WO2015172664A1 - 降低可全降解镁合金血管支架降解速率的表面涂层制备方法 - Google Patents

降低可全降解镁合金血管支架降解速率的表面涂层制备方法 Download PDF

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WO2015172664A1
WO2015172664A1 PCT/CN2015/077943 CN2015077943W WO2015172664A1 WO 2015172664 A1 WO2015172664 A1 WO 2015172664A1 CN 2015077943 W CN2015077943 W CN 2015077943W WO 2015172664 A1 WO2015172664 A1 WO 2015172664A1
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coating
magnesium alloy
vascular stent
silane coupling
polymer
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PCT/CN2015/077943
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English (en)
French (fr)
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奚廷斐
刘婧
王敏
张志雄
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奚廷斐
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Priority to EP15792801.1A priority Critical patent/EP3144018B1/en
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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
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/08—Materials for coatings
    • A61L31/10—Macromolecular materials
    • 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
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/02—Inorganic materials
    • A61L31/022—Metals or alloys
    • 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
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • 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

Definitions

  • the invention relates to the preparation of a magnesium alloy biomaterial, in particular to a method for preparing a surface coating for reducing the degradation rate of a fully degradable magnesium alloy vascular stent.
  • Interventional vascular stent therapy has become the most important means in the field of cardiovascular disease treatment for more than ten years.
  • the research of vascular stent materials has also experienced permanent bare stents, permanent drug-loading stents, fully degradable metal stents and polymer stents. Three stages of development.
  • the permanent bare stents such as stainless steel, cobalt-chromium alloy and nickel-titanium alloy are used in the clinic. After the treatment function is completed, it remains as a foreign body in the human body, stimulating the blood vessel wall, and significantly increasing the intimal hyperplasia rate of the blood vessel.
  • the blood vessel is re-stenosis, and the thickness and volume of the polymer stent are large, and the end of the blood vessel cannot be reached.
  • the X-ray traceability is not ideal. The heating is required to make the application inconvenient, the radial support force is poor, and the resilience is also large.
  • the degradable magnesium alloy stent has obvious advantages, (1) degradable, the standard electrode potential of magnesium is -2.37V, relatively low, in the presence of Cl - The corrosion resistance of the human physiological environment is even worse. After the vascular lesion is placed according to the specified path, the degradation is completed after the vascular occlusion is completed within a predetermined time, and the degradation product is slowly absorbed by the normal metabolism of the human body.
  • magnesium as an essential trace metal element, has good biocompatibility and group Compatibility, participation in protein synthesis, can activate a variety of enzymes in the body, regulate the activity of the neuromuscular and central nervous system, and ensure the normal contraction of the myocardium, so the appropriate rate of ion release will not cause local inflammation; (3) mechanical properties and human body The microstructure is well matched.
  • the magnesium and magnesium alloys have higher specific strength and specific stiffness. The Young's modulus is about 41-45 GPa, and less than half of the titanium alloy 110-117 GPa, which can effectively alleviate the stress shielding effect.
  • Chinese patent CN201310306991.1 discloses a preparation method of a surface coating capable of regulating the degradation rate of a magnesium alloy vascular stent, which is a Mg-Nd-Zn-Zr magnesium alloy coated with an additive particle containing an alkaline earth metal or the like.
  • a polymer such as polylactic acid controls the degradation rate of the coating by adjusting the content of the additive, thereby controlling the degradation rate of the blood vessel stent, but the coating has poor adhesion to the substrate.
  • Chinese patent CN200920089853.1 discloses a cardiovascular composite coating drug eluting branch, stent It is made of metal tube by laser cutting, the surface of the stent is etched by electrochemical acid solution to cause nanopores, and the surface of the main body is a non-degradable bioactive coating with a thickness of 10 to 50 microns, in non-degradable bioactive coating.
  • the outer layer is a layer of degradable biocompatible polymer drug coating with a thickness of 10 to 100 microns.
  • the drug coating consists of degrading biocompatible polymer and anti-restenosis drug components.
  • Chinese patent CN200910245022.3 discloses an inorganic organic anticorrosive biocompatible composite coating of an absorbable magnesium alloy stent and a preparation thereof.
  • the magnesium alloy stent base is composed of a mass fraction of Y3.7-4.3%, RE(Nd: 2.0-2.5%): 2.4-4.4%, Zr>0.4% magnesium alloy WE4, the dry surface of the stent is an inorganic porous anti-corrosion coating, and the inorganic porous anti-corrosion coating is a dense organic sealing coating, dense organic coating.
  • the drug release coating is a drug release coating.
  • the organic film layer improves the surface biocompatibility, while the degradation products have no side effects, can be absorbed by the human body, biocompatibility and blood compatibility.
  • the drug release coating can reduce the drug release and ensure the sustained release of the drug.
  • Chinese patent CN200610130594.3 discloses an absorbable magnesium alloy stent having a dual controllable release coating and a preparation method thereof.
  • the base of the support is a magnesium alloy WE43 containing a metal element such as lanthanum, cerium, zirconium, lanthanum or cerium, and the surface layer of the base is a dense anticorrosive coating of magnesium aluminum oxide or cerium oxide, and the outer surface is composed of chitosan or collagen.
  • a compact drug-loaded coating in addition to a non-crosslinked drug-loaded coating of poly-L-lactic acid or polyglycolic acid, the outermost layer is a controlled release coating composed of poly-L-lactic acid or polyglycolic acid, the advantages of the stent
  • the coating on the stent is a double controllable release coating that is firmly bonded and does not fall off easily.
  • the commonly used method is coating the polymer coating, and the polymer is polylactic acid.
  • Polyester polymer such as polycaprolactone, but the direct coating method makes the coating with weak adhesion to the magnesium alloy matrix, resulting in poor coating protection ability. The coating degrades too early and degrades, and the peeling loses its protection. effect.
  • the present invention uses a silane coupling agent as an intermediate coating, focusing on improving the bonding force between the polymer coating and the magnesium alloy matrix, and exerting its physical barrier function to block the erosion of corrosive ions such as Cl - in the body fluid, thereby improving The protective properties of the coating on the substrate to reduce the corrosion rate of the substrate and improve the biocompatibility.
  • the main object of the present invention is to provide a surface coating preparation method for reducing the degradation rate of a fully degradable magnesium alloy vascular stent, and a method for preparing a surface coating for reducing the degradation rate of a fully degradable magnesium alloy vascular stent.
  • the surface coating preparation method for the degradation rate of the alloy vascular stent by using the technical scheme, using the excellent mechanical properties, biocompatibility and degradability, the amino group formed by the special silane coupling agent and the hydroxyl group formed by the hydrolysis can be respectively combined with the poly
  • the combination of ester polymer and magnesium alloy improves the bonding force between polyester polymer coating and magnesium alloy substrate; utilizes the characteristics of alkalization and acidification of polyester polymer during corrosion degradation of magnesium alloy matrix to regulate magnesium
  • the corrosion degradation rate of the alloy and the pH of the surrounding solution reduce the corrosion of surrounding tissue to meet the needs of medical magnesium alloys as a cardiovascular scaffolding material.
  • a method for preparing a surface coating for reducing the degradation rate of a fully degradable magnesium alloy vascular stent is as follows:
  • silane coupling agent coating mixing silane coupling agent and organic solvent to form silane coupling grafting agent, grafting silane coupling grafting agent to magnesium alloy for biodegradable vascular stent by dip coating method Surface, heat curing to form a crosslinked silane coupling agent layer;
  • the granular polymer is dissolved in an organic solvent to form a polymer spin coating solvent, and the polymer spin coating solvent is applied by spin coating to the silane coupling grafting agent coated in the above step (1).
  • the surface of the sample layer is vacuum dried, and the polymer spin coating solvent volatilizes to form a polymer coating.
  • the silane coupling agent is ⁇ -aminopropyltriethoxysilane KH550, N-( ⁇ -aminoethyl)- ⁇ -aminopropylmethyldimethoxysilane KH602, ⁇ -aminoethylaminopropyl Any of the trimethoxysilane KH792.
  • the surface of the magnesium alloy for the biodegradable vascular stent is washed with a cleaning solvent, and the cleaning solvent is any one of anhydrous ethanol, anhydrous diethyl ether and deionized water.
  • the magnesium alloy for the biodegradable vascular stent is placed in a silane-coupled grafting agent having a volume percentage of 3.0% to 10.0% (v/v), the dip coating time is 30 to 60 minutes, and the heat curing temperature is 60. ⁇ 120 ° C, curing time is 60 ⁇ 120min.
  • the biodegradable polymer material of the polymer particles is polylactic acid, polycaprolactone, polytrimethylene Any one of a carbonate, a polylactic acid-trimethylene carbonate copolymer, a polycaprolactone-trimethylene carbonate copolymer, a polyglycolic acid, and a polylactic acid-glycolic acid copolymer.
  • the organic solvent is any one of dichloromethane, chloroform, methanol, absolute ethanol, and acetone having a mass percentage concentration of 1.0% to 4.0% (w/v).
  • the spin coating speed in the step (2) is 200 to 6000 r/min, and the spin coating time is 6 to 20 s.
  • the vacuum drying temperature in the step (2) is 37 ° C, and the time is 48 to 60 h.
  • the thickness of the polymer coating produced in the step (2) is 20 to 100 ⁇ m.
  • the magnesium alloy for the biodegradable vascular stent is a Mg-RE series alloy, a WE series alloy, an AZ series alloy, an AM series alloy, a ZK series alloy, a ZM series alloy, a Mg-Li series alloy, and a Mg-Ca series alloy. Any one.
  • the beneficial effect after adopting the above technical solution is: a surface coating preparation method for reducing the degradation rate of the fully degradable magnesium alloy vascular stent, and the magnesium alloy polymer coating pretreated by the silane coupling agent by the technical scheme, Compared with the direct coating of the polymer coating, it can form a chemical bond between the polymer coating and the magnesium alloy substrate, which significantly hinders the erosion of the magnesium alloy substrate by the internal and external environment, greatly reduces the corrosion rate in the internal and external environment, and can Effectively alleviate the problem of peeling off the surface of the magnesium alloy on the vascular stent; 2 magnesium alloy polymer coating pretreated by silane coupling agent, wherein the silane coupling agent is alkaline after degradation, and can neutralize the degradation of the coating.
  • the acidic micro-environment, inhibiting the degradation of the matrix, and the content is extremely low, and finally the substrate and the polymer coating are completely degraded in the human body, and no side effects are caused to the human body; 3 the magnesium alloy polymer coated by the silane coupling agent is coated
  • the layer can control the degree of crosslinking with the surface of the magnesium alloy and the polymer by the amount of the silane coupling agent, thereby controlling the degradation rate of the polymer and the silane coupling agent coating, and further A vascular stent made of magnesium alloy with a degradation rate; 4 technical solution is easy to operate, efficient and environmentally friendly.
  • 1 is an electrochemical open circuit potential OCP curve of MgZnYNd, 2% PLGA-MgZnYNd, 2% PLGA-KH550-MgZnYNd in the examples of the present invention.
  • 3 is an electrochemically polarized Tafel curve of MgZnYNd, 2% PLGA-MgZnYNd, 2% PLGA-KH550-MgZnYNd in the examples of the present invention.
  • Fig. 5 is a diagram showing the EDS of long-term immersion of MgZnYNd for 30 days in the embodiment of the present invention.
  • Figure 6 is a graph showing the EDS of long-term immersion of 2% PLGA-MgZnYNd for 30 days in the embodiment of the present invention.
  • Figure 7 is a graph showing the EDS of (c) 2% PLGA-KH550-MgZnYNd immersed for 30 days in the examples of the present invention.
  • Figure 8 is a SEM image of VSMC and ECV304 cell adhesion of MgZnYNd, 2% PLGA-MgZnYNd, 2% PLGA-KH550-MgZnYNd in the examples of the present invention.
  • Figure 9 is a (a) VSMC cytotoxicity test of MgZnYNd, 2% PLGA-MgZnYNd, 2% PLGA-KH550-MgZnYNd in the examples of the present invention: 1, 3, 5 day survival rate.
  • Figure 10 is a (b) ECV304 cytotoxicity test of MgZnYNd, 2% PLGA-MgZnYNd, 2% PLGA-KH550-MgZnYNd in the examples of the present invention: 1, 3, 5 day survival rate.
  • the invention relates to a method for preparing a surface coating for reducing the degradation rate of a fully degradable magnesium alloy vascular stent, and the method is carried out as follows:
  • silane coupling agent coating mixing silane coupling agent with organic solvent to form silane coupling grafting agent, grafting silane coupling grafting agent to magnesium alloy for biodegradable vascular stent by dip coating method
  • Surface formed by heating to form a crosslinked silane coupling agent layer
  • the granular polymer is dissolved in an organic solvent to form a polymer spin coating solvent, and the polymer spin coating solvent is applied by spin coating to the silane coupling grafting agent coated in the above step (1).
  • the surface of the sample layer is vacuum dried, and the polymer spin coating solvent volatilizes to form a polymer coating.
  • the silane coupling agent is ⁇ -aminopropyltriethoxysilane KH550, N-( ⁇ -aminoethyl)- ⁇ -aminopropylmethyldimethoxysilane KH602, ⁇ -amino B. Any one of propylaminotrimethoxysilane KH792.
  • the surface of the magnesium alloy for the biodegradable vascular stent is washed with a cleaning solvent, and the cleaning solvent is any one of anhydrous ethanol, anhydrous diethyl ether and deionized water.
  • the magnesium alloy for the biodegradable vascular stent after washing is placed
  • the silane coupling grafting agent having a volume percentage of 3.0% to 10.0% (v/v) has a dip coating time of 30 to 60 minutes, a heat curing temperature of 60 to 120 ° C, and a curing time of 60 to 120 minutes.
  • the biodegradable polymer material of the polymer particles is polylactic acid, polycaprolactone, polytrimethylene carbonate, polylactic acid-trimethylene carbonate copolymer, polycaprolactone-Sanya Any one of a methyl carbonate copolymer, a polyglycolic acid, and a polylactic acid-glycolic acid copolymer.
  • the organic solvent is any one of dichloromethane, chloroform, methanol, absolute ethanol, and acetone having a mass percentage concentration of 1.0% to 4.0% (w/v).
  • the spin coating speed in the step (2) is 200 to 6000 r/min, and the spin coating time is 6 to 20 s.
  • the vacuum drying temperature in the step (2) is 37 ° C, and the time is 48 to 60 h.
  • the thickness of the polymer coating produced in the step (2) is from 20 to 100 ⁇ m.
  • the magnesium alloy for biodegradable vascular stent is Mg-RE series alloy, WE series alloy, AZ series alloy, AM series alloy, ZK series alloy, ZM series alloy, Mg-Li series alloy, Mg-Ca Any of a series of alloys.
  • the magnesium alloy for the biodegradable vascular stent is Mg-Zn-Y-Nd
  • the silane coupling agent is ⁇ -aminopropyltriethoxysilane KH550
  • the organic solvent is a dichloromethane solution
  • the surface of the product was set to 200 rpm for 6 s, 6000 rpm for 20 s, and dried in a vacuum oven at 37 ° C for 48 h. The solvent was evaporated to form a polylactic acid-glycolic acid coating.
  • the product prepared in the first embodiment was compared with the Mg-Zn-Y-Nd magnesium alloy which was not pretreated with the silane coupling grafting agent KH550, and the EIS in the electrochemical experiment.
  • the curve shows that the radius of the capacitive reactance arc increases significantly.
  • the corrosion potential E corr obtained by fitting the Tafel polarization curve increases from -1.64V to -0.499V, and the corrosion current I corr decreases from 5.192 ⁇ A ⁇ cm 2 to 1.539 ⁇ A ⁇ cm 2 ;
  • the average degradation rate in Hank's simulated body fluid decreased from 0.12 mg / (cm 2 ⁇ day) to 0.02 mg / (cm 2 ⁇ day); in cytotoxicity experiments, including smooth muscle cell VSMC survival rate decreased in 1-3 days 10 About %, the survival rate of endothelial cell ECV304 increased by about 3-50% in 1-5 days, indicating that it has the potential to promote endothelial cell healing and prevent vascular restenosis.
  • the surface of VSMC and ECV304 cells treated with silane coupling agent The number of adhesions was much greater than that of the untreated group.
  • the method comprises the following steps:
  • the effect of the preparation of the product prepared in the second embodiment is compared with the magnesium alloy which is not pretreated by the silane coupling grafting agent KH550.
  • the EIS curve in the electrochemical experiment shows that the radius of the capacitive arc resistance is significantly increased, and the Tafel polarization curve is fitted.
  • the corrosion potential E corr was increased from -0.401 V to -0.259 V, the corrosion current I corr was decreased from 1.130 ⁇ A ⁇ cm 2 to 0.141 ⁇ A ⁇ cm 2 ; the average degradation rate in Hank's simulated body fluid was 0.12 mg/(cm 2 ).
  • ⁇ day decreased to 0.04mg / (cm 2 ⁇ day); cytotoxicity experiments, including smooth muscle cell VSMC survival rate decreased by 10-25% in 1-3 days, endothelial cell ECV304 survival rate increased 1-5 days 12-45%, indicating that it has the potential to promote endothelial cell healing and prevent vascular restenosis.
  • cytotoxicity experiments including smooth muscle cell VSMC survival rate decreased by 10-25% in 1-3 days, endothelial cell ECV304 survival rate increased 1-5 days 12-45%, indicating that it has the potential to promote endothelial cell healing and prevent vascular restenosis.
  • the number of cell adhesions of VSMC and ECV304 on the surface of the material treated with silane coupling agent was much higher than that of the untreated group.
  • the method comprises the following steps:
  • the product prepared in the third embodiment is compared with the magnesium alloy which is not pretreated by the silane coupling grafting agent KH550.
  • the EIS curve in the electrochemical experiment shows that the radius of the capacitive arc resistance is significantly increased, and the Tafel polarization curve is fitted.
  • the corrosion potential E corr was increased from -1.614V to -0.625V, the corrosion current I corr was reduced from 5.540 ⁇ A ⁇ cm 2 to 0.734 ⁇ A ⁇ cm 2 ; the average degradation rate in Hank's simulated body fluid was 0.15mg/(cm 2 ).
  • ⁇ day decreased to 0.07mg / (cm 2 ⁇ day); cytotoxicity experiments, including smooth muscle cell VSMC survival rate decreased by about 4-8% in 1-3 days, endothelial cell ECV304 survival rate increased by about 1-5 days 3-20%, indicating that it has the potential to promote endothelial cell healing and prevent vascular restenosis.
  • cytotoxicity experiments including smooth muscle cell VSMC survival rate decreased by about 4-8% in 1-3 days, endothelial cell ECV304 survival rate increased by about 1-5 days 3-20%, indicating that it has the potential to promote endothelial cell healing and prevent vascular restenosis.
  • the number of cell adhesions of VSMC and ECV304 on the surface of the material treated with silane coupling agent is much higher than that of the untreated group.
  • the method comprises the following steps:
  • Step 1 preparation of silane coupling agent coating: dissolving silane coupling agent N-( ⁇ -aminoethyl)- ⁇ -aminopropylmethyldimethoxysilane KH602 in absolute ethanol to form volume percent A solution of 5% (v/v) silane-coupled grafting agent KH602 in ethanol, stirred for 1 h, and the biodegradable vascular stent was cut into diameter by magnesium alloy wire.
  • Step 2 Preparation of polymer coating: Dissolving polyglycolic acid particles having a molecular weight of 150,000 in methylene chloride, polymer spin coating solvent to form a mass percentage concentration of 4% (w/v) PGA solution, using spin coating method The polymer was coated on the surface of the sample treated with the silane-coupled grafting agent, the rotation speed was set to 200 rpm for 6 s, 8000 rpm for 20 s, and dried in a vacuum drying oven at 37 ° C for 48 hours, and the solvent was volatilized to form a polyglycolic acid coating.
  • the electrochemical Tafel curve fitting of the product prepared in the fourth embodiment has a significant increase in the corrosion voltage E corr and a significant decrease in the corrosion current I corr , EIS
  • the curve obtained the radius of the capacitive anti-arc; the average degradation rate in Hank's simulated body fluid was significantly reduced, and the survival rate and cell adhesion number of VSMC and ECV304 cells were also increased.
  • the method comprises the following steps:
  • Step 1 preparation of silane coupling agent coating: dissolving silane coupling agent N-( ⁇ -aminoethyl)- ⁇ -aminopropylmethyldimethoxysilane KH792 in absolute ethanol to form volume percent The 5% (v/v) silane coupling grafting agent KH792 in ethanol solution was stirred for 1 h, and the biodegradable magnesium alloy vascular stent was wire-cut into diameter.
  • the branching agent KH792 was grafted onto the surface of the magnesium alloy and cured by heating at 120 ° C for 30 min to form a crosslinked silane coupling agent layer;
  • Step 2 preparation of polymer coating: dissolving polylactic acid particles with a molecular weight of 80,000 in dichloro Methane, polymer spin-on solvent to form a mass percentage concentration of 4% (w/v) PLA solution, the polymer was coated on the surface of the sample treated by silane coupling grafting agent by spin coating, and the rotation speed was set to 200 rpm for 6 s. It was kept at 6000 rpm for 20 s, dried in a vacuum drying oven at 37 ° C for 60 h, and the solvent was volatilized to form a polylactic acid coating.
  • the electrochemical Tafel curve fitting of the product prepared in the fifth embodiment significantly improved the corrosion voltage E corr and significantly reduced the corrosion current I corr .
  • the EIS curve obtained an increase in the radius of the capacitive anti-arc; the average degradation rate in Hank's simulated body fluid was significantly reduced, and the survival rate and cell adhesion number of VSMC and ECV304 cells were also increased.
  • the negative control was serum-containing DMEM medium and the positive control was 10% DMSO.
  • the silane coupling agent-pretreated magnesium alloy polymer coating prepared by the method of the invention can ultimately reduce the degradation rate of the magnesium alloy for biodegradable vascular stent and improve the biocompatibility thereof, and the method of the invention Simple, effective, high efficiency, environmentally friendly, and has a good application prospect.

Abstract

一种降低可降解镁合金血管支架降解速率的表面涂层制备方法，包括，首先将通过浸涂法将硅烷偶联剂接枝到镁合金表面，加热固化，在镁合金表面形成硅烷偶联剂涂层；然后采用旋涂法将聚合物涂覆在硅烷偶联剂涂层表面，真空干燥，形成聚合物涂层。所述经硅烷偶联剂预处理后的镁合金表面涂覆的聚合物涂层能够增强与镁合金血管支架表面的结合力，抑制镁合金基体过快降解，改善血管支架的生物相容性。

Description

降低可全降解镁合金血管支架降解速率的表面涂层制备方法 技术领域
本发明涉及一种镁合金生物材料制备，特别是涉及一种降低可全降解镁合金血管支架降解速率的表面涂层制备方法。
背景技术
介入性血管支架治疗已经成为近十余年以来心血管疾病治疗领域中最重要的手段，血管支架材料的研究也经历了永久性裸支架，永久性载药支架，全降解金属支架和高分子支架三个发展阶段。
目前临床中所使用的多为不锈钢、钴铬合金和镍钛合金等永久性裸支架，完成治疗功能后仍作为外来异物留在人体内，刺激血管壁，显著提高血管的内膜增生率，容易造成血管的再次狭窄，而聚合物支架厚度与体积较大，无法达到末端较细血管，X射线示踪性不理想，使用时需要加热使得应用不便，径向支撑力差且回弹力也很大，从而对血管造成了潜在的危；相比而言，可降解镁合金支架具有明显的优势，(1)可降解，镁的标准电极电位为-2.37V，相对很低，在含有Cl-的人体生理环境中的耐腐蚀性更差，按照指定路径置入血管病变处之后，在预定时间内完成疏导堵塞血管的作用后降解完毕，降解产物随人体正常的新陈代谢被慢慢吸收，血管内部无异物存留，血管再狭窄的几率也得到降低；(2)镁作为人体必需的微量金属元素，具有良好的生物相容性和组织相容性，参与蛋白质合成，能激活体内多种酶，调节神经肌肉和中枢神经系统的活动，保障心肌正常收缩，因此适当速率的离子释放不会引发局部炎症反应；(3)力学性能与人体组织匹配性好，镁及镁合金有较高的比强度和比刚度，杨氏模量约为41-45GPa，且不到钛合金110-117GPa的一半，可有效缓解应力遮挡效应。
中国专利CN201310306991.1公开了一种可调控镁合金血管支架降解速率的表面涂层的制备方法，该支架基材为Mg-Nd-Zn-Zr镁合金，表面涂覆含碱土金属等添加剂颗粒的聚乳酸等聚合物，通过调节添加剂的含量控制涂层的降解速度，从而控制血管支架的降解速度，然而涂层与基底结合力欠佳。
中国专利CN200920089853.1公开了一种心血管复合涂层药物洗脱支，支架 是由金属管材经激光切割制成，支架表面经电化学酸溶液腐蚀致纳米孔，主体表面为一层非降解性生物活性涂层，厚度为10～50微米，在非降解性生物活性涂层的外面为一层可降解生物相容性高分子药物涂层，厚度为10～100微米，药物涂层是由降解生物相容性高分子聚合物、抗再狭窄药物成分组成，此专利优点在于药物释放缓慢，能有效减少支架植入后期的再狭窄及血栓形成。
中国专利CN200910245022.3公开了一种无机有机防腐生物相容性复合涂层的可吸收镁合金支架及其制备方，镁合金支架基干是由质量分数为Y3.7-4.3％，RE(Nd：2.0-2.5％)：2.4-4.4％，Zr>0.4％组成的镁合金WE4，支架基干表层是无机多孔防腐涂层，无机多孔防腐涂层之外是致密有机封孔涂层，致密有机涂层之外是药物释放涂层，药物释放涂层之外是药物缓释涂层。有效地提高镁合金基体的耐腐蚀性和有效控制镁离子的释放速率，同时有机膜层改善表面生物相容性，同时降解产物无副作用，可被人体吸收，生物相容性与血液相容性好，药物释放涂层能够减少药物突释，保证药物持续缓慢释放。
中国专利CN200610130594.3公开了具有双重可控释放涂层的可吸收镁合金支架及其制备方法。该支架基干为含钇、钕、锆、镱、铒等金属元素镁合金WE43，基干表层是镁铝氧化物或铈氧化物的致密防腐涂层，之外是壳聚糖或胶原蛋白构成的交联致密载药涂层，再之外是聚左旋乳酸或聚羟基乙酸构成的非交联载药涂层，最外层是聚左旋乳酸或聚羟基乙酸构成的控释涂，该支架的的优点在于该支架上的涂层为双重可控释放涂层，结合牢固，不易脱落。
由此可见，为解决镁合金作为血管支架用材料降解过快，存在时间不足以完成疏导血管、促进内皮愈合的作用等缺陷，常用的方法为涂覆聚合物涂层，采用聚合物为聚乳酸、聚己内酯等聚酯类聚合物，但是直接涂覆的方法使得涂层与镁合金基体的结合力较弱造成涂层保护能力欠佳，涂层过早过快降解、剥离失去其保护作用。
目前研究较多的解决方案是在聚合物涂层与镁合金基底之间采用各种方法制备一层或多层有机或无机的中间膜层，从而达到增强聚合物涂层与镁合金基底的结合能力、降低基底材料降解速率的目的。
因此，本发明采用硅烷偶联剂作为中间涂层，着眼于提高聚合物涂层与镁合金基体的结合力，并发挥其物理屏障作用，阻挡体液中Cl-等腐蚀性离子的侵蚀， 从而提高涂层对基体的保护性能，以达到降低基体腐蚀速度、改善生物相容性的作用。
发明内容
有鉴于此，本发明的主要目的在于提供一种降低可全降解镁合金血管支架降解速率的表面涂层制备方法降低可全降解镁合金血管支架降解速率的表面涂层制备方法降低可全降解镁合金血管支架降解速率的表面涂层制备方法，通过本技术方案，利用优异的力学性能，生物相容性及可降解性，利用特殊硅烷偶联剂所带氨基及水解形成的羟基可分别与聚酯类聚合物及镁合金键合等特点，提高聚酯类聚合物涂层与镁合金基底的结合力；利用镁合金基体腐蚀降解时碱化、聚酯类聚合物酸化的特点，以调控镁合金的腐蚀降解速率和周围溶液的pH值，从而降低对周围组织的腐蚀，以满足医用镁合金作为心血管支架材料的需要。
为了达到上述目的，本发明的技术方案是这样实现的：
一种降低可全降解镁合金血管支架降解速率的表面涂层制备方法，所述方法按如下步骤进行：
⑴硅烷偶联剂涂层的制备，将硅烷偶联剂后有机溶剂混合形成硅烷偶联接枝剂，采用浸涂法将硅烷偶联接枝剂接枝到可生物降解血管支架用镁合金的表面，加热固化后形成交联硅烷偶联剂层；
⑵聚合物涂层的制备，将颗粒状聚合物溶于有机溶剂混合形成聚合物旋涂溶剂，采用旋涂法将聚合物旋涂溶剂涂覆在具有上述步骤⑴中硅烷偶联接枝剂涂层的样品表面，进行真空干燥，聚合物旋涂溶剂挥发后形成聚合物涂层。
所述硅烷偶联剂为γ-氨丙基三乙氧基硅烷KH550、N-(β-氨乙基)-γ-氨丙基甲基二甲氧基硅烷KH602、γ-氨乙基氨丙基三甲氧基硅烷KH792中的任意一种。
所述可生物降解血管支架用的镁合金表面，采用清洗溶剂进行清洗，所述清洗溶剂为无水乙醇、无水乙醚、去离子水中的任意一种。
将可生物降解血管支架用的镁合金放入到体积百分含量为3.0％～10.0％(v/v)的硅烷偶联接枝剂中，浸涂时间为30～60min，加热固化温度为60～120℃，固化时间为60～120min。
所述聚合物颗粒的可生物降解的高分子材料为聚乳酸、聚己内酯、聚三亚甲 基碳酸酯、聚乳酸-三亚甲基碳酸酯共聚物、聚己内酯-三亚甲基碳酸酯共聚物、聚羟基乙酸、聚乳酸-羟基乙酸共聚物中的任意一种。
所述有机溶剂为质量百分比浓度为1.0％～4.0％(w/v)的二氯甲烷、三氯甲烷、甲醇、无水乙醇、丙酮中的任意一种。
所述步骤⑵中的旋涂转速为200～6000r/min，旋涂时间为6～20s。
所述步骤⑵中真空干燥温度为37℃，时间为48～60h。
所述步骤⑵中所产生的聚合物涂层的厚度为20～100μm。
所述可生物降解血管支架用镁合金为Mg-RE系列合金、WE系列合金、AZ系列合金、AM系列合金、ZK系列合金、ZM系列合金、Mg-Li系列合金、Mg-Ca系列合金中的任意一种。
采用上述技术方案后的有益效果是：一种降低可全降解镁合金血管支架降解速率的表面涂层制备方，通过本技术方案，1经硅烷偶联剂预处理的镁合金聚合物涂层，相比直接涂覆聚合物涂层，能在聚合物涂层与镁合金基底间形成化学键，显著阻碍体内外环境对镁合金基底的侵蚀，大大降低其在体内外环境中的腐蚀速率，并能有效缓解涂层在血管支架用镁合金表面的脱落问题；2经硅烷偶联剂预处理的镁合金聚合物涂层，其中硅烷偶联剂降解后呈碱性，能中和涂层降解所带来的酸性微环境，抑制基体降解，且含量极低，最终与基体及聚合物涂层在人体内完全降解，不会对人体产生副作用；3经硅烷偶联剂预处理的镁合金聚合物涂层，可通过硅烷偶联剂的用量，控制其与镁合金表面及聚合物的交联程度，从而控制聚合物及硅烷偶联剂涂层的降解速度，进而控制血管支架用镁合金的降解速度；4本技术方案易于操作，高效，环保。
附图说明
图1为本发明实施例中MgZnYNd、2％PLGA-MgZnYNd、2％PLGA-KH550-MgZnYNd的电化学开路电位OCP曲线。
图2为本发明实施例中MgZnYNd、2％PLGA-MgZnYNd、2％PLGA-KH550-MgZnYNd的电化学交流阻抗EIS曲线。
图3为本发明实施例中MgZnYNd、2％PLGA-MgZnYNd、2％PLGA-KH550-MgZnYNd的电化学极化Tafel曲线。
图4为本发明实施例中(a)MgZnYNd、(b)2％PLGA-MgZnYNd、 (c)2％PLGA-KH550-MgZnYNd长期浸泡30天SEM图。
图5为本发明实施例中(a)MgZnYNd长期浸泡30天EDS图。
图6为本发明实施例中(b)2％PLGA-MgZnYNd长期浸泡30天EDS图。
图7为本发明实施例中(c)2％PLGA-KH550-MgZnYNd长期浸泡30天EDS图。
图8为本发明实施例中MgZnYNd、2％PLGA-MgZnYNd、2％PLGA-KH550-MgZnYNd的VSMC、ECV304细胞粘附SEM图。
图9为本发明实施例中MgZnYNd、2％PLGA-MgZnYNd、2％PLGA-KH550-MgZnYNd的(a)VSMC细胞毒性测试：1，3，5天存活率。
图10为本发明实施例中MgZnYNd、2％PLGA-MgZnYNd、2％PLGA-KH550-MgZnYNd的(b)ECV304细胞毒性测试：1，3，5天存活率。
具体实施方式
以下结合附图及具体实施例对本发明的技术方案做进一步详细介绍，但本发明的保护范围并不局限于此。
如图1-图8所示。
本发明涉及的降低可全降解镁合金血管支架降解速率的表面涂层制备方法，所述方法按如下步骤进行：
⑴硅烷偶联剂涂层的制备，将硅烷偶联剂与有机溶剂混合形成硅烷偶联接枝剂，采用浸涂法将硅烷偶联接枝剂接枝到可生物降解血管支架用镁合金的表面，加热固化后形成形成交联硅烷偶联剂层；
⑵聚合物涂层的制备，将颗粒状聚合物溶于有机溶剂混合形成聚合物旋涂溶剂，采用旋涂法将聚合物旋涂溶剂涂覆在具有上述步骤⑴中硅烷偶联接枝剂涂层的样品表面，进行真空干燥，聚合物旋涂溶剂挥发后形成聚合物涂层。
作为优化，所述硅烷偶联剂为γ-氨丙基三乙氧基硅烷KH550、N-(β-氨乙基)-γ-氨丙基甲基二甲氧基硅烷KH602、γ-氨乙基氨丙基三甲氧基硅烷KH792中的任意一种。
作为进一步的技术方案，所述可生物降解血管支架用的镁合金表面，采用清洗溶剂进行清洗，所述清洗溶剂为无水乙醇、无水乙醚、去离子水中的任意一种。
作为进一步的技术方案，将经过清洗后的可生物降解血管支架用的镁合金放 入到体积百分含量为3.0％～10.0％(v/v)的硅烷偶联接枝剂中，浸涂时间为30～60min，加热固化温度为60～120℃，固化时间为60～120min。本发明中，所述聚合物颗粒的可生物降解的高分子材料为聚乳酸、聚己内酯、聚三亚甲基碳酸酯、聚乳酸-三亚甲基碳酸酯共聚物、聚己内酯-三亚甲基碳酸酯共聚物、聚羟基乙酸、聚乳酸-羟基乙酸共聚物中的任意一种。
本发明中，所述有机溶剂为质量百分比浓度为1.0％～4.0％(w/v)的二氯甲烷、三氯甲烷、甲醇、无水乙醇、丙酮中的任意一种。
作为进一步的技术方案，所述步骤⑵中的旋涂转速为200～6000r/min，旋涂时间为6～20s。
本发明中，所述步骤⑵中真空干燥温度为37℃，时间为48～60h。
作为优化，所述步骤⑵中所产生的聚合物涂层的厚度为20～100μm。
本发明中，所述可生物降解血管支架用镁合金为Mg-RE系列合金、WE系列合金、AZ系列合金、AM系列合金、ZK系列合金、ZM系列合金、Mg-Li系列合金、Mg-Ca系列合金中的任意一种。
实施例1。
本发明涉及的降低可全降解镁合金血管支架降解速率的表面涂层制备方法的实施例一中，所用可生物降解血管支架用的镁合金为Mg-Zn-Y-Nd，硅烷偶联剂为γ-氨丙基三乙氧基硅烷KH550，颗粒状聚合物为100,000(LA:PA＝75：25)聚乳酸-羟基乙酸颗粒溶，有机溶剂为二氯甲烷溶液，所述方法包括如下步骤：
步骤1，硅烷偶联剂涂层的制备：将硅烷偶联剂γ-氨丙基三乙氧基硅烷KH550溶于有机溶剂二氯甲烷，形成体积百分含量5％(v/v)的硅烷偶联接枝剂KH550的二氯甲烷溶液，搅拌0.5h，将可生物降解的Mg-Zn-Y-Nd镁合金线切割加工为直径
Figure PCTCN2015077943-appb-000001
壁厚为d＝0.8mm的薄片，打磨至2000#，经丙酮、去离子水清洗后，在无水乙醇中超声清洗30min；将样品浸泡在5％(v/v)硅烷偶联接枝剂KH550溶液中0.5h，同时接枝到Mg-Zn-Y-Nd镁合金表面，60℃加热固化100min，形成交联硅烷偶联剂层；
步骤2，聚合物涂层的制备：将相对分子质量100,000(LA:PA＝75：25)聚乳酸-羟基乙酸颗粒溶于二氯甲烷，聚合物旋涂溶剂形成质量百分比浓度2％(w/v)的PLGA溶液，采用旋涂法将聚合物涂覆在硅烷偶联接枝剂处理后的样 品表面，转速设置为200rpm保持6s，6000rpm保持20s，真空干燥箱37℃干燥48h，溶剂挥发形成聚乳酸-羟基乙酸涂层。
如图1至图10所示，通过实验，本实施例1制得的产品与不经硅烷偶联接枝剂KH550预处理的Mg-Zn-Y-Nd镁合金相比，电化学实验中EIS曲线显示容抗弧半径显著增大，Tafel极化曲线拟合所得腐蚀电位Ecorr从-1.644V升高至-0.499V，腐蚀电流Icorr从5.192μA·cm2降低至1.339μA·cm2；在Hank‘s模拟体液中的平均降解速率由0.12mg/(cm2·day)降低至0.02mg/(cm2·day)；细胞毒性实验中，包括平滑肌细胞VSMC存活率在1-3天均降低10％左右，内皮细胞ECV304存活率1-5天提高约3-50％，说明其有促进内皮细胞愈合及防止血管再狭窄的潜能，此外经硅烷偶联剂处理的材料表面VSMC、ECV304两种细胞粘附数目均远多于未处理组。
实施例2。
本发明涉及的降低可全降解镁合金血管支架降解速率的表面涂层制备方法的实施例二中，所述方法包括如下步骤：
步骤1，硅烷偶联剂涂层的制备：将硅烷偶联剂γ-氨丙基三乙氧基硅烷KH550溶于二氯甲烷，形成体积百分含量5％(v/v)的硅烷偶联接枝剂KH550的二氯甲烷溶液，搅拌0.5h；将可生物降解的镁合金线切割加工为直径
Figure PCTCN2015077943-appb-000002
壁厚为d＝0.8mm的薄片，打磨至2000#，经丙酮、去离子水清洗后，在无水乙醇中超声清洗30min；将样品浸泡在5％(v/v)硅烷偶联接枝剂KH550溶液中1.0h，硅烷偶联接枝剂KH550接枝到镁合金表面，100℃加热固化60min，形成交联硅烷偶联剂层；
步骤2，聚合物涂层的制备：将相对分子质量100,000(LA:PA＝75：25)聚乳酸-羟基乙酸颗粒溶于二氯甲烷，聚合物旋涂溶剂形成质量百分比浓度4％(w/v)的PLGA溶液，采用旋涂法将聚合物涂覆在硅烷偶联接枝剂处理后的样品表面，转速设置为200rpm保持6s，8000rpm保持20s，真空干燥箱37℃干燥60h，溶剂挥发形成聚乳酸-羟基乙酸涂层。
实施效果，本实施例2制得的产品与不经硅烷偶联接枝剂KH550预处理的镁合金相比，电化学实验中EIS曲线显示容抗弧半径显著增大，Tafel极化曲线拟合所得腐蚀电位Ecorr从-0.401V升高至-0.259V，腐蚀电流Icorr从1.130μA·cm2 降低至0.141μA·cm2；在Hank‘s模拟体液中的平均降解速率由0.12mg/(cm2·day)降低至0.04mg/(cm2·day)；细胞毒性实验中，包括平滑肌细胞VSMC存活率在1-3天均降低10-25％左右，内皮细胞ECV304存活率1-5天提高约12-45％，说明其有促进内皮细胞愈合及防止血管再狭窄的潜能，此外经硅烷偶联剂处理的材料表面VSMC、ECV304两种细胞粘附数目均远多于未处理组。
实施例3。
本发明涉及的降低可全降解镁合金血管支架降解速率的表面涂层制备方法的实施例三中，所述方法包括如下步骤：
步骤1，硅烷偶联剂涂层的制备：将硅烷偶联剂γ-氨丙基三乙氧基硅烷KH550溶于二氯甲烷，形成体积百分含量3％(v/v)的硅烷偶联接枝剂KH550的二氯甲烷溶液，搅拌0.5h；将可生物降解的镁合金线切割加工为直径
Figure PCTCN2015077943-appb-000003
壁厚为d＝0.8mm的薄片，打磨至2000#，经丙酮、去离子水清洗后，在无水乙醇中超声清洗30min；将样品浸泡在3％(v/v)硅烷偶联接枝剂KH550溶液中1.0h，硅烷偶联接枝剂KH550接枝到镁合金表面，60℃加热固化60min，形成交联硅烷偶联剂层；
步骤2，聚合物涂层的制备：将相对分子质量100,000(LA:PA＝75：25)聚乳酸-羟基乙酸颗粒溶于二氯甲烷，聚合物旋涂溶剂形成质量百分比浓度1％(w/v)的PLGA溶液，采用旋涂法将聚合物涂覆在硅烷偶联接枝剂处理后的样品表面，转速设置为200rpm保持6s，4000rpm保持20s，真空干燥箱37℃干燥60h，溶剂挥发形成聚乳酸-羟基乙酸涂层。
实施效果，本实施例3制得的产品与不经硅烷偶联接枝剂KH550预处理的镁合金相比，电化学实验中EIS曲线显示容抗弧半径显著增大，Tafel极化曲线拟合所得腐蚀电位Ecorr从-1.614V升高至-0.625V，腐蚀电流Icorr从5.540μA·cm2降低至0.734μA·cm2；在Hank‘s模拟体液中的平均降解速率由0.15mg/(cm2·day)降低至0.07mg/(cm2·day)；细胞毒性实验中，包括平滑肌细胞VSMC存活率在1-3天均降低4-8％左右，内皮细胞ECV304存活率1-5天提高约3-20％，说明其有促进内皮细胞愈合及防止血管再狭窄的潜能，此外经硅烷偶联剂处理的材料表面VSMC、ECV304两种细胞粘附数目均远多于未处理组。
实施例4。
本发明涉及的降低可全降解镁合金血管支架降解速率的表面涂层制备方法的实施例四中，所述方法包括如下步骤：
步骤1，硅烷偶联剂涂层的制备：将硅烷偶联剂N-(β-氨乙基)-γ-氨丙基甲基二甲氧基硅烷KH602溶于无水乙醇，形成体积百分含量5％(v/v)的硅烷偶联接枝剂KH602的乙醇溶液，搅拌1h，将生物降解血管支架用镁合金线切割加工为直径
Figure PCTCN2015077943-appb-000004
壁厚为d＝0.8mm的薄片，打磨至2000#，在无水乙醇中超声清洗30min；将样品浸泡在5％(v/v)硅烷偶联接枝剂KH602溶液中0.5h，硅烷偶联接枝剂KH602接枝到镁合金表面，75℃加热固化40min，形成交联硅烷偶联剂层；
步骤2，聚合物涂层的制备：将相对分子质量150,000的聚羟基乙酸颗粒溶于二氯甲烷，聚合物旋涂溶剂形成质量百分比浓度4％(w/v)的PGA溶液，采用旋涂法将聚合物涂覆在硅烷偶联接枝剂处理后的样品表面，转速设置为200rpm保持6s，8000rpm保持20s，真空干燥箱37℃干燥48h，溶剂挥发形成聚羟基乙酸涂层。
实施效果：本实施例4制得的产品与硅烷偶联接枝剂KH602预处理的镁合金相比，其电化学Tafel曲线拟合得到腐蚀电压Ecorr明显提高、腐蚀电流Icorr显著降低，EIS曲线得到容抗弧半径增大；在Hank‘s模拟体液中的平均降解速率显著降低，VSMC、ECV304两种细胞的存活率和细胞粘附数目也得到相应提高。
实施例5。
本发明涉及的降低可全降解镁合金血管支架降解速率的表面涂层制备方法的实施例五中，所述方法包括如下步骤：
步骤1，硅烷偶联剂涂层的制备：将硅烷偶联剂N-(β-氨乙基)-γ-氨丙基甲基二甲氧基硅烷KH792溶于无水乙醇，形成体积百分含量5％(v/v)的硅烷偶联接枝剂KH792的乙醇溶液，搅拌1h，将生物降解镁合金血管支架线切割加工为直径
Figure PCTCN2015077943-appb-000005
壁厚为d＝0.8mm的薄片，打磨至2000#，无水乙醇中超声清洗30min；将样品浸泡在5％(v/v)硅烷偶联接枝剂KH792溶液中0.5h，硅烷偶联接枝剂KH792接枝到镁合金表面，120℃加热固化30min，形成交联硅烷偶联剂层；
步骤2，聚合物涂层的制备：将相对分子质量80,000的聚乳酸颗粒溶于二氯 甲烷，聚合物旋涂溶剂形成质量百分比浓度4％(w/v)的PLA溶液，采用旋涂法将聚合物涂覆在硅烷偶联接枝剂处理后的样品表面，转速设置为200rpm保持6s，6000rpm保持20s，真空干燥箱37℃干燥60h，溶剂挥发形成聚乳酸涂层。
实施效果：本实施例5制得的产品与不经硅烷偶联接枝剂KH792预处理的镁合金相比，其电化学Tafel曲线拟合得到腐蚀电压Ecorr明显提高、腐蚀电流Icorr显著降低，EIS曲线得到容抗弧半径增大；在Hank‘s模拟体液中的平均降解速率显著降低，VSMC、ECV304两种细胞的存活率和细胞粘附数目也得到相应提高。
本发明的图9和图10中，阴性对照为含血清的DMEM培养基，阳性对照为10％DMSO。
综上所述，本发明方法制备的经硅烷偶联剂预处理的镁合金聚合物涂层，最终可以降低可生物降解血管支架用镁合金降解速率，且提高其生物相容性，本发明方法简单，效果显著，效率高，环保，具有较好的应用前景。
以上所述，仅是本发明的较佳实施例，并非对本发明做任何形式上的限制，任何未脱离本发明技术方案的内容，依据本发明的技术实质对以上实施例所作的任何简单修改、等同变化与修饰，均属于本发明技术方案的范围。

Claims (10)

  1. 一种降低可全降解镁合金血管支架降解速率的表面涂层制备方法，其特征在于，所述方法按如下步骤进行：
    ⑴硅烷偶联剂涂层的制备，将硅烷偶联剂与有机溶剂混合形成硅烷偶联接枝剂，采用浸涂法将硅烷偶联接枝剂接枝到可生物降解血管支架用镁合金的表面，加热固化后形成交联硅烷偶联剂层涂层；
    ⑵聚合物涂层的制备，将颗粒状聚合物溶于有机溶剂混合形成聚合物旋涂溶剂，采用旋涂法将聚合物旋涂溶剂涂覆在具有上述步骤⑴中硅烷偶联接枝剂涂层的样品表面，进行真空干燥，聚合物旋涂溶剂挥发后形成聚合物涂层。
  2. 根据权利要求1所述的降低可全降解镁合金血管支架降解速率的表面涂层制备方法，其特征在于，所述硅烷偶联剂为γ-氨丙基三乙氧基硅烷KH550、N-(β-氨乙基)-γ-氨丙基甲基二甲氧基硅烷KH602、γ-氨乙基氨丙基三甲氧基硅烷KH792中的任意一种。
  3. 根据权利要求1所述的降低可全降解镁合金血管支架降解速率的表面涂层制备方法，其特征在于，所述可生物降解血管支架用的镁合金表面，采用清洗溶剂进行清洗，所述清洗溶剂为无水乙醇、无水乙醚、去离子水中的任意一种。
  4. 根据权利要求1所述的降低可全降解镁合金血管支架降解速率的表面涂层制备方法，其特征在于，将可生物降解血管支架用的镁合金放入到体积百分含量为3.0％～10.0％(v/v)的硅烷偶联接枝剂中，浸涂时间为30～60min，加热固化温度为60～120℃，固化时间为60～120min。
  5. 根据权利要求1所述的降低可全降解镁合金血管支架降解速率的表面涂层制备方法，其特征在于，所述聚合物颗粒的可生物降解的高分子材料为聚乳酸、聚己内酯、聚三亚甲基碳酸酯、聚乳酸-三亚甲基碳酸酯共聚物、聚己内酯-三亚甲基碳酸酯共聚物、聚羟基乙酸、聚乳酸-羟基乙酸共聚物中的任意一种。
  6. 根据权利要求1所述的降低可全降解镁合金血管支架降解速率的表面涂层制备方法，其特征在于，所述有机溶剂为质量百分比浓度为1.0％～4.0％(w/v)的二氯甲烷、三氯甲烷、甲醇、无水乙醇、丙酮中的任意一种。
  7. 根据权利要求1所述的降低可全降解镁合金血管支架降解速率的表面涂层制备方法，其特征在于，所述步骤⑵中的旋涂转速为200～6000r/min，旋涂时 间为6～20s。
  8. 根据权利要求1所述的降低可全降解镁合金血管支架降解速率的表面涂层制备方法，其特征在于，所述步骤⑵中真空干燥温度为37℃，时间为48～60h。
  9. 根据权利要求1所述的降低可全降解镁合金血管支架降解速率的表面涂层制备方法，其特征在于，所述步骤⑵中所产生的聚合物涂层的厚度为20～100μm。
  10. 根据权利要求1所述的降低可全降解镁合金血管支架降解速率的表面涂层制备方法，其特征在于，所述可生物降解血管支架用镁合金为Mg-RE系列合金、WE系列合金、AZ系列合金、AM系列合金、ZK系列合金、ZM系列合金、Mg-Li系列合金、Mg-Ca系列合金中的任意一种。
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