrombin III Human genes 0.000 description 1
- 108090000935 Antithrombin III Proteins 0.000 description 1
- 229920002799 BoPET Polymers 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- CWYNVVGOOAEACU-UHFFFAOYSA-N Fe2+ Chemical compound [Fe+2] CWYNVVGOOAEACU-UHFFFAOYSA-N 0.000 description 1
- 102000009123 Fibrin Human genes 0.000 description 1
- 108010073385 Fibrin Proteins 0.000 description 1
- BWGVNKXGVNDBDI-UHFFFAOYSA-N Fibrin monomer Chemical compound CNC(=O)CNC(=O)CN BWGVNKXGVNDBDI-UHFFFAOYSA-N 0.000 description 1
- 229920002683 Glycosaminoglycan Polymers 0.000 description 1
- 208000007536 Thrombosis Diseases 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 239000011149 active material Substances 0.000 description 1
- 238000013019 agitation Methods 0.000 description 1
- 239000003146 anticoagulant agent Substances 0.000 description 1
- 229940127219 anticoagulant drug Drugs 0.000 description 1
- 229960005348 antithrombin iii Drugs 0.000 description 1
- 239000011260 aqueous acid Substances 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- 239000012620 biological material Substances 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 230000004154 complement system Effects 0.000 description 1
- 230000000536 complexating effect Effects 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 125000003700 epoxy group Chemical group 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 229910001448 ferrous ion Inorganic materials 0.000 description 1
- 229950003499 fibrin Drugs 0.000 description 1
- 238000011010 flushing procedure Methods 0.000 description 1
- 238000007710 freezing Methods 0.000 description 1
- VOZRXNHHFUQHIL-UHFFFAOYSA-N glycidyl methacrylate Chemical compound CC(=C)C(=O)OCC1CO1 VOZRXNHHFUQHIL-UHFFFAOYSA-N 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 238000013507 mapping Methods 0.000 description 1
- 125000005395 methacrylic acid group Chemical group 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000000465 moulding Methods 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229960004839 potassium iodide Drugs 0.000 description 1
- 235000007715 potassium iodide Nutrition 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 125000006850 spacer group Chemical group 0.000 description 1
- 230000003335 steric effect Effects 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 1
- 238000006557 surface reaction Methods 0.000 description 1
- 238000004381 surface treatment Methods 0.000 description 1
- 230000001732 thrombotic effect Effects 0.000 description 1
- 238000004448 titration Methods 0.000 description 1
Landscapes
- Polysaccharides And Polysaccharide Derivatives (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Materials For Medical Uses (AREA)
- Treatments Of Macromolecular Shaped Articles (AREA)
Abstract
The method is featured as washing and extracting polymer film by alcohol, placing it in ammonium persulfate aqueous solution for forming peroxide perssad with activation initiating polymerization of vinyl monomer containing carboxy on surface by ferrisulphas ammonium, converting carboxyl to be end azyl by using 1-ethyl-3-(3-dimethyl propyl) EDC as cross-linking agent to react with a,W-aminopropyl-polyglycol and fixing heparin on polymer film surface by covalent bond through condensation of carboxyl and azyl in heparin structure.
Description
Technical field
The present invention relates to a kind of heparin is grafted on the polymeric film surface by covalent linkage,, belong to biomedical engineering field to improve the method for anticoagulation function.
Technical background
Heparin (Heparin) is a kind of negatively charged ion mucopolysaccharide, feature pentasaccharides unit in its structure is because effectively complexing and improve the activity of antiprothrombin III in the blood (antithrombin III) bind thrombin former (thrombin) formation non-activity product, and then stop by the conversion of the Fibrinogen (fibrinogen) of zymoplasm control to scleroproein (fibril), deposition, thereby has a good anticoagulation function [Kwon OH, Nho YC et al.Biocompatible surfaces byimmobilization of heparin on diamond-like carbon films deposited on varioussubstrates.Surf.Interface Anal., 2000,29:386].
In numerous synthetic materialss, polyethylene (PE), polypropylene (PP) or polyethylene terephthalate (PET) etc. are widely used as medicine equipments such as disposable syringe, blood bag, hemodialysis membrane and oxygenator with its superior chemical stability, good mechanical performance and transparent, the nontoxic characteristics such as moulding that are easy to.But the surface of handling without anti-freezing with bring out the reaction of blood pool cascaded, activating complement system easily after blood contact, the deposition and the platelet adhesion reaction of stimulation fibrin, the formation thrombus has greatly restricted its range of application and product result of use.Studies show that, with anticoagulation function superior bioactive macromole heparin efficiently covalence graft be to improve goods blood compatibility, the thrombotic effective ways of reduction (elimination) on the surface.
Though lack active reaction functional group in this type of polymer chain structure, but pass through plasma surface treatment, high energy particle irradiation, ozone activation, the free radical initiation that chemical activation produces has hydroxyl, the vinyl monomer such as the hydroxyethyl methyl acrylate (HEMA) of active functional group such as amino or epoxy group(ing), vinylformic acid (AAc), methacrylic acid (MAA), above-mentioned functional group is introduced in acrylamide (AAm) or glycidyl methacrylate graft polymerizations such as (GMA), again with heparin by the condensation reaction of the carboxyl in its minor structure with above-mentioned functional group, covalence graft is a kind of common method at material surface.Wherein, chemical activation method is owing to have easy, efficient, activation products definite ingredients and advantages such as the material body damage is less are used widely gradually.Bamford etc. introduce hydroxyl by Potassium Persulphate (KPS) activation, again with ceric ammonium nitrate (Ce
4+) for oxidation-reduction initiator, AAm are monomer, introduce active function groups-NH
2, subsequently with the heparin molecule covalence graft on PP film or tubular fibre surface.In above-mentioned KPS reactivation process, Bamford etc. do not detect the peroxidation group, think not have hydrogen peroxide by activation back material surface (OOH) wait and can decompose the functional group that produces free radical, the while is except with Ce
4+Outside oxidation-reduction initiator, other systems all can not initiating polymerization of vinyl monomer [Bamford CH, Al-Lamee KG.Studies in polymer surfacefunctionalization and grafting for biomedical and other applications.Polymer, 1994,35:2884].Patent of the present invention proves that by experiment after the similar reactivation process of above-mentioned process, material surface exists can decompose the peroxidation group that produces free radical, uses other oxidation-reduction initiators such as ferrous ion (Fe simultaneously
2+) still can cause above-mentioned vinyl monomer at surface grafting polymerization.
Consider by aforesaid method with the heparin molecule covalence graft after because to a certain degree variation unavoidably can take place its native conformation, and then have influence on its physiologically active.In the actual procedure, adopting long chain molecule such as polyoxyethylene glycol (PEG) etc. is that arm molecule (Spacer molecules) will help to keep its native conformation between between material surface and the heparin molecule.Studies show that, PEG is owing to have good hydrophilicity and macromolecular chain snappiness, it is grafted on material surface, because the high reactivity of space steric effect and macromolecular chain, can effectively prevent adhesion [the Ko YG of absorption of proteins, deposition and cell, Kim YHet al.Immobilization of poly (ethylene glycol) or its sulfonate onto polymersurfaces by ozone oxidation.Biomaterials 2001,22:2115].α, ω-aminopropyl-polyoxyethylene glycol (Jeffamine
ED) similar to the PEG molecular structure, have good hydrophilicity and biocompatibility equally, also rarely have report but utilize in its structure free end amino that heparin molecule is fixed on material surface.
Summary of the invention
The object of the present invention is to provide that a kind of technology is simple, the method for the polymeric film surface covalence graft heparin that is easy to accomplish scale production, to improve the polymer surfaces anticoagulation function.
The method of a kind of polymeric film surface covalence graft heparin that the present invention proposes, it is characterized in that: this method is at first cleaned polymeric film with the ethanol extracting, puts it into to activate in the certain density ammonium persulfate aqueous solution to form the peroxidation group again; Cause carboxylic vinyl monomer at surface aggregate with ferrous ammonium sulphate then; Be coupling agent with 1-ethyl-3-(3-dimethyl propyl) carbodiimide hydrochloride (EDC) again, by with α, the reaction of ω-aminopropyl-polyoxyethylene glycol will hold carboxyl to be converted into end amino; By carboxyl in the heparin structure and amino condensation reaction heparin is fixed on the polymeric film surface with covalent linkage again, described method is carried out successively as follows:
(1) polymeric film pre-treatment
With polymeric film dehydrated alcohol extracting, ultrasonic cleaning, vacuum-drying;
(2) polymeric film surface active
The film of step (1) processing is placed the oxygenant ammonium persulphate (NH of 5～30% (w/v)
4)
2S
2O
8In the solution, logical N
2, 50～90 ℃ of activation are down taken out and are used rinsed with deionized water, and ultrasonic cleaning under the room temperature is dipped in the deionized water, and is standby;
(3) surperficial carboxyl functional groupization
Step (2) activatory film is placed the carboxyl terminated vinyl monomer solution of 5～30% (v/v), N
2Purging is removed the O in the solution
2, the ferrous ammonium sulphate (NH of adding 0.3～3.0ml concentration
4)
2Fe (SO
4)
2The aqueous solution, N
2Purging, 20～50 ℃ of following graft polymerizations; After reaction finishes, film is taken out, ultrasonic cleaning under the room temperature, is dipped in the deionized water and preserves;
(4) surface grafting
To be dipped in morpholino b acid (MES) aqueous solution through step (3) grafted film, add the amino polyoxyethylene glycol of end, with HCl regulation system pH to 4-6, add N-maloyl imines (NHS) and 1-ethyl-3-(3-diamino propyl group) carbodiimide again, stirring reaction; After reaction finishes, film is taken out ultrasonic cleaning;
(5) heparin covalence graft
To be dipped in solution morpholino b acid (MES) aqueous solution through step (4) grafted film, add heparin sodium, N-maloyl imines and 1-ethyl-3-(3-diamino propyl group) carbodiimide respectively, under the room temperature, stirring reaction 12～48h; Reaction is taken out usefulness with film, ultrasonic cleaning after finishing;
In aforesaid method, the described polymeric film of step (1) is any in polyethylene, polypropylene, the polyethylene terephthalate.
In aforesaid method, the described oxygenant of step (2) can also be Potassium Persulphate K
2S
2O
8
In aforesaid method, after the described priming reaction of step (2) finishes, immediately film is taken out from ammonium persulfate aqueous solution and cleans.
In aforesaid method, the described carboxyl terminated vinyl monomer of step (3) is vinylformic acid, methacrylic acid.
Heparin covalence graft method provided by the invention is simple, can effectively improve medical article such as surface anticoagulant performances such as disposable syringe, blood bag, hemodialysis membrane and oxygenator hollow-fibre membrane such as common PE, PP or PET.
Embodiment
The present invention will be further described below by embodiment:
The present invention uses Fe by surperficial ammonium persulphate activation
2+Causing the vinyl monomer surface grafting polymerization contain carboxyl, is coupling agent with EDC, by with Jeffamine
The ED reaction will hold carboxyl to be converted into end amino, and the linked reaction of carboxyl in heparin structure and film surface amino is fixed in film surface with heparin with covalent linkage.Comprise following steps:
(1) film pre-treatment
Film is used dehydrated alcohol extracting 1～12h on apparatus,Soxhlet's, take out ultrasonic cleaning 5～30min, vacuum-drying 24h, stand-by.This patent is characterised in that film can be polyethylene (PE), polypropylene (PP) or polyethylene terephthalate (PET) etc.
(2) film surface activation
Step (1) film is placed the ammonium persulphate (NH of 5～30% (w/v)
4)
2S
2O
8(APS) in the solution, logical N
2, 50～100 ℃ activate 30～180min down, take out immediately and use rinsed with deionized water 4 times, and ultrasonic cleaning 3 * 10min under the room temperature is dipped in the deionized water, and is standby.This patent is characterised in that oxygenant can also be Potassium Persulphate K
2S
2O
8(KPS) and after the priming reaction end immediately film is taken out from the APS aqueous solution and cleans.
(3) surperficial concentration of hydrogen peroxide [OOH] is measured
The mensuration of film surface concentration of hydrogen peroxide [OOH] adopts iodimetry,iodometry.Will be through step (2) activatory film (2 * 2cm
2) be dipped in the 20mL distilled water, to wherein adding 2ml HAc and 1g KI, vibration is even respectively, the 8h that keeps in Dark Place under the room temperature, and solution is owing to there is I
2Separate out and present pale brown look, use Na
2S
2O
3The solution titration is to colourless, according to the Na that consumes
2S
2O
3The volume calculation surface [OOH] of solution.
(4) surperficial carboxyl functional groupization
To place carboxyl terminated vinyl monomer such as the vinylformic acid (AAc) or methacrylic acid (MAA) aqueous solution of 5～30% (v/v), N through step (2) activatory film
2Purging 20min removes the O in the solution
2, adding 0.3～3.0ml concentration is the ferrous ammonium sulphate (NH of 15mM
4)
2Fe (SO
4)
2(AFS) aqueous solution, N
2Purging, 20～70 ℃ of following graft polymerization 4～24h; After reaction finishes, film is taken out, at 0.1wt%Triton
Ultrasonic cleaning 3 * 20min in the X-100 aqueous solution removes the homopolymer of surface adhesion, under the room temperature, is dipped in the deionized water and preserves.
(5) mensuration of surperficial carboxyl concentration [COOH]
The mensuration of film surface carboxyl concentration [COOH] adopts toluidine blue (TBO) staining.7 cuvettes are got in the drafting of typical curve, successively to wherein adding 0.5ml, 0.4ml, 0.25ml, 0.2ml, 0.1ml, 0.05ml, the TBO aqueous solution and the 3.5ml of 0.02ml concentration 1mM, 3.6ml, 3.75ml, 3.8ml, 3.9ml, 3.95ml, 3.98ml deionized water reads the absorption value at 631nm place on the UV spectrophotometer; Suppose that TBO combines in strict accordance with 1: 1 with COOH, with TBO molar content (COOH molar content) absorption value A is figure, getting wherein, linear portion is a typical curve.
Will be through the film (1 * 1cm of step (4) surface grafting
2) immerse the containing in the 1ml 0.5mM TBO solution of 10ml pH=10, under the room temperature, stirring reaction 3h, the NaOH solution that takes out with pH=9 washes 3 times, places cuvette then, adds 1ml HAc and 3ml deionized water respectively, vibration evenly, read the absorption value at 631nm place on the UV spectrophotometer, the reference standard curve obtains film surface [COOH].
(6) Jeffamine
The ED surface grafting
The Jeffamine that in morpholino b acid (MES) solution of 10～50ml pH=4.5, adds 1～3ml 0.1M
The ED aqueous solution, with 0.1M HCl regulation system pH to 4.7, to be dipped in wherein through step (4) grafted film, add 0.5～3ml20mM N-maloyl imines (NHS) solution and 10～100mg 1-ethyl-3-(3-diamino propyl group) carbodiimide (EDC) again, magnetic agitation reaction 12～48h; After reaction finishes, film is taken out with the careful flushing of deionized water 3 times, ultrasonic cleaning 20min removes unreacted Jeffamine
ED.This patent is characterised in that Jeffamine
The molecular weight of ED can be 600,900,2000.
(7) heparin covalence graft
The heparin that adds 0.5～3ml 10mg/ml in the MES of 10～50ml pH=4.5 solution is received the aqueous solution and 0.5～3ml20mM NHS solution and 10～80mg EDC, and stirring reaction 0.5h is with the carboxyl in the activation heparin structure; Again will be through the amidized film (3 * 2cm of step (6) endmost surface
2) be dipped in wherein, under the room temperature, stirring reaction 4～48h; After reaction finished, with film taking-up deionized water rinsing 3 times, ultrasonic cleaning 2 * 10min removed the heparin of surface adsorption.
(8) mensuration of heparin grafting amount
The mensuration of film surface heparin grafting amount adopts the TBO staining.The drafting of typical curve adds the TBO solution of 0.5ml 1mM respectively in 7 test tubes, adds 100 μ l, 80 μ l more respectively successively, 50 μ l, 30 μ l, 20 μ l, 10 μ l, heparin solution and the 0.4ml of 5 μ l 1mg/ml, 0.42ml, 0.45ml, 0.47ml, 0.48ml, 0.49ml, 0.495ml react 10～180min under the deionized water, room temperature; Again respectively to wherein adding the 3ml normal hexane, on the vortex mixing tank, mix, leave standstill 20min, pipette lower floor's aqueous phase solution of certain volume, put into cuvette, add a certain amount of deionized water, on the UV spectrophotometer, read the absorption value at 631nm place, to absorption value A mapping, obtain typical curve with the heparin add-on.
Will be set by step (7) grafted film (1 * 1cm
2) immerse and contain in the test tube of 0.5ml 1mM TBO solution and 0.5ml deionized water, react 10～180min under the room temperature, add the 3ml normal hexane again, vibration mixes 20min, leaves standstill 20min, and lower floor's aqueous phase solution of drawing certain volume places cuvette, add a certain amount of deionized water, read the absorption value at 631nm place on the UV spectrophotometer, the reference standard curve obtains film surface heparin grafting amount.
Material therefor of the present invention and reagent are as follows:
Polyethylene (PE), polypropylene (PP) or polyethylene terephthalate (PET) film, commercially available; Sulfothiorine (Na
2S
2O
3), ammonium persulphate ((NH
4)
2S
2O
8), anhydrous acetic acid (HAc), potassiumiodide (KI), Sulfothiorine (Na
2S
2O
3), ferrous ammonium sulphate ((NH
4)
2Fe (SO
4)
2, AFS), vinylformic acid (AAc), methacrylic acid (MMA), Beijing benefit Li Jingxihuaxuepinchang; N-maloyl imines (NHS) is held amino polyoxyethylene glycol (Jeffamine
ED-600, ED-900, ED-2000), Fluka
Co.Ltd; 1-ethyl-3-(3-dimethyl propyl) carbodiimide hydrochloride (EDC), toluidine blue (TBO), Shanghai chemical reagent factory of Chinese Medicine group; Triton
X-100 (1wt%), Farco Chemical Supplies; Heparin sodium (Heparin, 120IU/mg), active material factory of Changzhou Xinhua.
Embodiment 1
With PP film (6 * 4cm
2) on the Soxhlet extractor, use dehydrated alcohol extracting 4h, take out ultrasonic cleaning 10min.Put into 10% the APS aqueous solution then, logical N
2, 70 ℃ of following activation 100min take out to clean and remove the APS and the degradation production thereof of surface attachment, method shown in (3) set by step, and surveying its surface [OOH] is 4.67 * 10
-7Mol/cm
2This film is placed the acrylic acid aqueous solution of 10% (v/v), logical N
220min removes the O in the solution
2, add 1ml 15mM Mohr ' the s salt aqueous solution, N
2Purging, 30 ℃ of following reaction 8h are taken at 0.1wt%Triton
Ultrasonic cleaning 3 * 15min in the X-100 aqueous solution removes the polyacrylic acid homopolymer of physical adsorption, and the mensuration surface of method shown in (5) [COOH] is 1.12 * 10 set by step
-7Mol/cm
2The Jeffamine that in 20ml pH=4.5MES solution, adds 1.5ml 0.1M
ED600, use HCl and the NaOH solution regulator solution pH to 4.7 of 0.1M respectively, put into the film of surface grafting carboxyl, add 20mg NHS and 20mgEDC respectively, behind the stirring reaction 24h, adding 20mg EDC again under the room temperature, question response finishes, take out, clean, the mensuration surface of method shown in (5) [COOH] is 3.12 * 10 set by step
-8Mol/cm
2Film is put into the MES aqueous solution of 20ml pH=4.5, add 1ml 10mg/ml heparin solution and 7mg NHS and 20mg EDC, take out behind the reaction 24h and clean, method shown in (8) is measured surperficial heparin grafting amount and is about 1.86 μ g/cm set by step
2
Embodiment 2
With PP film (6 * 4cm
2) on the Soxhlet extractor, use dehydrated alcohol extracting 4h, take out ultrasonic cleaning 10min.Put into 20% the APS aqueous solution then, logical N
2, 90 ℃ of following activation 80min take out to clean and remove the APS and the degradation production thereof of surface attachment, method shown in (3) set by step, and surveying its surface [OOH] is 5.23 * 10
-7Mol/cm
2This film is placed the methacrylic aqueous acid of 30% (v/v), logical N
220min removes the O in the solution
2, add 1ml 15mM Mohr ' the s salt aqueous solution, N
2Purging, 50 ℃ of following reaction 3h are taken at 0.1wt%Triton
Ultrasonic cleaning 3 * 15min in the X-100 aqueous solution removes the polymethyl acrylic acid homopolymer (PMAA) of physical adsorption, and the mensuration surface of method shown in (5) [COOH] is 1.09 * 10 set by step
-7Mol/cm
2The Jeffamine that in 20ml pH=4.5MES solution, adds 1.5ml 0.1M
ED600, use HCl and the NaOH solution regulator solution pH to 5.5 of 0.1M respectively, put into the film of surface grafting carboxyl, adding 10mgNHS and 20mg EDC respectively, behind the stirring reaction 24h, question response finishes under the room temperature, takes out, clean, the mensuration surface of method shown in (5) [COOH] is 2.97 * 10 set by step
-8Mol/cm
2Film is put into the MES aqueous solution of 20ml pH=4.5, add 1ml 10mg/ml heparin solution and 7mg NHS and 20mg EDC, take out behind the reaction 24h and clean, method shown in (8) is measured surperficial heparin grafting amount and is about 1.95 μ g/cm set by step
2
Embodiment 3
With PP film (6 * 4cm
2) on the Soxhlet extractor, use dehydrated alcohol extracting 4h, take out ultrasonic cleaning 10min.Put into 5% the APS aqueous solution then, logical N
2, 80 ℃ of following activation 150min take out to clean and remove the APS and the degradation production thereof of surface attachment, method shown in (3) set by step, and surveying its surface [OOH] is 5.54 * 10
-7Mol/cm
2This film is placed the acrylic acid aqueous solution of 20% (v/v), logical N
220min removes the O in the solution
2, add 1ml 15mM Mohr ' the s salt aqueous solution, N
2Purging, 20 ℃ of following reaction 12h are taken at 0.1wt%Triton
Ultrasonic cleaning 3 * 15min in the X-100 aqueous solution removes the polyacrylic acid homopolymer of physical adsorption, and the mensuration surface of method shown in (5) [COOH] is 1.21 * 10 set by step
-7Mol/cm
2The Jeffamine that in 20ml pH=4.5MES solution, adds 1.5ml 0.1M
ED600 uses HCl and the NaOH solution regulator solution pH to 4.0 of 0.1M respectively, puts into the film of surface grafting carboxyl, adding 10mgNHS and 30mgEDC respectively, stirring reaction 24h under the room temperature, reaction finishes, take out, clean, the mensuration surface of method shown in (5) [COOH] is 3.08 * 10 set by step
-8Mol/cm
2Film is put into the MES aqueous solution of 20ml pH=4.5, add 1ml 10mg/ml heparin solution and 7mg NHS and 20mg EDC, take out behind the reaction 24h and clean, method shown in (8) is measured surperficial heparin grafting amount and is about 2.03 μ g/cm set by step
2
Embodiment 4
With PP film (6 * 4cm
2) on the Soxhlet extractor, use dehydrated alcohol extracting 4h, take out ultrasonic cleaning 10min.Put into 30% the APS aqueous solution then, logical N
2, 60 ℃ of following activation 100min take out to clean and remove the APS and the degradation production thereof of surface attachment, method shown in (3) set by step, and surveying its surface [OOH] is 5.42 * 10
-7Mol/cm
2This film is placed the acrylic acid aqueous solution of 5% (v/v), logical N
220min removes the O in the solution
2, add 1ml 15mM Mohr ' the s salt aqueous solution, N
2Purging, 30 ℃ of following reaction 8h are taken at 0.1wt%Triton
Ultrasonic cleaning 3 * 15min in the X-100 aqueous solution removes the polyacrylic acid homopolymer of absorption, and the mensuration surface of method shown in (5) [COOH] is 1.18 * 10 set by step
-7Mol/cm
2The Jeffamine that in 20ml pH=4.5MES solution, adds 1.5ml 0.1M
ED900 uses HCl and the NaOH solution regulator solution pH to 4.7 of 0.1M respectively, puts into the film of surface grafting carboxyl, adding 10mg NHS and 30mgEDC respectively, stirring reaction 24h under the room temperature, reaction finishes, take out, clean, the mensuration surface of method shown in (5) [COOH] is 5.87 * 10 set by step
-8Mol/cm
2Film is put into the MES aqueous solution of 20ml pH=4.5, add 1ml 10mg/ml heparin solution and 10mg NHS and 20mg EDC, take out behind the reaction 24h and clean, method shown in (8) is measured surperficial heparin grafting amount and is about 0.86 μ g/cm set by step
2
Embodiment 5
With PP film (6 * 4cm
2) on the Soxhlet extractor, use dehydrated alcohol extracting 4h, take out ultrasonic cleaning 10min.Put into 20% the APS aqueous solution then, logical N
2, 50 ℃ of following activation 150min take out to clean and remove the APS and the degradation production thereof of surface attachment, method shown in (3) set by step, and surveying its surface [OOH] is 5.48 * 10
-7Mol/cm
2This film is placed the acrylic acid aqueous solution of 10% (v/v), logical N
220min removes the O in the solution
2, add 1ml 15mM Mohr ' the s salt aqueous solution, N
2Purging, 20 ℃ of following reaction 12h are taken at 0.1wt%Triton
Ultrasonic cleaning 3 * 15min in the X-100 aqueous solution removes the polyacrylic acid homopolymer of physical adsorption, and the mensuration surface of method shown in (5) [COOH] is 1.27 * 10 set by step
-7Mol/cm
2The Jeffamine that in 20ml pH=4.5MES solution, adds 1.5ml 0.1M
ED2000 uses HCl and the NaOH solution regulator solution pH to 6.0 of 0.1M respectively, puts into the film of surface grafting carboxyl, adding 10mg NHS and 30mgEDC respectively, stirring reaction 24h under the room temperature, reaction finishes, take out, clean, the mensuration surface of method shown in (5) [COOH] is 8.17 * 10 set by step
-8Mol/cm
2Film is put into the MES aqueous solution of 20ml pH=4.5, add 1ml 10mg/ml heparin solution and 7mg NHS and 20mg EDC, take out behind the reaction 24h and clean, method shown in (8) is measured surperficial heparin grafting amount and is about 0.49 μ g/cm set by step
2
Embodiment 6
With PE film (6 * 4cm
2) on the Soxhlet extractor, use dehydrated alcohol extracting 4h, take out ultrasonic cleaning 10min.Put into 15% the APS aqueous solution then, logical N
2, 90 ℃ of following activation 90min take out to clean and remove the APS and the degradation production thereof of surface attachment, method shown in (3) set by step, and surveying its surface [OOH] is 6.13 * 10
-7Mol/cm
2This film is placed the acrylic acid aqueous solution of 20% (v/v), logical N
220min removes the O in the solution
2, add 1ml 15mM Mohr ' the s salt aqueous solution again, N
2Purging, 30 ℃ of following reaction 8h are taken at 0.1wt%Triton
Ultrasonic cleaning 3 * 15min in the X-100 aqueous solution removes the polyacrylic acid homopolymer of physical adsorption, and the mensuration surface of method shown in (5) [COOH] is 1.32 * 10 set by step
-7Mol/cm
2The Jeffamine that in 20ml pH=4.35MES solution, adds 1.5ml 0.1M
ED600, use HCl and the NaOH solution regulator solution pH to 4.7 of 0.1M respectively, put into the film of surface grafting carboxyl, add 10mg NHS and 20mgEDC respectively, behind the stirring reaction 24h, adding 20mg EDC again under the room temperature, question response finishes, take out, clean, the mensuration surface of method shown in (5) [COOH] is 2.41 * 10 set by step
-8Mol/cm
2Film is put into the MES aqueous solution of 20ml pH=4.35, add 1ml 10mg/ml heparin solution and 10mg NHS and 30mg EDC, take out behind the reaction 24h and clean, method shown in (8) is measured surperficial heparin grafting amount and is about 2.35 μ g/cm set by step
2
Embodiment 7
With PET film (5 * 4cm
2) on the Soxhlet extractor, use dehydrated alcohol extracting 4h, take out ultrasonic cleaning 10min.Put into 20% the APS aqueous solution then, logical N
2, 70 ℃ of following activation 120min take out to clean and remove the APS and the degradation production thereof of surface attachment, method shown in (3) set by step, and surveying its surface [OOH] is 5.63 * 10
-7Mol/cm
2This film is placed the acrylic acid aqueous solution of 15% (v/v), logical N
220min removes the O in the solution
2, add 1ml 15mM Mohr ' the s salt aqueous solution again, N
2Purging, 40 ℃ of following reaction 6h are taken at 0.1wt%Triton
Ultrasonic cleaning 3 * 15min in the X-100 aqueous solution removes the polyacrylic acid homopolymer of physical adsorption, and the mensuration surface of method shown in (5) [COOH] is 1.08 * 10 set by step
-7Mol/cm
2The Jeffamine that in 20ml pH=4.35 MES solution, adds 1.5ml 0.1M
ED600, use HCl and the NaOH solution regulator solution pH to 4.8 of 0.1M respectively, put into the film of surface grafting carboxyl, add 10mgNHS and 20mgEDC respectively, behind the stirring reaction 24h, adding 20mg EDC again under the room temperature, question response finishes, take out, clean, the mensuration surface of method shown in (5) [COOH] is 4.52 * 10 set by step
-8Mol/cm
2Film is put into the MES aqueous solution of 20ml pH=4.5, add 1ml 10mg/ml heparin solution and 10mg NHS and 30mg EDC, take out behind the reaction 24h and clean, method shown in (8) is measured surperficial heparin grafting amount and is about 1.58 μ g/cm set by step
2
Claims (5)
1, the method for the surperficial covalence graft heparin of a kind of polymeric film, it is characterized in that: this method is at first cleaned polymeric film with the ethanol extracting, puts it into activation formation peroxidation group in the certain density ammonium persulfate aqueous solution again; Cause carboxylic vinyl monomer at surface aggregate with ferrous ammonium sulphate then; Be coupling agent with 1-ethyl-3-(3-dimethyl propyl) carbodiimide hydrochloride (EDC) again, by with α, the reaction of ω-aminopropyl-polyoxyethylene glycol will hold carboxyl to be converted into end amino; By carboxyl in the heparin structure and amino condensation reaction heparin is fixed on the polymeric film surface with covalent linkage again, described method is carried out successively as follows:
(1) polymeric film pre-treatment
With polymeric film dehydrated alcohol extracting, ultrasonic cleaning, vacuum-drying;
(2) polymeric film surface active
The film of step (1) processing is placed the oxygenant ammonium persulphate (NH of 5～30% (w/v)
4)
2S
2O
8In the solution, logical N
2, 50～90 ℃ of activation are down taken out and are used rinsed with deionized water, and ultrasonic cleaning under the room temperature is dipped in the deionized water, and is standby;
(3) surperficial carboxyl functional groupization
Step (2) activatory film is placed the carboxyl terminated vinyl monomer solution of 5～30% (v/v), N
2Purging is removed the O in the solution
2, add ferrous ammonium sulphate (NH
4)
2Fe (SO
4)
2, N
2Purging, 20～50 ℃ of following graft polymerizations; After reaction finishes, film is taken out, ultrasonic cleaning under the room temperature, is dipped in the deionized water and preserves;
(4) surface grafting
To be dipped in morpholino b acid (MES) aqueous solution through step (3) grafted film, add the amino polyoxyethylene glycol of end, with HCl regulation system pH to 4-6, add N-maloyl imines (NHS) and 1-ethyl-3-(3-diamino propyl group) carbodiimide again, stirring reaction; After reaction finishes, film is taken out ultrasonic cleaning;
(5) heparin covalence graft
To be dipped in solution morpholino b acid (MFS) aqueous solution through step (4) grafted film, add heparin sodium, N-maloyl imines and 1-ethyl-3-(3-diamino propyl group) carbodiimide respectively, under the room temperature, stirring reaction; Reaction is taken out usefulness with film, ultrasonic cleaning after finishing;
2, according to the method for the described polymeric film of claim 1 surface covalence graft heparin, it is characterized in that: the described polymeric film of step (1) is any in polyethylene, polypropylene, the polyethylene terephthalate.
3, according to the method for the described polymeric film of claim 1 surface covalence graft heparin, it is characterized in that: the described oxygenant of step (2) can also be Potassium Persulphate K
2S
2O
8
4, according to the method for the described polymeric film of claim 1 surface covalence graft heparin, it is characterized in that: after the described priming reaction of step (2) finishes, immediately film is taken out from ammonium persulfate aqueous solution and cleans.
5, according to the method for the described polymeric film of claim 1 surface covalence graft heparin, it is characterized in that: the described carboxyl terminated vinyl monomer of step (3) is vinylformic acid, methacrylic acid.
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|---|---|---|---|
| CN 200410009002 CN1246372C (en) | 2004-04-05 | 2004-04-05 | Method for covalent grafting heparin on surface of polymer film |
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|---|---|---|---|
| CN 200410009002 CN1246372C (en) | 2004-04-05 | 2004-04-05 | Method for covalent grafting heparin on surface of polymer film |
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| CN101837149A (en) * | 2010-06-18 | 2010-09-22 | 华中科技大学 | Anti-coagulation anti-bacterial biomedical material and preparation method thereof |
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| CN101837149A (en) * | 2010-06-18 | 2010-09-22 | 华中科技大学 | Anti-coagulation anti-bacterial biomedical material and preparation method thereof |
| US8834932B2 (en) | 2011-12-19 | 2014-09-16 | Industry Technology Research Institute | Anticoagulant-conjugated carbon nanocapsule, antithrombotic agent containing thereof |
| CN102698323A (en) * | 2012-05-14 | 2012-10-03 | 西南交通大学 | Preparation method of anticlotting materials |
| CN102698323B (en) * | 2012-05-14 | 2014-07-23 | 西南交通大学 | Preparation method of anticlotting materials |
| CN103316596A (en) * | 2013-05-14 | 2013-09-25 | 中国科学院宁波材料技术与工程研究所 | Preparation method of anticoagulation polylactic acid hemodialysis membrane |
| CN103316596B (en) * | 2013-05-14 | 2014-11-26 | 中国科学院宁波材料技术与工程研究所 | Preparation method of anticoagulation polylactic acid hemodialysis membrane |
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| CN110028692A (en) * | 2019-03-14 | 2019-07-19 | 江苏赛腾医疗科技有限公司 | A kind of preparation method cooperateing with surface heparinization anticoagulation medical apparatus based on ionic bond-covalent bond |
| CN110746630A (en) * | 2019-11-15 | 2020-02-04 | 上海海洋大学 | Grafted antibacterial degradable preservative film and preparation method and application thereof |
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