A method for in-situ generation of zinc phosphate protective layer on zinc alloy and application thereof

Abstract

The application discloses a method for generating a zinc phosphate protective layer on a zinc alloy in situ and application thereof. The method comprises the following steps: soaking the zinc alloy in a reaction solution containing phosphate, nitrate and nitrite for 3-30 min, and generating the zinc phosphate protective layer on the zinc alloy in situ. The reaction solution is configured to react with the zinc alloy on the surface, and zinc phosphate and other salts are generated in situ, so that a light and thin and dense zinc phosphate layer is formed, a traditional physical combination mode is broken, the generated coating is metallurgically combined with the matrix, the interface bonding force is stronger, and thus the problem that the coating on the surface of the zinc alloy is easy to fall off in the prior art is solved.

Description

Technical Field

[0001] This invention belongs to the field of materials, specifically relating to a method for in-situ generating a zinc phosphate protective layer on a zinc alloy and its application. Background Technology

[0002] Zinc and zinc alloys are widely used in medical devices due to their excellent mechanical properties and degradation characteristics, and are currently widely used in sports medicine and orthopedics. However, continuous use has revealed that pure zinc is unstable in corrosive environments in body fluids, prone to rapid pitting corrosion and localized excessively rapid degradation, leading to early mechanical failure after implantation. This corrosion instability also results in excessively high zinc ion concentrations during the rapid degradation phase, inhibiting cell proliferation and inducing local redness, swelling, and inflammatory reactions related to the foreign body. Furthermore, pure zinc has high surface activity and numerous surface defects, which are detrimental to cell adhesion and growth. Therefore, a technical solution of applying coatings to the surface of zinc alloys has been proposed. Coating materials have evolved from Ca-Zn-P coatings to calcium phosphate ceramic coatings and polymer coatings, and from single-layer coatings to composite coatings. Clearly, coatings can regulate degradation behavior, reduce cytotoxicity, and promote tissue integration, making them a key modification method for achieving safe clinical application of biodegradable zinc alloy medical devices.

[0003] However, in the field of luminal stents, which are mainly coronary stents, the mainstream materials on the market are still non-degradable stents made of materials such as cobalt-chromium alloys. This is because the harsh operating conditions inside coronary blood vessels not only require that mechanical properties meet the standards, but also that they withstand the shear force of blood flow and the periodic pulsation of blood vessels. Compared with materials such as nickel-titanium alloys, the relatively poor physicochemical properties of degradable materials will be continuously amplified in the coronary blood vessel scenario, making it difficult for simple material replacement to face many problems such as mismatch in mechanical properties and degradation cycles.

[0004] Although coating can partially alleviate the above problems, the oxide layer on the surface of zinc alloy is loose. Films deposited by physical methods such as ion deposition, surface coating, and vapor deposition are prone to peeling off under long-term periodic pulsation. Partial peeling can lead to sudden release of zinc alloy, making it impossible to control the release stably. Summary of the Invention

[0005] The present invention aims to solve at least one of the technical problems existing in the prior art. To this end, the present invention proposes a method for in-situ generating a zinc phosphate protective layer on a zinc alloy.

[0006] The present invention also proposes a zinc alloy prepared by the above method.

[0007] The present invention also proposes applications of the zinc alloy prepared by the above method.

[0008] According to one aspect of the present invention, a method for in-situ generating a zinc phosphate protective layer on a zinc alloy is provided, the method comprising the following steps: immersing the zinc alloy in a reaction solution containing phosphate, nitrate and nitrite for 3-30 min, thereby generating a zinc phosphate protective layer in-situ on the zinc alloy.

[0009] In some embodiments of the present invention, the zinc alloy contains 90%-99.99% zinc by mass.

[0010] In some embodiments of the present invention, the trace element content in the zinc alloy is 0-3% by mass.

[0011] In some embodiments of the present invention, the zinc alloy is an alloy comprising zinc and at least one of copper, magnesium, calcium, strontium, iron, manganese, silicon, lithium, silver, tin and rare earth elements.

[0012] In some embodiments of the present invention, the rare earth elements include at least one of lanthanum (La), cerium (Ce), praseodymium (Pr), neodymium (Nd), promethium (Pm), samarium (Sm), europium (Eu), gadolinium (Gd), terbium (Tb), dysprosium (Dy), holmium (Ho), erbium (Er), thulium (Tm), ytterbium (Yb), lutetium (Lu), yttrium (Y), and scandium (Sc).

[0013] In some embodiments of the present invention, the phosphate includes zinc dihydrogen phosphate.

[0014] In some embodiments of the present invention, the nitrate includes zinc nitrate.

[0015] In some embodiments of the present invention, the nitrite includes sodium nitrite.

[0016] In some embodiments of the present invention, the phosphate content in the reaction solution is 45-55 g / L. For example, it can be 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55 g / L or any two of these numbers as any intermediate value between the endpoints.

[0017] In some embodiments of the present invention, the nitrate content in the reaction solution is 55-65 g / L. For example, it can be 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65 g / L or any two of these numbers as any intermediate value between the endpoints.

[0018] In some embodiments of the present invention, the nitrite content in the reaction solution is 0.5-2 g / L. For example, it can be 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0 g / L, or any two of these numbers as any intermediate value between the endpoints.

[0019] In some embodiments of the present invention, the solvent of the reaction solution includes water.

[0020] In some embodiments of the present invention, the pH value of the reaction solution is 2-7.

[0021] In some embodiments of the present invention, the pH value of the reaction solution is 4-6. Specifically, the pH value is 4, 5, 6, or any two of these numbers as any intermediate value between the endpoints.

[0022] In some embodiments of the present invention, the pH value of the reaction solution is adjusted by phosphoric acid or sodium hydroxide.

[0023] In some embodiments of the present invention, the reaction time is 5-20 min.

[0024] In some embodiments of the present invention, the reaction time is 5-15 min. Specifically, the reaction time can be 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 min or any two of these numbers as any intermediate value between the endpoints.

[0025] In some embodiments of the present invention, the temperature of the reaction is 10-50°C.

[0026] In some embodiments of the present invention, the reaction temperature is 20-40°C.

[0027] In some embodiments of the present invention, the reaction temperature is 25-35°C. Specifically, the reaction temperature may be 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35°C.

[0028] In some embodiments of the present invention, the zinc alloy is further subjected to a pretreatment step before the reaction, the steps being as follows: the zinc alloy is placed in acetone for 4-6 minutes for cleaning, then cleaned with ethanol; and finally rinsed with deionized water.

[0029] In some embodiments of the present invention, after the reaction is completed, a step of rinsing the zinc alloy with deionized water is also included.

[0030] In some embodiments of the present invention, the zinc phosphate layer covers the entire surface of the zinc alloy body.

[0031] According to a second aspect of the present invention, a zinc alloy material prepared by the above-described preparation method is provided.

[0032] In some embodiments of the present invention, the zinc alloy material includes a medical intraluminal stent.

[0033] In some embodiments of the present invention, a functional layer is further provided on the outer side of the medical intraluminal stent. The functional layer may be a polymer coating or a drug-loaded coating.

[0034] In some embodiments of the present invention, the medical endovascular stent is a coronary artery stent, aortic stent, intracranial vascular stent, peripheral vascular stent, intraoperative stent, heart valve stent, biliary stent, esophageal stent, intestinal stent, pancreatic duct stent, urethral stent, or tracheal stent.

[0035] According to a third aspect of the present invention, the application of the above-mentioned zinc alloy material in the manufacture of implantable medical devices is proposed.

[0036] In some embodiments of the present invention, the implantable medical device is a medical intraluminal stent.

[0037] In some embodiments of the present invention, the medical endovascular stent is a coronary artery stent, aortic stent, intracranial vascular stent, peripheral vascular stent, intraoperative stent, heart valve stent, biliary stent, esophageal stent, intestinal stent, pancreatic duct stent, urethral stent, or tracheal stent.

[0038] According to some embodiments of the present invention, at least the following beneficial effects are achieved: This invention provides a method for applying a coating to the surface of a zinc alloy substrate. Unlike traditional physical methods such as spraying or dipping, this method involves preparing a reaction solution that reacts with the zinc alloy on the surface to generate zinc phosphate and other salts in situ, thereby forming a thin and dense zinc phosphate layer. This method breaks through the traditional physical bonding method, and the resulting coating is metallurgically bonded to the substrate with stronger interfacial adhesion, thus overcoming the problem of easy peeling off of zinc alloy surface coatings in the prior art.

[0039] Meanwhile, the coating in this invention is not a traditional polymer layer, but a zinc phosphate coating. The zinc phosphate coating itself is a stable phosphate phase that dissolves slowly and steadily, uniformly regulating the Zn content. 2+ The release process inhibits pitting and crevice corrosion of zinc alloys and can induce surface bone-like apatite mineralization, improve endothelial cell adhesion, and accelerate vascular endothelialization without creating an acidic environment. The release of zinc alloys is more stable and controllable.

[0040] The luminal stents, especially vascular stents, prepared using the method of this invention have an intermediate layer that physically blocks the contact between the substrate and the blood, preventing the explosive release of zinc ions in a short period of time, and thus avoiding the prominent problem of early in-stent stenosis caused by fibrin aggregation in the blood. Attached Figure Description

[0041] The present invention will be further described below with reference to the accompanying drawings and embodiments, wherein: Figure 1 This is a 200x scanning electron microscope image of the surface of the zinc alloy vascular stent in an embodiment of the present invention; Figure 2 This is a 2000x scanning electron microscope image of the surface of the zinc alloy vascular stent in an embodiment of the present invention; Figure 3 This is a 10,000x scanning electron microscope image of the surface of the zinc alloy vascular stent in an embodiment of the present invention. Figure 4 This is a 2000x scanning electron microscope image of the surface of the zinc alloy vascular stent in an embodiment of the present invention; Figure 5 As described in the embodiments of the present invention Figure 4 Middle spectrum Figure 11 EDS image of the location; Figure 6 This is a 1000x scanning electron microscope image of the cross-section of the zinc alloy vascular stent in an embodiment of the present invention; Figure 7 This is a scanning electron microscope image of the cross-section of the zinc alloy vascular stent in an embodiment of the present invention, magnified 5000 times. Figure 8 This is a 10,000x scanning electron microscope image of the cross-section of the zinc alloy vascular stent in an embodiment of the present invention; Figure 9 This is a scanning electron microscope image of the cross-section of the zinc alloy vascular stent in an embodiment of the present invention, magnified 5000 times. Figure 10 As described in the embodiments of the present invention Figure 9 Middle spectrum Figure 1 EDS image of the location; Figure 11 This is a schematic diagram of the vascular stent structure in an embodiment of the present invention. Detailed Implementation

[0042] The following will describe the concept and technical effects of the present invention clearly and completely with reference to embodiments, so as to fully understand the purpose, features and effects of the present invention. Obviously, the described embodiments are only some embodiments of the present invention, not all embodiments. Other embodiments obtained by those skilled in the art based on the embodiments of the present invention without creative effort are all within the scope of protection of the present invention.

[0043] Unless otherwise specified in the examples, the procedures should be performed under standard conditions or conditions recommended by the manufacturer. Reagents or instruments whose manufacturers are not specified are all commercially available products.

[0044] Example 1 This embodiment provides a method for in-situ generating a zinc phosphate protective layer on a zinc alloy. The method involves immersing the zinc alloy substrate in a solution containing nitrates and nitrites, allowing the combination of nitrates and nitrites to react with zinc to form a core redox reaction, generating zinc ions. The phosphates provide phosphate ions, and when the concentrations of zinc ions and phosphate ions in the solution reach supersaturation, zinc phosphate crystallizes and precipitates on the surface of the zinc substrate, thereby generating a zinc phosphate protective layer in situ on the zinc alloy.

[0045] 1. The main chemical principles are as follows: (1) The zinc matrix reacts with the free phosphoric acid in the phosphating solution and begins to dissolve: Zn + 2H3PO4 → Zn + +2(H2PO4) - +H2↑; In the reaction solution, zinc dihydrogen phosphate releases hydrogen ions after hydrolysis, maintaining the weak acidity of the solution and achieving ideal reaction conditions in conjunction with phosphoric acid.

[0046] (2) Sodium nitrite acts as an oxidation promoter, with the following main reaction formula: 2NO 2- +2H + +3H2→N2↑+4H2O; Hydrogen depolarization: Hydrogen gas produced by the oxidation reaction prevents bubbles from hindering the formation of the phosphating film; Oxidation: This process converts Fe in the solution into Fe. 2+ (If present) Oxidized to Fe 3+ The resulting phosphate residue is removed. Accelerate the deposition of insoluble salts: gradually isolate the metal matrix from the bath solution.

[0047] (3) Zinc dihydrogen phosphate hydrolyzes in water to produce free phosphoric acid and zinc hydrogen phosphate: ; Zinc hydrogen phosphate undergoes further hydrolysis: ; Phosphoric acid further ionizes: .

[0048] (4) Formation of zinc phosphate film When zinc ions (Zn) are in the solution 2+ ) and phosphate ions (PO4) 3-When the concentration of zinc phosphate reaches supersaturation, zinc phosphate crystallizes and precipitates on the surface of the zinc matrix. 3Zn 2+ +2PO4 3 +4H₂O→Zn 3 (PO4)2·4H2O; Zinc, as a substrate, consumes itself to form a zinc phosphate film in situ.

[0049] 2. The method specifically includes the following steps: (1) Preparation of experimental materials and reagents Sample: 3009 specification zinc alloy stent (original strength 145kPa, mass 8-9mg).

[0050] Phosphating solution: An aqueous solution containing 50 g / L zinc dihydrogen phosphate, 60 g / L zinc nitrate, and 1 g / L sodium nitrite, titrated with phosphoric acid / sodium hydroxide to a pH of 4-6.

[0051] Cleaning agents: acetone, anhydrous ethanol, deionized water.

[0052] (2) Experimental steps Phase 1: Pre-processing 1) Degreasing: Place the bracket in acetone and ultrasonically clean for 5 minutes to remove surface oil stains; 2) Rinsing: Immerse in anhydrous ethanol and rinse with deionized water.

[0053] Phase Two: Coating Preparation 1) Solution preparation: Prepare the phosphating solution according to the formula, and slowly titrate it to the target pH value using phosphoric acid / sodium hydroxide (pH 4-6 is acceptable).

[0054] 2) Constant temperature: Place the phosphating solution in a water bath and preheat it to the set temperature of 30℃ (20-40℃ is also acceptable).

[0055] 3) Reaction: Use tweezers or a basket to immerse the support in the phosphating solution and soak for 10 minutes.

[0056] 4) Post-treatment: Rinse immediately with warm deionized water after removal to prevent residual liquid from continuing to corrode the surface, and then dry.

[0057] Test case This experimental example tested the method of Example 1 in the application of a zinc alloy vascular stent (the zinc alloy is a Zn-Cu alloy, wherein copper accounts for 2% and the balance is zinc, as shown in the schematic diagram). Figure 11 A zinc alloy vascular stent with an in-situ zinc phosphate protective layer was prepared on the stent (as shown in the figure).

[0058] Experimental samples: such as Figure 1The zinc alloy vascular stent shown is in situ generated with a zinc phosphate protective layer.

[0059] Experimental methods: Scanning electron microscopy / energy dispersive spectroscopy.

[0060] pass Figures 1-4 It can be seen that the surface is covered with a large number of near-spherical and ellipsoidal fine and dense particles, which are uniformly stacked, which is a typical microstructure of metal corrosion and surface deposition layer.

[0061] according to Figure 5 As can be seen from Table 1, high levels of zinc, oxygen, and phosphorus were detected in this section. The zinc content is from the zinc alloy matrix itself and the degradation products of zinc oxide or zinc hydroxide generated by corrosion. The oxygen content is from metal oxides, hydroxides, and phosphate structures. The phosphorus content comes from phosphate ions in the reaction solution, indicating that zinc phosphate and bone apatite-like biomineralization layers were induced on the material surface.

[0062] Based on the principles of this invention, it is not difficult to conclude that zinc alloys undergo uniform and controllable degradation under physiological conditions, while simultaneously forming a bioactive calcium-phosphorus / phosphate salt deposition layer on the surface. This is beneficial for improving biocompatibility and cell affinity in vivo, and slowing down excessively rapid local corrosion. It is an ideal surface behavior for biodegradable medical metals.

[0063] Table 1

[0064] Figure 6-9 The microscopic images of the cross-section show a wavy gray thin layer above the substrate, which is a composite coating of degradation and biomineralization on the surface of the scaffold or a corrosion product layer. The local thicknesses of the degradation layer are 1.9 μm, 2.2 μm, and 2.9 μm, respectively. The overall thickness of the layer fluctuates little, and the layer structure is continuous and complete, with only slight unevenness in thickness. This indicates that the degradation and mineralization on the zinc alloy surface is uniform overall, with no local severe corrosion perforation. exist Figure 10 As can be seen from Table 2, the surface layer is a zinc oxide-phosphate composite biodegradable active layer.

[0065] Table 2

[0066] Among them, Zn (zinc): the strongest characteristic peak, comes from zinc matrix substrate + degraded zinc salt; O (oxygen): strong peak, corresponding to oxidation and corrosion products such as ZnO and Zn(OH)2; P (phosphorus): Extremely high intensity characteristic peak, proving that the surface layer is enriched with a large amount of phosphorus-containing biophase (zinc phosphate, hydroxyapatite-like), which is a biomineralization deposition induced by physiological environment; C (carbon): A weak peak, originating from the embedded resin, the carbon-sprayed conductive layer, and trace amounts of organic contaminants.

[0067] Combining the two sets of test images confirms that the method of this invention can generate zinc phosphate in situ, and the generated zinc phosphate densely and uniformly covers the surface of the substrate; it can also be seen that the generated coating has formed a metallurgical bond with the cross-section of the substrate. Obviously, the film formed by the above method has a higher bonding strength than the film formed by coating or other methods. The coating of coating is usually only attached to the surface of the substrate. For products such as lumen supports, it is subject to the pressure of the lumen wall and the scouring of the fluid in the lumen, which can easily lead to damage or peeling. However, the film formed by the above method is formed by the outermost zinc element participating in the reaction, achieving a near metallurgical bond with the substrate, which is obviously more robust.

[0068] The embodiments of the present invention have been described in detail above with reference to the accompanying drawings. However, the present invention is not limited to the above embodiments. Within the scope of knowledge possessed by those skilled in the art, various changes can be made without departing from the spirit of the present invention. Furthermore, unless otherwise specified, the embodiments of the present invention and the features thereof can be combined with each other.

Claims

1. A method for in-situ forming a zinc phosphate protective layer on a zinc alloy, characterized in that, The method includes the following steps: immersing a zinc alloy in a reaction solution containing phosphate, nitrate and nitrite for 3-30 minutes to generate a zinc phosphate protective layer in situ on the zinc alloy.

2. The method according to claim 1, characterized in that, The zinc alloy contains 50%-99.99% zinc by mass.

3. The method according to claim 1, characterized in that, The phosphate includes zinc dihydrogen phosphate; And / or, the nitrate includes zinc nitrate; And / or, the nitrite includes sodium nitrite.

4. The method according to claim 1, characterized in that, The phosphate content in the reaction solution is 45-55 g / L; And / or, the nitrate content in the reaction solution is 55-65 g / L; And / or, the nitrite content in the reaction solution is 0.5-2 g / L.

5. The method according to claim 1, characterized in that, The pH value of the reaction solution is 2-7; Preferably, the pH value of the reaction solution is 4-6; Preferably, the pH value of the reaction solution is adjusted by phosphoric acid or sodium hydroxide.

6. The method according to claim 1, characterized in that, The reaction time is 5-20 minutes; Preferably, the reaction time is 5-15 minutes; And / or, the temperature of the reaction is 10-50°C; Preferably, the reaction temperature is 20-40°C.

7. The method according to claim 1, characterized in that, Before the zinc alloy undergoes the reaction, a pretreatment step is also included, which is as follows: the zinc alloy is placed in acetone for 4-6 minutes for cleaning, then cleaned with ethanol; and finally rinsed with deionized water.

8. A zinc alloy material, characterized in that, Prepared by the method described in any one of claims 1-7.

9. The application of the zinc alloy material according to claim 8 in the manufacture of implantable medical devices; Preferably, the implantable medical device is a medical intraluminal stent.

10. The application according to claim 9, characterized in that, The medical endovascular stents include coronary artery stents, aortic stents, intracranial stents, peripheral stents, intraoperative stents, heart valve stents, biliary stents, esophageal stents, intestinal stents, pancreatic duct stents, urethral stents, or tracheal stents.

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