A near-infrared light responsive thermoelectric coupling titanium-based implant, a preparation method and application thereof

Abstract

The application discloses a near-infrared light responsive thermal-electric coupling titanium-based implant as well as a preparation method and application thereof, and belongs to the technical field of biomedical materials. The near-infrared light responsive thermal-electric coupling titanium-based implant provided by the application comprises a porous titanium substrate and a composite hydrogel coating. The surface of the porous titanium substrate is sequentially provided, from inside to outside, with a TiO2 / SrTiO3 heterojunction, up-conversion nanoparticles and barium titanate nanoparticles. The up-conversion nanoparticles are Yb 3+ and Er 3+ co-doped NaYF4 up-conversion nanoparticles. The composite hydrogel coating is arranged on the surface of the barium titanate nanoparticles, and the composite hydrogel coating comprises MXene, a medicinal active ingredient and a hydrogel carrier. The application realizes the synergistic coupling of photo-thermal effect and photo-electric-pyroelectric effect under near-infrared light irradiation by constructing a multi-layer synergistic structure on the surface of the porous titanium substrate, and realizes multiple functions such as bone formation promotion, antibiosis and anti-tumor.

Description

Technical Field

[0001] This invention relates to the field of biomedical materials technology, and in particular to a near-infrared light-responsive thermo-electrically coupled titanium-based implant, its preparation method, and its application. Background Technology

[0002] Osteosarcoma is a primary malignant bone tumor that commonly affects children and adolescents. Clinical treatment typically involves surgical resection of the lesion, followed by postoperative chemotherapy or radiotherapy to eliminate residual tumor cells. However, current treatment modalities still have several shortcomings. On the one hand, while postoperative adjuvant chemotherapy and radiotherapy kill tumor cells, they inevitably cause non-specific damage to surrounding normal tissues, and there is a potential risk of tumor residue or recurrence. On the other hand, bone defects formed after bone tumor resection require repair, and the filling site is prone to bacterial infection during the healing process, increasing the risk of implantation failure.

[0003] In the field of bone repair materials, titanium and its alloys have become commonly used materials for bone implants due to their excellent mechanical properties, biocompatibility, and corrosion resistance. Especially with the development of additive manufacturing technology, 3D-printed porous titanium implants can achieve personalized matching with the morphology of bone defects in patients and facilitate bone tissue ingrowth, showing broad application prospects in bone defect repair. However, the integration ability of 3D-printed titanium implants with surrounding bone tissue still needs improvement, and they themselves do not possess anti-tumor and anti-infection functions. Postoperative residual tumor cells and potential bacterial colonization around the implant can both lead to implantation failure or disease recurrence. Therefore, how to endow implants with anti-tumor and antibacterial capabilities while achieving bone repair is a technical problem that urgently needs to be solved in this field. Summary of the Invention

[0004] In view of this, the present invention provides a near-infrared light-responsive thermo-electrically coupled titanium-based implant, its preparation method, and its application. The present invention achieves synergistic coupling of photothermal and photoelectric-pyroelectric effects under near-infrared light irradiation by constructing a multi-layered synergistic structure on the surface of a porous titanium substrate, generating surface temperature rise and microcurrent, thereby simultaneously achieving multiple functions including efficient bone promotion, antibacterial activity, and antitumor activity.

[0005] In a first aspect, the present invention provides a near-infrared light-responsive thermo-electrically coupled titanium-based implant, comprising a porous titanium substrate and a composite hydrogel coating. The porous titanium substrate surface is provided with TiO2 / SrTiO3 heterojunction, upconversion nanoparticles and barium titanate nanoparticles in sequence from the inside to the outside. The upconversion nanoparticles are Yb 3+ and Er 3+ Co-doped NaYF4 upconversion nanoparticles; The composite hydrogel coating is disposed on the surface of the barium titanate nanoparticles, and the composite hydrogel coating includes MXene, a pharmaceutically active ingredient, and a hydrogel carrier.

[0006] Preferably, in the upconversion nanoparticle layer, Yb 3+ The doping molar concentration is 15~25%, Er 3+ The doping molar concentration is 1~5%.

[0007] Preferably, the hydrogel carrier is a gelatin-sodium alginate hydrogel; in the composite hydrogel coating, the concentration of gelatin is 8-15 wt%, and the mass ratio of gelatin to sodium alginate is (3-5):1; the pharmaceutical active ingredient includes at least one of curcumin and doxorubicin; in the composite hydrogel coating, the mass ratio of MXene to the pharmaceutical active ingredient is 1:(2-3).

[0008] In a second aspect, the present invention provides a method for preparing the above-mentioned near-infrared light-responsive thermo-electrically coupled titanium-based implant, comprising the following steps: Provide porous titanium substrates; A TiO2 / SrTiO3 heterojunction was constructed on the surface of the porous titanium substrate. Upconversion nanoparticles were deposited on the surface of the TiO2 / SrTiO3 heterojunction. Barium titanate nanoparticles were grown in situ on the surface of the upconversion nanoparticles. The barium titanate nanoparticles are filled with a composite hydrogel, which is then cross-linked to obtain the final product.

[0009] Preferably, the step of constructing the TiO2 / SrTiO3 heterostructure includes: sequentially acid etching and anodic oxidation of a porous titanium substrate to construct a TiO2 nanotube array, followed by annealing and alkaline heat treatment in a Sr(OH)2 solution.

[0010] Furthermore, the annealing temperature is 400~550℃, and the annealing time is 0.5~2h.

[0011] Furthermore, in the alkaline heat treatment, the concentration of the Sr(OH)2 solution is 0.05~0.2M, the treatment temperature is 160~200℃, and the treatment time is 0.5~4h.

[0012] Preferably, the step of depositing upconversion nanoparticles includes: preparing a rare earth solution by dissolving Y salt, Yb salt, Er salt and urea in water; immersing a porous titanium substrate with a TiO2 / SrTiO3 heterostructure in the rare earth solution at 80~100℃ for 2~5h; removing the substrate and immersing it in a mixed solution of NaF and HF; reacting the substrate at 90~110℃; and washing and drying the substrate.

[0013] Preferably, the step of in-situ growth of barium titanate nanoparticles includes: placing a porous titanium substrate with deposited upconversion nanoparticles in a hydrothermal reaction medium containing Ba(OH)2, and carrying out a hydrothermal reaction in an autoclave at a reaction temperature of 240~280℃ for a reaction time of 2~8h.

[0014] Thirdly, the present invention provides the application of the above-mentioned near-infrared light-responsive thermo-electrically coupled titanium-based implant or the near-infrared light-responsive thermo-electrically coupled titanium-based implant prepared by the above-mentioned preparation method in the preparation of bone tissue defect repair materials.

[0015] Compared with the prior art, the present invention has achieved the following beneficial effects: (1) This invention constructs TiO2 / SrTiO3 heterojunction and Yb sequentially from the inside to the outside on the surface of a porous titanium substrate. 3+ and Er 3+ A titanium-based implant with a multi-layered functional structure was constructed by co-doping NaYF4 upconversion nanoparticles and barium titanate nanoparticles, with an outermost layer of a composite hydrogel coating containing MXene, pharmaceutical active ingredients, and a hydrogel carrier. This structural design enables the implant to generate a synergistic thermo-electric coupling effect under near-infrared light irradiation: the upconversion nanoparticles absorb near-infrared light and emit ultraviolet / visible light, generating heat; ultraviolet / visible light excites the TiO2 / SrTiO3 heterojunction to generate a photocurrent; the heat excites the barium titanate nanoparticles to generate a pyroelectric current; the three-dimensional conductive network constructed by MXene promotes electrical signal conduction; and the pharmaceutical active ingredients in the hydrogel carrier are released in a controlled manner under thermo-electric stimulation. This results in multiple biological effects on the implant surface, combining photothermal heating, microcurrent stimulation, and sustained drug release, synergistically achieving bone-promoting, antibacterial, and anti-tumor functions, thus realizing an organic combination of physical and chemical therapy.

[0016] (2) This invention significantly promotes the osteogenic differentiation capacity of mesenchymal stem cells through the synergistic effect of multilayer functional structures. The bioactive interface provided by the TiO2 / SrTiO3 heterostructure, the electrical stimulation generated by barium titanate nanoparticles, and the biomimetic microenvironment created by the hydrogel coating work together to effectively improve the integration capacity of the implant with the surrounding bone tissue; the introduction of MXene further enhances the conductivity and mechanical properties of the composite hydrogel, providing a better microenvironment for cell adhesion, proliferation and differentiation, thereby achieving bone regeneration while repairing bone defects. Attached Figure Description

[0017] The accompanying drawings, which form part of this specification, are used to provide a further understanding of the invention. The illustrative embodiments and descriptions of the invention are used to explain the invention and do not constitute an undue limitation thereof. Obviously, those skilled in the art can obtain other drawings based on these drawings without any inventive effort.

[0018] Figure 1 These are the Fourier transform infrared spectra of the Ti-SC-DB sample of Example 1 and the Ti-SC sample of Comparative Example 7 of this invention. Figure 2 These are scanning electron microscope (SEM) images of the Ti-SC-DB sample of Example 1, the Ti sample of Comparative Example 1, and the Ti-SC sample of Comparative Example 7 of the present invention. Figure 3 These are X-ray diffraction (XRD) patterns of the Ti-SC-DB sample of Example 1, the Ti sample of Comparative Example 1, and the Ti-SC sample of Comparative Example 7 of the present invention. Figure 4 These are the surface temperature variation curves over time for the Ti-SC-DB sample of Example 1, the Ti sample of Comparative Example 1, and the Ti-SC sample of Comparative Example 7 of the present invention. Figure 5 This is the current density-time response curve of the porous titanium implant Ti-SC-DB in Embodiment 1 of the present invention; Figure 6 This is a comparison of the killing effects of the porous titanium implant (Ti-SC-DB) of Example 1 and the porous titanium implant (Ti) of Comparative Example 1 on osteosarcoma cells (HOS) under near-infrared light and no near-infrared light conditions; where ns indicates no significant difference, p≥0.05; **** indicates p<0.0001; "+NIR" indicates near-infrared light irradiation; Figure 7 This diagram illustrates the expression of COL-1, OPN, OCN, BMP-2, ALP, and Runx2 genes in rat bone marrow mesenchymal stem cells on the surface of the porous titanium implant (Ti-SC-DB) of Example 1 and the porous titanium implant (Ti) of Comparative Example 1. In the diagram, A represents the COL-1 gene, B represents the OPN gene, C represents the OCN gene, D represents the BMP-2 gene, E represents the ALP gene, and F represents the Runx2 gene. In the diagram, ** indicates p < 0.01; *** indicates p < 0.001; **** indicates p < 0.0001; and "+NIR" indicates near-infrared light irradiation. Detailed Implementation

[0019] It should be noted that the following detailed descriptions are exemplary and intended to provide further illustration of the invention. Unless otherwise specified, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains.

[0020] This invention provides a near-infrared light-responsive thermo-electrically coupled titanium-based implant, comprising a porous titanium substrate and a composite hydrogel coating; The porous titanium substrate surface is provided with TiO2 / SrTiO3 heterojunction, upconversion nanoparticles and barium titanate nanoparticles in sequence from the inside to the outside. The upconversion nanoparticles are Yb 3+ and Er 3+ Co-doped NaYF4 upconversion nanoparticles; The composite hydrogel coating is disposed on the surface of the barium titanate nanoparticles, and the composite hydrogel coating includes MXene, a pharmaceutically active ingredient, and a hydrogel carrier.

[0021] This invention achieves synergistic coupling of multiple physical fields—optical, thermal, and electrical—through the spatial configuration design of the aforementioned multi-layered functional structure. Specifically, upconversion nanoparticles absorb near-infrared light and then emit ultraviolet / visible light, generating heat. The ultraviolet / visible light excites the TiO2 / SrTiO3 heterojunction to generate a photocurrent, solving the problem of insufficient absorption of long-wavelength light by the TiO2 / SrTiO3 heterojunction. The heat excites barium titanate nanoparticles to generate a pyroelectric current, and the three-dimensional conductive network constructed by MXene promotes electrical signal conduction. The pharmaceutical active ingredients in the hydrogel carrier are released in a controlled manner under thermo-electric stimulation, thereby forming multiple biological effects on the implant surface that combine photothermal heating, microcurrent stimulation, and sustained drug release, synergistically achieving bone-promoting, antibacterial, and anti-tumor functions.

[0022] In this invention, the porous titanium substrate serves as the structural support unit of the entire implant. The porous titanium substrate is preferably pure titanium or a titanium alloy, with the titanium alloy more preferably being a Ti-6Al-4V alloy, which possesses high strength, good biocompatibility, and corrosion resistance. The porosity of the porous titanium substrate is preferably 50-90%, for example, it can be 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or any combination of the above values, more preferably 60-80%; the pore size is preferably 300-800 μm, more preferably 400-600 μm. This porosity and pore size range is compatible with the microstructure of natural cancellous bone, providing sufficient space for osteoblast migration, proliferation, and blood vessel ingrowth, promoting bone integration, and providing a rough interface for subsequent surface functionalization, enhancing the adhesion of each functional layer. The porous titanium substrate is preferably prepared using 3D printing technology, specifically selective laser melting technology, to achieve precise control of porosity, pore size, and connectivity.

[0023] In this invention, the TiO2 / SrTiO3 heterojunction is disposed on the surface of a porous titanium substrate as the innermost functional unit. The TiO2 nanotubes provide a high specific surface area and directional charge transport channels, while SrTiO3 forms a heterojunction interface with TiO2. The mismatch between the conduction band and valence band positions between TiO2 and SrTiO3 can create a built-in electric field at the interface, promoting the separation of photogenerated electron-hole pairs and suppressing carrier recombination, thereby improving photoelectric conversion efficiency.

[0024] In this invention, the upconversion nanoparticles are disposed on the surface of a TiO2 / SrTiO3 heterojunction, serving as intermediate layer functional units. The upconversion nanoparticles are Yb. 3+ and Er 3+ Co-doped NaYF4 upconversion nanoparticles, in which Yb 3+ As a sensitizer, it can efficiently absorb near-infrared light around 980nm; Er 3+ As an activator, energy transfer from Yb 3+ Upon gaining excitation energy, energy level transitions occur, emitting high-energy photons with wavelengths in the visible or ultraviolet range. This upconversion process converts near-infrared light, which has a large tissue penetration depth and causes minimal biological damage, into short-wavelength light that can be directly absorbed by the TiO2 / SrTiO3 heterojunction, solving the problem of low utilization of long-wavelength light by wide-bandgap semiconductor materials. In the upconversion nanoparticles, Yb 3+ The preferred molar concentration of the doping is 15-25%, more preferably 18-22%; Er 3+ The preferred molar concentration of the doping is 1 to 5%, and more preferably 1 to 3%.

[0025] In this invention, the barium titanate nanoparticles are disposed on the surface of upconversion nanoparticles as outer functional units. Barium titanate is a typical perovskite ferroelectric material with a significant pyroelectric effect; that is, lattice distortion occurs with temperature changes, leading to changes in spontaneous polarization intensity, thereby generating bound charges on the material surface and forming a pyroelectric current. When the upconversion nanoparticles generate heat under near-infrared light irradiation, this heat is transferred to the barium titanate nanoparticles, causing lattice vibration and changes in polarization intensity, thus generating a microcurrent. The preferred crystal form of the barium titanate nanoparticles is tetragonal, as tetragonal barium titanate exhibits a stronger pyroelectric effect.

[0026] In this invention, a specific spatial relationship is formed between the TiO2 / SrTiO3 heterojunction, the upconversion nanoparticles, and the barium titanate nanoparticles: the TiO2 / SrTiO3 heterojunction is located in the innermost layer, in direct contact with the porous titanium substrate; the upconversion nanoparticles are located in the middle layer, in close contact with the TiO2 / SrTiO3 heterojunction; and the barium titanate nanoparticles are located in the outermost layer, in close contact with the upconversion nanoparticles. This spatial configuration optimizes the energy transfer path: the ultraviolet / visible light emitted by the upconversion nanoparticles can directly excite the TiO2 / SrTiO3 heterojunction below, without penetrating other functional layers and causing energy loss; the heat generated by the upconversion nanoparticles can be directly transferred to the barium titanate nanoparticles above, maximizing the excitation of the pyroelectric effect. Meanwhile, this sequence ensures the structural integrity of each functional layer—the TiO2 / SrTiO3 heterojunction needs to be built directly on the titanium substrate, the rare earth layer needs to be deposited on the surface of the heterojunction to achieve close contact and energy transfer, and the barium titanate layer needs to be grown on the surface of the rare earth layer to achieve efficient heat transfer and limited diffusion doping of rare earth elements.

[0027] In this invention, the composite hydrogel coating is disposed on the surface of barium titanate nanoparticles as the outermost functional unit. The composite hydrogel coating includes MXene, a pharmaceutically active ingredient, and a hydrogel carrier. MXene is a type of two-dimensional transition metal carbide / nitride material with excellent conductivity, hydrophilicity, and photothermal conversion efficiency. MXene is uniformly dispersed in the hydrogel, forming a three-dimensional conductive network. On the one hand, it can efficiently conduct the pyroelectric current generated by the barium titanate layer, transmitting the electrical signal to the entire hydrogel volume; on the other hand, it can enhance the photothermal conversion capability of the composite hydrogel, synergistically generating heat with the upconversion nanoparticles. The MXene is preferably Ti3C2T. x T x The surface functional groups (such as -OH, -O, -F, etc.) are indicated. The hydrogel carrier is a biocompatible polymer material, preferably a gelatin-sodium alginate hydrogel. Gelatin provides cell adhesion sites, promoting cell spreading and proliferation; sodium alginate can form a stable three-dimensional network through calcium ion cross-linking, encapsulating MXene and pharmaceutically active ingredients. In the composite hydrogel coating, the concentration of gelatin is 8~15wt%, and the mass ratio of gelatin to sodium alginate is (3~5):1.

[0028] In this invention, the pharmaceutically active ingredient includes at least one of curcumin and doxorubicin. Curcumin has anti-inflammatory, antibacterial, and osteogenic differentiation-promoting activities, while doxorubicin has antitumor activity. In the composite hydrogel coating, the mass ratio of MXene to the pharmaceutically active ingredient is 1:(2~3).

[0029] The present invention also provides a method for preparing the above-mentioned near-infrared light-responsive thermo-electrically coupled titanium-based implant, comprising the following steps: Provide porous titanium substrates; A TiO2 / SrTiO3 heterojunction was constructed on the surface of the porous titanium substrate. Upconversion nanoparticles were deposited on the surface of the TiO2 / SrTiO3 heterojunction. Barium titanate nanoparticles were grown in situ on the surface of the upconversion nanoparticles. The barium titanate nanoparticles are filled with a composite hydrogel, which is then cross-linked to obtain the final product.

[0030] This invention does not impose any special restrictions on the source of the porous titanium substrate; it can be obtained commercially or prepared using conventional methods in the field. Preferably, this invention uses 3D printing technology to prepare the porous titanium substrate, specifically selective laser melting (SLM). By adjusting parameters such as laser power, scanning speed, and powder thickness, precise control over porosity, pore size, and pore connectivity can be achieved. Before use, the prepared porous titanium substrate needs to be cleaned sequentially with acetone, anhydrous ethanol, and deionized water using ultrasonic cleaning for 10–30 minutes each to remove surface oil and impurities. After cleaning, it is vacuum dried at 60–80°C.

[0031] In this invention, the step of constructing the TiO2 / SrTiO3 heterojunction includes: acid etching and anodic oxidation of a porous titanium substrate to construct a TiO2 nanotube array, followed by annealing and alkaline heat treatment in a Sr(OH)2 solution.

[0032] In this invention, the purpose of the acid etching treatment is to remove the natural oxide layer on the surface of the titanium substrate to obtain a clean surface. The purpose of the anodic oxidation treatment is to grow a TiO2 nanotube array in situ on the surface of the titanium substrate. This invention does not impose any special limitations on the specific methods for constructing the TiO2 nanotube array through acid etching and anodic oxidation treatments; methods commonly used in the art for acid etching and anodic oxidation treatments can be referred to.

[0033] In this invention, the solvent used for acid etching is preferably a mixed solution of hydrofluoric acid and nitric acid, wherein the HF concentration is 1-3M, the HNO3 concentration is 3-5M, and the volume ratio is preferably 1:(2-4). The acid etching time is preferably 30-120s, more preferably 60-90s. After acid etching, the solution is repeatedly rinsed with deionized water and dried with nitrogen gas.

[0034] In this invention, the voltage for the anodizing treatment is preferably 10-30V, more preferably 15-25V; the treatment time is preferably 1-3h, more preferably 1.5-2.5h; the solvent for the anodizing treatment is preferably an organic electrolyte system containing ammonium fluoride, specifically a glycerol solution of 0.1-0.5M NH4F and 2-5 vol% H2O. After the anodizing treatment, the sample is rinsed with deionized water and dried with nitrogen.

[0035] In this invention, the purpose of the annealing treatment is to transform the amorphous TiO2 after anodizing into a crystalline anatase phase. The annealing temperature is preferably 400~550℃, for example, 400℃, 420℃, 450℃, 480℃, 500℃, 520℃, 550℃, or any combination of the above values, more preferably 420~480℃; the annealing time is preferably 0.5~2h, more preferably 1h; the heating rate of the annealing treatment is preferably 5~15℃ / min. After annealing, the furnace is cooled to room temperature.

[0036] In this invention, the purpose of the alkaline heat treatment is to generate a thin SrTiO3 shell in situ on the surface of TiO2 nanotubes, forming a TiO2 / SrTiO3 heterojunction. During the alkaline heat treatment, the concentration of the Sr(OH)2 solution is preferably 0.05~0.2M, for example, 0.05M, 0.08M, 0.1M, 0.12M, 0.15M, 0.18M, ​​0.2M, or any range of the above values, more preferably 0.08~0.15M; the treatment temperature is preferably 160~200℃, for example, 160℃, 170℃, 180℃, 190℃, 200℃, or any range of the above values, more preferably 170~190℃; the treatment time is preferably 0.5~4h, for example, 0.5h, 1h, 1.5h, 2h, 3h, 4h, or any range of the above values. After alkaline heat treatment, the sample is repeatedly rinsed with deionized water to remove residual alkaline solution from the surface and then dried at 60~80℃.

[0037] In this invention, the step of depositing upconversion nanoparticles includes: preparing a rare earth solution by dissolving Y salt, Yb salt, Er salt and urea in water; immersing a porous titanium substrate with a TiO2 / SrTiO3 heterostructure in the rare earth solution at 80~100℃ for 2~5h; removing the substrate and immersing it in a mixed solution of NaF and HF; reacting the substrate at 90~110℃; and washing and drying the substrate.

[0038] In this invention, the rare earth solution is prepared by dissolving urea in deionized water, then sequentially adding Y salt, Yb salt, and Er salt, and stirring until completely dissolved. The concentration of urea is preferably 0.005~0.02 g / mL, more preferably 0.008~0.015 g / mL. The Y salt, Yb salt, and Er salt are preferably their nitrates, namely Y(NO3)3, Yb(NO3)3, and Er(NO3)3, or their corresponding hydrated salts. Urea hydrolyzes to produce OH-. -This process allows rare earth ions to form hydroxide precursors on the surface of the TiO2 / SrTiO3 heterojunction. Simultaneously, the OH groups on the surface of the rare earth hydroxide undergo dehydration condensation with the OH groups on the surface of TiO2 / SrTiO3 to form Ti-O-RE or Sr-O-RE covalent bonds (RE represents rare earth elements, specifically Y, Yb, and Er in this invention), thereby anchoring the rare earth precursors to the substrate surface.

[0039] In this invention, the immersion temperature is preferably 80~100℃, for example, it can be 80℃, 85℃, 90℃, 95℃, 100℃ or any range of the above values, and more preferably 85~95℃; the immersion time is preferably 2~5h, and more preferably 3~4h. After immersion, the sample is taken out and gently rinsed with deionized water to remove unbound rare earth ions on the surface.

[0040] In this invention, the preparation method of the NaF and HF mixed solution is as follows: NaF is dissolved in deionized water, and then HF is added to adjust to the desired concentration. The concentration of NaF in the mixed solution is preferably 0.005~0.02 g / mL, more preferably 0.008~0.015 g / mL, for example, it can be 0.005 g / mL, 0.008 g / mL, 0.01 g / mL, 0.012 g / mL, 0.015 g / mL, 0.018 g / mL, 0.02 g / mL, or any range of the above values; the concentration of HF is preferably 0.01~0.05 M, for example, it can be 0.01 M, 0.02 M, 0.03 M, 0.04 M, 0.05 M, or any range of the above values, more preferably 0.02~0.04 M. The sample deposited with the rare earth hydroxide precursor is immersed in the mixed solution and reacted at 90~110℃. - Yb is formed by in-situ crystallization with rare earth ions under heating conditions. 3+ and Er 3+ Co-doped NaYF4 upconversion nanoparticles. The reaction temperature is preferably 90~110℃, more preferably 95~105℃, for example, it can be 90℃, 95℃, 100℃, 105℃, 110℃ or any combination of the above values; the reaction time is preferably 20~40 min, more preferably 25~35 min. After the reaction, the sample is taken out, repeatedly washed with deionized water to remove residual salts on the surface, and vacuum dried at 60~80℃ to obtain a titanium substrate with deposited upconversion nanoparticles.

[0041] In this invention, the step of in-situ growth of barium titanate nanoparticles includes: placing a porous titanium substrate with deposited upconversion nanoparticles in a hydrothermal reaction medium containing Ba(OH)2, and carrying out a hydrothermal reaction in an autoclave at a reaction temperature of 240~280℃ for a reaction time of 2~8h, so that barium titanate nanoparticles grow on the surface.

[0042] The hydrothermal reaction medium is prepared by dissolving Ba(OH)₂·8H₂O in water, heating and stirring at 70-90°C until completely dissolved, and then adding ethanol and ammonia to adjust the polarity and pH of the reaction medium. The preferred volume ratio of water, ethanol, and ammonia in the hydrothermal reaction medium is (1.5-2.5):(1.5-2.5):(0.5-1.5), more preferably (1.8-2.2):(1.8-2.2):(0.8-1.2), for example, 2:2:1. The addition of ammonia brings the pH of the mixed solution to 12-14, more preferably 12.5-13.5. The concentration of Ba(OH)2 is preferably 0.05~0.2M, more preferably 0.08~0.15M, for example, it can be 0.05M, 0.08M, 0.1M, 0.12M, 0.15M, 0.18M, ​​0.2M or any range of the above values.

[0043] A titanium substrate with deposited upconversion nanoparticles was horizontally placed at the bottom of a high-pressure reactor lined with polytetrafluoroethylene (PTFE). The aforementioned hydrothermal reaction medium was added to ensure complete immersion of the sample. The reactor was sealed and placed in an oven for hydrothermal reaction. The reaction temperature was preferably 240–280°C, for example, 240°C, 250°C, 260°C, 270°C, 280°C, or any combination thereof, more preferably 250–270°C; the reaction time was preferably 2–8 h, for example, 2 h, 3 h, 4 h, 5 h, 6 h, 7 h, 8 h, or any combination thereof, more preferably 4–6 h. During the hydrothermal reaction, Ba… 2+ The particles react with TiO2 or TiO2 / SrTiO3 on the substrate surface to form BaTiO3 nanoparticles through in-situ crystallization under alkaline high-temperature conditions. Simultaneously, the rare earth elements in the upconversion nanoparticles induce lattice vibrations within the barium titanate crystal structure at high temperatures, generating microcurrents. Furthermore, limited diffusion can occur, with some elements partially entering the BaTiO3 lattice to achieve rare earth doping, further enhancing the pyroelectric properties of BaTiO3.

[0044] After the reaction, the reactor was cooled to room temperature along with the furnace. The sample was removed and repeatedly rinsed with deionized water to remove loosely attached particles and residual alkali. Then, it was ultrasonically cleaned in anhydrous ethanol for 5-10 minutes to remove organic residues from the surface. The cleaned sample was then vacuum dried at 60-80℃ to obtain a titanium substrate with barium titanate nanoparticles grown on it.

[0045] In this invention, the preparation and filling steps of the composite hydrogel coating include: preparing a composite hydrogel solution containing MXene, a pharmaceutically active ingredient, and a hydrogel carrier; injecting the solution into a porous titanium substrate with barium titanate nanoparticles for filling; and then immersing the solution in a calcium salt solution for crosslinking treatment. The purpose of the crosslinking treatment is to enable sodium alginate to form a stable three-dimensional network structure, with calcium ions specifically binding to the guluronic acid units on the sodium alginate molecular chain to form an "egg-box" structure, thereby achieving crosslinking and curing of the hydrogel. The calcium salt solution is preferably an aqueous solution of calcium chloride with a concentration of 1-3 wt%, more preferably 1.5-2.5 wt%. The immersion time is preferably 5-15 min, more preferably 8-12 min. After the crosslinking treatment, the sample is removed, and the surface is gently rinsed with deionized water to remove unbound calcium ions, thus obtaining the near-infrared light-responsive thermo-electrically coupled titanium-based implant of this invention.

[0046] In this invention, the composite hydrogel solution is prepared as follows: MXene is dispersed in deionized water and ultrasonically treated for 10-30 minutes to achieve uniform dispersion, resulting in an MXene dispersion. The pharmaceutically active ingredient is dispersed in deionized water and then stirred and mixed uniformly with the MXene dispersion. The concentration of MXene is preferably 0.1-1.0 mg / mL, more preferably 0.3-0.8 mg / mL; the concentration of the pharmaceutically active ingredient is preferably 1-2 mg / mL, more preferably 1-1.5 mg / mL. Gelatin and sodium alginate are added to the above mixture, and the mixture is heated and stirred at 35-50°C for 1-3 hours to fully dissolve the gelatin and sodium alginate, forming a uniform composite hydrogel solution. The concentration of gelatin is preferably 8-15 wt%, and the mass ratio of gelatin to sodium alginate is (3-5):1, preferably 4:1.

[0047] In this invention, necessary post-processing is required after each step, including cleaning and drying. Cleaning can be performed using solvents such as deionized water or anhydrous ethanol, by ultrasonic cleaning or immersion cleaning; drying can be performed by vacuum drying, forced air drying, or natural air drying, with the preferred temperature being room temperature to 80°C. The specific process parameters for each step can be adjusted according to actual needs, and those skilled in the art can determine the optimal conditions through a limited number of experiments.

[0048] This invention also provides the application of the above-described near-infrared light-responsive thermo-electrically coupled titanium-based implant or the near-infrared light-responsive thermo-electrically coupled titanium-based implant prepared by the above method in the preparation of bone tissue defect repair materials. The bone tissue defect repair material is particularly suitable for repairing bone defects after osteosarcoma surgery, achieving synergistic anti-tumor, antibacterial, and osteopromoting treatment through thermo-electric coupling effects under near-infrared light irradiation.

[0049] Specifically, after the implant of the present invention is implanted into the bone defect site, it is subjected to in vitro near-infrared light irradiation: Upconversion nanoparticles absorb near-infrared light, emit ultraviolet / visible light, and generate heat. Ultraviolet / visible light excites the TiO2 / SrTiO3 heterojunction to generate photogenerated electron-hole pairs, which separate under the influence of a built-in electric field, forming a photocurrent. Heat is transferred to the barium titanate nanoparticles, causing lattice vibrations and changes in spontaneous polarization intensity, generating a pyroelectric current. A three-dimensional conductive network constructed with MXene efficiently conducts the photocurrent and pyroelectric current to the entire implant surface. Surface microcurrents stimulate mesenchymal stem cells, promoting their osteogenic differentiation and upregulating AL. Expression of osteogenic-related genes such as P, RUNX2, and OCN promotes the formation of mineralized nodules; the temperature rise generated by the photothermal effect (reaching 45~55℃) directly ablates residual tumor cells, while the reactive oxygen species (such as superoxide anions and hydroxyl radicals) generated at the same time effectively kill surrounding bacteria; thermo-electric stimulation promotes the controlled release of pharmaceutical active ingredients in the hydrogel, which exert anti-inflammatory, osteogenic, and / or anti-tumor effects; the porous structure provides space for osteoblast migration, proliferation, and blood vessel ingrowth, promoting the integration of the implant with the surrounding bone tissue.

[0050] Through the synergistic effect of the above-mentioned multi-physical fields, the implant of the present invention can effectively remove residual tumor cells and prevent bacterial infection while repairing bone defects, thus realizing the integration of structural support, physical therapy and chemotherapy. It is particularly suitable for the repair of complex bone defects after osteosarcoma surgery.

[0051] The technical solution of the present invention will be further described below with reference to specific embodiments. The present invention does not impose any special restrictions on the source of reagents used in the following embodiments; commercially available products well known to those skilled in the art can be used.

[0052] In the following embodiments, the Triply Periodic Minimal Surface (TPMS) is a surface that extends infinitely periodically in three-dimensional space along three independent directions (such as the X, Y, and Z axes). Its core characteristic is that the average curvature is zero everywhere. The TPMS structure is highly matched with the zero curvature characteristics of natural bone trabeculae, and its connecting channels promote bone cell ingrowth and angiogenesis.

[0053] Example 1 This embodiment provides a near-infrared light-responsive thermo-electrically coupled titanium-based implant and its preparation method.

[0054] (1) Preparation of porous titanium substrate: A porous Ti-6Al-4V substrate with a pore size of 700 μm and a porosity of 70%, based on a three-period minimal surface, was prepared using selective laser melting. Its dimensions were 10 × 10 × 2 mm. 3The prepared porous titanium substrate was ultrasonically cleaned with acetone, anhydrous ethanol and deionized water for 15 min each to remove surface oil and impurities, and then vacuum dried at 60℃.

[0055] (2) Construction of TiO2 / SrTiO3 heterojunction: A mixed acid solution was prepared by uniformly mixing 5 mL of 2 wt% hydrofluoric acid and 31 mL of 20 wt% nitric acid. This solution was then used to perform flow etching on each surface of the porous titanium substrate from step (1), with a total treatment time of 90 s, to remove the natural oxide layer. Then, anodizing was performed for 2 h in a glycerol solution containing 0.27 M NH4F and 3 vol% H2O at a DC voltage of 25 V to construct a TiO2 nanotube array on the titanium substrate surface. After anodizing, the substrate was rinsed with deionized water and dried with nitrogen. The sample was then placed in a tube furnace and annealed at 450 °C for 1 h at a heating rate of 10 °C / min to convert amorphous TiO2 into a crystalline anatase phase, resulting in a porous titanium substrate with TiO2 on its surface.

[0056] The porous titanium substrate sample with TiO2 on the surface after annealing was placed in a 0.1M Sr(OH)2 solution and subjected to alkaline heat treatment at 180℃ for 1 h, which caused the in-situ transformation of the TiO2 nanotube surface into a SrTiO3 thin shell, forming a TiO2 / SrTiO3 heterojunction. After alkaline heat treatment, the sample was repeatedly rinsed with deionized water to remove residual alkaline solution on the surface and dried at 60℃ to obtain a porous titanium substrate with a TiO2 / SrTiO3 heterojunction on the surface.

[0057] (3) Deposition of upconversion nanoparticles: Dissolve 0.25 g of urea in 25 mL of deionized water, then add sequentially 250 μL of 1.0 M Y(NO3)3 aqueous solution, 100 μL of 0.63 M Yb(NO3)3 aqueous solution, and 15 μL of 0.4 M Er(NO3)3 aqueous solution, i.e., Yb 3+ The doping molar concentration is approximately 19.75%, Er 3+ The doping molar concentration was approximately 1.88%; the mixture was stirred until homogeneous to obtain a rare earth solution. The porous titanium substrate with a TiO2 / SrTiO3 heterostructure on its surface obtained in step (2) was immersed in the above rare earth solution and soaked in a 90°C water bath for 3 hours to allow rare earth ions to form hydroxide precursors on the substrate surface. The sample was removed, gently rinsed with deionized water, and then immersed in a 10 mL mixed solution of 0.01 g / mL NaF and 0.03 M HF. The solution was heated in a 100°C water bath for 30 minutes to allow the rare earth precursors to crystallize in situ to generate Yb. 3+ and Er 3+Co-doped NaYF4 upconversion nanoparticles. After the reaction, the sample was removed, repeatedly washed with deionized water to remove residual salts on the surface, and then vacuum dried at 60°C to obtain a porous titanium substrate with deposited upconversion nanoparticles.

[0058] (4) In-situ growth of barium titanate nanoparticles: 16.9 g of Ba(OH)₂·8H₂O was dissolved in deionized water and heated and stirred in an 80°C water bath until completely dissolved. Then, ethanol and ammonia were added to adjust the polarity and pH of the reaction medium, controlling the volume ratio of water, ethanol, and ammonia to be 2:2:1. The pH of the mixed solution reached 13, and the concentration of Ba(OH)₂ was 0.1 M, thus obtaining the hydrothermal reaction medium. The porous titanium substrate with upconversion nanoparticles deposited in step (3) was placed horizontally at the bottom of a high-pressure reactor lined with polytetrafluoroethylene. The above-mentioned hydrothermal reaction medium was added to ensure that the sample was completely submerged. The reactor was sealed and placed in an oven for hydrothermal reaction at 260°C for 4 h, allowing barium titanate nanoparticles to grow in situ on the surface. After the reaction, the reactor was cooled to room temperature with the furnace. The sample was taken out, rinsed repeatedly with deionized water, and then ultrasonically cleaned in anhydrous ethanol for 5 min to remove loosely attached particles on the surface. It was then vacuum dried at 60°C to obtain a porous titanium substrate with barium titanate nanoparticles grown on it.

[0059] (5) Preparation and filling of composite hydrogel coating: MXene (Ti3C2T) x MXene was dispersed in deionized water and sonicated for 20 min to ensure uniform dispersion, thus preparing an MXene dispersion. Curcumin and doxorubicin were then dispersed in deionized water and mixed thoroughly with the MXene dispersion to obtain a mixed solution. The concentration of MXene in the mixed solution was controlled at 0.5 mg / mL, and the concentration of curcumin was 1.47 × 10⁻⁶ mg / mL. -4 The concentration of doxorubicin was 1.25 mg / mL. Gelatin and sodium alginate were added to the above mixture, with the concentration of gelatin controlled at 10 wt% and the mass ratio of gelatin to sodium alginate at 4:1. The mixture was heated and stirred at 45°C for 2 hours to fully dissolve the gelatin and sodium alginate, forming a homogeneous composite hydrogel solution.

[0060] The composite hydrogel solution was injected into the porous titanium substrate with barium titanate nanoparticles grown in step (4) using a syringe, allowing the hydrogel to fully penetrate the porous structure. Then, it was immersed in a 2wt% CaCl2 aqueous solution for crosslinking treatment for 10 min. After crosslinking treatment, the sample was removed, the surface was gently rinsed with deionized water, and stored at 4℃ to obtain a near-infrared responsive thermo-electrically coupled titanium-based implant, denoted as Ti-SC-DB.

[0061] Example 2 The difference between this embodiment and embodiment 1 is that in step (2) of this embodiment, the annealed sample is placed in a 0.1M Sr(OH)2 solution and subjected to alkaline heat treatment at 180°C for 3 hours.

[0062] Example 3 The difference between this embodiment and embodiment 1 is that in step (5) of this embodiment, a 0.1 mg / mL MXene dispersion is prepared.

[0063] Comparative Example 1 The difference between this comparative example and Example 1 is that this comparative example only performs the flow acid etching treatment in steps (1) and (2), with a total treatment time of 90s, to remove the natural oxide layer on the surface. The resulting sample is denoted as Ti.

[0064] Comparative Example 2 The difference between this comparative example and Example 1 is that this comparative example does not perform the in-situ growth of barium titanate nanoparticles in step (4), that is, after the deposition of upconversion nanoparticles in step (3), the preparation and filling of the composite hydrogel coating in step (5) are carried out directly.

[0065] Comparative Example 3 The difference between this comparative example and Example 1 is that this comparative example does not perform the preparation of the SrTiO3 thin shell in step (2), that is, after the anodic oxidation and annealing treatment in step (2), the deposition of upconversion nanoparticles in step (3) is carried out directly.

[0066] Comparative Example 4 The difference between this comparative example and Example 1 is that the deposition of upconversion nanoparticles in step (3) is not performed. That is, after constructing the TiO2 / SrTiO3 heterojunction in step (2), the in-situ growth of barium titanate nanoparticles in step (4) is performed directly.

[0067] Comparative Example 5 The difference between this comparative example and Example 1 is that this comparative example first performs barium titanate growth, followed by the deposition of upconversion nanoparticles. The specific steps are as follows: (1) Same as step (1) in Example 1.

[0068] (2) Same as step (2) in Example 1.

[0069] (3) In-situ growth of barium titanate nanoparticles: Same as step (4) in Example 1, the porous titanium substrate with TiO2 / SrTiO3 heterostructure on the surface obtained in step (2) is subjected to barium titanate growth to obtain a porous titanium substrate with barium titanate nanoparticles.

[0070] (4) Deposition of upconversion nanoparticles: Same as step (3) in Example 1, deposit upconversion nanoparticles on the porous titanium substrate with barium titanate nanoparticles obtained in step (3).

[0071] (5) Preparation and filling of composite hydrogel coating: Same as step (5) in Example 1.

[0072] Comparative Example 6 The difference between this comparative example and Example 1 is that MXene was constructed as a separate layer, rather than dispersed in a hydrogel. The specific steps are as follows: (1) Same as step (1) in Example 1.

[0073] (2) Same as step (2) in Example 1.

[0074] (3) Same as step (3) in Example 1.

[0075] (4) Same as step (4) in Example 1.

[0076] (5) Construction of the MXene layer: MXene (Ti3C2T) is constructed. x MXene was dispersed in deionized water to prepare a 1 mg / mL MXene dispersion. A dense MXene film was constructed on the surface of the sample obtained in step (4) by vacuum filtration and then vacuum dried at 60 °C.

[0077] (6) Preparation and filling of the hydrogel coating: Curcumin and doxorubicin were dissolved in a small amount of ethanol, and then added to deionized water, controlling the curcumin concentration to be 1.47 × 10⁻⁶. -4 The concentration of doxorubicin was 1.25 mg / mL. Gelatin and sodium alginate were added to the solution, with the gelatin concentration controlled at 0.1 g / mL and the sodium alginate concentration at 0.03 g / mL. The solution was heated and stirred at 45°C for 2 h to form a hydrogel solution (without MXene). The sample with an MXene layer on its surface obtained in step (5) was immersed in the hydrogel solution for 10 min, and then soaked in a 2 wt% CaCl2 aqueous solution for crosslinking treatment for 10 min to obtain a control sample with MXene layered alone.

[0078] Comparative Example 7 The difference between this comparative example and Example 1 is that step (5) is not performed in this comparative example, and a porous titanium substrate with barium titanate nanoparticles is finally obtained, which is denoted as Ti-SC.

[0079] Test case 1. Fourier Transform Infrared Spectroscopy (FTIR) Measurement Fourier transform infrared spectroscopy was performed on the Ti-SC-DB sample of Example 1 and the Ti-SC sample of Comparative Example 7, as follows: Figure 1As shown, the infrared spectrum of the Ti-SC sample exhibits characteristic peaks of Ti-O bonds related to BaTiO3 and the implant surface. The presence of C=C and -COO bonds in the infrared spectrum of the Ti-SC-DB sample indicates that the hydrogel successfully bound to the implant surface.

[0080] 2. Microscopic morphology determination: Scanning electron microscope (SEM) images of the Ti-SC-DB sample from Example 1, the Ti sample from Comparative Example 1, and the Ti-SC sample from Comparative Example 7 are shown below. Figure 2 As shown in the SEM images of the Ti samples, the flow acid etching process completely removed residual particles from the inner and outer surfaces of the porous implants. High-magnification observation revealed micro-grooves formed by laser scanning and acid etching on the surface. Lattice-like rare-earth nanoparticles and spherical BaTiO3 nanoparticles were observed in the Ti-SC samples, providing a basis for the construction of heterojunctions. In the Ti-SC-DB group, the internal porous surface was filled with hydrogel, with a small number of nanoparticles dispersed within.

[0081] 3. X-ray diffraction (XRD) measurement: The XRD patterns of the Ti-SC-DB sample of Example 1, the Ti sample of Comparative Example 1, and the Ti-SC sample of Comparative Example 7 are shown below. Figure 3 As shown, a distinct titanium peak was observed on the surface of the Ti sample. In the Ti-SC sample, the characteristic peak of BaTiO3 was very prominent, confirming its successful deposition. In the Ti-SC-DB sample, the titanium peak was almost masked, and the characteristic peak of the hydrogel dominated the entire spectrum.

[0082] 4. Measurement of photothermal conversion performance Using a wavelength of 808nm and a power of 2W / cm 2 Near-infrared light was used to irradiate the surfaces of porous titanium implants in Examples 1-3 and Comparative Examples 1-7, and the surface temperature changes of the samples were monitored in real time. The surface temperature was recorded after 300 seconds of irradiation. Three parallel samples were set up for each group of samples, and the average value was taken. The results are shown in Table 1. The surface temperature change curves of the Ti-SC-DB sample of Example 1, the Ti sample of Comparative Example 1, and the Ti-SC sample of Comparative Example 7 over time are shown in Table 1. Figure 4 As shown.

[0083] Table 1. Average surface temperature of samples at 300 s

[0084] from Figure 4As shown in Table 1, the surface temperatures of Examples 1-3 and Comparative Examples 2, 3, 5, and 6 all reached above 53°C after 300s of near-infrared light irradiation, exhibiting excellent photothermal conversion performance. In contrast, the temperature of Comparative Example 1 remained essentially unchanged, and the temperature of Comparative Example 4 was only 42.5°C, significantly lower than other samples containing rare earth layers. The results indicate that the upconversion effect and photothermal effect of the rare earth layer are key to the photothermal temperature rise of the porous titanium-based implant. The temperature of Comparative Example 7 was 52.2°C, indicating that the deposition of rare earth elements on the surface effectively enhanced the photothermal conversion effect; however, due to the lack of MXene photothermal synergy, its temperature was slightly lower than that of Example 1.

[0085] 5. Surface photoelectric properties testing The photoelectric properties of the porous titanium implants in Examples 1 and Comparative Examples 1-7 were tested using an electrochemical workstation. The sample was used as the working electrode, a platinum wire as the counter electrode, and a saturated calomel electrode as the reference electrode. Electrolysis was performed in 0.1 M Na₂SO₄ electrolyte using a wavelength of 808 nm and a power of 2 W / cm². 2 Near-infrared light was used to irradiate the lamp in a cycle of switching it on and off (20s on, 20s off), and the photocurrent density-time response curve was recorded.

[0086] Calculate the average value of the peak current density at the instant the light is turned on (I) on ) and the average value of the valley current density at the moment the light is turned off (I off ), calculate the peak-valley current density difference ΔI = I on - I off The current density-time response curve of the porous titanium implant Ti-SC-DB in Example 1 is shown below. Figure 5 As shown in the figure, the peak-valley current density difference data for each group of samples are summarized in Table 2.

[0087] Table 2. Peak-valley current density difference data for Example 1 and Comparative Examples 1-7

[0088] As can be seen from Table 2, the peak-valley current density difference in Examples 1-3 reached 2.5 μA / cm. 2 The above values ​​are significantly higher than those of the comparative examples. Comparative Example 1 showed the weakest response, indicating that it produces almost no response without a functional layer. The response of Comparative Example 2 was 1.42 μA / cm. 2 This indicates that the pyroelectric effect of the barium titanate layer contributes approximately half of the electrical signal. The response of Comparative Example 3 is 0.86 μA / cm. 2 This indicates that the photoelectric effect of the TiO2 / SrTiO3 heterojunction significantly contributes to the electrical signal. The response of Comparative Example 4 is 0.31 μA / cm. 2This indicates that the upconversion effect of the rare-earth layer is a prerequisite for exciting photoelectric and pyroelectric responses. The responses of Comparative Examples 5 and 6 are both lower than those of Example 1, demonstrating that a specific deposition sequence and MXene dispersion method are crucial for achieving efficient electrical signal responses. For Comparative Example 7, the surface current response is 2.36 μA / cm². 2 This indicates that the synergistic effect of heterojunction, upconversion nanoparticles and barium titanate nanoparticles can generate a strong thermo-electric coupling current. However, due to the lack of a three-dimensional conductive network constructed by MXene, its current response is lower than that of Example 1, proving that MXene has an enhancing effect on efficient electrical signal conduction.

[0089] 6. Antibacterial performance test The inhibition rates of *Escherichia coli* (ATCC25922) and *Staphylococcus aureus* (ATCC6538) on the surfaces of porous titanium implants in Examples 1 and Comparative Examples 1-7 were determined using the plate count method. The test method was as follows: bacteria were inoculated into LB medium and cultured at 37°C for 24 h, then diluted with PBS buffer to 1×10⁻⁶. 6 CFU / mL bacterial suspension was added. Samples from each group were placed in 24-well plates, with 1 mL of bacterial suspension added to each well, and incubated at 37°C for 24 hours. For the near-infrared light irradiation group, a wavelength of 808 nm and a power of 2 W / cm² were used daily during the incubation process. 2 Irradiate the bacteria with near-infrared light for 10 min. After incubation, dilute the bacterial suspension and spread it onto LB solid medium, incubate at 37℃ for 24 h, and count the colonies. The inhibition rate is calculated using the formula: Inhibition rate (%) = (1 - number of colonies in the experimental group / number of colonies in the blank group) × 100%. The blank group is a bacterial suspension without any sample. Three replicates are set up for each group, and the average value is taken. The results are shown in Table 3.

[0090] Table 3. Antibacterial performance test results of porous titanium implants in Examples 1 and 1-7

[0091] As shown in Table 3, without near-infrared light irradiation, the antibacterial rates of all samples, except for Comparative Examples 1 and 7, were between 50% and 55%, mainly due to the sustained-release antibacterial effect of curcumin and doxorubicin in the hydrogel. Under near-infrared light irradiation, the antibacterial rates of Examples 1-3 significantly increased to over 86%, demonstrating excellent photothermal-photoelectric synergistic antibacterial performance. The antibacterial rate of Comparative Example 1 was extremely low regardless of whether it was irradiated or not. The antibacterial rate of Comparative Example 2 after irradiation was approximately 75%, lower than that of Example 1, indicating that the pyroelectric effect of the barium titanate layer contributed to the antibacterial effect. The antibacterial rate of Comparative Example 3 after irradiation was approximately 69%, significantly lower than that of Example 1, indicating that the photoelectric effect of the TiO2 / SrTiO3 heterojunction made an important contribution to antibacterial activity. The antibacterial rate of Comparative Example 4 after irradiation only increased to approximately 55-57%, indicating that the upconversion effect of the rare earth layer is a prerequisite for activating the photothermal and photoelectric effects. Comparative Examples 5 and 6 showed antibacterial rates of approximately 72-77% after light irradiation, both lower than that of Example 1, demonstrating that the deposition sequence and MXene dispersion method synergistically enhance antibacterial performance. Comparative Example 7 showed an antibacterial rate of approximately 12% in the absence of light irradiation, indicating that without the hydrogel coating, there is no drug release effect, resulting in weaker antibacterial ability under light-free conditions. However, after the addition of light irradiation, the surface antibacterial rate reached approximately 34%, indicating that the thermo-electric coupling effect (photothermal heating and reactive oxygen species generation) itself can endow the implant with a certain antibacterial ability, but this effect is significantly weaker than that of Example 1, demonstrating that drug release and thermo-electric coupling synergistically enhance the antibacterial effect.

[0092] 7. Antitumor performance determination The killing effect of the porous titanium implant (Ti-SC-DB) of Example 1 and the porous titanium implant (Ti) of Comparative Example 1 on osteosarcoma cells (HOS) was determined by CCK-8 assay. HOS cells were incubated at 5 × 10⁻⁶ cells per cell line. 4 Inoculations were performed on the surface of each group of samples at a density of 100 individuals / mL and incubated in a 37°C, 5% CO2 incubator. For the near-infrared irradiation group, a wavelength of 808 nm and a power of 2 W / cm² were used daily during the incubation process. 2 The samples were irradiated with near-infrared light for 10 min. After 3 days of culture, the samples were transferred to new well plates, fresh culture medium and CCK-8 solution were added, and after incubation for 2 h, the absorbance at 450 nm was measured, and cell viability was calculated (with the blank group as 100%). Three replicates were set up for each group, and the average value was taken. The results are as follows: Figure 6 As shown.

[0093] from Figure 6It can be seen that after 3 days of culture, the porous titanium implant (Ti) in Comparative Example 1 showed no significant killing effect on osteosarcoma cells (HOS) under both near-infrared and non-near-infrared light conditions (cell viability ≥95%). In contrast, the porous titanium implant (Ti-SC-DB) in Example 1 showed approximately 54% cell viability without near-infrared light irradiation, mainly due to the sustained-release antitumor effect of doxorubicin in the hydrogel; under near-infrared light irradiation, cell viability further decreased to approximately 22%, demonstrating a synergistic antitumor effect enhanced by photothermal-photoelectric-chemotherapy.

[0094] 8. Osteogenic differentiation capacity assessment The osteogenic capacity of the porous titanium implant (Ti-SC-DB) in Example 1 and the porous titanium implant (Ti) in Comparative Example 1 was evaluated by detecting the expression of osteogenic-related genes in rat bone marrow mesenchymal stem cells (rBMSCs). rBMSCs were fed at a concentration of 1 × 10⁻⁶. 5 Inoculations were performed on the surface of each group of samples at a density of 100 individuals / mL and incubated in a 37°C, 5% CO2 incubator. For the near-infrared irradiation group, a wavelength of 808 nm and a power of 2 W / cm² were used daily during the incubation process. 2 The cells were irradiated with near-infrared light for 10 min. After 7 days of culture, total RNA was extracted from the cells and reverse transcribed into cDNA. The expression levels of osteogenic related genes (ALP, RUNX2, OCN, COL-I, OPN, BMP-2) were detected by real-time quantitative PCR, with GAPDH as an internal reference gene. -ΔΔCt The relative expression level was calculated using the method (with Comparative Example 1, the group without NIR, as the baseline, set to 1). The results are as follows: Figure 7 As shown.

[0095] It can be seen that, in Example 1, the expression levels of the six osteogenic-related genes of Ti-SC-DB without near-infrared light irradiation were more than 1.5 times that of Comparative Example 1. After near-infrared light treatment, the expression levels of the six osteogenic-related genes were more than 2.2 times that of Comparative Example 1. This indicates that Ti-SC-DB of Example 1 can significantly promote osteogenic differentiation of rat bone marrow mesenchymal stem cells, and the microcurrent and photothermal effect generated by near-infrared light irradiation can further enhance the upregulation of osteogenic-related genes.

[0096] 9. Cell mineralization capacity assay Alizarin Red S staining was used to assess the formation of intracellular calcium nodules. Cells were injected at a rate of 5 × 10⁶ cells / mL. 4Cells were seeded at a density of [number] cells onto the sample surface. After 21 days of culture, the cells were fixed with 4 wt% paraformaldehyde at 4°C for 25 minutes. Alizarin Red S staining solution was added to each culture dish and incubated at room temperature for 30 minutes. To quantify calcium deposition, 400 μL of 10% acetic acid aqueous solution was added to each culture dish and incubated at room temperature for 30 minutes to dissolve calcium nodules. The resulting solution was transferred to centrifuge tubes and centrifuged at 12,000 rpm for 30 seconds. After removing the supernatant, the solution was neutralized with 10 wt% ammonia. The absorbance of the solution was then measured at 405 nm using a microplate reader. The test results are summarized in Table 4.

[0097] Table 4. Summary of Cell Mineralization Capacity Data for Porous Titanium Implants in Examples and Comparative Cases

[0098] As shown in Table 4, without near-infrared light irradiation, the cell mineralization capacity of Example 1 was significantly higher than that of Comparative Example 1, indicating that the drug and conductive network in the hydrogel have a promoting effect on osteogenic mineralization. Under near-infrared light irradiation, the mineralization capacity of each group of samples was improved, with Example 1 showing the largest improvement (0.075→0.102), while Comparative Example 4 showed the smallest improvement (0.054→0.062), indicating that the near-infrared light-induced thermo-electric coupling effect has a synergistic enhancing effect on promoting extracellular matrix mineralization, and this effect depends on the upconversion function of the rare earth layer. In addition, Comparative Example 7 had an absorbance of 0.052 without near-infrared light irradiation, but its absorbance increased to 0.065 under near-infrared light irradiation, indicating that the near-infrared light-induced thermo-electric coupling effect can effectively promote the extracellular matrix mineralization of bone marrow mesenchymal stem cells, thereby enhancing osteogenic differentiation capacity. However, due to the lack of the drug and MXene conductive network in the hydrogel coating, its improvement was less than that of Example 1.

[0099] 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 present invention by those skilled in the art. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the scope of protection of the present invention.

Claims

1. A near-infrared light-responsive thermo-electrically coupled titanium-based implant, characterized in that, Including porous titanium substrates and composite hydrogel coatings; The porous titanium substrate surface is provided with TiO2 / SrTiO3 heterojunction, upconversion nanoparticles and barium titanate nanoparticles in sequence from the inside to the outside. The upconversion nanoparticles are Yb 3+ and Er 3+ Co-doped NaYF4 upconversion nanoparticles; The composite hydrogel coating is disposed on the surface of the barium titanate nanoparticles, and the composite hydrogel coating includes MXene, a pharmaceutical active ingredient, and a hydrogel carrier. The Yb 3+ The doping molar concentration is 15~25%, Er 3+ The molar concentration of the dopant is 1-5%; The hydrogel carrier is a gelatin-sodium alginate hydrogel; in the composite hydrogel coating, the concentration of gelatin is 8-15 wt%, and the mass ratio of gelatin to sodium alginate is (3-5):1; the pharmaceutical active ingredient includes at least one of curcumin and doxorubicin; in the composite hydrogel coating, the mass ratio of MXene to the pharmaceutical active ingredient is 1:(2-3); The steps for constructing the TiO2 / SrTiO3 heterostructure include: sequentially acid etching and anodic oxidation of a porous titanium substrate to construct a TiO2 nanotube array; after annealing, placing it in an Sr(OH)2 solution for alkaline heat treatment; the annealing temperature is 400~550℃, and the annealing time is 0.5~2h; in the alkaline heat treatment, the concentration of the Sr(OH)2 solution is 0.05~0.2M, the treatment temperature is 160~200℃, and the treatment time is 0.5~4h.

2. The method for preparing a near-infrared light-responsive thermo-electrically coupled titanium-based implant as described in claim 1, characterized in that, Includes the following steps: Provide porous titanium substrates; A TiO2 / SrTiO3 heterojunction was constructed on the surface of the porous titanium substrate. Upconversion nanoparticles were deposited on the surface of the TiO2 / SrTiO3 heterojunction. Barium titanate nanoparticles were grown in situ on the surface of the upconversion nanoparticles. The barium titanate nanoparticles are filled with a composite hydrogel, which is then cross-linked to obtain the final product.

3. The preparation method according to claim 2, characterized in that, The steps for depositing upconversion nanoparticles include: preparing a rare earth solution by dissolving Y salt, Yb salt, Er salt and urea in water; immersing a porous titanium substrate with a TiO2 / SrTiO3 heterostructure in the rare earth solution at 80~100℃ for 2~5h; removing the substrate and immersing it in a mixed solution of NaF and HF; reacting the substrate at 90~110℃; and washing and drying the substrate.

4. The preparation method according to claim 2, characterized in that, The steps for in-situ growth of barium titanate nanoparticles include: placing a porous titanium substrate with deposited upconversion nanoparticles in a hydrothermal reaction medium containing Ba(OH)2, and carrying out a hydrothermal reaction in an autoclave at a reaction temperature of 240~280℃ for 2~8h.

5. The application of the near-infrared light-responsive thermo-electrically coupled titanium-based implant as described in claim 1 or the near-infrared light-responsive thermo-electrically coupled titanium-based implant prepared by the preparation method according to any one of claims 2 to 4 in the preparation of bone tissue defect repair materials.

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