CN111494725A - Preparation method and application of anticoagulant layer on metal surface - Google Patents
Preparation method and application of anticoagulant layer on metal surface Download PDFInfo
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- CN111494725A CN111494725A CN202010623287.9A CN202010623287A CN111494725A CN 111494725 A CN111494725 A CN 111494725A CN 202010623287 A CN202010623287 A CN 202010623287A CN 111494725 A CN111494725 A CN 111494725A
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- heparin
- preparation
- anticoagulant
- silanized
- metal surface
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- 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
- A61L33/06—Use of macromolecular materials
- A61L33/08—Polysaccharides
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- 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
- A61L33/0076—Chemical modification of the substrate
- A61L33/0088—Chemical modification of the substrate by grafting of a monomer onto the substrate
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
- C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
- C08B37/006—Heteroglycans, i.e. polysaccharides having more than one sugar residue in the main chain in either alternating or less regular sequence; Gellans; Succinoglycans; Arabinogalactans; Tragacanth or gum tragacanth or traganth from Astragalus; Gum Karaya from Sterculia urens; Gum Ghatti from Anogeissus latifolia; Derivatives thereof
- C08B37/0063—Glycosaminoglycans or mucopolysaccharides, e.g. keratan sulfate; Derivatives thereof, e.g. fucoidan
- C08B37/0075—Heparin; Heparan sulfate; Derivatives thereof, e.g. heparosan; Purification or extraction methods thereof
-
- 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
- A61L2420/00—Materials or methods for coatings medical devices
- A61L2420/02—Methods for coating medical devices
Abstract
Heparin which is clinically used as a first-choice anticoagulant drug is connected with isocyanate siloxane, isocyanate groups of the isocyanate siloxane are combined with hydroxyl groups of the heparin through reaction, and after further hydrolysis, silanized heparin is obtained and is connected to the surface of metal in a covalent bond mode through a self-assembly mode, so that an anticoagulant coating is formed on the surface of the metal. On one hand, the coating keeps the self space structure and has high anticoagulation performance; meanwhile, the heparin is bonded to the surface of the metal through covalent bonds, so that the heparin molecules are not easy to fall off, and the long-acting anticoagulant effect is achieved. Meanwhile, the invention provides the application of the method in the surface anticoagulant coating of the artificial heart titanium alloy blood pump.
Description
Technical Field
The invention relates to a preparation method and application of an anticoagulant layer on a metal surface, and belongs to the technical field of metal surface treatment.
Background
Heart disease is the second leading killer of human death. When the human heart is partially or completely disabled due to damage and can not maintain normal circulation of the whole body, a mechanical device made of artificial materials can be transplanted to temporarily or permanently partially or completely replace the heart function and promote blood circulation, and the device is an artificial heart. The magnetic suspension artificial heart is a mechanical device which utilizes a magnetic suspension bearing without mechanical contact, and a part or all of the magnetic suspension bearing replaces the blood pumping function of the heart, thereby helping the failing heart to complete the blood circulation function, simultaneously reducing the myocardial oxygen consumption of the patient, improving the myocardial contractility and promoting the recovery of the heart function of the patient.
The blood pump is the core of artificial heart, according to the physiological need of human body, the functional and performance requirements of the blood pump are good implantation property, light weight, no hemolysis and no thrombus. Hemolysis refers to the rupture of erythrocytes and the overflow of albumin. Thrombosis refers to the coagulation of flowing blood within a blood vessel or heart chamber to form a blood clot. Hemolysis and thrombosis are the most important and critical issues that blood pumps are urgently in need of solution.
Heparin, as an anticoagulant, is a polymer formed by alternately connecting two polysaccharides and has anticoagulant effects both inside and outside the body. The heparin coating can greatly improve the biocompatibility and the blood compatibility, reduce the inflammatory reaction, reduce the blood damage, reduce the postoperative complications and the like. The medical titanium alloy has the characteristics of high specific strength, fatigue resistance, corrosion resistance, excellent biocompatibility and the like, and is preferably used as a material of a blood pump. Improving the blood compatibility of the blood pump surface and the blood contact part is an effective means for controlling hemolysis and thrombus.
Prior art document 1 (chenopodium depository et al. preparation methods of anti-coagulation titanium oxide thin films on titanium alloy surfaces by photoelectrocatalytic oxidation [ P ]. CN101250738B, 2011-09-14.) describes that titanium oxide thin films are made on titanium alloy surfaces by photoelectrocatalytic oxidation to serve as an anti-coagulation layer, but no evaluation is made on anti-coagulation effects. At present, anticoagulation treatment of titanium alloy surfaces remains a difficult problem.
Disclosure of Invention
In order to overcome the defects of the prior art, the invention provides a preparation method and application of a metal surface anticoagulant layer. The siloxane-oxidized heparin solution is connected to the metal surface oxide layer in a self-assembly and chemical bond combination mode, and the formed heparin anticoagulation layer keeps the self spatial structure through self-assembly, so that the high anticoagulation performance is kept; meanwhile, the heparin molecules are not easy to fall off by connecting the chemical bonds with the metal surface oxidation layer.
The invention adopts the following technical scheme:
a preparation method of a metal surface anticoagulant layer is characterized by comprising the following steps:
step 1, preparation of siloxane-alkylated heparin: isocyanate groups in the isocyanate siloxane react with hydroxyl groups in the heparin to obtain siloxane-alkylated heparin, and the specific reaction formula is as follows:
wherein: r1, R2 and R3 are alkyl groups, preferably-CH 3, -CH2CH3
n is an integer greater than 0, preferably an integer between 2 and 10
Step 2, preparation of silanized heparin: preparing the product obtained in the step 1 into an aqueous solution, and performing hydrolysis reaction of alkoxy to obtain the heparin with silanol groups, wherein the specific reaction formula is as follows:
step 3, reaction of the silanized heparin with the metal surface layer: and (2) performing plasma cleaning treatment on the surface of the prefabricated metal part, further soaking the metal part into the silanized heparin aqueous solution obtained in the step (2), taking out and drying to finish the coupling process of the silanized heparin on the metal surface, wherein the specific reaction process is as follows:
the molar ratio of the isocyanate siloxane to the heparin in the step 1 is more than 1: 1; the reaction temperature is 40-60 ℃; the reaction time is 4-6 hours.
The weight ratio of the siloxanylated heparin in the step 2 in the whole aqueous solution is 1-20%, preferably 3-10%.
The soaking time of the metal part in the silanized heparin aqueous solution in the step 3 is 10-300 s; taking out and drying at the temperature of 30-60 ℃ for 1-48 h.
The invention also provides application of the preparation method of the metal surface anticoagulant layer, and the preparation method is applied to the preparation of the surface anticoagulant coating of the artificial heart titanium alloy blood pump.
The invention achieves the following beneficial effects: heparin which is clinically used as a first-choice anticoagulant drug is connected with isocyanate siloxane, and after further hydrolysis, the heparin is connected to the surface of metal in a covalent bond mode through self-assembly, so that an anticoagulant coating is formed on the surface of the metal, and the coating keeps the spatial structure of the coating and has high anticoagulant performance; meanwhile, the heparin is bonded to the surface of the metal through covalent bonds, so that the heparin molecules are not easy to fall off, and the long-acting anticoagulant effect is achieved.
Detailed Description
In order that those skilled in the art can better understand the present invention, the following embodiments are provided to further illustrate the present invention. It will be apparent that those skilled in the art can make many modifications and variations based on the spirit of the present invention.
As used herein, the singular forms "a", "an", "the" and "the" are intended to include the plural forms as well, unless the context clearly indicates otherwise. It will be further understood that the terms "comprises" and/or "comprising," when used in this specification, specify the presence of stated features, integers, steps, operations, elements, and/or components, but do not preclude the presence or addition of one or more other features, integers, steps, operations, elements, components, and/or groups thereof. It will be understood that when an element, component or section is referred to as being "connected" to another element, component or section, it can be directly connected to the other element or section or intervening elements or sections may also be present. As used herein, the term "and/or" includes any and all combinations of one or more of the associated listed items.
It will be understood by those skilled in the art that, unless otherwise defined, all terms (including technical and scientific terms) used herein have the same meaning as commonly understood by one of ordinary skill in the art.
The preparation method of the anticoagulant coating on the metal surface comprises the following steps:
step 1, preparation of siloxane-alkylated heparin: isocyanate siloxane and heparin react, the reaction takes place between isocyanate group of the isocyanate siloxane and hydroxyl in the heparin, in order to guarantee heparin is completely oxidized by siloxane, the isocyanate group is excessive, namely the molar ratio of the isocyanate siloxane to the heparin is more than 1: 1; the reaction temperature is controlled to be 40-60 ℃; the reaction time is controlled to be 4-6 hours. Siloxane-alkylated heparins are obtained according to the following specific reaction formula:
wherein: r1, R2 and R3 are alkyl groups, preferably-CH 3, -CH2CH3
n is an integer greater than 0, preferably an integer between 2 and 10
Step 2, preparation of silanized heparin: preparing the product obtained in the step 1 into an aqueous solution, wherein the weight ratio of the siloxane-alkylated heparin in the whole aqueous solution is 1-20%, and preferably 3-10%. Hydrolysis reaction of alkoxy takes place to obtain heparin with silanol group, and the specific reaction formula is as follows:
step 3, reaction of the silanized heparin with the metal surface layer: performing plasma cleaning treatment on the surface of a prefabricated metal part, and further soaking the metal part into the silanized heparin aqueous solution obtained in the step 2, wherein the soaking time of the metal part in the silanized heparin aqueous solution is 10-300 s; then taking out and drying for 1-48 h to finish the coupling process of the silanized heparin on the metal surface, wherein the specific reaction process is as follows:
and 4, a platelet adsorption test, namely soaking the treated titanium alloy sheet in phosphate buffer solution (PBS, Ph = 7.2) for 24 hours, taking out the titanium alloy sheet and drying the titanium alloy sheet at room temperature, taking 9m L of whole blood of a healthy person, adding 1m L sodium citrate solution with the concentration of 109 mmol/L and 8m L PBS buffer solution, fully mixing, centrifuging for 5 minutes at the rotation speed of 1200rpm/min, taking supernatant, soaking the titanium alloy sheet in the supernatant for 1 hour, washing the titanium alloy sheet for 3 times by using the PBS buffer solution to remove platelets with weak surface adsorption, soaking the titanium alloy sheet in glutaraldehyde solution with the mass concentration of 2.5 percent by weight for fixing for 12 hours, then dehydrating and naturally drying in the air, spraying gold, and observing the platelet adsorption quantity and morphology under a Scanning Electron Microscope (SEM).
Comparative example 1
And (4) carrying out a platelet adsorption test by taking the untreated titanium alloy sheet as a reference sample, and carrying out sample preparation and test according to the method in the step 4, wherein the result shows that a layer of platelets is adsorbed on the surface of the sample, and the sample is seriously deformed and seriously aggregated.
Examples 1 to 3
Siloxane oxidation of heparin by dissolving 15g of heparin in 100m L anhydrous THF, placing in a three-necked flask, stirring well and introducing dry N2Heating to 60 ℃, dissolving 0.5g of 3-isocyanatopropyltriethoxysilane in 20m L anhydrous THF, placing in a dropping funnel, slowly dropping into a three-necked bottle, completing dropping for 30min, continuously keeping the temperature for reaction for 4h, precipitating twice by anhydrous ether, and placing in a vacuum oven for drying for 24h to obtain the siloxane-alkylated heparin.
Preparation of silanized heparin: siloxane-alkylated heparin and purified water were added to a 500ml beaker in the weight shown in table 1, respectively, stirred uniformly at room temperature and dissolved sufficiently, and the resulting solution was used after standing for 24 hours.
TABLE 1 formulation of various concentrations of siloxane-alkylated heparin solutions
Coating preparation of the metal surface: ultrasonically cleaning the titanium alloy sheet in absolute ethyl alcohol for 10min, drying the titanium alloy sheet in a forced air drying oven at the temperature of 80 ℃ for 2h, further cleaning the surface of the titanium alloy sheet by using a plasma gun, respectively putting the titanium alloy sheet into No. 1-3 silanized heparin solution, soaking the titanium alloy sheet for 30s, taking out the titanium alloy sheet, and drying the titanium alloy sheet in the forced air drying oven at the temperature of 40 ℃ for 24 h.
Platelet adsorption assay: the samples obtained in examples 1 to 3 were subjected to sample preparation and testing in accordance with the procedure of step 4, and the results of the testing are shown in Table 2 below. As can be seen from the results in Table 2, the titanium alloy surface coating of the present invention has a good anticoagulation effect.
Table 2 platelet adsorption test results for different samples
Example 4
Siloxane oxidation of heparin by dissolving 15g of heparin in 100m L anhydrous THF, placing in a three-necked flask, stirring well and introducing dry N2Heating to 60 ℃, dissolving 0.65g of isocyanic octyl triethoxysilane in 20m L anhydrous THF, placing in a dropping funnel, slowly dropping into a three-necked bottle, dropping for 30min, continuing to keep the temperature for reaction for 4h, precipitating with anhydrous ether twice, and placing in a vacuum oven for drying for 24h to obtain the siloxane-alkylated heparin.
Preparation of silanized heparin: 5g of siloxane-alkylated heparin was added to a 500ml beaker, followed by addition of 95g of purified water, stirred uniformly and sufficiently dissolved at room temperature, and the resulting solution was used after leaving for 24 hours.
Coating preparation of the metal surface: ultrasonically cleaning the titanium alloy sheet in absolute ethyl alcohol for 10min, drying the titanium alloy sheet in a forced air drying oven at 80 ℃ for 2h, further cleaning the surface of the titanium alloy sheet by using a plasma gun, respectively putting the titanium alloy sheet into a silanized heparin solution, soaking the titanium alloy sheet for 30s, taking the titanium alloy sheet out, and drying the titanium alloy sheet in the forced air drying oven at 40 ℃ for 24 h.
Platelet adsorption assay: the sample obtained in example 4 is subjected to sample preparation and testing according to the method in step 4, and the test result shows that no obvious platelet adsorption exists and the sample has good anticoagulant property.
As described above, although the embodiments of the present invention have been described in detail, it will be apparent to those skilled in the art that many modifications are possible without substantially departing from the spirit and scope of the present invention. Therefore, such modifications are also all included in the scope of protection of the present invention.
Claims (5)
1. A preparation method of a metal surface anticoagulant layer is characterized by comprising the following steps:
step 1, preparation of siloxane-alkylated heparin: isocyanate groups in the isocyanate siloxane react with hydroxyl groups in the heparin to obtain siloxane-alkylated heparin, and the specific reaction formula is as follows:
wherein: r1, R2 and R3 are-CH 3 or-CH 2CH3
n is an integer of 2 to 10
Step 2, preparation of silanized heparin: preparing the product obtained in the step 1 into an aqueous solution, and performing hydrolysis reaction of alkoxy to obtain the heparin with silanol groups, wherein the specific reaction formula is as follows:
step 3, reaction of the silanized heparin with the metal surface layer: and (2) performing plasma cleaning treatment on the surface of the prefabricated metal part, further soaking the metal part into the silanized heparin aqueous solution obtained in the step (2), taking out and drying to finish the coupling process of the silanized heparin on the metal surface, wherein the specific reaction process is as follows:
2. the method for preparing the anticoagulant layer on the metal surface according to claim 1, wherein the molar ratio of the isocyanate siloxane to the heparin in the step 1 is greater than 1: 1; the reaction temperature is 40-60 deg.c and the reaction time is 4-6 hr.
3. The method according to claim 1, wherein the weight ratio of the siloxanylated heparin in step 2 to the whole aqueous solution is 3-10%.
4. The method for preparing the anticoagulant layer on the metal surface according to claim 1, wherein the soaking time of the metal part in the aqueous solution of the silanized heparin in the step 3 is 10s to 300 s; taking out and drying at the temperature of 30-60 ℃ for 1-48 h.
5. The application of the preparation method of the metal surface anticoagulant layer according to one of claims 1 to 4, which is characterized in that the preparation method is applied to the preparation of the surface anticoagulant coating of the artificial heart titanium alloy blood pump.
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| CN202010623287.9A CN111494725A (en) | 2020-07-02 | 2020-07-02 | Preparation method and application of anticoagulant layer on metal surface |
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4082727A (en) * | 1975-10-21 | 1978-04-04 | Agency Of Industrial Science & Technology | Method for manufacture of non-coagulative organosilicone polymer |
| US6361819B1 (en) * | 1998-08-21 | 2002-03-26 | Medtronic Ave, Inc. | Thromboresistant coating method |
| CN101264351A (en) * | 2008-04-07 | 2008-09-17 | 易生科技(北京)有限公司 | Composite coating cardiovascular medicaments elution stent and preparation thereof |
| CN105744966A (en) * | 2013-11-28 | 2016-07-06 | 东丽株式会社 | Anti-thrombotic material |
| TW201718767A (en) * | 2015-09-04 | 2017-06-01 | 諾華公司 | Soft silicone medical devices with durable lubricious coatings thereon |
-
2020
- 2020-07-02 CN CN202010623287.9A patent/CN111494725A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4082727A (en) * | 1975-10-21 | 1978-04-04 | Agency Of Industrial Science & Technology | Method for manufacture of non-coagulative organosilicone polymer |
| US6361819B1 (en) * | 1998-08-21 | 2002-03-26 | Medtronic Ave, Inc. | Thromboresistant coating method |
| CN101264351A (en) * | 2008-04-07 | 2008-09-17 | 易生科技(北京)有限公司 | Composite coating cardiovascular medicaments elution stent and preparation thereof |
| CN105744966A (en) * | 2013-11-28 | 2016-07-06 | 东丽株式会社 | Anti-thrombotic material |
| TW201718767A (en) * | 2015-09-04 | 2017-06-01 | 諾華公司 | Soft silicone medical devices with durable lubricious coatings thereon |
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Application publication date: 20200807 |