Anti-stone degradable medical magnesium alloy and preparation method thereof

Abstract

The application discloses an anti-stone degradable medical magnesium alloy and a preparation method thereof, relates to the technical field of biomedical materials, and aims to solve the technical problems that the prior art cannot simultaneously realize degradable control, interface stability and active anti-stone. The application comprises the following steps: S1. Rheocasting preparation of a magnesium alloy base body: magnesium alloy raw materials are melted under a protective atmosphere, overheated to 50-80 DEG C above the liquidus, poured onto a cooling plate with an inclination angle ranging from 30 to 60 DEG to form a semi-solid slurry, pressed into a mold at a pressure of 80-150 MPa and a speed of 0.2-0.5 m / s, and the mold is opened after pressure and heat preservation for 5-10 min, so that the magnesium alloy base body is obtained. The application has excellent anti-stone performance. On a physical level, the composition gradient transition structure uniformly releases the corrosion products of the magnesium alloy in the form of fine particles, and avoids the accumulation of large products to form stone cores.

Description

Technical Field

[0001] This invention relates to the technical field of biomedical materials, specifically to an anti-stone degradable medical magnesium alloy and its preparation method. Background Technology

[0002] In minimally invasive endoscopic treatment of urinary tract diseases such as stones, strictures, and tumors, ureteral stents, catheters, and other implantable devices are core consumables for maintaining urinary tract patency and ensuring tissue repair. Their material properties directly determine the treatment effect and patient prognosis. Currently, commonly used clinical implantable materials and existing preparation technologies still have limitations that are difficult to overcome. The core challenges can be summarized into two main aspects: inherent material defects and bottlenecks in the preparation process.

[0003] Currently, the main types of urinary tract implant materials used in clinical practice include non-degradable metals, degradable polymers, and degradable magnesium alloys, all of which have significant drawbacks. Non-degradable metal stents, represented by stainless steel and titanium alloys, while possessing excellent mechanical support and bioinertness, have two major drawbacks: First, they impose a burden of secondary surgery, requiring periodic removal via invasive procedures such as cystoscopy after implantation, significantly increasing patient suffering, medical costs, and the risk of postoperative infection and mucosal damage. Second, they pose a high risk of stone adhesion, as the metal surface easily becomes the core substrate for calcium salt crystal deposition. Clinical data shows that approximately 80% of long-term indwelling stents experience significant stone deposition within 6 months, leading to stent blockage, recurrent infections, and severe pain.

[0004] Biodegradable polymer stents, represented by polylactic acid (PLA), polyglycolic acid (PGA), and their copolymers, can avoid secondary surgery, but they have significant performance shortcomings: their elastic modulus and radial support strength are much lower than those of metal stents, making them prone to collapse and failure under the physiological peristaltic pressure of the ureter, thus failing to maintain urinary tract patency; at the same time, the acidic products released during the degradation process can easily induce local tissue inflammation, interfere with the normal healing of the urothelium, and the surface still easily adsorbs stone crystals, failing to solve the stone problem at its root.

[0005] As a material that has emerged in recent years, biodegradable magnesium alloy stents, while possessing good biocompatibility, mechanical compatibility, and in vivo biodegradability, are considered an ideal alternative. However, they still face core bottlenecks in the dynamic fluid environment of the urinary tract: the corrosion rate is fast and the process is uneven in the complex ionic environment of urine, and the degradation products are prone to aggregate into large particles, which in turn become heterogeneous nucleation nuclei for calcium oxalate, calcium phosphate, and other stone crystals, exacerbating stone formation. At the same time, existing technologies cannot endow the magnesium alloy surface with the ability to actively inhibit crystal nucleation and growth, making it unable to cope with the urinary tract stone-forming environment.

[0006] Existing technologies for the preparation and modification of biodegradable magnesium alloy stents generally suffer from the problems of "fragmented processes and lack of synergy," directly leading to two major pain points: "uncontrollable degradation" and "easy coating failure." Traditional processes adopt a chain-like model of "material preparation → tube forming → structural processing → post-processing," with each step relatively independent and lacking systematic design: macroscopic structure manufacturing (such as precision machining and 3D printing) only focuses on macroscopic morphology such as meshes and pores, neglecting the microstructure control of the matrix, resulting in coarse grains and uneven corrosion resistance; the performance of each step is discontinuous, making it impossible to achieve a gradient design from the matrix to the surface, and it is difficult to match the dynamic needs of the complex urinary tract environment. Current surface modification methods mostly employ a "post-modification" strategy, which involves treating the molded substrate with methods such as plasma spraying of hydroxyapatite, electrochemical deposition, or physical coating of superhydrophobic coatings. These methods have inherent shortcomings: the coating and the substrate are mostly physically adsorbed or mechanically intercalated, with a clear interface and no component transition, belonging to a "hard bond" with low bonding strength, which is prone to detachment and failure under long-term urine flushing and pH fluctuations; the coating can only provide a physical barrier and lacks the chemical function of actively chelating calcium ions and inhibiting crystal growth, thus failing to block stone formation at its source; the weak interfacial bonding also leads to the coating being prone to rapid degradation or peeling, making it difficult to maintain its effect throughout the entire treatment cycle.

[0007] To address these challenges, researchers have conducted extensive studies on materials systems, surface modification, and structural design, but no systematic solution has yet been found. Regarding materials systems, biodegradable iron-based and zinc-based alloys have become research hotspots. However, iron-based alloys degrade too slowly to match the 4-6 week healing cycle of the urothelial lining; the biocompatibility and in vivo degradation mechanism of zinc-based alloys still require further verification, and their safety for clinical application remains questionable. In terms of surface modification, constructing superhydrophobic coatings (such as fluoropolymer coatings and biomimetic micro / nanostructure coatings) to reduce crystal adhesion is the mainstream approach. However, due to poor interfacial bonding and abrupt performance changes, these coatings are difficult to maintain stability under long-term physiological conditions, failing to achieve a lasting anti-stone effect. Regarding structural design, while 3D-printed porous scaffolds can promote tissue ingrowth, they only focus on tissue integration and do not optimize degradation characteristics and surface functions from the material's inherent nature, thus failing to solve the core problem of degradation products inducing stones.

[0008] In summary, while existing research has made breakthroughs in single dimensions, it has consistently failed to achieve synergistic optimization of controllable degradation, interfacial stability, and active anti-stone properties, lacking a systematic design scheme covering the entire process from matrix preparation and coating deposition to surface functionalization. Therefore, the goal is to develop a biodegradable medical magnesium alloy with a compositional gradient transition structure, precisely controllable degradation rate, strong interfacial bonding, active anti-stone properties, and excellent biocompatibility, in order to achieve a balance between anti-stone properties and controllable degradation in the urinary tract environment. Summary of the Invention

[0009] To address the aforementioned problems, namely the issues raised in the background section, this invention proposes an anti-stone degradable medical magnesium alloy and its preparation method.

[0010] Technical solution: The first aspect of this invention proposes a method for preparing a biodegradable medical magnesium alloy for preventing gallstones, comprising the following steps: S1. Preparation of a magnesium alloy substrate by rheological casting: The magnesium alloy raw material is melted under a protective atmosphere, superheated to 50-80° above the liquidus, and poured onto a cooling plate with an inclination angle of 30-60° to form a semi-solid slurry. This slurry is then injected into a mold at an injection pressure of 80-150 MPa and an injection speed of 0.2-0.5 m / s, preferably 100 MPa, and preferably 0.3 m / s. After holding the pressure and temperature for 5-10 minutes, the mold is opened to obtain the magnesium alloy substrate; S2. Deposition of a mixed calcium phosphate composite coating by single-step hydrothermal method: The magnesium alloy substrate is pretreated by sequential cleaning, pickling, and rinsing, and then vertically immersed in a reaction solution. It is sealed in a high-pressure reactor and placed in an oven, reacting at 120-200°C for 2-8 hours to form a mixed calcium phosphate composite coating; the reaction solution contains 0.08-0.12 mg / L of magnesium alloy. 0.048-0.072 mol / L calcium source, 0.01-0.05 mol / L phosphorus source, and 0.01-0.05 mol / L mineralization regulator, wherein the calcium-to-phosphorus molar ratio is 1.5-1.67; S3. Ultrasonic surface treatment: The magnesium alloy substrate with a mixed calcium phosphate composite coating is immersed in the treatment solution to graft a transition layer, and treated at an ultrasonic power of 300-500W and a temperature of 40-60℃ for 20-40 minutes, followed by rinsing with a buffer solution, cleaning with deionized water, and 50 After drying in a vacuum drying oven at -60℃ for 4-5 hours, a biodegradable medical magnesium alloy with anti-calculi properties is obtained. The treatment solution includes: dissolving 0.5-2wt% of silane coupling agent in a mixed solvent of ethanol and deionized water, hydrolyzing for 15-20 minutes, then adding 1-5wt% of modified nanoparticles, treating at an ultrasonic power of 300-500W and a temperature of 40-60℃ for 20-40 minutes, and finally adding 0.01-0.1wt% of bioactive peptides and gently stirring to mix.

[0011] A further setting of the present invention is as follows: In step S1, the magnesium alloy matrix is ​​medical-grade AZ31 magnesium alloy, the protective atmosphere includes a mixture of CO2 and SF6; the cooling plate is made of stainless steel, the tilt angle of the cooling plate is preferably 45°, the cooling plate is preheated to 250-300°C, the mold is preheated to 150-250°C, preferably 200°C, and the semi-solid slurry is spherical grains with a grain size range of 50-80μm.

[0012] A further provision of the present invention is as follows: In step S2, the pretreatment of the magnesium alloy substrate includes: ultrasonic cleaning with an organic solvent for 10-15 minutes, wherein the organic solvent is one or more combinations of acetone, ethanol and isopropanol; activating by immersion in a 1-2% acidic solution for 20-30 seconds, wherein the acidic solution is one of nitric acid, hydrochloric acid, phosphoric acid or sulfuric acid, preferably nitric acid; rinsing with deionized water 3-5 times, wherein the sample is slightly shaken or ultrasonically assisted during each rinse; and drying with nitrogen gas after the pH value is 6.9-7.1.

[0013] A further feature of the present invention is that, in step S2, the reaction solution uses water as a solvent, the calcium source is one of calcium nitrate, calcium chloride, or calcium acetate, the phosphorus source is one of diammonium hydrogen phosphate, ammonium phosphate, or urea phosphate, and the mineralization regulator is one or more combinations of urea and sodium citrate; the lining of the high-pressure reactor is made of polytetrafluoroethylene.

[0014] A further feature of the present invention is that, in step S2, the thickness of the mixed calcium phosphate composite coating is 30-50 μm, and it comprises hydroxyapatite and octacalcium phosphate. A magnesium phosphate transition phase is generated at the interface between the mixed calcium phosphate composite coating and the magnesium alloy substrate.

[0015] A further setting of the present invention is as follows: in step S3, the silane coupling agent is one of γ-aminopropyltriethoxysilane or γ-aminopropyltrimethoxysilane, preferably γ-aminopropyltriethoxysilane, and the solvent of the treatment solution is a mixture of ethanol and deionized water in a volume ratio of 1:1.

[0016] A further feature of the present invention is that, in step S3, the modified nanoparticles have a particle size range of 50-100 nm, and the modified nanoparticles are citric acid-modified calcium phosphate nanoparticles.

[0017] A further provision of the present invention is that, in step S3, the bioactive peptide is one of osteogenic growth peptide OGP or polyaspartic peptide, wherein the polyaspartic peptide contains hexamethylenetetramine and the polyaspartic peptide is derived from the acidic functional fragment of osteopontin.

[0018] A further provision of the present invention is that in step S3, the buffer solution is a phosphate buffer solution with a pH range of 6.5-7.5, and the number of rinsing cycles is 3-5.

[0019] The second aspect of this invention proposes a biodegradable medical magnesium alloy for preventing gallstones prepared by the aforementioned method: a mixed calcium phosphate composite coating is provided on the surface of the magnesium alloy substrate, and the mixed calcium phosphate composite coating is grafted to form a transition layer through biochemical ultrasonic treatment, and the magnesium alloy substrate, the mixed calcium phosphate composite coating and the transition layer form a compositional gradient transition structure.

[0020] The beneficial technical effects of this invention are as follows: 1. This invention has excellent anti-stone performance. At the physical level, the gradient transition structure of the composition allows the corrosion products of magnesium alloy to be released uniformly in the form of fine particles, avoiding the accumulation of large products to form stone cores, thus eliminating the basis for stone nucleation from the source. At the chemical level, the citrate ions grafted on the surface can effectively chelate calcium ions in urine, directly inhibiting the heterogeneous nucleation and growth of crystals such as calcium oxalate and calcium phosphate. At the biological level, the bioactive peptides promote the adhesion and healing of urothelial cells, reduce the exposed surface of the material, and further reduce the probability of crystal adhesion.

[0021] 2. This invention features controllable degradation behavior. The gradient transition layer acts as a corrosion buffer, delaying the direct erosion of the magnesium alloy matrix by body fluids. This allows the overall degradation rate to precisely match the 4-6 week healing cycle of urothelial tissue. This avoids the problems of excessively rapid degradation and local pitting corrosion of existing magnesium alloy stents, and also solves the defects of excessively slow degradation and long-term material retention of iron-based alloys. At the same time, it eliminates tissue inflammation caused by acidic products of polymer stent degradation, significantly reducing the risk of premature stent failure or prolonged retention.

[0022] 3. This invention has a stable interfacial bonding capability. The spherical crystalline magnesium alloy matrix prepared by rheological casting, combined with the magnesium phosphate transition phase generated in situ by hydrothermal reaction, achieves metallurgical bonding and component interlocking between the coating and the matrix. The interfacial bonding strength is significantly higher than that of traditional spray or coating, and it is not easy to peel off under long-term rinsing of urine.

[0023] 4. This invention has good biocompatibility. The medical-grade AZ31 magnesium alloy, calcium phosphate salt, silane coupling agent and bioactive peptides used all have good biosafety and release no toxic or harmful substances. The surface of the material after ultrasonic functionalization has moderate hydrophilicity, which is conducive to the adhesion and spreading of urothelial cells without promoting crystal adsorption. The infiltration of inflammatory cells at the material and tissue interface is slight, and there are no adverse tissue reactions such as foreign body granulomas and thick fibrous cysts. Compared with existing stents, it significantly reduces the incidence of postoperative urinary tract infections, ureteral strictures and other complications.

[0024] 5. The three-step method of "rheological casting, hydrothermal deposition, and ultrasonic functionalization" in this invention is an organic and synergistic whole. From the microstructure control of substrate preparation to the gradient structure construction of coating deposition, and then to the multi-component grafting of surface functionalization, it solves the problems of fragmented links and discontinuous performance in the existing chain-like preparation process, and achieves synergistic optimization of controllable degradation, interface stability, active anti-stone formation and good biocompatibility. Attached Figure Description

[0025] Figure 1 A schematic diagram of a magnesium alloy-mixed calcium phosphate composite structure is shown.

[0026] Figure 2 The process diagram for preparing the alloy according to the present invention is shown.

[0027] Figure 3 A scanning electron microscope image of the product of Example 1 is shown.

[0028] Figure 4 The Fourier transform infrared spectrum of Example 1 is shown.

[0029] Figure 5 The static water contact angle test diagram of Example 1 is shown.

[0030] Figure 6 A scanning electron microscope image of the product of Example 2 is shown.

[0031] Figure 7 A scanning electron microscope image of the product of Example 3 is shown. Detailed Implementation

[0032] The following is with reference to the attached diagram. Figures 1-7 The preferred embodiments of the present invention will be described below. Those skilled in the art should understand that these embodiments are merely illustrative of the technical principles of the present invention and are not intended to limit the scope of protection of the present invention.

[0033] The “gradient transition layer” described in this invention specifically refers to the interface region with a gradient change in composition formed between the magnesium alloy substrate and the mixed calcium phosphate composite coating through the hydrothermal reaction described in step S2.

[0034] Example 1 S1. Preparation of magnesium alloy matrix by rheocasting: Medical-grade AZ31 magnesium alloy ingots were melted at 680°C under a mixed protective atmosphere of CO2 and SF6. After refining and slag removal, the melt was superheated to about 65°C (about 630°C) above the liquidus line (about 565°C). The melt was then poured onto a stainless steel cooling plate preheated to 250°C and tilted at a 45° angle. The melt flowed downwards along the inclined cooling plate, and under the combined action of gravity shear and plate surface cooling, primary α-M crystals with fine, near-spherical grains were formed. A semi-solid slurry of g phase (grain size approximately 65μm) was kept at a temperature of 580℃±5℃ in a collection tank at the end of the plate. It was then injected into a tubular mold (simulating a support blank) preheated to 200℃ at an injection pressure of 100MPa and an injection speed of 0.3m / s. After holding the pressure and temperature for 8 minutes, the mold was opened to obtain a magnesium alloy tubular casting (outer diameter 3.0mm, wall thickness 0.3mm) with a smooth surface and uniform internal structure, which served as the substrate for subsequent coating.

[0035] S2. Single-step hydrothermal deposition of mixed calcium phosphate composite coating: Magnesium alloy tubular castings were pretreated by ultrasonic cleaning with acetone and anhydrous ethanol for 15 minutes in sequence, followed by etching in 1% nitric acid solution for 30 seconds to activate the surface, and finally rinsed thoroughly with deionized water 3 times. The sample was gently shaken during each rinse, and dried with nitrogen when the pH value was 7. Preparation of reaction solution: A mixed aqueous solution of calcium nitrate (Ca(NO3)2) with a concentration of 0.1 mol / L and diammonium hydrogen phosphate ((NH4)2HPO4) with a calcium-to-phosphorus molar ratio of Ca / P = 1.60, and 0.05 mol / L sodium citrate as a mineralization regulator. The pretreated magnesium alloy matrix was vertically immersed in the reaction solution and sealed in a high-pressure reactor with a polytetrafluoroethylene liner. The reactor was then placed in an oven and reacted at 160°C for 6 hours. After the reaction is complete, allow the substrate to cool naturally to room temperature. Remove the magnesium alloy substrate, gently rinse with deionized water, and dry at 60°C for 12 hours. Figure 3 As can be seen from the scanning electron microscope (SEM), a uniform coating of about 40 μm is formed on the substrate surface. The coating is mainly composed of a mixture of platy and microspherical calcium phosphate salts (mainly hydroxyapatite, with a small amount of octacalcium phosphate). At the same time, a compositional gradient transition layer is formed at the interface between the coating and the magnesium alloy substrate, and it is tightly bonded to the magnesium alloy substrate.

[0036] S3. Ultrasonic surface treatment: Preparation of treatment solution: Dissolve 1.0 wt% of silane coupling agent (γ-aminopropyltriethoxysilane, KH550) in a 1:1 volume ratio of ethanol and deionized water, hydrolyze for 15 min, then add 2.0 wt% of citric acid modified hydroxyapatite nanoparticles (particle size 50 nm), ultrasonically disperse for 30 min to make it uniform, and finally add 0.05 wt% of osteogenic growth peptide, and gently stir to mix. The magnesium alloy substrate with the mixed calcium phosphate composite coating was immersed in the above treatment solution and placed in an ultrasonic cleaner for 30 minutes under the conditions of ultrasonic power of 400W and water temperature controlled at 50℃. After processing, the substrate was removed and gently rinsed three times with phosphate buffered saline (PBS, pH 7.4) and deionized water, respectively, to remove physically adsorbed molecules. Then, it was dried in a vacuum drying oven at 60°C for 4 hours to solidify and stabilize the grafted layer, thus obtaining a stone-resistant biodegradable medical magnesium alloy.

[0037] Example 2 The preparation method is the same as in Example 1, except that: S1. Preparation of magnesium alloy matrix by rheocasting: Medical-grade AZ31 magnesium alloy ingots were melted at approximately 690°C under a protective atmosphere of CO2 and SF6. After refining and slag removal, the melt was superheated to 80°C (approximately 645°C) above the liquidus line (approximately 565°C). The melt was then poured onto a stainless steel cooling plate preheated to 250°C and tilted at a 60° angle. The melt flowed at a steeper angle and higher superheat, and under the combined effects of gravity shear and plate cooling, a primary α-Mg phase with fine, near-spherical grains (grain size approximately 40 μm) was formed. The semi-solid slurry (m) is rapidly transferred and injected into a tubular mold preheated to 250°C at an injection pressure of 150MPa and an injection speed of 0.5m / s. After holding the pressure and temperature for 10 minutes, the mold is opened to obtain a magnesium alloy tubular casting. Due to the large inclination angle, the grains are finer under higher shear and pressure. To prevent excessive oxidation, the design of the gating system is optimized to reduce the time the melt is exposed to air, or the melt temperature is precisely controlled to not exceed 645°C to avoid excessively high temperatures that could exacerbate the oxidation reaction.

[0038] S2. Single-step hydrothermal deposition of mixed calcium phosphate composite coating: Preparation of reaction solution: Slightly increasing the concentration will also increase the thickness of the composite coating. Take a mixed aqueous solution of calcium chloride with a concentration of 0.12 mol / L and ammonium phosphate with a concentration of 0.072 mol / L, with a calcium-to-phosphorus molar ratio of Ca / P = 1.67, and add 0.05 mol / L urea. The pretreated magnesium alloy matrix was vertically immersed in the reaction solution and sealed in a high-pressure reactor lined with polytetrafluoroethylene. The reactor was then placed in an oven and reacted at 200°C for 8 hours. Because the reaction temperature is higher and the time is longer, by Figure 6 As can be seen, a uniform coating of about 50 μm thickness is formed on the substrate surface, which is close to the upper limit of the range. The crystallinity is higher and the bonding with the substrate is still strong.

[0039] S3. Ultrasonic surface treatment: Preparation of treatment solution: After hydrolyzing 2.0 wt% of silane coupling agent (γ-aminopropyltrimethoxysilane), add 5.0 wt% of citric acid modified hydroxyapatite nanoparticles, and finally add 0.1 wt% of osteogenic growth peptide. Immerse the coated sample in the treatment solution and treat it for 40 min under the conditions of ultrasonic power 500W and water temperature 60℃.

[0040] Example 3 The preparation method is the same as in Example 1, except that: S1. Preparation of magnesium alloy matrix by rheocasting: After melting medical-grade AZ31 magnesium alloy ingots under a protective atmosphere, the melt is superheated to 50°C above the liquidus (approximately 615°C) and poured onto a cooling plate preheated to 250°C with a 30° inclination angle. Under the combined action of gravity shearing and plate surface cooling, a semi-solid slurry with fine, near-spherical primary α-Mg phase (grain size approximately 80μm) is formed. Then, it is injected into a mold preheated to 150°C at an injection pressure of 80MPa and an injection speed of 0.2m / s. After holding the pressure and temperature for 5 minutes, the mold is opened to obtain the casting. Under these conditions, the slurry fluidity is relatively weak, and it is necessary to ensure complete filling.

[0041] S2. Single-step hydrothermal deposition of mixed calcium phosphate composite coating: Preparation of reaction solution: To adapt to milder conditions, a slightly lower concentration was used. A mixed aqueous solution of 0.08 mol / L calcium acetate and 0.048 mol / L urea phosphate was prepared, with a calcium-to-phosphorus molar ratio of Ca / P = 1.50. 0.05 mol / L sodium citrate and urea were added. The pretreated magnesium alloy substrate was vertically immersed in the reaction solution and sealed in a high-pressure reactor with a polytetrafluoroethylene liner. The reactor was then placed in an oven and reacted at 120°C for 2 hours. Under milder reaction conditions, by Figure 6 It can be seen that a uniform coating of about 30 μm is formed on the substrate surface, which is close to the lower limit of the range, and contains more amorphous components or precursor phases (such as octacalcium phosphate).

[0042] S3. Ultrasonic surface treatment: Preparation of treatment solution: After hydrolyzing 0.5 wt% of silane coupling agent (γ-aminopropyltriethoxysilane, KH550), add 1.0 wt% of citric acid modified hydroxyapatite nanoparticles, and finally add 0.01 wt% of osteogenic growth peptide. Immerse the coated sample in the treatment solution and treat it for 20 min under the conditions of ultrasonic power 300W and water temperature 40℃.

[0043] Figure 4 This is a Fourier transform infrared (FT-IR) spectrum, used to characterize the surface chemical structure of the three sample examples and verify the successful grafting of the coating with functional molecules. The horizontal axis (wavenumber, cm⁻¹) is used to characterize the surface chemical structure of the three sample examples and verify the successful grafting of the coating with functional molecules. -1 The ordinate (wavenumber) represents the wavenumber of infrared light, corresponding to the characteristic vibrational frequencies of different chemical bonds and functional groups, and is the core basis for identifying chemical structures. The ordinate (transmittance, %) represents transmittance; the lower the value, the stronger the absorption at that wavenumber, and the higher the content of the corresponding functional group. The three curves represent: Dark blue: Example 1; Green: Example 2; Light blue: Example 3.

[0044] Depend on Figure 4 The FT-IR infrared spectroscopy results show that all three sets of sample samples were within 1650 cm⁻¹.-1 With 1540cm -1 The presence of typical amide bond characteristic absorption peaks nearby further confirms the successful grafting of the bioactive peptide; simultaneously, at 1000-1100 cm⁻¹... -1 The presence of characteristic peaks such as PO and Si-O-Si in the region indicates that both the mixed calcium phosphate coating and the silane coupling agent are effectively formed, resulting in a complete coating structure and stable interfacial bonding.

[0045] The above results corroborate the XPS surface elemental analysis results (see Table 1), fully demonstrating that the ultrasonic surface functionalization process of this invention can achieve stable grafting of functional molecules. As shown in Table 1, obvious nitrogen (N) signals were detected on the surfaces of samples from Examples 1, 2, and 3. The N element mainly originates from the amide and amino bonds of the bioactive peptides, confirming that the bioactive peptides have been successfully grafted onto the coating surface. Example 2, due to its higher concentration of functional components and stronger ultrasonic treatment parameters, exhibited the highest surface N content and the most significant grafting effect. Example 3 had a relatively lower grafting amount, but still showed a noticeable characteristic signal, indicating successful grafting.

[0046] Table 1 XPS Surface Elements

[0047] The static water contact angle test results are shown in Table 2. The average contact angle of Example 1 was 98.464°, that of Example 2 was 85.843°, and that of Example 3 was 102.818°. After ultrasonic functionalization, the hydrophilicity of the sample surface was effectively regulated. Among them, Example 2 had the best hydrophilicity, while Example 1 had moderate hydrophilicity, which is more conducive to cell adhesion and spreading. At the same time, it can reduce the non-specific adsorption of calcium salt crystals, providing a basis for good biocompatibility and anti-stone performance.

[0048] Table 2 Contact Angle

[0049] Comparative Example 1 The preparation method is the same as in Example 1, except that the magnesium alloy matrix is ​​prepared by traditional melting and casting and plastic processing.

[0050] This comparative example aims to verify the unique advantages of step S1 (tilted plate rheo casting) of the present invention. The S1 process is replaced with the more conventional "gravity casting and hot extrusion" process for preparing biodegradable magnesium alloy pipes, while S2 and S3 remain exactly the same as in Example 1. The specific steps are as follows: S1. Traditional casting and hot extrusion methods for preparing magnesium alloy tube blanks: Using the same medical-grade AZ31 magnesium alloy ingot as in Example 1, the ingot was melted and refined at 680°C under the same protective atmosphere of CO2 and SF6 mixture. The melt was then poured into a cylindrical metal mold preheated to 300°C and allowed to cool naturally to obtain an ingot with a diameter of 80 mm. After removing surface defects by machining the ingot, it was homogenized and annealed at 350°C for 12 hours. The homogenized ingot was then hot-extruded at 350°C with an extrusion ratio of 25:1 to obtain a tube with an outer diameter of 6 mm. Subsequently, it underwent multiple cold drawing and intermediate annealing to finally process it into a precision tube with an outer diameter of 3.0 mm and a wall thickness of 0.3 mm. The tube was cut to the required length and used as the substrate for subsequent coating. This substrate has a typical deformed structure, with elongated grains along the processing direction and the presence of texture and residual stress.

[0051] Comparative Example 2 The preparation method is the same as in Example 1, except that micro-arc oxidation (MAO) is used instead of hydrothermal deposition coating.

[0052] This comparative example aims to verify the irreplaceability of step S2 (single-step hydrothermal deposition of gradient composite coating) of the present invention. S1 (rheological casting substrate) and S3 (ultrasonic functionalization) of Example 1 are retained, but S2 is replaced with the most commonly used surface ceramicization technology for magnesium alloys (micro-arc oxidation). The specific steps are as follows: S2. Preparation of ceramic coatings by micro-arc oxidation treatment: The substrate obtained in S1 underwent the same pretreatment (acetone and ethanol cleaning, acid washing and activation, rinsing and drying). An electrolyte solution of 0.08 mol / L Na2SiO3 and 0.05 mol / L KOH aqueous solution was prepared. Using a magnesium alloy substrate as the anode and a stainless steel tank as the cathode, micro-arc oxidation was performed under a pulsed power supply with the following parameters: voltage 350V, frequency 500Hz, duty cycle 20%, treatment time 10min, and electrolyte temperature maintained at 20-30℃. After treatment, the sample was removed, thoroughly rinsed with deionized water, and dried at 60℃ to obtain a porous, gray MgO-based ceramic coating with a thickness of approximately 10-20μm. This coating is mechanically intercalated and partially metallurgically bonded to the substrate, but the composition changes abruptly without a gradient transition.

[0053] Comparative Example 3 The preparation method is the same as in Example 1, except that a single silanization treatment is used instead of the multifunctional treatment liquid.

[0054] This comparative example aims to verify the necessity of the synergistic effect of the multifunctional components in step S3 (ultrasound functionalization of citric acid-modified nanoparticles and bioactive peptides) of the present invention. S1 and S2 of Example 1 are retained, but the processing solution of S3 is simplified to a solution containing only silane coupling agent. The specific steps are as follows: S3. Single silanization surface treatment: Preparation of treatment solution: Dissolve 1.0 wt% of silane coupling agent (γ-aminopropyltriethoxysilane, KH550) in a 1:1 volume ratio of ethanol and deionized water and hydrolyze for 15 min; Key modification: Do not add citric acid modified hydroxyapatite nanoparticles and osteogenic growth peptides. Immerse the coated sample obtained in S2 in the above treatment solution and treat it at the same ultrasonic power of 400 W and temperature of 50 °C for 30 min; After treatment, take out the sample, rinse it three times with phosphate buffer (PBS, pH 7.4) and deionized water, and vacuum dry it at 60 °C for 4 h.

[0055] Table 3 shows the comparison of the physicochemical properties of the products in the examples and comparative examples. The magnesium alloy materials prepared in Examples 1-3 of this invention have a matrix of uniform and fine equiaxed spherical crystals, an interfacial bonding strength of approximately 45 N, uniform and controllable degradation behavior, optimal anti-stone performance, and good biocompatibility. Since the effects are similar, individual evaluations are not provided. Compared to the traditional matrix in Comparative Example 1, the micro-arc oxidation coating in Comparative Example 2, and the single silanization treatment in Comparative Example 3, this invention has significant advantages in matrix uniformity, interfacial bonding strength, controllable degradation, anti-stone ability, and biocompatibility, fully demonstrating the synergistic effect of the three-step process of "rheological casting-hydrothermal deposition-ultrasonic functionalization".

[0056] Table 3. Physical and chemical properties of the product

[0057] Example 1 uses moderate and balanced process parameters, and the material has stable comprehensive performance and good repeatability, making it more suitable as a standard control sample. Therefore, the functionalized magnesium alloy ureteral stent prepared by the complete process of Example 1 was selected, with a specification of 5Fr and a length of 30mm, and 8 pieces in each group; at the same time, Comparative Example 1, Comparative Example 2, and Comparative Example 3 were set as controls, with 8 pieces in each group.

[0058] Comparative Example 1: The substrate was made by traditional casting and extrusion molding, and the coating and surface treatment steps were the same as in Example 1; Comparative Example 2: A coating was prepared using micro-arc oxidation MAO, and the substrate and surface treatment steps were the same as in Example 1; Comparative Example 3: Surface treatment was performed using a single silanization method, and the substrate and coating steps were the same as in Example 1.

[0059] Four groups of stent samples were placed in simulated body fluid (SBF, pH 7.4) and immersed in a 37°C constant temperature water bath for 8 weeks, with fresh simulated body fluid replaced weekly. Scanning electron microscopy (SEM) was used to observe the sample cross-sections and measure the coating thickness before and after immersion. Five samples were tested in each group, and the average value was taken. The results are summarized in Table 4. Table 4 shows that after 8 weeks of immersion in simulated body fluid, the coating thickness change rate of Example 1 was only 10%, with uniform thinning while maintaining integrity, without peeling or disintegration, indicating highly controllable degradation behavior and stable interfacial bonding. Comparative Example 1 showed a coating thickness change rate of 30% and localized peeling; Comparative Example 2 showed a coating thickness change rate as high as 46.7% and severe disintegration; Comparative Example 3 showed a more uniform thickness change, but obvious crystal adhesion appeared on the surface, indicating insufficient anti-stone effect. These results further demonstrate that the present invention can achieve stable bonding between the coating and the substrate and precise control of the degradation rate, meeting the clinical needs for long-term stable service of urinary tract implantable devices.

[0060] Table 4 Comparison of coating thickness changes before and after corrosion in each group of supports

[0061] Based on the above characterization and comparative results, it is evident that this invention successfully prepared a biodegradable medical magnesium alloy with a compositional gradient transition structure through a three-step synergistic process of rheological casting, single-step hydrothermal deposition, and ultrasonic functionalization. This material significantly outperforms existing traditional processes and modification methods in terms of anti-stone properties, controllable degradation, interfacial bonding strength, and biocompatibility. It can simultaneously address key issues existing in clinical stents, such as stone adhesion, uncontrollable degradation, easy coating detachment, and the burden of secondary surgeries, demonstrating significant theoretical and practical clinical application value.

[0062] The above description is merely a preferred embodiment of the present invention, and the scope of protection of the present invention is not limited to the above embodiments. For those skilled in the art, any modifications, equivalent substitutions, or improvements made without departing from the technical concept of the present invention should be included within the scope of protection of the present invention.

Claims

1. A method for preparing a biodegradable medical magnesium alloy for preventing kidney stones, characterized in that: Includes the following steps: S1. Preparation of magnesium alloy matrix by rheocasting: The magnesium alloy raw material is melted under a protective atmosphere and superheated to 50-80° above the liquidus. It is then poured onto a cooling plate with an inclination angle of 30-60° to form a semi-solid slurry. The slurry is then injected into the mold at an injection pressure of 80-150MPa and an injection speed of 0.2-0.5m / s. After holding the pressure and temperature for 5-10 minutes, the mold is opened to obtain the magnesium alloy matrix. S2. Single-step hydrothermal deposition of mixed calcium phosphate composite coating: The magnesium alloy substrate is pretreated by cleaning, pickling and rinsing in sequence, and then vertically immersed in the reaction solution, sealed in a high-pressure reactor and placed in an oven, and reacted at 120-200℃ for 2-8 hours to form a mixed calcium phosphate composite coating. The reaction solution contains: 0.08-0.12 mol / L calcium source, 0.048-0.072 mol / L phosphorus source and 0.01-0.05 mol / L mineralization regulator, wherein the calcium-phosphorus molar ratio is 1.5-1.67; S3. Ultrasonic surface treatment: The magnesium alloy substrate with a mixed calcium phosphate composite coating is immersed in the treatment solution to graft the transition layer. It is treated at an ultrasonic power of 300-500W and a temperature of 40-60℃ for 20-40 minutes. After rinsing with a buffer solution, cleaning with deionized water, and drying in a vacuum drying oven at 50-60℃ for 4-5 hours, an anti-calcification biodegradable medical magnesium alloy is obtained. The treatment solution consists of: dissolving 0.5-2 wt% of silane coupling agent in a mixed solvent of ethanol and deionized water, hydrolyzing for 15-20 min, then adding 1-5 wt% of modified nanoparticles, treating with ultrasonic power of 300-500 W and temperature of 40-60℃ for 20-40 min, and finally adding 0.01-0.1 wt% of bioactive peptides and gently stirring to mix.

2. The method for preparing an anti-calculus biodegradable medical magnesium alloy according to claim 1, characterized in that: In step S1, the magnesium alloy matrix is ​​medical-grade AZ31 magnesium alloy, and the protective atmosphere includes a mixture of CO2 and SF6; the cooling plate is made of stainless steel and is preheated to 250-300℃; the mold is preheated to 150-250℃; and the semi-solid slurry has spherical grains with a particle size range of 50-80μm.

3. The method for preparing an anti-calculus biodegradable medical magnesium alloy according to claim 1, characterized in that: In step S2, the pretreatment of the magnesium alloy substrate includes: ultrasonic cleaning with an organic solvent for 10-15 minutes, wherein the organic solvent is one or a combination of acetone, ethanol and isopropanol; activating by immersion in a 1-2% acidic solution for 20-30 seconds, wherein the acidic solution is one of nitric acid, hydrochloric acid, phosphoric acid or sulfuric acid; rinsing with deionized water 3-5 times, wherein the sample is slightly shaken or ultrasonically assisted during each rinse; and drying with nitrogen gas after the pH value is 6.9-7.

1.

4. The method for preparing an anti-calculus biodegradable medical magnesium alloy according to claim 1, characterized in that: In step S2, the reaction solution uses water as a solvent, the calcium source is one of calcium nitrate, calcium chloride or calcium acetate, the phosphorus source is one of diammonium hydrogen phosphate, ammonium phosphate or urea phosphate, and the mineralization regulator is one or more combinations of urea and sodium citrate; the lining of the high-pressure reactor is made of polytetrafluoroethylene.

5. The method for preparing an anti-calculus biodegradable medical magnesium alloy according to claim 1, characterized in that: In step S2, the thickness of the mixed calcium phosphate composite coating is 30-50 μm, and it consists of hydroxyapatite and octacalcium phosphate. A magnesium phosphate transition phase is generated at the interface between the mixed calcium phosphate composite coating and the magnesium alloy substrate.

6. The method for preparing an anti-calculus biodegradable medical magnesium alloy according to claim 1, characterized in that: In step S3, the silane coupling agent is one of γ-aminopropyltriethoxysilane or γ-aminopropyltrimethoxysilane, and the solvent of the treatment solution is a mixture of ethanol and deionized water in a volume ratio of 1:

1.

7. The method for preparing an anti-calculus biodegradable medical magnesium alloy according to claim 1, characterized in that: In step S3, the modified nanoparticles have a particle size range of 50-100 nm, and the modified nanoparticles are citric acid modified calcium phosphate nanoparticles.

8. The method for preparing an anti-calculus biodegradable medical magnesium alloy according to claim 1, characterized in that: In step S3, the bioactive peptide is either osteogenic growth peptide OGP or polyaspartic peptide fragment. The polyaspartic peptide fragment contains hexameric aspartic acid and is derived from the acidic functional fragment of osteopontin.

9. The method for preparing an anti-calculus biodegradable medical magnesium alloy according to claim 1, characterized in that: In step S3, the buffer solution is a phosphate buffer solution with a pH range of 6.5-7.5, and the number of rinses is 3-5.

10. A biodegradable medical magnesium alloy for treating gallstones, prepared by the method according to any one of claims 1-9, characterized in that: A mixed calcium phosphate composite coating is provided on the surface of a magnesium alloy substrate. The mixed calcium phosphate composite coating is grafted to form a transition layer through biochemical ultrasonic treatment. The magnesium alloy substrate, the mixed calcium phosphate composite coating and the transition layer form a composition gradient transition structure.

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