A medical titanium surface drug sustained-release coating and a preparation method thereof

Abstract

The application relates to the technical field of bone defect implant materials, and discloses a medical titanium surface drug release coating and a preparation method thereof. First, medical titanium material is cut into titanium pieces, dried after cleaning and placed in a sterile environment for standby; then, a constant voltage electrolysis system is built with the titanium pieces serving as anodes and platinum pieces serving as cathodes, and titanium dioxide nanotube arrays (TNT) are obtained through electrolysis; naringin solution and GelMA solution are mixed, and a drug-loaded GelMA hydrogel solution is obtained through cross-linking after standing; then, a drug-loaded GelMA hydrogel film is constructed on the surface of the nanotube through a spin coating method; the titanium pieces after spin coating are placed under ultraviolet light for photo-crosslinking reaction, and the medical titanium surface drug release coating is obtained. According to the scheme, the titanium dioxide nanotube, naringin and GelMA hydrogel are coupled at a multi-scale interface, a composite coating system of "titanium base material-nanotube-drug-hydrogel" is constructed, mechanical properties, biological activity and drug release functions are considered, and the limitation of traditional single modification of titanium implants is broken through.

Description

Technical Field

[0001] This invention relates to the field of bone defect implantation materials, specifically to a medical titanium surface drug sustained-release coating and its preparation method. Background Technology

[0002] While bone tissue possesses a certain capacity for self-regeneration and repair, when bone defects exceed a critical threshold, they cannot heal on their own and require the assistance of artificial bone implants to aid in bone regeneration and structural reconstruction. Titanium-based implants, with their excellent mechanical properties, good corrosion resistance, and reliable biocompatibility, are widely used in orthopedics, dentistry, and other clinical medical fields, making them one of the most mature medical implant materials currently available. However, pure titanium substrates exhibit significant bioinertness, lacking the bioactivity to actively induce bone formation in the early stages of implantation. This makes it difficult to quickly form a stable osseointegration with the surrounding natural bone tissue, easily leading to problems such as insufficient early implant stability, long healing periods, and poor long-term osseointegration, significantly reducing clinical implantation success rates. Therefore, functional modification of the titanium-based implant surface to enhance its osseointegration capacity, shorten the bone healing period, and ensure long-term stable service is of great significance for improving the clinical efficacy of bone defect repair.

[0003] To overcome the bioinertia of titanium-based implant surfaces and improve their integration with surrounding natural bone tissue, current technologies primarily rely on biomimetic modification approaches. This involves simulating the microstructure and biological microenvironment of natural bone tissue to functionalize and optimize the surface of titanium substrates. The mainstream technique currently involves constructing micro- and nano-structures on titanium substrates, using various surface modification processes to create micro- and nano-composite biomimetic structures on the titanium surface, thereby improving the substrate's surface morphology and biocompatibility. Among these, titanium nanotube array structures prepared through anodizing possess advantages such as highly ordered topological morphology, simple and controllable fabrication processes, and excellent drug loading and containment capabilities. They can serve as efficient delivery carriers for bioactive molecules and are currently the mainstream modification method for improving the bioactivity of titanium implants and optimizing osseointegration performance, providing crucial technical support for improving the osseointegration effect of titanium implants.

[0004] Although existing titanium substrate surface micro-nano structure modification technology can optimize the surface morphology of implants and improve biocompatibility to a certain extent, there are still obvious technical defects in actual clinical applications, making it difficult to meet the clinical needs of efficient and long-term osseointegration. (1) Existing medical titanium implants generally have the problems of strong surface bioinertness and poor inherent osseointegration ability. Simple titanium nanotubes and other micro-nano physical structures can only improve the surface topology and do not have the biological function of actively promoting bone and regulating the microenvironment of bone regeneration. They cannot fundamentally solve the problem of bioinertness of titanium materials, and the early bone induction ability is insufficient, making it difficult to achieve rapid osseointegration. (2) Traditional drug-loaded modified titanium implants generally have the phenomenon of drug burst release. The drug is released rapidly and in large quantities in the early stage of implantation, which can easily cause excessively high local drug concentration and increased risk of toxic stimulation. Moreover, the drug is consumed quickly, resulting in a short duration of drug effect. It is difficult to continuously and stably release active substances during the bone healing cycle, making it difficult to regulate bone tissue regeneration and inhibit inflammatory response for a long time. Postoperative complications such as inflammatory infection and bone resorption are prone to occur, which seriously affect the long-term osseointegration effect. (3) Existing micro / nano structure modification technologies only achieve structural optimization without combining with long-acting drug sustained-release systems for synergistic modification. The structural advantages and drug bioactivity cannot be coupled to exert their effects. The modification methods are singular, functionally limited, and the overall osseointegration improvement effect is limited, severely restricting the application of titanium-based implants in complex bone defect repair scenarios. In summary, there is an urgent need to develop a titanium surface modification coating technology that combines structural biomimetic advantages, avoids drug burst release problems, and possesses long-acting drug sustained-release function, in order to efficiently improve the osseointegration capacity of titanium implants and meet the application needs of clinical bone defect repair. Summary of the Invention

[0005] The present invention aims to provide a drug sustained-release coating on the surface of medical titanium and its preparation method, so as to solve the technical problems of strong surface bioinertness and poor intrinsic bone integration ability of existing medical titanium implants.

[0006] To achieve the above objectives, the present invention adopts the following technical solution: a method for preparing a drug sustained-release coating on a medical titanium surface, comprising the following steps: Step S1, Titanium substrate pretreatment: Cut the medical titanium material into titanium sheets, and then place them in acetone, anhydrous ethanol and double-distilled water in sequence for ultrasonic cleaning; after cleaning, dry them and place them in a sterile environment for later use. Step S2, Preparation of titanium dioxide nanotube array: Using pretreated titanium sheet as anode and platinum sheet as cathode, a constant voltage electrolysis system is built; electrolysis yields a uniform titanium dioxide nanotube array, which serves as a loading carrier for hydrogel; Step S3, GelMA hydrogel preparation: Dissolve gelatin in PBS buffer, heat and stir until dissolved; then slowly add methacrylic anhydride, heat and stir the reaction, add PBS dilution solution and stop the reaction; after dialysis, freeze dry to obtain GelMA hydrogel; Step S4, Naringin drug loading: Naringin and GelMA hydrogel were prepared into solutions separately and then mixed. The mixture was placed in a sterile environment and allowed to stand to obtain a drug-loaded GelMA hydrogel solution. Step S5, Construction of drug-loaded GelMA hydrogel coating: First, the drug-loaded GelMA hydrogel solution is uniformly dropped onto the surface of the titanium dioxide nanotube array, and then a drug-loaded hydrogel film is constructed on the surface of the nanotubes using a spin coating method. Step S6, Photocrosslinking Polymerization: The titanium sheet after spin coating is placed under ultraviolet light to carry out a photocrosslinking reaction to obtain a drug sustained-release coating on the surface of medical titanium.

[0007] The principles and advantages of this scheme are as follows: 1. Multi-material synergistic coupling innovation: Titanium dioxide nanotubes, naringin, and GelMA hydrogel are coupled at multiple scales to construct a composite coating system of "titanium substrate-nanotube-drug-hydrogel", which takes into account mechanical properties, bioactivity and drug sustained release function, and breaks through the limitations of single modification of traditional titanium implants.

[0008] 2. Bionic Design Innovation: Simulating the extracellular matrix (ECM) structure of natural bone tissue, a three-dimensional network structure is constructed using GelMA hydrogel to provide a suitable microenvironment for cell adhesion, proliferation and differentiation. At the same time, combined with the bone-promoting and anti-inflammatory functions of naringin, the dual goals of "structural biomimicry + functional biomimicry" are achieved, thereby enhancing the bone integration capacity of titanium implants.

[0009] 3. Significant sustained-release effect: The tubular structure of titanium dioxide nanotubes enables efficient loading of naringin. Combined with the physical degradation properties of GelMA hydrogel, the release rate of naringin is effectively controlled, allowing it to sustainably exert its effects of promoting bone formation, inhibiting bone resorption, anti-inflammation, and antibacterial activity. This effectively solves the problems of drug burst release and short duration of effect in traditional drug-loaded implants, enabling the drug to continuously exert its effects of promoting bone formation, anti-inflammation, and antibacterial activity throughout the entire bone repair cycle. Furthermore, GelMA hydrogel mimics natural ECM, promoting cell adhesion and proliferation, and significantly improving the early stability of titanium implants and the success rate of clinical implantation.

[0010] 4. Enhanced Osteointegration Capacity: The micro-nano composite coating constructed from titanium dioxide nanotubes and GelMA hydrogel mimics the extracellular matrix structure of natural bone tissue. Combined with the osteogenic function of naringin, it can significantly promote osteoblast adhesion, proliferation and differentiation, enhance the integration capacity of titanium implants with surrounding natural bone tissue, and improve early implantation stability and clinical implantation success rate.

[0011] 5. Significant advantages in preparation process: The entire preparation process does not require complex and expensive equipment, the operation steps are simple and easy, the preparation cycle is short, the cost is low, and the process parameters are controllable, enabling large-scale production. It solves the problems of complex surface modification processes for traditional titanium implants and difficulty in clinical translation, and has good clinical application prospects and industrialization potential. It can also provide theoretical basis and technical support for the research and development of titanium implants, and broaden the application scope of titanium-based biomedical materials.

[0012] 6. Excellent biocompatibility: The selected GelMA hydrogel and naringin both have excellent biocompatibility, no obvious toxic side effects, and the coating structure is stable and will not have adverse effects on tissues in the body, making it suitable for medical implantation.

[0013] Preferably, as an improvement, in step S2, the electrolyte of the constant voltage electrolysis system is a 0.26-0.28 mol / L ammonium fluoride solution prepared with a glycerol solution of 49-51% by volume; the electrolysis conditions of the constant voltage electrolysis system are electrolysis for 1-2 h at a constant voltage of 20-30 V and a constant temperature of 36-38 ℃.

[0014] Beneficial Effects: This scheme, employing the aforementioned method, ensures uniform electrolyte mixing and prevents precipitation. Furthermore, the electrolyte ratio and the defined electrolysis parameters are well-matched, enabling the formation of uniformly shaped, controllable-pore-size nanotube structures on the surface of titanium-based materials. The resulting film exhibits excellent adhesion, effectively enhancing the biocompatibility and osteoinductive activity of implantable materials, thus meeting the requirements for bone defect repair material preparation. Maintaining stable system temperature during electrolysis helps prevent excessively high temperatures from affecting nanotube morphology. Through long-term experiments, the inventors discovered that if the glycerol volume fraction is too high, the electrolyte viscosity increases significantly, hindering ion migration, resulting in slow nanotube growth and uneven tube diameter. If the volume fraction is too low, the electrolyte's lubrication and inhibition effects weaken, leading to excessive corrosion, easily causing tube wall damage, excessive substrate etching, and a decline in material mechanical properties. Conversely, if the ammonium fluoride concentration is too high, the fluoride ion corrosion ability is too strong, making the nanotube structure prone to collapse and fragmentation. If the concentration is too low, the etching driving force is insufficient, failing to form a complete tubular morphology and resulting in an insufficient number of surface active sites. If the electrolysis voltage exceeds the upper limit, the electric field becomes too intense, leading to disordered nanotube arrangement, significant differences in wall thickness, and easy film detachment. If the voltage is below the lower limit, the reaction cannot proceed fully, resulting in low tube formation efficiency and poor structural uniformity. If the reaction temperature is too high, the electrolyte evaporates faster, the reaction stability deteriorates, and nanotube defects increase. If the temperature is too low, molecular reactivity is insufficient, the growth cycle becomes abnormal, and the array regularity is significantly reduced. If the electrolysis time is too short, the nanotube growth height is insufficient, and the specific surface area is too small. If the time is too long, continuous etching damages the formed structure, impairs the overall interfacial properties of the material, and ultimately reduces the bone integration repair effect.

[0015] Preferably, as an improvement, in step S2, the diameter of the obtained titanium dioxide nanotube array is 60~80nm.

[0016] Beneficial Effects: This scheme, employing the aforementioned approach, facilitates the adaptation of the array structure to cell attachment and growth, achieving both ideal specific surface area and mechanical stability. It enhances drug loading capacity, osteoinductive activity, and optimizes the osseointegration effect of bone defect implant materials. Through long-term experiments, the inventors discovered that if the tube diameter is too large, the tube wall support strength decreases, making the nanotubes prone to bending and collapse, thus reducing the overall mechanical properties of the material. Excessively large pore sizes lead to unstable cell attachment, rapid drug leakage, and an inability to achieve long-term drug release. Conversely, if the tube diameter is too small, the internal space is limited, restricting the specific surface area utilization and significantly reducing drug loading. Insufficient pore permeability hinders substance transport, impeding cell extension and differentiation, and significantly weakening the bone repair induction effect.

[0017] Preferably, as an improvement, in step S4, the concentration of the naringin solution is 0.3~1.0 mg / mL; the concentration of the GelMA hydrogel solution is 100~200 mg / mL, and the standing time after mixing with the drug naringin is 20~60 min.

[0018] Beneficial effects: The above-mentioned scheme facilitates the uniform cross-linking of naringin and GelMA hydrogel, balances drug loading and interfacial binding stability, fully leverages the bone-promoting and anti-inflammatory effects of the drug, and enhances the bioactivity of bone repair materials.

[0019] Preferably, as an improvement, in step S5, the drug-loaded GelMA hydrogel solution contains a photoinitiator with a mass-volume percentage of 0.4% to 0.6% w / v; the photoinitiator is any one of Irgacure 2959 (I2959), LAP (lithium phenyl-2,4,6-trimethylbenzoylphosphonate), and VA-086 (azo).

[0020] Preferably, as an improvement, in step S4, the conditions for spin coating are controlled as follows: start the spin coater and set the coating parameters as follows: low speed 400~600rpm, rotation time 15~20s, to ensure the initial spreading of the hydrogel; then adjust to high speed 1500~2000rpm, rotation time 15~20s, so that the hydrogel uniformly covers the surface of the nanotubes and forms a hydrogel film of uniform thickness.

[0021] Beneficial Effects: This solution employs a two-stage spin coating process of "low-speed spreading + high-speed uniform coating." By progressively controlling the spin speed and spin coating time, hydrogel can be gradually and uniformly coated on the surface of titanium dioxide nanotube arrays. Precise control of the gel film thickness and density ensures both the interfacial bonding strength between the hydrogel and the nanotube substrate and the uniformity of drug loading and sustained-release stability, ultimately improving the biocompatibility, osteogenic induction ability, and surface structure uniformity of the bone implant material. Through long-term experiments, the inventors discovered that if the low-speed spin speed is too low or the spin coating time is less than 15 seconds, the hydrogel cannot be fully wetted and spread, easily leading to localized missed coating, substrate exposure, and gel agglomeration spots, resulting in discontinuous film formation. Conversely, if the low-speed spin speed is too high or the time is too long, too much gel solution will be prematurely ejected, resulting in insufficient gel adhesion to the substrate, leading to a thinner film and insufficient drug loading during subsequent high-speed coating, thus weakening the material's repair performance. If the high-speed rotation speed is too low or the spin coating time is less than 15 seconds, the centrifugation homogenization effect will be poor, the hydrogel surface will be uneven and the thickness will vary greatly, there will be local accumulation and protrusions, the film density will be poor, and problems such as peeling, shedding and uneven drug release will easily occur in the later stage. If the high-speed rotation speed is too high or the time is too long, excessive centrifugation will excessively peel off the gel coating, resulting in an excessively thin film, local damage and exposure of pores, which will not achieve stable drug sustained release, and will destroy the smooth structure of the material surface, which is not conducive to cell adhesion and bone integration.

[0022] Preferably, as an improvement, in step S6, the photocrosslinking reaction is carried out in an ultraviolet light polymerization device at an ultraviolet light wavelength of 360~400 nm for a polymerization time of 2~3 min.

[0023] Beneficial effects: The above-mentioned scheme facilitates the full cross-linking of GelMA hydrogel, forming a stable three-dimensional network structure that tightly encapsulates titanium dioxide nanotubes.

[0024] Preferably, as an improvement, this solution also provides a drug-releasing coating on a medical titanium surface, prepared by the above method.

[0025] Preferably, as an improvement, this solution also provides the application of a medical titanium surface drug-releasing coating in the preparation of titanium-based implants, including the use of the above-mentioned medical titanium surface drug-releasing coating for implantation at bone defect sites after forming the above-mentioned medical titanium surface drug-releasing coating on the surface of the titanium-based implant. Attached Figure Description

[0026] Figure 1 These are SEM images of different titanium surfaces in Experimental Example 1 of this invention.

[0027] Figure 2 This is a comparison of the contact angle measurement results of different titanium surfaces in Experiment Example 1 of the present invention.

[0028] Figure 3This describes the release of naringin from the drug-loaded coated titanium sheet in Experimental Example 2 of this invention.

[0029] Figure 4 This shows the osteoblast proliferation on different titanium surfaces in Experimental Example 3 of the present invention.

[0030] Figure 5 This is an example of collagen secretion from osteoblasts on different titanium surfaces in Experiment 3 of the present invention. Detailed Implementation

[0031] The present invention will be further described in detail below with reference to embodiments, but the implementation of the present invention is not limited thereto. Unless otherwise specified, the technical means used in the following embodiments and experimental examples are conventional means well known to those skilled in the art, and the materials and reagents used can all be obtained commercially.

[0032] Addressing the issues of strong bioinertness and poor osseointegration on the surface of existing medical titanium implants, as well as the problems of drug burst release and short duration of effect in traditional drug-loaded implants, the core objective of this invention is to construct a bone-promoting sustained-release drug coating on the surface of medical titanium. This coating utilizes the ordered tubular structure of titanium dioxide nanotubes to achieve efficient loading of the hydrogel coating, while simultaneously utilizing GelMA hydrogel and cross-linking to form a stable three-dimensional network structure for loading naringin. Leveraging the controllable degradation properties of the hydrogel, slow and programmed release of naringin is achieved, thereby improving the early implantation stability of the titanium implant, promoting osseointegration, and increasing the clinical implantation success rate. This provides a simple, efficient, and low-cost technical solution for the surface modification of medical titanium implants.

[0033] Example 1 This solution provides a method for preparing a drug sustained-release coating on a medical titanium surface, comprising the following steps: Step S1, Titanium Substrate Pretreatment: Cut medical titanium material into 1 cm × 1 cm titanium sheets, and place them in acetone, anhydrous ethanol, and double-distilled water in sequence for ultrasonic cleaning for 10-30 min each (use standard laboratory parameters for ultrasonic power to ensure removal of oil, oxide layer and impurities from the titanium sheet surface); after cleaning, place the titanium sheets in a 37℃ oven to dry to constant weight, and then place them in a sterile environment for later use.

[0034] Step S2, Preparation of Titanium Dioxide Nanotube Array: Nanotube carriers were prepared by anodic oxidation, using pretreated titanium sheets as the anode and platinum sheets as the cathode, and a constant voltage electrolysis system was constructed. The electrolyte was a 0.27 mol / L ammonium fluoride solution prepared with 50% glycerol solution to ensure uniform mixing and no precipitation. The electrolysis conditions were set to a constant voltage of 20 V and an electrolysis time of 1 h. The system temperature was controlled to be stable during the electrolysis process (to avoid excessive temperature affecting the morphology of the nanotubes). Finally, a titanium dioxide nanotube array with a diameter of about 70 nm and a uniform structure was prepared, which served as the loading carrier for the hydrogel.

[0035] Step S3, GelMA hydrogel preparation: First, dissolve 10 g of gelatin in 100 mL of PBS buffer and stir at 50 °C until fully dissolved; then slowly add 8 mL of methacrylic anhydride and stir at 50 °C for 2-3 h to achieve high functionalization of the methacryloyl groups; then add 100 mL of PBS dilution solution to stop the reaction. The solution is then transferred to a dialysis bag and dialyzed with triple-distilled water for 7 days, changing the water at least once a day; finally, freeze-dry for 7 days to obtain the GelMA hydrogel. Step S4, Naringin drug loading: Prepare a 0.5 mg / mL naringin solution by mixing naringin with water, and prepare a 150 mg / mL GelMA hydrogel solution by mixing GelMA hydrogel with water. Then mix the naringin solution and the GelMA hydrogel solution for cross-linking, and let it stand in a sterile environment for 30 min to complete the drug loading and obtain the drug-loaded GelMA hydrogel solution.

[0036] Step S5, Construction of drug-loaded GelMA hydrogel coating: First, the drug-loaded GelMA hydrogel solution (containing 0.5% w / v photoinitiator Irgacure 2959 (I2959)) is uniformly dropped onto the surface of the titanium dioxide nanotube array, and then a drug-loaded hydrogel film is constructed on the surface of the nanotubes using a spin coating method. The conditions for spin coating are controlled as follows: start the spin coater and set the coating parameters as follows: low speed 400~600 rpm, rotation time 15~20 s to ensure the initial spreading of hydrogel; then adjust to high speed 1500~2000 rpm, rotation time 15~20 s to make the hydrogel uniformly cover the surface of the nanotubes and form a hydrogel film of uniform thickness.

[0037] Step S6, Photocrosslinking Polymerization: The spin-coated titanium sheet is placed under an ultraviolet light polymerization device, the ultraviolet light wavelength is controlled at 380nm, and the polymerization time is 2~3 min, so that the GelMA hydrogel undergoes a full crosslinking reaction to form a stable three-dimensional network structure that tightly wraps the titanium dioxide nanotubes, and finally completes the preparation of the entire medical titanium surface drug sustained-release coating.

[0038] To verify the performance of the coating of this invention, the following tests can be conducted to ensure the feasibility and superiority of the technical solution. The test contents are as follows: Experimental Example 1: Characterization of Coating Morphology Scanning electron microscopy (SEM) was used to observe the microstructure of the titanium dioxide nanotube array and the GelMA hydrogel coating, verifying the nanotube diameter (approximately 70 nm), the uniformity and coverage of the hydrogel coating, and ensuring the integrity of the nanotube structure and the full cross-linking of the hydrogel.

[0039] Depend on Figure 1 The SEM results show that titanium dioxide nanotubes with a diameter of 70 nm were formed on the surface of the titanium material after anodizing. After spin coating with GelMA hydrogel and naringin-loaded GelMA hydrogel and UV polymerization, the nanotube structure was completely covered.

[0040] The contact angle of different titanium surface materials was tested using the following steps: First, using clean tweezers, the titanium sheets from different treatment groups were placed stably at the center of the horizontal worktable of the measuring instrument, and the sample position was adjusted to ensure the test surface was flat. Second, the micro-injection needle was manipulated to slowly expel ultrapure water, controlling the water droplet volume to be constant at 2~5 μL, so that the water droplet fell completely and steadily onto the flat surface of the titanium material. Then, the water droplet was allowed to stand still for 3~5 seconds until the droplet shape was completely stable, and the instrument's camera was immediately activated to capture the image. Finally, the contact angle value of a single measurement was recorded using the instrument.

[0041] Figure 2 The study demonstrates the changes in hydrophilicity and hydrophobicity of titanium surfaces treated with different methods. The Ti group (pure titanium) exhibits the strongest hydrophobicity, with a contact angle of 70.1 ± 2.1 °, showing strong hydrophobicity and weak hydrophilicity, significantly different from the other three groups. Secondly, the TNT group (nanotubes) shows a water contact angle of approximately 19.0 ± 3.7 °, indicating strong hydrophilicity. In the nanotube-hydrogel and nanotube-hydrogel (naringin) groups, the water contact angles are 29.6 ± 3.7 ° and 35.2 ± 3.9 °, respectively, with no significant difference between the two groups, both exhibiting strong hydrophilicity. These results also demonstrate the successful construction of the naringin-loaded hydrogel coating on the titanium surface and its excellent hydrophilicity.

[0042] Experiment Example 2: Drug Sustained-Release Performance Test An in vitro drug release test was conducted, in which the prepared drug-loaded coated titanium sheet was placed in simulated body fluid, and samples were taken at different time points. The release amount of naringin was detected by ultraviolet spectrophotometer at 284 nm, and the drug release curve was plotted to verify the sustained-release effect of the coating, ensuring that there was no obvious drug burst release phenomenon and that the release rate met the physiological requirements of bone repair.

[0043] like Figure 3 As shown, the release of naringin was detected using a spectrophotometer. The cumulative release of naringin showed a trend of rapid increase followed by stabilization over time. The rapid release phase was from day 1 to day 7, after which the release rate significantly decreased and remained at a plateau. By day 14, the cumulative release remained relatively stable. The results indicate that the hydrogel coating on the nanotube surface has a good sustained-release effect on naringin.

[0044] Experiment Example 3: Biocompatibility and Osteogenesis Performance Testing Osteoblast culture assay was used to seed osteoblasts onto the coating surface. After a certain period of culture, cell activity was detected by CCK-8 assay to observe cell adhesion and proliferation, thus verifying the growth-promoting effect of the coating on osteoblasts. At the same time, the osteogenic potential of the coating was evaluated by collagen secretion.

[0045] osteoblast proliferation on different titanium surfaces, such as Figure 4 As shown, there was no difference among the groups on day 4. However, after 7 days of culture, compared with the Ti group (i.e., pure titanium), cell viability was significantly improved in the nanotube-hydrogel group and the nanotube-hydrogel (naringin) group. Osteoblasts cultured on titanium dioxide nanotubes covered with naringin-loaded GelMA hydrogel membranes exhibited good viability (p<0.01), indicating that titanium nanotubes loaded with naringin have good biocompatibility.

[0046] Collagen secretion from osteoblasts on different titanium surfaces, such as Figure 5 As shown, regardless of day 7 or day 14, osteoblasts grown on the nanotube-hydrogel (naringin) group expressed the highest collagen content (p<0.05 or p<0.01) compared to other groups, indicating that the continuous release of naringin promotes osteoblast differentiation.

[0047] In summary, this method first cuts medical-grade titanium material into titanium sheets, cleans and dries them, and then places them in a sterile environment for later use. Next, using the aforementioned titanium sheets as the anode and platinum sheets as the cathode, a constant-voltage electrolysis system is constructed to electrolyze and obtain titanium dioxide nanotube arrays (TNT). Naringin solution is uniformly dropped onto the TNT surface and allowed to stand to obtain drug-loaded nanotubes. Then, a GelMA hydrogel film is constructed on the surface of the drug-loaded nanotubes using a spin-coating method. The spin-coated titanium sheets are then subjected to photocrosslinking under ultraviolet light to obtain a sustained-release drug coating on the surface of the medical-grade titanium. The core working principle of this method is as follows: through the synergistic effect of the titanium nanotube array, GelMA hydrogel, and naringin, the organic unity of bioactivity modification of the titanium implant surface, long-term sustained-release of drugs, and improved bone integration is achieved. The specific mechanisms of each component and their synergistic effects are as follows: (I) Mechanism of action of titanium nanotube arrays: Titanium nanotube arrays are prepared by anodizing process. Their ordered micro-nano structure can simulate the topological morphology of natural bone tissue. At the same time, the hollow tubular structure can serve as a storage carrier for hydrogels, providing a structural basis for subsequent drug sustained release. (II) Mechanism of action of GelMA hydrogel: The hydroxyl and amide groups in the molecular structure of GelMA hydrogel can form hydrogen bonds with the hydroxyl groups on the surface of titanium nanotubes, which significantly improves the interfacial bonding strength between the composite coating and the titanium substrate and effectively prevents the coating from falling off under physiological conditions in vivo; its three-dimensional network structure has suitable porosity and can serve as a secondary barrier for drug sustained release. (III) Naringin and the synergistic mechanism of the three: The three form a synergistic system: Titanium nanotubes provide structural support and drug storage space, GelMA hydrogel ensures interface stability and sustained drug release, and naringin exerts anti-inflammatory and osteointegration functions, which are significantly better than single modification technology. Furthermore, all the key parameters mentioned above have been experimentally verified, and their core purpose is to achieve a balance among various properties: controlling the size of titanium nanotubes can balance drug loading and release rate; controlling the concentration of naringin can balance bioactivity and toxicity; controlling GelMA-related parameters can balance coating stability and biocompatibility; and controlling the thickness of the composite coating can balance drug sustained release effect and implant mechanical properties, avoiding the overall effect being affected by improper parameters.

[0048] The above descriptions are merely embodiments of the present invention, and common knowledge such as specific technical solutions and / or characteristics are not described in detail here. It should be noted that those skilled in the art can make various modifications and improvements without departing from the technical solutions of the present invention, and these should also be considered within the scope of protection of the present invention. These modifications and improvements will not affect the effectiveness of the implementation of the present invention or the practicality of the patent. The scope of protection claimed in this application should be determined by the content of its claims, and the specific embodiments described in the specification can be used to interpret the content of the claims.

Claims

1. A method for preparing a drug sustained-release coating on a medical titanium surface, characterized in that: Includes the following steps: Step S1, Titanium substrate pretreatment: Cut the medical titanium material into titanium sheets, and then place them in acetone, anhydrous ethanol and double-distilled water in sequence for ultrasonic cleaning; after cleaning, dry them and place them in a sterile environment for later use. Step S2, Preparation of titanium dioxide nanotube array: Using pretreated titanium sheet as anode and platinum sheet as cathode, a constant voltage electrolysis system is built; electrolysis yields a uniform titanium dioxide nanotube array, which serves as a loading carrier for hydrogel; Step S3, GelMA hydrogel preparation: Dissolve gelatin in PBS buffer, heat and stir until dissolved; then slowly add methacrylic anhydride, heat and stir the reaction, add PBS dilution solution and stop the reaction; after dialysis, freeze dry to obtain GelMA hydrogel; Step S4, Naringin drug loading: Naringin and GelMA hydrogel were prepared into solutions separately and then mixed. The mixture was placed in a sterile environment and allowed to stand to obtain a drug-loaded GelMA hydrogel solution. Step S5, Construction of drug-loaded GelMA hydrogel coating: First, the drug-loaded GelMA hydrogel solution is uniformly dropped onto the surface of the titanium dioxide nanotube array, and then a drug-loaded hydrogel film is constructed on the surface of the nanotubes using a spin coating method. Step S6, Photocrosslinking Polymerization: The titanium sheet after spin coating is placed under ultraviolet light to carry out a photocrosslinking reaction to obtain a drug sustained-release coating on the surface of medical titanium.

2. The method for preparing a sustained-release drug coating on a medical titanium surface according to claim 1, characterized in that: In step S2, the electrolyte of the constant voltage electrolysis system is a 0.26-0.28 mol / L ammonium fluoride solution prepared with a glycerol solution of 49-51% by volume; the electrolysis conditions of the constant voltage electrolysis system are electrolysis for 1-2 hours under a constant voltage of 20-30 V and a constant temperature of 36-38℃.

3. The medical titanium surface drug sustained-release coating and its preparation method according to claim 2, characterized in that: In step S2, the diameter of the obtained titanium dioxide nanotube array is 60~80 nm.

4. The method for preparing a sustained-release drug coating on a medical titanium surface according to claim 3, characterized in that: In step S4, the concentration of the naringin solution is 0.3~1.0 mg / mL; the concentration of the GelMA hydrogel solution is 100~200 mg / mL, and the standing time after mixing with the drug naringin is 20~60 min.

5. A method for preparing a sustained-release drug coating on a medical titanium surface according to claim 1, characterized in that: In step S5, the drug-loaded GelMA hydrogel solution contains a photoinitiator with a mass-volume percentage of 0.4% to 0.6% w / v.

6. A method for preparing a drug-releasing coating on a medical titanium surface according to claim 5, characterized in that: The photoinitiator is any one of Irgacure 2959 (I2959), LAP (lithium phenyl-2,4,6-trimethylbenzoylphosphonate), or VA-086 (azo).

7. A method for preparing a drug-releasing coating on a medical titanium surface according to claim 6, characterized in that: In step S5, the conditions for spin coating are controlled as follows: start the spin coater and set the coating parameters as follows: low speed 400~600 rpm, rotation time 15~20 s, to ensure the initial spreading of the hydrogel; then adjust to high speed 1500~2000 rpm, rotation time 15~20 s, so that the hydrogel uniformly covers the surface of the nanotube and forms a hydrogel film of uniform thickness.

8. A method for preparing a sustained-release drug coating on a medical titanium surface according to claim 1, characterized in that: In step S6, the photocrosslinking reaction is carried out in an ultraviolet light polymerization device at an ultraviolet light wavelength of 360~400 nm for a polymerization time of 2~3 min.

9. A drug-releasing coating on a medical titanium surface, characterized in that: Prepared by the method described in any one of claims 1 to 8.

10. The application of a medical-grade titanium surface drug-release coating in the preparation of titanium-based implants, characterized in that: This includes implantation at bone defect sites after forming the medical titanium surface drug-releasing coating as described in claim 9 on the surface of a titanium-based implant.

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