A photothermally controllable antibacterial titanium alloy implant and its preparation method

Abstract

This invention relates to the field of medical material manufacturing technology, and more specifically, to a photothermally controllable antibacterial titanium alloy implant and its preparation method. The implant substrate is titanium or a titanium alloy, and its surface is activated by alkaline heat treatment. Polydopamine and copper ions are polymerized in situ at room temperature to coat the implant substrate surface. The implant obtained by this invention has no significant toxicity to osteoblasts, excellent biocompatibility, and combines multiple functions such as synergistic antibacterial activity, high hydrophilicity, osteopromoting properties, photothermally controllable properties, and safe sustained release. It can be widely applied in medical implantation fields such as orthopedic implants, bone fixation devices, and cardiovascular stents, providing a safe, efficient, and feasible new solution for effectively addressing key issues such as clinical infection and poor osseointegration in medical titanium alloys.

Description

Technical Field

[0001] This invention relates to the field of medical material manufacturing technology, and more specifically, to a photothermally controllable antibacterial titanium alloy implant and its preparation method. Background Technology

[0002] Titanium and titanium alloys, due to their advantages such as light weight, mechanical properties that match human bone, and resistance to bio-corrosion, have become the core matrix materials for implantable devices such as orthopedic artificial joints, bone fixation stents, and cardiovascular stents. However, these materials face three major bottlenecks in clinical applications: first, their surface bioinertness leads to poor cell adhesion and bone integration, easily causing fibrous encapsulation and implant loosening; second, contact with blood easily activates platelets, posing a high risk of thrombosis; and third, postoperative bacterial infection rates are high, and antibiotic overuse leads to the development of drug-resistant bacteria, ultimately causing implant failure. While existing surface modification techniques have shown some effectiveness in addressing these issues, they still have significant shortcomings. For example, magnetron sputtering can prepare inorganic composite films, but the equipment is expensive, the process is demanding, and the antibacterial methods are limited and poorly controllable; anodizing and hydrothermal methods can improve surface bioactivity, but it is difficult to impart highly efficient antibacterial functions; simple polydopamine coatings or metal ion loading modifications can improve some properties, but they suffer from problems such as limited functionality, uncontrollable ion release, and insufficient safety. In summary, existing technologies struggle to simultaneously integrate mild preparation, controlled sustained release, triple synergistic antibacterial properties, high hydrophilicity, and excellent osteogenic capacity. Polydopamine (PDA) possesses excellent adhesion, biocompatibility, and near-infrared photothermal conversion properties, making it a potential functionalization platform; copper ions (Cu... 2+ It possesses broad-spectrum antibacterial, angiogenesis-promoting, and osteogenic effects, and is safe and harmless at low concentrations. PDA and Cu... 2+ By combining these technologies and utilizing near-infrared light for remote control, it is hoped that a triple synergistic antibacterial effect of photothermal stimulation, copper ion stimulation, and reactive oxygen species can be achieved, reducing the amount of copper ions required while improving antibacterial efficiency, thus balancing safety and functionality. However, there is currently no publicly available technology that combines PDA / Cu composite coatings with near-infrared photothermal control for surface modification of titanium and titanium alloy implants to simultaneously address the risks of infection, poor osseointegration, and thrombosis. Therefore, developing a simple, stable, and easily clinically applicable method for preparing photothermally controllable antibacterial titanium alloys is of great significance. Summary of the Invention

[0003] The present invention aims to at least solve one of the technical problems existing in the prior art. To this end, one aspect of the present invention is to provide a photothermally controllable antibacterial titanium alloy implant, wherein the implant substrate is titanium or titanium alloy, the surface of the implant substrate is activated by alkaline heat treatment, and polydopamine and copper ions are coated onto the surface of the implant substrate by in-situ polymerization at room temperature.

[0004] Another objective of this invention is to provide a method for preparing a photothermally controllable antibacterial titanium alloy implant, the specific steps of which are as follows: S1. The substrate is cut, and then subjected to progressive grinding, ultrasonic cleaning, and drying to obtain sample T; S2. The sample T prepared in S1 is placed in NaOH solution for alkaline treatment and activation to obtain the activated matrix T-NaOH; S3. Dissolve dopamine hydrochloride in Tris buffer, adjust the pH, and prepare mixed solution I; S4. Copper sulfate pentahydrate and hydrogen peroxide are added sequentially to solution I obtained in S3 to obtain mixed solution II; S5. Immerse the activated matrix T-NaOH prepared in S2 into solution II in S4 for reaction, sonicate and then dry to obtain the implant T / PDA-Cu.

[0005] Preferably, the matrix in S1 is titanium or a titanium alloy.

[0006] Preferably, the substrate in S1 is a sample with a diameter of 5 mm and a thickness of 2 mm.

[0007] Preferably, in step S1, 100# to 2000# sandpaper is used for polishing, and the ultrasonic cleaning solvents are deionized water, acetone and anhydrous ethanol in sequence, with ultrasonic time of 10 to 30 minutes for each.

[0008] Preferably, the concentration of NaOH solution in S2 is 3.0–6.0 mol / L, the reaction temperature is 50–70°C, and the reaction time is 20–28 hours; after alkali treatment, it is soaked in deionized water at 70–90°C for 16–24 hours.

[0009] Preferably, the mass of dopamine hydrochloride in S3 is 100-500 mg, which is dissolved in 100 mL of Tris buffer solution with a concentration of 45-60 mmol / L, and the pH is adjusted to 8.3-8.7 with hydrochloric acid to obtain mixed solution I.

[0010] Preferably, the concentration of copper sulfate pentahydrate in S4 is 1.0–7.0 mmol / L, the concentration of hydrogen peroxide is 12–20 mmol / L, and the volume ratio of the mixed solution I, copper sulfate pentahydrate, and hydrogen peroxide is 100:1:20 to 100:5:20.

[0011] Preferably, the reaction conditions in S5 are: room temperature reaction for 1 to 6 hours, the ultrasonication is performed using deionized water for 10 to 30 minutes, and the drying temperature is 40 to 60°C.

[0012] The beneficial effects of this invention are as follows: The preparation process is mild, low-cost, and highly scalable: This invention uses a polydopamine / copper organic-inorganic composite coating, which is prepared by alkali activation and room temperature in-situ polymerization. The process is mild, simple to operate, and does not require expensive equipment. It is suitable for the mass production of implants with complex morphology, significantly reducing the preparation cost and showing good prospects for clinical translation and application.

[0013] Achieving triple synergistic and highly effective antibacterial action and reducing the risk of drug resistance: In response to the shortcomings of single antibacterial methods in clinical practice, such as limited bactericidal efficiency, single target, and easy induction of bacterial drug resistance, this invention achieves highly efficient, controllable, and broad-spectrum antibacterial action through the triple synergistic effect of near-infrared photothermal effect, copper ion release, and reactive oxygen generation. This significantly reduces the bacterial infection rate and the risk of drug resistance, effectively solving the clinical problem of difficult-to-control implant-related infections.

[0014] Controlled sustained release of copper ions ensures biosafety: This invention achieves the release behavior of copper ions with "early rapid release and later stable sustained release". The concentration of copper ions in the coating is always within the biosafety range, effectively avoiding cytotoxicity caused by burst release of ions, and taking into account both antibacterial efficacy and biosafety.

[0015] Significantly enhanced hydrophilicity and osteogenic capacity: The modified implant surface exhibits significantly improved hydrophilicity, which can effectively promote protein adsorption and osteoblast adhesion, spread and proliferation, improve the bioinertness of titanium alloy surface, enhance bone integration potential, and facilitate early postoperative bone healing and long-term stability.

[0016] Stable and controllable photothermal performance, meeting the long-term anti-infection needs after surgery: The coating obtained by this invention has stable and reliable photothermal performance, and can be used in multiple cycles, which facilitates remote, non-invasive and on-demand photothermal therapy according to the infection risk in clinical practice, meeting the clinical needs for long-term anti-infection after surgery.

[0017] Excellent biocompatibility and multifunctional integration: In vitro experiments have confirmed that the implant obtained by this invention has no significant toxicity to osteoblasts, excellent biocompatibility, and integrates multiple functions such as synergistic antibacterial, high hydrophilicity, osteopromoting, controllable photothermal, and safe sustained release. It can be widely used in medical implantation fields such as orthopedic implants, bone fixation devices, and cardiovascular stents, providing a safe, efficient, and feasible new solution for effectively solving key problems such as clinical infection and poor osseointegration of medical titanium alloys.

[0018] Additional aspects and advantages of the invention will become apparent from the description which follows, or may be learned by practice of the invention. Attached Figure Description

[0019] The above and / or additional aspects and advantages of the present invention will become apparent and readily understood from the description of the embodiments taken in conjunction with the following drawings, in which: Figure 1This is a schematic diagram illustrating the construction and antibacterial mechanism of the TC4 / PDA-Cu coating in an embodiment of the present invention; Figure 2 These are SEM microstructure images of the surface in an embodiment of the present invention; Figure 3 This is an infrared spectrum of dopamine monomer and TC4 / PDA-Cu in an embodiment of the present invention; Figure 4 This is the cumulative release curve of copper ions from TC4 / PDA-Cu in an embodiment of the present invention; Figure 5 This is a comparison diagram of water contact angles of different samples in embodiments of the present invention; Figure 6 This is a graph showing the photothermal performance and cycling stability under an 808nm laser in an embodiment of the present invention. Figure 7 These are plate charts showing the antibacterial performance of different treatment groups and statistical charts showing bacterial survival rates in embodiments of the present invention. Figure 8 This refers to the amount of ROS generated under light / no light conditions in embodiments of the present invention. Figure 9 These are fluorescent staining images of bacteria in live or dead states according to embodiments of the present invention; Figure 10 These are osteoblast proliferation, survival rate, and adhesion morphology diagrams from embodiments of the present invention. Detailed Implementation

[0020] To better understand the above-mentioned objectives, features, and advantages of the present invention, the present invention will be further described in detail below with reference to the accompanying drawings and specific embodiments. It should be noted that, unless otherwise specified, the embodiments and features described in these embodiments can be combined with each other.

[0021] Many specific details are set forth in the following description in order to provide a full understanding of the invention. However, the invention may also be implemented in other ways different from those described herein. Therefore, the scope of protection of the invention is not limited to the specific embodiments disclosed below.

[0022] The schematic diagram of the construction and antibacterial mechanism of the TC4 / PDA-Cu coating in this embodiment of the invention is shown below. Figure 1 As shown.

[0023] Example 1 S1. Cut TC4 into samples with a diameter of 5mm and a thickness of 2mm. Polish them step by step with 100#, 600#, 1000# and 2000# sandpaper. Sonicate them with deionized water, acetone and anhydrous ethanol for 10 minutes in sequence. Dry them at 50℃ to obtain sample TC4. S2. The sample TC4 prepared in S1 was placed in a 3.0 mol / L NaOH solution and reacted at 60°C for 20 hours to activate it with alkali treatment. After alkali treatment, it was soaked in deionized water at 80°C for 16 hours to obtain the activated titanium alloy matrix TC4-NaOH. S3. Dissolve 200 mg of dopamine hydrochloride in 100 mL (50 mmol / L) Tris buffer, adjust the pH to 8.5 with hydrochloric acid, and prepare mixed solution I; S4. Add 2 mL (5 mmol / L) copper sulfate pentahydrate aqueous solution and 20 mL (18 mmol / L) H2O2 to solution I obtained in S3 to obtain mixed solution II; S5. Immerse the activated titanium alloy matrix TC4-NaOH prepared in S2 into solution II in S4 and react at room temperature for 4 hours. Then, sonicate with deionized water for 20 minutes and dry in an oven at 50°C to obtain the titanium alloy implant TC4 / PDA-Cu.

[0024] Example 2 S1. Cut TC4 into samples with a diameter of 5mm and a thickness of 2mm. Polish them step by step with 100#, 600#, 1000# and 2000# sandpaper. Sonicate them with deionized water, acetone and anhydrous ethanol for 10 minutes in sequence. Dry them at 60℃ to obtain sample TC4. S2. The sample TC4 prepared in S1 was placed in a 4.0 mol / L NaOH solution and reacted at 70°C for 25 hours to activate it with alkali treatment. After alkali treatment, it was soaked in deionized water at 80°C for 16 hours to obtain the activated titanium alloy matrix T-NaOH. S3. Dissolve 150 mg of dopamine hydrochloride in 100 mL (50 mmol / L) Tris buffer, adjust the pH to 8.5 with hydrochloric acid, and prepare mixed solution I; S4. Add 1 mL (4.0 mmol / L) copper sulfate pentahydrate and 20 mL (15 mmol / L) H2O2 to solution I obtained in S3 to obtain mixed solution II; S5. Immerse the activated titanium alloy matrix TC4-NaOHH prepared in S2 into solution II in S4 and react at room temperature for 4 hours. Then, sonicate with deionized water for 20 minutes and dry in an oven at 50°C to obtain the titanium alloy implant TC4 / PDA-Cu.

[0025] Example 3 S1. Cut TC4 into samples with a diameter of 5mm and a thickness of 2mm. Polish them step by step with 100#, 600#, 1000# and 2000# sandpaper. Sonicate them with deionized water, acetone and anhydrous ethanol for 20 minutes in sequence. Dry them at 50℃ to obtain sample TC4. S2. The sample TC4 prepared in S1 was placed in a 3.0 mol / L NaOH solution and reacted at 80℃ for 20 hours to activate it with alkali treatment. After alkali treatment, it was soaked in deionized water at 70℃ for 20 hours to obtain the activated titanium alloy matrix TC4-NaOH. S3. Dissolve 300 mg of dopamine hydrochloride in 100 mL (55 mmol / L) Tris buffer, adjust the pH to 8.4 with hydrochloric acid, and prepare mixed solution I; S4. Add 3 mL (6.0 mmol / L) copper sulfate pentahydrate and 20 mL (15 mmol / L) H2O2 to solution I obtained in S3 to obtain mixed solution II; S5. Immerse the activated titanium alloy matrix TC4-NaOH prepared in S2 into solution II in S4 and react at room temperature for 4 hours. Then, sonicate with deionized water for 30 minutes and dry in an oven at 60°C to obtain the titanium alloy implant TC4 / PDA-Cu.

[0026] Testing and Experiment Microscopic morphology characterization of embodiments one to three of the present invention was performed. The test results showed that a uniform and continuous dense network composite coating was formed on the surface of TC4 / PDA-Cu. The results are as follows: Figure 2 As shown; Infrared spectroscopy characterization was performed on embodiments one to three of the present invention. The detection results showed that the characteristic functional groups were clearly defined, and PDA was successfully polymerized onto the titanium alloy surface. The results are as follows. Figure 3 As shown; Cu ion cumulative release was detected in Examples 1 to 3 of the present invention. The detection results showed that Cu in TC4 / PDA-Cu... 2+ The loading capacity is 16 μg / cm³ 2 The cumulative release of copper ions is as follows Figure 4 As shown; Water contact angle analysis was performed on Examples 1 to 3 of the present invention. The PDA-Cu coating imparts stronger hydrophilicity to the TC4 surface, and the results are as follows: Figure 5 As shown; The photothermal performance and cycle stability of Examples 1 to 3 of this invention under 808 nm laser light were analyzed. With increasing power, the sample surface temperature increased, indicating that the photothermal performance can be controlled by changing the laser power density. The samples were tested at 1.8 W / cm². 2 The photothermal performance was evaluated by irradiation with an 808nm laser for 4 minutes, followed by 5 laser on-off cycles (1.8W / cm²). 2 The photothermal stability was tested, and the results are as follows: Figure 6 As shown; Antibacterial performance and ROS generation were analyzed in Examples 1 to 3 of this invention. As the laser irradiation time increased from 0 min to 4 min, the bacterial survival rate of the TC4 / PDA-Cu group gradually decreased from 60% to approximately 2.7%, indicating that TC4 / PDA-Cu has good antibacterial performance. This is because, firstly, PDA and copper ions themselves have certain antibacterial properties; secondly, with increasing irradiation time, the bacterial survival rate of the PDA-Cu group decreased from 60% to approximately 2.7%. 2+ The thermal ionization effect leads to an increase in sample surface temperature, enhancing the antibacterial effect; furthermore, under laser irradiation, the ROS intensity of the illuminated group is significantly higher than that of the unilluminated group, disrupting bacterial structure and ultimately achieving synergistic and controllable antibacterial activity. Results are as follows: Figure 7 and Figure 8 As shown; Bacterial viability fluorescence staining analysis was performed on Examples 1 to 3 of the present invention, and the results are as follows: Figure 9 As shown; Osteoblast biocompatibility analysis was performed on embodiments one to three of the present invention, and the results are as follows: Figure 10 As shown.

[0027] In summary, thanks to the unique polydopamine / copper composite coating and near-infrared photothermal synergistic control design, the titanium alloy implant prepared by this invention successfully integrates multiple key properties: mild preparation conditions, simple method, stable coating structure, and controllable copper ion sustained release provide excellent biocompatibility; near-infrared photothermal effect, copper ions, and reactive oxygen species synergistic antibacterial effect achieve an antibacterial rate of up to 97.3%, demonstrating highly efficient and controllable antibacterial performance; at the same time, the surface hydrophilicity of the material is significantly improved, with no obvious toxicity to osteoblasts, good adhesion and proliferation, and excellent in vitro biocompatibility and osteogenic capacity, providing a stable and reliable new solution for postoperative anti-infection and bone integration optimization of medical titanium alloy implants.

[0028] The above description is merely a preferred embodiment of the present invention and is not intended to limit the invention. Various modifications and variations can be made to the invention by those skilled in the art. Any modifications, equivalent substitutions, or improvements made within the spirit and principles of the invention should be included within the scope of protection of the invention.

Claims

1. A photo-thermally controllable antibacterial titanium alloy implant, characterized in that: The implant substrate is made of titanium or titanium alloy. The surface of the implant substrate is activated by alkaline heat treatment, and polydopamine and copper ions are polymerized in situ at room temperature to cover the surface of the implant substrate.

2. A method for preparing a photo-thermally controllable antibacterial titanium alloy implant, characterized in that: The specific steps of the preparation method are as follows: S1. The substrate is cut, and then subjected to progressive grinding, ultrasonic cleaning, and drying to obtain sample T; S2. The sample T prepared in S1 is placed in NaOH solution for alkaline treatment and activation to obtain the activated matrix T-NaOH; S3. Dissolve dopamine hydrochloride in Tris buffer, adjust the pH, and prepare mixed solution I; S4. Copper sulfate pentahydrate and hydrogen peroxide are added sequentially to solution I obtained in S3 to obtain mixed solution II; S5. Immerse the activated matrix T-NaOH prepared in S2 into solution II in S4 for reaction, sonicate and then dry to obtain the implant T / PDA-Cu.

3. The method of claim 2, wherein the method further comprises: The matrix in S1 is titanium or a titanium alloy. ​ 4. The method of claim 2, wherein the method further comprises: The substrate in S1 is a sample with a diameter of 5 mm and a thickness of 2 mm.

5. The method of claim 2, wherein the method further comprises: applying a photo-thermal control to the implant to control the growth of bacteria on the implant. In S1, 100# to 2000# sandpaper is used for polishing, and the ultrasonic cleaning solvents are deionized water, acetone and anhydrous ethanol in sequence, with ultrasonic time of 10 to 30 minutes for each.

6. The method of claim 2, wherein the method further comprises: The concentration of NaOH solution in S2 is 3.0–6.0 mol / L, the reaction temperature is 50–70℃, and the reaction time is 20–28 hours; after alkali treatment, it is soaked in deionized water at 70–90℃ for 16–24 hours.

7. The method of claim 2, wherein the method further comprises: The S3 solution contains 100–500 mg of dopamine hydrochloride, which is dissolved in 100 mL of 45–60 mmol / L Tris buffer solution. The pH is then adjusted to 8.3–8.7 with hydrochloric acid to prepare mixed solution I.

8. The method of claim 2, wherein the method further comprises: applying a photo-thermal control to the implant to control the growth of bacteria on the implant. The concentration of copper sulfate pentahydrate in S4 is 1.0–7.0 mmol / L, and the concentration of hydrogen peroxide is 12–20 mmol / L. The volume ratio of the mixed solution I, copper sulfate pentahydrate, and hydrogen peroxide is 100:1:20 to 100:5:

20.

9. The method of claim 2, wherein the method further comprises: applying a photo-thermal control to the implant to control the growth of bacteria on the implant. The reaction conditions in S5 are: room temperature reaction for 1 to 6 hours; the ultrasonication is performed using deionized water for 10 to 30 minutes; and the drying temperature is 40 to 60°C.

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