CN102698323A - Preparation method of anticlotting materials - Google Patents
Preparation method of anticlotting materials Download PDFInfo
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- CN102698323A CN102698323A CN2012101472636A CN201210147263A CN102698323A CN 102698323 A CN102698323 A CN 102698323A CN 2012101472636 A CN2012101472636 A CN 2012101472636A CN 201210147263 A CN201210147263 A CN 201210147263A CN 102698323 A CN102698323 A CN 102698323A
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- bivalirudin
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- anticlotting
- anticoagulant
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Abstract
The invention discloses a preparation method of anticlotting materials, which is used for performing the anticlotting modification on the surface of an implanting device material so as to improve the anticoagulant activity of an intravascular stent. The preparation method comprises the following steps: dissolving 0.1mug/ml-10mg/ml of bivalirudin in a water soluble carbohydrate (WSC) solution, wherein the WSC solution is composed of 9.76mg/ml of 2-(N-morpholine) ethanesulfonic acid buffer solution, 1mg/ml of 1-ethyl-3-(3-dimethylamino propyl) carbodiimide and 0.24mg/ml of N-hydroxy-succinamide; obtaining bivalirudin-WSC solution; immersing the biomedical materials containing amido on surface in the bivalirudin-WSC solution to react for 1-48 hours, and then fully rinsing the biomedical materials by phosphate buffer solution (PBS) with pH value of 7.4 and distilled water respectively, and drying to obtain the objective matter. The anticlotting materials or an apparatus obtained by the invention can play the role of anticlotting by directly or specially imhibiting the activity of thrombin. The preparation method of the anticlotting materials is definite in the anticlotting effect, safe in use and simple in operation of the method, and free from the limit of the physical structure of materials or apparatus.
Description
Affiliated technical field
The invention belongs to bio-medical engineering material, especially the surface anticoagulant technical field of material.
Background technology
Plant intervention apparatus like extracorporeal circulation conduit, oxygenator, hemodialysis membrane, intravascular stent and artificial blood vessel for what contact with blood, improving its surperficial antithrombotic property is a nonvolatil problem.Effective method is that the anticoagulant property that the anticoagulant modification improves intravascular stent is carried out on the device material surface the most.Because thrombin plays crucial effects in thrombosis, the target of most of Therapeutic Method is through stopping thrombin generation or suppressing its activity.Heparin is widely used in clinical anticoagulant as a kind of, and its anticoagulant mechanism is through combining Antithrombin III, to reach the deactivation to thrombin or thrombin.Material surface usually improves its anticoagulation function through Fixed Liver and is widely used.Yet heparin has the limitation of using self biology, like: narrow treatment window, cause thrombocytopenia, serious entail dangers to life, causes bleeding and the loose disease of sclerotin.Therefore be necessary to develop a kind of novel anticoagulation sufacing to remedy the deficiency that heparin is used for material surface anticoagulant design.Bivalirudin, the synthetic small peptide is a kind of strong effectively reversible thrombin inhibitor of high specific.In U.S.'s listing, its effective anticoagulant composition was the hirudin derivative fragment to bivalirudin in approval in 2000, brought into play anticoagulation through direct and specificity enzymatic activity anticoagulant.Clinical studies show: bivalirudin anticoagulant definite effect, and the incidence rate of bleeding episode is lower, compare with traditional anticoagulant heparin treatment use safer.Yet it is considerably less that bivalirudin is used for the finishing report of anticoagulant material, in order to widen the application window of anticoagulant apparatus, the invention discloses the method that a kind of thrombin inhibitor bivalirudin is used for the anticoagulant material surface modification.
Summary of the invention
In view of the above shortcoming of prior art, the objective of the invention is, a kind of method for preparing of anticoagulant material is provided, make it to have significant anticoagulant of enzymatic activity, have the excellent activated performance of antiplatelet.
The objective of the invention is to realize through following means.
A kind of method for preparing of anticoagulant material is carried out the anticoagulant property that the anticoagulant modification improves intravascular stent to the implantation instrument material surface, comprises following steps:
Bivalirudin is dissolved in WSC (water-soluble carbodiimide) solution by 0.1 μ g/ml-10mg/ml; The 2-that consists of 9.76mg/ml of WSC solution (N-morphine quinoline) ethyl sulfonic acid (MES) buffer solution, 1-ethyl-3-(3-dimethylamino-propyl) carbodiimide (EDC) of 1mg/ml and the N-hydroxyl succinamide (NHS) of 0.24mg/ml obtain bivalirudin-WSC solution; The bio-medical material of surperficial amino-contained was soaked in said bivalirudin-WSC solution reaction 1 hour-48 hours, and using pH value then respectively is 7.4 PBS (phosphate buffer) and the abundant rinsing of distilled water, and drying promptly gets goal object.
Adopt method of the present invention, at biomaterial and the surperficial Schiff alkali reaction of apparatus thereof through quinonyl and amido, and the condensation reaction Covalent Immobilization thrombin inhibitor bivalirudin that passes through amido and carboxyl.
Compared with prior art, the invention has the beneficial effects as follows:
The anticoagulant material of bivalirudin modification or apparatus are brought into play anticoagulation through direct and specificity enzymatic activity anticoagulant.Anticoagulant definite effect, and the incidence rate of bleeding episode is lower is compared with traditional anticoagulant heparin treatment and to be used saferly, uses window more wide.In addition; Proved also that through our existing experiment the material list of bivalirudin modification reveals the function that good promotion endotheliocyte adheres to propagation; This improves the performance of cardiovascular artificial organ and apparatus and puies forward important meaning for being applied to modification cardiovascular implantation instrument such as intravascular stent and artificial blood vessel.On the basis, this method is simple to operate, and expensive device that need not be special realizes easily, to the not restriction of three-dimensional-structure of material or apparatus, can realize having in the industry the various biomedical devices of complex shape structure or the surface biological modification of pick off.
Description of drawings:
Fig. 1 is that the 316L stainless steel surfaces contacts the stereoscan photograph of cultivating 60 minutes samples with fresh healthy subjects platelet rich plasma.
Fig. 2 contacts the stereoscan photograph of cultivating 60 minutes samples for the material modified surface of bivalirudin of the inventive method preparation with fresh healthy subjects platelet rich plasma.
Fig. 3 contacts cultivation sample surfaces platelet activation amount after 60 minutes for the platelet with the material modified surface of bivalirudin of the present invention the 1st embodiment preparation and common 316L stainless steel surfaces with fresh healthy subjects platelet rich plasma.
Fig. 4 is the shows fluorescent microscopy images that 316L rustless steel endotheliocyte adheres to
The shows fluorescent microscopy images that Fig. 5 adheres to for the material modified endotheliocyte of bivalirudin with the present invention the 2nd embodiment preparation.
The specific embodiment
Below in conjunction with accompanying drawing and practical implementation the present invention is further described.
The method for preparing of 1 one kinds of anticoagulant materials of embodiment.The steps include:
Bivalirudin is dissolved in the WSC solution 2-that consists of 9.76mg/ml of WSC solution (N-morphine quinoline) ethyl sulfonic acid (MES) buffer solution, 1-ethyl-3-(3-dimethylamino-propyl) carbodiimide (EDC) of 1mg/ml and the N-hydroxyl succinamide (NHS) of 0.24mg/ml by 0.1 μ g/ml.The 316L rustless steel that will have a plasma polyallylamine coatings was soaked in bivalirudin-WSC solution reaction 1 hour, and using pH value then respectively is 7.4 PBS and the abundant rinsing of distilled water, and drying promptly gets.
The method for preparing of 2 one kinds of anticoagulant materials of embodiment.The steps include:
Bivalirudin is dissolved in the WSC solution 2-that consists of 9.76mg/ml of WSC solution (N-morphine quinoline) ethyl sulfonic acid (MES) buffer solution, 1-ethyl-3-(3-dimethylamino-propyl) carbodiimide (EDC) of 1mg/ml and the N-hydroxyl succinamide (NHS) of 0.24mg/ml by 10mg/ml.The 316L rustless steel of plasma polyallylamine coatings was soaked in bivalirudin-WSC solution reaction 48 hours, and using pH value then respectively is 7.4 PBS and the abundant rinsing of distilled water, and drying promptly gets.
The method for preparing of 3 one kinds of anticoagulant materials of embodiment.The steps include:
Bivalirudin is dissolved in the WSC solution 2-that consists of 9.76mg/ml of WSC solution (N-morphine quinoline) ethyl sulfonic acid (MES) buffer solution, 1-ethyl-3-(3-dimethylamino-propyl) carbodiimide (EDC) of 1mg/ml and the N-hydroxyl succinamide (NHS) of 0.24mg/ml by 400 μ g/ml.The 316L rustless steel of plasma polyallylamine coatings was soaked in bivalirudin-WSC solution reaction 24 hours, and using pH value then respectively is 7.4 PBS and the abundant rinsing of distilled water, and drying promptly gets.
The method for preparing of 4 one kinds of anticoagulant materials of embodiment.The steps include:
Bivalirudin is dissolved in the WSC solution 2-that consists of 9.76mg/ml of WSC solution (N-morphine quinoline) ethyl sulfonic acid (MES) buffer solution, 1-ethyl-3-(3-dimethylamino-propyl) carbodiimide (EDC) of 1mg/ml and the N-hydroxyl succinamide (NHS) of 0.24mg/ml by 2mg/ml.The 316L rustless steel of plasma polyallylamine coatings was soaked in bivalirudin-WSC solution reaction 12 hours, and using pH value then respectively is 7.4 PBS and the abundant rinsing of distilled water, and drying promptly gets.
Can find out among comparison diagram 1 and Fig. 2; Common 316L stainless steel surfaces adheres to the platelet distortion and reunites more serious; Have a large amount of pseudopodium to produce, and the meaningful logistics of part platelet goes out, it is bigger that this is illustrated in common 316L stainless steel surfaces platelet activation degree.
Fig. 3 then shows and the 316L rustless steel of the bivalirudin modification that the inventive method prepares; Though its surperficial platelet adhesion amount does not obviously descend; But platelet does not take place to assemble and degeneration; This 316L rustless steel that shows the bivalirudin modification of the inventive method preparation demonstrates very strong opposing platelet adhesion activation capability, thereby reaches the effect of anticoagulant.
The quantitative result of platelet activation can be found out from Fig. 3, the material surface of the bivalirudin modification of the inventive method preparation to the suppression ratio of platelet activation up to more than 70%.
The result that endotheliocyte adheres among comparison diagram 4 and Fig. 5 can find out that the material surface of the bivalirudin modification of the inventive method preparation has significantly promoted the adhesion of endotheliocyte.
Find in the experiment that the bio-medical material of surperficial amino-contained adopts the polylysine coating, such as the 316L rustless steel with polylysine coating, the technique effect similar with the plasma polyallylamine coatings is arranged also.
Claims (2)
1. the method for preparing of an anticoagulant material is carried out the anticoagulant property that the anticoagulant modification improves intravascular stent to the implantation instrument material surface, comprises following steps:
Bivalirudin is dissolved in the WSC solution by 0.1 μ g/ml-10mg/ml; The 2-that consists of 9.76mg/ml of WSC solution (N-morphine quinoline) ethyl sulfonic acid buffer solution, 1-ethyl-3-(3-dimethylamino-propyl) carbodiimide of 1mg/ml and the N-hydroxyl succinamide of 0.24mg/ml obtain bivalirudin-WSC solution; The bio-medical material of surperficial amino-contained was soaked in said bivalirudin-WSC solution reaction 1 hour-48 hours, and using pH value then respectively is 7.4 PBS and the abundant rinsing of distilled water, and drying promptly gets goal object.
2. the method for preparing of anticoagulant material according to claim 1 is characterized in that, the bio-medical material of said surperficial amino-contained is one of plasma polyallylamine coatings material and polylysine coating material.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104758985A (en) * | 2015-03-20 | 2015-07-08 | 西南交通大学 | Preparation method of novel anticoagulant stents coating capable of capturing endothelial progenitor cells |
| CN111773440A (en) * | 2020-05-22 | 2020-10-16 | 南京大学 | Anticoagulation material based on enzyme-like catalytic reaction |
| CN112915267A (en) * | 2020-02-19 | 2021-06-08 | 西南交通大学 | Coating with function of catalytically releasing nitric oxide, preparation method of coating, anticoagulant material, preparation method of anticoagulant material and application of anticoagulant material |
| CN114159623A (en) * | 2020-12-12 | 2022-03-11 | 复旦大学 | Self-anti-coagulation elastomer material and preparation method thereof |
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| CN1563157A (en) * | 2004-04-05 | 2005-01-12 | 清华大学 | Method for covalent grafting heparin on surface of polymer film |
| WO2007146261A2 (en) * | 2006-06-09 | 2007-12-21 | The Regents Of The University Of California | Biomolecule-linked biomimetic scaffolds |
| CN101361992A (en) * | 2008-09-12 | 2009-02-11 | 西南交通大学 | Method for fixing heparin multilayer film on the surface of titanium dioxide |
| US20090062511A1 (en) * | 2007-09-05 | 2009-03-05 | Raghavendracharyulu Venkata Palle | Process for the preparation of bivalirudin and its pharmaceutical compositions |
| CN101837149A (en) * | 2010-06-18 | 2010-09-22 | 华中科技大学 | Anti-coagulation anti-bacterial biomedical material and preparation method thereof |
| CN102038955A (en) * | 2009-10-30 | 2011-05-04 | 中南大学湘雅医院 | Method for preparing anticoagulant polysulfones material by fourier reaction grafting |
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2012
- 2012-05-14 CN CN201210147263.6A patent/CN102698323B/en not_active Expired - Fee Related
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1563157A (en) * | 2004-04-05 | 2005-01-12 | 清华大学 | Method for covalent grafting heparin on surface of polymer film |
| WO2007146261A2 (en) * | 2006-06-09 | 2007-12-21 | The Regents Of The University Of California | Biomolecule-linked biomimetic scaffolds |
| US20090062511A1 (en) * | 2007-09-05 | 2009-03-05 | Raghavendracharyulu Venkata Palle | Process for the preparation of bivalirudin and its pharmaceutical compositions |
| CN101361992A (en) * | 2008-09-12 | 2009-02-11 | 西南交通大学 | Method for fixing heparin multilayer film on the surface of titanium dioxide |
| CN102038955A (en) * | 2009-10-30 | 2011-05-04 | 中南大学湘雅医院 | Method for preparing anticoagulant polysulfones material by fourier reaction grafting |
| CN101837149A (en) * | 2010-06-18 | 2010-09-22 | 华中科技大学 | Anti-coagulation anti-bacterial biomedical material and preparation method thereof |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104758985A (en) * | 2015-03-20 | 2015-07-08 | 西南交通大学 | Preparation method of novel anticoagulant stents coating capable of capturing endothelial progenitor cells |
| CN112915267A (en) * | 2020-02-19 | 2021-06-08 | 西南交通大学 | Coating with function of catalytically releasing nitric oxide, preparation method of coating, anticoagulant material, preparation method of anticoagulant material and application of anticoagulant material |
| CN112915267B (en) * | 2020-02-19 | 2022-05-31 | 西南交通大学 | Coating with function of catalytically releasing nitric oxide, preparation method of coating, anticoagulant material, preparation method of anticoagulant material and application of anticoagulant material |
| CN111773440A (en) * | 2020-05-22 | 2020-10-16 | 南京大学 | Anticoagulation material based on enzyme-like catalytic reaction |
| CN114159623A (en) * | 2020-12-12 | 2022-03-11 | 复旦大学 | Self-anti-coagulation elastomer material and preparation method thereof |
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| CN102698323B (en) | 2014-07-23 |
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