Medical magnesium alloy intravascular stent and preparation method thereof

Abstract

The invention discloses a medical magnesium alloy intravascular stent and a preparation method thereof, and belongs to the technical field of medical biological materials and medical instruments. The stent comprises a magnesium alloy matrix, a hollow tubular structure and a surface modification layer, wherein the magnesium alloy matrix consists of the following components in percentage by mass: 90-98% of Mg, 1-5% of Zn, 0.1-1% of Ca, 0.5-3% of Y and unavoidable impurities; the pipe diameter of the hollow tubular structure is 2-5mm, the pipe wall thickness is 0.1-0.3 mm, the length is 8-30mm, and the hollow tubular structure is a rhombic grid (the side length is 0.5-1.5 mm); and the surface modification layer is a hydroxyapatite-chitosan composite coating with the thickness of 5-20 microns. The preparation method comprises the steps of magnesium alloy cast ingot preparation, pipe preparation, stent forming, surface modification and sterilization. The degradation period of the stent is 3-6 months (matched with the vascular repair period), the radial supporting force is larger than or equal to 8 N, the bending radius is smaller than or equal to 5 mm, the hydrogen generation amount is reduced by 40-60% compared with that of a pure magnesium stent, biocompatibility is good, adhesion and proliferation of vascular endothelial cells can be promoted, the preparation process is simple, cost is low, and the stent is suitable for treating vascular stenosis or clogging diseases.

Description

Technical Field

[0001] This invention relates to the field of biomaterials and medical device technology, and in particular to a medical magnesium alloy vascular stent and its preparation method. Background Technology

[0002] Vascular diseases (such as coronary heart disease and peripheral artery disease) have become one of the major diseases threatening human health, and vascular stent implantation is currently the main method for treating vascular stenosis or blockage. Traditional vascular stents are mainly made of non-degradable metal materials such as stainless steel and titanium alloys, or polymer materials.

[0003] While non-degradable metallic stents possess good mechanical strength and support performance, long-term implantation can easily lead to complications such as vascular intimal hyperplasia and in-stent thrombosis. Furthermore, patients require long-term anticoagulant medication, and the stents cannot be absorbed by the body through natural vascular repair, posing long-term safety risks. Although polymer-degradable stents can degrade in vivo, they generally suffer from insufficient mechanical strength, difficulty in controlling the degradation rate (too rapid degradation leads to insufficient support time, or too slow degradation affects normal vascular physiological function), and poor biocompatibility, making it difficult to meet the comprehensive performance requirements of vascular stents in clinical practice.

[0004] Magnesium alloys, as a novel biodegradable metallic material for medical use, possess excellent biocompatibility (magnesium is an essential trace element for the human body, and its degradation products can be excreted through normal metabolism) and suitable mechanical properties (its elastic modulus is close to that of human bones, which can reduce irritation to the blood vessel wall), making them promising candidates for vascular stents. However, existing medical magnesium alloy vascular stents still have the following drawbacks: First, magnesium alloys themselves degrade relatively quickly, and the stent is prone to losing its supporting capacity before the blood vessel has been fully repaired; second, magnesium alloys generate hydrogen gas during degradation, which may form bubbles in the blood vessel, affecting blood flow; and third, the surface bioactivity of the stent is insufficient, making it difficult to effectively promote the adhesion and proliferation of vascular endothelial cells, which is not conducive to the rapid repair of blood vessels. Therefore, the development of a medical magnesium alloy vascular stent with controllable degradation rate, excellent mechanical properties, good biocompatibility, and the ability to effectively promote vascular repair, as well as its preparation method, is of significant clinical importance. Summary of the Invention

[0005] The purpose of this invention is to provide a medical magnesium alloy vascular stent and its preparation method. The stent has the advantages of controllable degradation rate, high mechanical strength, good biocompatibility, effective promotion of vascular repair, and low hydrogen production during degradation. At the same time, the preparation method is simple and easy to implement, with low cost, and is suitable for large-scale production.

[0006] The above-mentioned technical objective of the present invention is achieved through the following technical solution: The technical solution of the present invention is divided into two parts: "scaffold structure composition" and "preparation method".

[0007] (1) Composition and structure of medical magnesium alloy vascular stents

[0008] Magnesium alloy matrix composition: A multi-element synergistic control design is employed, with the following mass percentages: Mg 90-98%, Zn 1-5%, Ca 0.1-1%, Y 0.5-3%, and the remainder being unavoidable impurities. The functions of each element are as follows:

[0009] Zn: Improves the mechanical strength and corrosion resistance of magnesium alloys and delays degradation;

[0010] Ca: Promotes bone growth and blood vessel repair, while precisely regulating the degradation rate of magnesium alloys;

[0011] Y: Refines the grain size of magnesium alloys, further improving mechanical and corrosion resistance, and alters the degradation mechanism, reducing the hydrogen production rate.

[0012] Stent structure: Employs a hollow tubular structure to adapt to the needs of blood vessels in different locations.

[0013] Dimensions: Pipe diameter 2-5mm, pipe wall thickness 0.1-0.3mm, length 8-30mm;

[0014] Hollowed-out design: diamond-shaped mesh structure (mesh side length 0.5-1.5mm). This design enables the stent to have a radial support force ≥8N and an axial flexible bending radius ≤5mm. It can effectively support diseased blood vessels and adapt to the physiological curvature and peristalsis of blood vessels, reducing stimulation to the blood vessel wall.

[0015] Surface modification layer: A hydroxyapatite (HA)-chitosan composite coating with a thickness of 5-20 μm was prepared on the surface of a magnesium alloy substrate.

[0016] Hydroxyapatite: It has good bioactivity and osteoconductivity, and can promote the adhesion and proliferation of vascular endothelial cells;

[0017] Chitosan: It has excellent biocompatibility and antibacterial properties, which can reduce the risk of infection after stent implantation, while further slowing down the degradation rate of magnesium alloy and making the degradation process controllable.

[0018] (2) Preparation method of medical magnesium alloy vascular stent

[0019] The integrated process of "melting-forming-modification-sterilization" is adopted, and the specific steps are as follows:

[0020] Step 1: Preparation of magnesium alloy ingots

[0021] Weigh out Mg, Zn, Ca, and Y metal raw materials with a purity ≥99.9% according to the matrix composition ratio, and place them into a vacuum induction melting furnace. First, evacuate the furnace to a vacuum degree ≤1×10⁻³Pa, and introduce argon gas with a purity ≥99.99% for protection (to prevent metal oxidation); then raise the temperature to 700-750℃, and hold the temperature for 15-30 minutes after the raw materials are completely melted (to ensure uniform alloy composition); finally, pour the molten alloy liquid into a mold preheated to 200-250℃, and cool it to room temperature to obtain a magnesium alloy ingot.

[0022] Step 2: Preparation of magnesium alloy tubing

[0023] ① Homogenization treatment: The ingot is kept at 350-400℃ for 8-12 hours and then cooled to room temperature in the furnace to eliminate internal stress and compositional segregation of the ingot;

[0024] ② Extrusion processing: Under the conditions of 350-400℃ and extrusion rate of 5-10mm / s, the ingot is extruded into magnesium alloy pipes with a diameter of 8-12mm and a wall thickness of 1-2mm.

[0025] ③ Drawing process: The extruded tube is drawn multiple times at 250-300℃, with the deformation controlled at 10-15% each time (to avoid cracking of the tube), and finally a magnesium alloy thin-walled tube with a diameter of 2-5mm and a wall thickness of 0.1-0.3mm is obtained (to meet the size requirements of the support base).

[0026] Step 3: Bracket forming and processing

[0027] ① Laser cutting: The thin-walled tube is hollowed out using laser cutting equipment (power 10-20W, cutting speed 50-100mm / s) and the bracket blank is cut according to the preset diamond grid parameters (side length 0.5-1.5mm);

[0028] ② Deburring and cleaning: Use 800-1200 grit sandpaper to polish the surface of the blank and the hollowed-out edges to remove burrs and sharp edges; then use anhydrous ethanol as a cleaning solution and clean it with an ultrasonic cleaner for 10-15 minutes (to remove surface impurities).

[0029] ③ Drying: Place the cleaned blank into a vacuum drying oven and dry it at 60-80℃ for 2-4 hours to obtain a clean magnesium alloy support substrate.

[0030] Step 4: Preparation of surface modification layer

[0031] ① Preparation of composite slurry: Mix hydroxyapatite powder with a particle size of 50-100nm with chitosan powder at a mass ratio of 3:1-5:1, add acetic acid solution with a concentration of 1-2% (mass ratio of solid powder to solution 1:10-1:20); place the mixed solution in an ultrasonic disperser (power 300-500W) and disperse for 20-30 minutes to obtain a uniform and stable composite coating slurry;

[0032] ②Immersion and Pull-out Coating: The scaffold substrate is immersed in the composite slurry for 10-20 seconds using the immersion and pull-out method, and then slowly pulled out at a speed of 5-10 mm / s to make the scaffold surface uniformly covered with a layer of slurry.

[0033] ③ Drying and curing: Place the coated support in a forced-air drying oven and dry at 60-80℃ for 1-2 hours (to remove solvent from the slurry); then transfer it to a muffle furnace and keep it at 300-350℃ for 1-2 hours to cure, so that the coating is tightly bonded to the substrate and forms a hydroxyapatite-chitosan composite coating with a thickness of 5-20μm.

[0034] Step 5: Sterilization

[0035] The stent was sterilized using ethylene oxide sterilization. The sterilization conditions were: ethylene oxide concentration 600-800 mg / L, temperature 30-50℃, relative humidity 40-60%, and time 4-6 h. After sterilization, the stent was ventilated and desorbed for 12-24 h to remove residual ethylene oxide, resulting in the final medical magnesium alloy vascular stent product.

[0036] The beneficial effects of this invention are:

[0037] 1. This invention aims to overcome the shortcomings of existing medical vascular stents (non-degradable metal stents have potential storage risks, polymer stents have insufficient performance, and existing magnesium alloy stents have degradation and bioactivity issues), and provides a medical magnesium alloy vascular stent and its preparation method. This invention achieves a match between the stent degradation cycle and the vascular repair cycle (3-6 months), ensuring reliable support and eliminating long-term storage risks. The stent exhibits excellent mechanical properties, balancing radial support force and axial flexibility to adapt to vascular physiological activities. It reduces hydrogen production during degradation, avoiding impact on blood flow. It enhances the bioactivity of the stent surface, promoting endothelial cell adhesion and proliferation, and accelerating vascular repair. The preparation process is simple, low-cost, and suitable for large-scale production.

[0038] 2. Controllable degradation rate: Through the dual effects of "matrix composition optimization (synergistic regulation of Zn, Ca, and Y) + surface composite coating (HA-chitosan)," the in vivo degradation cycle of the stent is precisely controlled within 3-6 months, which is completely matched with the vascular repair cycle. This ensures that the stent maintains sufficient support before vascular repair is completed and gradually degrades after repair, avoiding long-term implantation risks.

[0039] Controllable degradation rate: Through the dual effects of "matrix composition optimization (synergistic regulation of Zn, Ca, Y) + surface composite coating (HA-chitosan)," the in vivo degradation cycle of the stent is precisely controlled within 3-6 months, which is completely matched with the vascular repair cycle. This ensures that the stent maintains sufficient support before vascular repair is completed and gradually degrades after repair, avoiding long-term implantation risks.

[0040] Excellent mechanical properties: The grain refinement effect of the Mg-Zn-Y system and the rhomboid grid structure design enable the stent to have a radial support force ≥8N (meeting the support requirements of diseased blood vessels) and an axial flexibility bending radius ≤5mm (adapting to the physiological bending and peristalsis of blood vessels). The mechanical properties take into account both "reliable support" and "flexible adaptation".

[0041] Excellent biocompatibility: ① The degradation products of the magnesium alloy matrix (Mg²⁺, Zn²⁺, Ca²⁺, Y³⁺) are all ions that can be metabolized by the human body and have no toxic accumulation; ② In the surface HA-chitosan coating, HA promotes the adhesion and proliferation of vascular endothelial cells (accelerating vascular repair), and chitosan reduces the risk of infection, thus improving the overall biosafety and repair efficiency of the stent.

[0042] Low hydrogen production: The addition of Y element changes the degradation path of magnesium alloy and reduces the hydrogen generation rate; as verified by in vitro simulated degradation experiments, the hydrogen production of the stent of this invention is reduced by 40-60% compared with pure magnesium stent, effectively avoiding the impact of air bubbles on blood circulation.

[0043] 7. The manufacturing process is suitable for large-scale production: It adopts conventional processes such as vacuum induction melting, extrusion drawing, laser cutting, and impregnation pulling. The equipment requirements are low, the operation is simple, the production cycle is short (single batch production cycle ≤ 72h), and the cost is low (20-30% lower than the cost of similar biodegradable stents), which can realize large-scale industrial production. Detailed Implementation

[0044] The technical solution of the present invention will now be clearly and completely described with reference to specific embodiments. Obviously, the described embodiments are merely some, not all, of the embodiments of the present invention. All other embodiments obtained by those skilled in the art based on the embodiments of the present invention without creative effort are within the scope of protection of the present invention.

[0045] Example 1

[0046] 1. Preparation of magnesium alloy ingots: Weigh the metal raw materials (purity ≥99.9%) according to the mass percentages of Mg 95%, Zn 3%, Ca 0.5%, and Y 1.5%, and place them in a vacuum induction melting furnace; evacuate to below 1×10⁻³ Pa, and introduce argon gas with a purity ≥99.99%; heat to 720℃ to completely melt the raw materials, and hold for 20 min; pour the molten alloy liquid into a mold at 220℃, and cool to room temperature to obtain magnesium alloy ingots.

[0047] 2. Preparation of magnesium alloy tubes: The ingots were homogenized by holding them at 380℃ for 10 hours and then cooled in the furnace. They were extruded at 380℃ and an extrusion rate of 8 mm / s to form tubes with a diameter of 10 mm and a wall thickness of 1.5 mm. Then, they were drawn multiple times at 280℃ with a deformation of 12% each time, finally yielding magnesium alloy thin-walled tubes with a diameter of 3 mm and a wall thickness of 0.2 mm.

[0048] 3. Support Forming Process: A laser cutting machine with a laser power of 15W and a cutting speed of 80mm / s is used to cut a diamond grid (1mm on each side) on the tube to obtain the support blank; the blank is then deburred by sanding with 1000-grit sandpaper, ultrasonically cleaned with anhydrous ethanol for 12 minutes, and vacuum dried at 80℃ for 3 hours to obtain the magnesium alloy support substrate.

[0049] 4. Preparation of surface modified layer: Hydroxyapatite powder with a particle size of 80 nm and chitosan powder were mixed at a mass ratio of 4:1, and 1.5% acetic acid solution was added (the mass ratio of solid powder to solution was 1:15); the mixture was ultrasonically dispersed at 300 W for 25 min to obtain a composite slurry; the scaffold substrate was immersed in the slurry for 15 s and pulled up at a speed of 8 mm / s; the mixture was dried at 80 °C for 1.5 h and cured at 320 °C for 1.5 h to form a composite coating with a thickness of 12 μm.

[0050] 5. Sterilization treatment: Sterilization was carried out using ethylene oxide (concentration 700mg / L, temperature 40℃, relative humidity 50%, time 5h); ventilation and desorption were performed for 18h to obtain medical magnesium alloy vascular stents.

[0051] Performance test results: radial support force 9.2N, bending radius 4.5mm, in vivo degradation period 4.5 months, hydrogen production reduced by 52% compared to pure magnesium stents, and endothelial cell adhesion rate on the stent surface increased by 60% compared to uncoated magnesium alloy stents.

[0052] Example 2

[0053] 1. Preparation of magnesium alloy ingots: Weigh the metal raw materials (purity ≥99.9%) according to the mass percentages of Mg 92%, Zn 5%, Ca 1%, and Y 2%, and place them in a vacuum induction melting furnace; evacuate to below 1×10⁻³ Pa, and introduce argon gas with a purity ≥99.99%; heat to 750℃ to completely melt the raw materials, and hold for 30 min; pour the molten alloy liquid into a mold at 250℃, and cool to room temperature to obtain magnesium alloy ingots.

[0054] 2. Preparation of magnesium alloy tubes: The ingots were homogenized by holding them at 400℃ for 8 hours and then cooled in the furnace. They were extruded at 400℃ and an extrusion rate of 10mm / s to form tubes with a diameter of 12mm and a wall thickness of 2mm. Then, they were drawn multiple times at 300℃ with a deformation of 15% each time, finally yielding magnesium alloy thin-walled tubes with a diameter of 5mm and a wall thickness of 0.3mm.

[0055] 3. Support Forming Process: Using a laser cutting machine with a laser power of 20W and a cutting speed of 100mm / s, a diamond grid (side length 1.5mm) is cut on the tube to obtain the support blank; the burrs are removed by sanding with 1200 grit sandpaper, and the tube is ultrasonically cleaned with anhydrous ethanol for 15min; the tube is then vacuum dried at 80℃ for 4h to obtain the magnesium alloy support substrate.

[0056] 4. Preparation of surface modified layer: Hydroxyapatite powder with a particle size of 100 nm and chitosan powder were mixed at a mass ratio of 5:1, and 2% acetic acid solution was added (the mass ratio of solid powder to solution was 1:20); the mixture was ultrasonically dispersed at 500 W for 30 min to obtain a composite slurry; the scaffold substrate was immersed in the slurry for 20 s and pulled up at a speed of 10 mm / s; the mixture was dried at 80 °C for 2 h and cured at 350 °C for 2 h to form a composite coating with a thickness of 20 μm.

[0057] 5. Sterilization treatment: Sterilization was carried out using ethylene oxide (concentration 800mg / L, temperature 50℃, relative humidity 60%, time 6h); ventilation and desorption were performed for 24h to obtain medical magnesium alloy vascular stents.

[0058] Performance test results: radial support force 10.5N, bending radius 4.8mm, in vivo degradation period 5.8 months, hydrogen production reduced by 58% compared to pure magnesium stents, and endothelial cell adhesion rate on stent surface increased by 65% ​​compared to uncoated magnesium alloy stents.

Claims

1. A medical magnesium alloy vascular stent, characterized in that: It includes a magnesium alloy substrate, a hollow tubular structure, and a surface modification layer. The magnesium alloy substrate is composed of the following substances in mass percentage: Mg 90-98%, Zn 1-5%, Ca 0.1-1%, Y 0.5-3%. The surface modification layer is a hydroxyapatite-chitosan composite coating.

2. The medical magnesium alloy vascular stent according to claim 1, characterized in that: The perforated tubular structure has a diameter of 2-5mm, a wall thickness of 0.1-0.3mm, and a length of 8-30mm. The perforated structure is a diamond-shaped grid with a grid side length of 0.5-1.5mm.

3. A medical magnesium alloy vascular stent according to claim 2, characterized in that: In the hydroxyapatite-chitosan composite coating, the mass ratio of hydroxyapatite to chitosan is 3-5:

1.

4. A method for preparing a medical magnesium alloy vascular stent as described in any one of claims 1-3, characterized in that: The preparation steps include the following: S1: Preparation of magnesium alloy ingots: Weigh Mg, Zn, Ca, and Y metal raw materials with a purity ≥99.9% according to the composition ratio of magnesium alloy matrix, and put them into a vacuum induction melting furnace; evacuate the vacuum degree in the furnace to ≤1×10⁻³Pa, introduce argon gas with a purity ≥99.99% as a protective gas, heat to 700-750℃ to completely melt the raw materials, hold for 15-30 minutes, pour the molten alloy liquid into a mold preheated to 200-250℃, and cool to room temperature to obtain magnesium alloy ingots; S2: Preparation of magnesium alloy tubes: The ingots obtained in step 1 are homogenized by holding them at 350-400℃ for 8-12 hours and then cooled to room temperature in the furnace; then they are extruded at 350-400℃ and extrusion rate of 5-10mm / s into tubes with a diameter of 8-12mm and a wall thickness of 1-2mm; then they are drawn multiple times at 250-300℃, with the deformation amount controlled at 10-15% each time, finally obtaining thin-walled magnesium alloy tubes with a diameter of 2-5mm and a wall thickness of 0.1-0.3mm. S3: Support Forming Process: The thin-walled tube obtained in step 2 is hollowed out using laser cutting equipment with a laser power of 10-20W and a cutting speed of 50-100mm / s. The support blank is cut according to the diamond grid parameters. The blank is deburred by sanding with 800-1200 grit sandpaper, and then cleaned with anhydrous ethanol as the cleaning solution by ultrasonic cleaning machine for 10-15 minutes. Finally, it is placed in a vacuum drying oven and dried at 60-80℃ for 2-4 hours to obtain a magnesium alloy substrate with a hollow structure. S4: The magnesium alloy substrate obtained in step S3 is immersed in the hydroxyapatite-chitosan composite slurry for 10-20 seconds using the dip-coating method, and then pulled out at a speed of 5-10 mm / s. The coated stent is placed in a forced-air drying oven and dried at 60-80℃ for 1-2 hours, and then transferred to a muffle furnace and cured at 300-350℃ for 1-2 hours to form a magnesium alloy vascular stent covered with a hydroxyapatite-chitosan composite coating with a thickness of 5-20 μm.

5. The medical magnesium alloy vascular stent and its preparation method according to claim 4, characterized in that: The hydroxyapatite-chitosan composite slurry is prepared by the following method: hydroxyapatite powder with a particle size of 50-100nm and chitosan powder are mixed at a mass ratio of 3:1-5:1, an acetic acid solution with a concentration of 1-2% is added, and the mixed solution is placed in an ultrasonic disperser and dispersed at a power of 300-500W for 20-30 minutes to obtain a uniform and stable composite coating slurry.

6. The medical magnesium alloy vascular stent and its preparation method according to claim 5, characterized in that: The mass ratio of the total solid powder formed by the hydroxyapatite powder and chitosan powder to the acetic acid solution is 1:10-1:

20.

7. The medical magnesium alloy vascular stent and its preparation method according to claim 4, characterized in that: The melting temperature in step S1 is 720-740℃, the holding time is 20-25min, and the mold preheating temperature is 220-240℃.

8. The medical magnesium alloy vascular stent and its preparation method according to claim 4, characterized in that: In step S2, the homogenization treatment temperature is 370-390℃, the time is 9-11h, the extrusion rate is 7-9mm / s, and the drawing temperature is 270-290℃.

9. The medical magnesium alloy vascular stent and its preparation method according to claim 4, characterized in that: In step S3, the laser power is 14-18W, the cutting speed is 70-90mm / s, the sandpaper grit is 900-1100 mesh, the ultrasonic cleaning time is 12-14min, and the vacuum drying temperature is 70-80℃ for 3-4h.

10. A medical magnesium alloy vascular stent and its preparation method according to claim 9, characterized in that: It also includes sterilization treatment: the magnesium alloy vascular stent obtained in step S4 is treated with ethylene oxide sterilization. The sterilization conditions are ethylene oxide concentration of 600-800 mg / L, temperature of 30-50℃, relative humidity of 40-60%, and time of 4-6 hours. After sterilization, the residual ethylene oxide is removed by ventilation and desorption for 12-24 hours to obtain the final product.