A heterojunction-enhanced injectable piezoelectric hydrogel and preparation method and application thereof

Abstract

The application relates to the technical field of biomedical materials, and particularly discloses an injection piezoelectric hydrogel with enhanced heterojunction and a preparation method and application thereof. The hydrogel is composed of 45% to 75% of polyvinyl alcohol, 3% to 15% of sodium carboxymethyl cellulose, 3% to 15% of gelatin, 1% to 10% of a zinc oxide / zinc sulfide heterojunction nano phase, 2% to 15% of magnesium chloride and 5% to 35% of trisodium citrate. The zinc oxide / zinc sulfide heterojunction nano phase is prepared through hydrothermal synthesis and chemical vapor deposition calcination. The interface type II band and the built-in electric field are used to drive charge separation, and the piezoelectric response is enhanced through oxygen vacancies. Compared with the prior art, the hydrogel prepared by the application has high wet-state ionic conductivity, injectability and morphological stability. Under ultrasonic stimulation, the piezoelectric signal output reaches 150 mV, and the hydrogel is suitable for repairing infectious bone defects such as periodontitis, and can promote osteogenic differentiation and microenvironment regulation in cooperation with ion release.

Description

Technical Field

[0001] This invention relates to the field of biomedical materials technology, and in particular to a heterojunction-reinforced injectable piezoelectric hydrogel, its preparation method, and its applications. Background Technology

[0002] Disease and Clinical Needs: Periodontitis is a common oral disease characterized by chronic inflammation and tissue destruction. Epidemiological studies show a high overall prevalence, a large number of severely affected individuals, and correlation with various systemic diseases. Long-term chronic inflammation can lead to tooth loss and infected bone defects. Current clinical treatment mainly relies on a comprehensive approach including basic treatment (scaling / root planing), flap debridement, bone / membrane regeneration, and systemic or local antibacterial drugs. However, under the complex infectious microenvironment, the recurrence rate remains high, and the quality and stability of alveolar bone repair are difficult to guarantee.

[0003] Advances in electrophysiological modulation research: Bone tissue possesses natural piezoelectric properties, and exogenous electrical stimulation (microcurrents, pulsed electromagnetics, ultrasound-triggered piezoelectricity, etc.) has been shown to promote osteogenic differentiation of stem cells, improve the inflammatory microenvironment, and potentially break the vicious cycle of "inflammation-bone suppression." Therefore, utilizing piezoelectric materials to achieve wireless, non-invasive local micro-electrical environment modulation has become an important direction for bone and periodontal regeneration. Current research extensively involves inorganic piezoelectric materials (such as BaTiO3 and ZnO) and organic / polymer piezoelectric materials (such as PVDF) and their composite systems. Although research in related fields has been effectively advanced from different angles through the construction of composite materials, focusing on solving a single aspect cannot meet the complex needs of practical applications.

[0004] Polymer-based piezoelectric materials, represented by PVDF, require polarization orientation treatment to achieve piezoelectric properties, and their performance is easily affected by thermal aging and aging effects, resulting in insufficient output stability under low external excitation conditions. Inorganic ceramic materials such as BaTiO3 possess good piezoelectric properties, but suffer from excessive rigidity and mismatch with the mechanical properties of soft tissues, making them unsuitable for fitting irregular bone defect cavities. Single-phase zinc oxide materials are limited by internal charge carrier shielding effects, leading to significant suppression of piezoelectric output intensity and long-term stability.

[0005] Existing research attempts to promote charge separation and band alignment through heterojunction interface band engineering combined with defect engineering strategies, but it still faces multiple challenges: the construction process of heterojunction interfaces is complex, the defect concentration is difficult to control precisely, and the dispersion of nanoparticles in the hydrogel matrix and the interfacial bonding strength are weak. These problems directly lead to low energy transfer efficiency and insufficient reproducibility of material properties.

[0006] Most traditional hydrogel systems suffer from poor electrical conductivity, with electrochemical impedance spectroscopy (EIS) showing high impedance values, leading to easy attenuation of piezoelectric signals in humid environments. The materials are poorly adaptable to the moist environment and dynamic stress conditions of the oral cavity, making it difficult to balance injectability and molding strength. Swelling and mass loss further contribute to unstable tissue adhesion. Regarding bioactivity, existing systems lack bone-immune synergistic functions, and simply adding salts or conductive fillers often results in safety risks such as component leakage and mechanical embrittlement, making it difficult to achieve long-term stable electrophysiological regulation at the lesion site.

[0007] These limitations mean that existing technologies cannot meet the comprehensive needs of integrated treatment for infectious bone defects, and breakthroughs are urgently needed through material innovation and system optimization.

[0008] In the prior art, patent CN120053749A relates to a photoinitiated hydrogel system using regenerated silk protein introduced into methacrylic anhydride SF-MA as a matrix and incorporating PVDF electrospun chips. This system achieves rapid cross-linking and shaping through ultraviolet irradiation for approximately 30 to 60 seconds, making it suitable for bone repair. This injectable piezoelectric composite hydrogel emphasizes ease of molding but lacks key quantitative data such as wet-state EIS ionic conductivity, long-term swelling, and cyclic stability. Furthermore, there is insufficient evidence of PVDF degradation, and the piezoelectric output is only about 30 to 50 mV.

[0009] In the prior art, another patent, CN120365502A, relates to a piezoelectric and ion-conductive integrated crosslinkable hydrogel for jawbone defect repair. By initiating and promoting crosslinking of the system, it can simultaneously provide mechanical electrical stimulation and promote bone regeneration at the jawbone defect site. Although this patent provides in vivo bone regeneration data, it does not clearly define the wet-state low impedance and long-cycle output performance, the ultrasonic drive parameter window, and the piezoelectric power source lacks bandgap interface engineering optimization.

[0010] In summary, while existing technologies have made some progress in areas such as piezoelectric particle enhancement, exogenous stimulation methods, and hydrogel support, they remain fragmented, exhibiting only isolated breakthroughs. Significant shortcomings exist in four key areas: efficient and stable piezoelectric power generation, low wet conductivity, lesion-adaptable injectable low-swelling good adhesion, and synergistic immunoosteogenic effects. This creates a bottleneck effect, severely limiting the translational application of electrophysiological strategies in periodontal regeneration. The industry urgently needs an injectable piezoelectric hydrogel material that combines high-voltage output, excellent wet conductivity and morphological stability, suitability for the complex oral environment, and synergistic immunoosteogenic effects. Summary of the Invention

[0011] The purpose of this invention is to overcome the defects of the prior art by providing a heterojunction-reinforced injectable piezoelectric hydrogel, its preparation method and application. This invention breaks through the technical bottlenecks of existing piezoelectric hydrogels in terms of piezoelectric power enhancement, wet conduction stability, ultrasonic drive adaptation and osteogenic immune synergy, and provides an efficient and controllable solution for infectious bone defects such as periodontitis.

[0012] The objective of this invention can be achieved through the following technical solutions:

[0013] The first aspect of the present invention provides a heterojunction-reinforced injectable piezoelectric hydrogel, which, by weight percentage, comprises the following components: 45% to 75% polyvinyl alcohol, 3% to 15% sodium carboxymethyl cellulose oxide, 3% to 15% gelatin, 1% to 10% zinc oxide / zinc sulfide heterojunction nanophase, 2% to 15% magnesium chloride, and 5% to 35% trisodium citrate.

[0014] The zinc oxide / zinc sulfide heterojunction nanophase is a functional nanomaterial prepared by hydrothermal synthesis and chemical vapor deposition calcination.

[0015] In the heterojunction-reinforced injectable piezoelectric hydrogel, the zinc oxide / zinc sulfide heterojunction nanophase forms a type II band and a built-in electric field at the interface, driving charge separation and utilizing oxygen vacancies to enhance the piezoelectric response. The wet ionic conductivity of the hydrogel is not less than 3.82 mS·cm. -1 It can output a piezoelectric signal of up to 150 mV under ultrasonic stimulation.

[0016] Furthermore, the porous structure of the hydrogel is achieved through the dual crosslinking of polyvinyl alcohol and sodium carboxymethyl cellulose oxide-gelatin network. Trisodium citrate promotes the crosslinking of polyvinyl alcohol segments through the salting-out effect, and magnesium chloride binds to the carboxyl groups of sodium carboxymethyl cellulose oxide through coordination bonds to form a dynamic reversible network. This ensures that the hydrogel's area expansion rate does not exceed 12% after 48 hours of immersion in physiological saline and that it possesses self-healing properties.

[0017] A second aspect of the present invention provides a method for preparing an injectable piezoelectric hydrogel with heterojunction reinforcement as described above, comprising the following steps:

[0018] S1. Preparation of solution A: Dissolve trisodium citrate in water, add gelatin, stir, and then pour into solution A;

[0019] S2. Preparation of solution B: Dissolve magnesium chloride in water, add sodium carboxymethyl cellulose oxide and zinc oxide / zinc sulfide heterostructure nanophase, stir evenly, then add polyvinyl alcohol, heat in an oil bath and degas and cool to obtain solution B;

[0020] S3. After heating solution A, add it to solution B, stir, degas by ultrasonication, mold, freeze-dry to obtain a heterostructure-reinforced injectable piezoelectric hydrogel.

[0021] Furthermore, in S1, the specific process for preparing solution A includes:

[0022] First, dissolve trisodium citrate in deionized water, then add gelatin at 50°C and stir continuously for 20 minutes to obtain solution A.

[0023] Furthermore, in S2, the specific process for preparing solution B includes:

[0024] First, magnesium chloride was dissolved in deionized water, then sodium carboxymethyl cellulose oxide and zinc oxide / zinc sulfide heterostructure nanophase were added, and the mixture was stirred at 60°C until homogeneous. Then, polyvinyl alcohol was added, and the mixture was heated in an oil bath at 90°C for 1 hour. Finally, the mixture was degassed and cooled to room temperature to obtain solution B.

[0025] Furthermore, in S3, the specific process includes:

[0026] First, heat solution A to 90°C and keep it warm for 10 minutes. Then add it to solution B and stir at 90°C for 20 minutes to achieve thorough mixing. Next, sonicate for 15 minutes to remove air bubbles. Then pour it into a mold and freeze at -20°C for 24 hours to form a heterostructure-reinforced injectable piezoelectric hydrogel.

[0027] Furthermore, in the zinc oxide / zinc sulfide heterojunction nanophase, zinc sulfide is generated in situ on the surface of zinc oxide through a hydrothermal reaction of thioacetamide at 180°C, forming a coating layer structure, and the mass ratio of thioacetamide to zinc oxide is 0.2:1 to 1:1.

[0028] After the zinc oxide / zinc sulfide heterojunction nanophase was calcined at 400°C in an argon atmosphere for 2 hours, the oxygen vacancy ratio at its interface was characterized by XPS, showing a shift in binding energy.

[0029] Furthermore, in the zinc oxide / zinc sulfide heterojunction nanophase, zinc sulfide is generated in situ on the surface of zinc oxide via a hydrothermal reaction at 180°C using thioacetamide, forming a coating layer structure, and the mass ratio of thioacetamide to zinc oxide is 0.2:1 to 1:1; after the heterojunction is calcined at 400°C in an argon atmosphere for 2 hours, the oxygen vacancy ratio at its interface is characterized by XPS, showing a shift in binding energy, thereby enhancing charge separation efficiency.

[0030] Further, in S1, the mass-to-volume ratio of trisodium citrate to water is 0.022 g / mL to 0.16 g / mL, and the mass-to-volume ratio of gelatin to water is 0.013 g / mL to 0.067 g / mL, to ensure the uniformity of ion concentration and gelatin dispersion in solution A;

[0031] In S2, the mass-to-volume ratio of magnesium chloride to water is 0.0045 g / mL to 0.033 g / mL, the mass-to-volume ratio of sodium carboxymethyl cellulose oxide to water is 0.0067 g / mL to 0.033 g / mL, the mass-to-volume ratio of zinc oxide / zinc sulfide heterojunction nanophase to water is 0.0022 g / mL to 0.022 g / mL, and the mass-to-volume ratio of polyvinyl alcohol to water is 0.1 g / mL to 0.17 g / mL.

[0032] In S3, the volume ratio of solution A to solution B is 1:1.5 to 1:3. Within this range, the compounding ratio is adjusted to optimize the network crosslinking density through the synergistic effect of the two salts, thereby balancing the injectability and morphological stability of the hydrogel.

[0033] Furthermore, the mixing temperature of solution A and solution B is controlled within the range of 80°C to 95°C, and the stirring time is not less than 10 minutes to ensure that gelatin and sodium carboxymethyl cellulose oxide are fully cross-linked through Schiff base reaction; the freeze-thaw stage needs to be maintained at -25°C to -15°C for 12 to 36 hours to allow the polyvinyl alcohol crystalline domains and ion network to solidify synchronously and form a stable three-dimensional porous structure.

[0034] A third aspect of the present invention provides an application of the heterojunction-reinforced injectable piezoelectric hydrogel as described above, used in the preparation of a drug for treating periodontitis-related bone defects.

[0035] Furthermore, after the hydrogel is injected into the periodontal pocket using a 22G syringe, it generates a piezoelectric signal under extrinsic ultrasonic stimulation, wherein the ultrasonic parameters are a frequency of 1 MHz and a wavelength of 0.5 W / cm². 2 Intensity, 20% duty cycle, continuous action for 15 minutes; the piezoelectric signal synergistically releases magnesium and zinc ions, promotes osteoblast alkaline phosphatase activity to increase to 2.3 times that of the control group, and induces calcium nodule deposition.

[0036] Furthermore, the heterojunction-reinforced injectable piezoelectric hydrogel can generate piezoelectric signals under exogenous ultrasound stimulation. These piezoelectric signals, in conjunction with the release of magnesium and zinc ions, promote the enhancement of osteoblast alkaline phosphatase activity and induce calcium nodule deposition.

[0037] Furthermore, after the hydrogel is injected into the periodontal pocket using a 22G syringe, it generates a piezoelectric signal under extrinsic ultrasonic stimulation, wherein the ultrasonic parameters are a frequency of 1 MHz and a wavelength of 0.5 W / cm². 2 Intensity, 20% duty cycle, continuous action for 15 minutes; the piezoelectric signal synergistically releases magnesium and zinc ions, promotes osteoblast alkaline phosphatase activity to increase to 2.3 times that of the control group, and induces calcium nodule deposition.

[0038] This invention achieves stable and efficient electrophysiological regulation in the complex and moist environment of the oral cavity by innovatively integrating heterojunction-enhanced piezoelectric nanophases, multi-network hydrogel frameworks, and a dual-salt synergistic strategy. The specific beneficial effects are reflected in the following four aspects:

[0039] I. Piezoelectric Source Enhancement. Through a triple coupling mechanism of heterojunction, oxygen vacancies, and the intrinsic piezoelectricity of ZnS, the internal charge shielding effect of ZnO is significantly weakened, thereby enhancing the piezoelectric response intensity. Compared to single-phase ZnO materials, this invention exhibits stronger external field excitability and stability, ensuring the reliability and continuity of the piezoelectric signal source.

[0040] II. Signal Transduction and Adaptation to Humid Environments. A dual-salt strategy using Na3Ct and MgCl2 was employed to significantly improve the hydrogel's ionic conductivity to approximately 3.82 mS·cm without sacrificing material injectability. -1 It also endows it with excellent anti-swelling properties (area change of only about 12% after 48 hours). This property ensures that the piezoelectric signal can still be effectively transmitted to the lesion in complex moist environments such as pus or blood seepage, making it particularly suitable for the treatment needs of infected bone defects.

[0041] III. User-friendly shaping and operation. The material is injectable, gels in situ, and self-healing, allowing it to closely adhere to irregular wound surfaces and reduce the risk of secondary surgery. Furthermore, it is compatible with ultrasound-triggered non-invasive control, simplifying operation and facilitating intraoperative and postoperative clinical application.

[0042] IV. Integrated Multidimensional Therapeutic Effects. The synergistic effect of piezoelectric stimulation and the release of magnesium ions and zinc components simultaneously regulates the anti-infection microenvironment and promotes osteogenic regeneration. A multi-network scaffold provides mechanical support for cell adhesion, migration, and nutrient exchange, achieving an integrated therapeutic effect of immune regulation and bone repair. Attached Figure Description

[0043] Figure 1 XPS spectra of ZnO / ZnS heterojunctions with different degrees of sulfidation synthesized in Examples 1, 2, and 3 of this invention;

[0044] Figure 2 These are SEM images of ZnO / ZnS with different S concentrations in Examples 1, 2, and 3 of this invention;

[0045] Figure 3 These are mapping images of ZnO / ZnS with different S concentrations in Examples 1, 2, and 3 of this invention;

[0046] Figure 4 The image shows a TEM image of ZnO / ZnS-0.04 in Embodiment 1 of the present invention.

[0047] Figure 5The PFM results for ZnO / ZnS-0.04 and ZnO and ZnS in Example 1 of this invention;

[0048] Figure 6 The FTIR infrared spectra of POG-HC and the main components in Example 1 of this invention are shown below.

[0049] Figure 7 This is a SEM image of POG-HC in Embodiment 1 of the present invention;

[0050] Figure 8 These are photographs of the injectability and self-healing properties of POG-HC in Example 1 of this invention;

[0051] Figure 9 This is a comparison of the swelling of POG-HC before and after 48 hours of immersion in physiological saline in Example 1 of the present invention;

[0052] Figure 10 The EIS curves of POG, POG-H, and POG-HC in Example 1 and Comparative Examples 1 and 2 of this invention are shown.

[0053] Figure 11 The Vt curves of POG, POG-H, and POG-HC under ultrasound in Example 1 and Comparative Examples 1 and 2 of this invention;

[0054] Figure 12 This is a long-cycle sensing stability test of POG-HC in Embodiment 1 of the present invention;

[0055] Figure 13 The cytotoxicity of POG, POG-H, and POG-HC in Example 1 and Comparative Examples 1 and 2 of this invention;

[0056] Figure 14 To assess the safety of POG-HC hydrogel subcutaneous implantation in animals in Example 1 of this invention;

[0057] Figure 15 This illustrates the osteogenic mineralization effect of POG, POG-H, and POG-HC hydrogels in Example 1 and Comparative Examples 1 and 2 of the present invention.

[0058] Figure 16 This is a schematic flowchart of the method for preparing heterojunction-reinforced injectable piezoelectric hydrogels in this invention. Detailed Implementation

[0059] This invention provides a piezoelectric hydrogel, denoted as POG-HC, for the treatment of infected bone defects. This system integrates a heterojunction-reinforced piezoelectric nanophase, a multi-network conductive hydrogel, and a dual-ion salt synergistic structure. The formulation, preparation of key raw materials, and process parameters are detailed below.

[0060] The proportions and functional boundaries of each component, based on dry matter percentage, are as follows:

[0061] Polyvinyl alcohol (PVA) accounts for 45% to 75% of the total content, forming the main network framework. When the content is below 45%, the mechanical strength is insufficient, while when it is above 75%, the viscosity of the system is too high, affecting the injection performance.

[0062] Oxidized carboxymethyl cellulose sodium (OCMC-Na) is used as a dynamic crosslinking medium, ranging from 3% to 15%. When the content is below 3%, the Schiff base and coordination network are not sufficiently constructed, while contents exceeding 15% lead to gel embrittlement and increased swelling.

[0063] Gelatin (Gel) accounts for 3% to 15% of the total content, providing a bioactive interface. Below 3%, cell adhesion decreases significantly, while above 15%, it leads to increased thermosensitivity and deterioration of mechanical properties.

[0064] The zinc oxide / zinc sulfide heterojunction nanophase ZnO / ZnS, with a content of 1% to 10%, serves as the core of the piezoelectric function. When the content is below 1%, the piezoelectric output is insufficient, and when it exceeds 10%, agglomeration is likely to occur, leading to an increase in electrochemical impedance.

[0065] Magnesium chloride (MgCl2) accounts for 2% to 15% of the total content, playing a role in modulating ion conductivity. Below 2%, the conductivity enhancement effect is not significant, while above 15%, there is a risk of osmotic pressure imbalance.

[0066] The trisodium citrate (Na3Ct) accounts for 5% to 35% of the total content and forms a synergistic regulation mechanism of salting out and salting out with MgCl2. Too low a content results in insufficient ionic conductivity, while too high a content easily leads to crystallization and increased brittleness.

[0067] Preparation methods of key raw materials

[0068] Synthesis of zinc oxide:

[0069] 1.552 g of zinc acetate dihydrate (Zn(CH3COO)2·2H2O) was dissolved in 40 mL of deionized water, and 3.2 g of sodium hydroxide (NaOH) was added. The mixture was stirred at room temperature for 1 hour to form a precursor solution. The solution was then transferred to a 100 mL reactor and reacted at 100°C for 24 hours. After centrifugation and washing, the solution was dried at 80°C for 10 hours to obtain high-purity zinc oxide nanomaterials.

[0070] Synthesis of oxygen-enriched vacancy zinc oxide and zinc sulfide heterojunction:

[0071] 0.1 g of zinc oxide was added to 70 mL of deionized water and stirred for 30 minutes. Then, varying amounts of thioacetamide (C₂H₅NS), ranging from 0.02 g to 0.1 g, were added, and stirring continued for another 30 minutes. The mixture was transferred to a 100 mL stainless steel reactor and reacted in an oven at 180°C for 24 hours to complete surface sulfidation. The product was then washed three times alternately with deionized water and ethanol, and dried at 80°C for 12 hours to obtain the precursor. This precursor was placed in a chemical vapor deposition system and calcined at 400°C for 2 hours under an argon atmosphere to obtain a zinc oxide / zinc sulfide heterojunction material. Based on the feed mass of thioacetamide, the heterojunction material is denoted as ZnO / ZnS-x, where x is 0.02, 0.04, 0.06, 0.08, or 0.1. Studies show that when x is about 0.04, it has the synergistic effect of type II band alignment, interfacial oxygen vacancy enrichment, and intrinsic piezoelectricity of zinc sulfide, which can maximize the reduction of internal charge shielding of zinc oxide and enhance the piezoelectric response.

[0072] Synthesis of sodium carboxymethyl cellulose oxide:

[0073] Weigh 2 g of sodium carboxymethyl cellulose and gradually add it to 40 mL of water, stirring until homogeneous. Simultaneously, dissolve 1.1 g of sodium periodate in 20 mL of water, stirring until fully dissolved under light-protected conditions. Then, add the sodium periodate solution to the sodium carboxymethyl cellulose solution, followed by 200 μL of hydrochloric acid, and continue stirring for 5 hours under light-protected conditions. Next, add excess ethanol to precipitate the product. The resulting white precipitate is washed with ethanol and centrifuged three times. The final product is dried overnight in a 35°C oven to obtain oxidized sodium carboxymethyl cellulose. Its Fourier transform infrared spectrum shows an aldehyde absorption peak near 1700 cm⁻¹, indicating successful oxidation to form a Schiff base precursor functional site.

[0074] The preparation of hydrogels includes the following steps:

[0075] Step A: Dissolve trisodium citrate in water, for example, 0.294 g in 3 ml of water, then add gelatin, for example, 0.10 g, and stir at 50 degrees Celsius for 20 minutes to obtain solution A.

[0076] Step B: Dissolve magnesium chloride in water, for example, 0.09 g dissolved in 6 mL of water, add sodium carboxymethyl cellulose oxide, for example, 0.10 g, and zinc oxide and zinc sulfide heterojunction nanophase, for example, 0.05 g, and stir at 60 degrees Celsius until homogeneous; then add polyvinyl alcohol, for example, 0.90 g, heat in an oil bath at 90 degrees Celsius for 1 hour, degas and cool to obtain solution B.

[0077] Step C: Heat solution A to 90 degrees Celsius and keep it warm for 10 minutes. Then add it to solution B and continue stirring at 90 degrees Celsius for 20 minutes. Then sonicate for 15 minutes to remove air bubbles. After molding, freeze at -20 degrees Celsius for 24 hours to obtain the finished hydrogel.

[0078] The optimal parameters for the process are as follows: mixing temperature of solution A and solution B is 80 to 95 degrees Celsius, stirring time is 10 to 40 minutes; freezing temperature is -25 to -15 degrees Celsius, time is 12 to 36 hours; and polyvinyl alcohol solid content is 45% to 75% by weight-volume ratio, so as to balance injection molding properties and molding strength.

[0079] The piezoelectric enhancement mechanism of the heterojunction in this invention is as follows: A type II band structure is formed at the interface between zinc oxide and zinc sulfide, generating a built-in electric field. This structure effectively drives the directional migration of charge carriers from the zinc oxide layer to the zinc sulfide layer. The oxygen vacancies enriched at the interface serve as electron trapping centers and transport channels, further accelerating the charge separation process. Combining the inherent piezoelectric properties of zinc sulfide with the synergistic effect of external mechanical stimuli or ultrasonic fields, the charge shielding effect within the material is significantly weakened, thereby achieving an overall improvement in piezoelectric response performance. Power piezoelectric microscopy (PFM) test data clearly show that the piezoelectric response intensity of the heterojunction sample is significantly higher than that of the single-component control group material.

[0080] The dual-salt synergy and multi-network adaptation mechanism in this invention involves trisodium citrate promoting cross-linking of polyvinyl alcohol (PVA) molecular chains through salting-out, effectively balancing the salt-dissolving effect of magnesium chloride. Gelatin and oxidized carboxymethyl cellulose sodium (OCMC-Na) construct a stable multi-network structure through Schiff base reaction and metal coordination, enabling the hydrogel to simultaneously possess good injectability, self-healing ability, and morphological stability. Electrochemical impedance spectroscopy (EIS) results show that the ionic conductivity of this POG-HC hydrogel system reaches 3.82 mS·cm. -1 Under specific ultrasound parameters (frequency 1 MHz, intensity 0.5 W / cm²), 2 With a duty cycle of 20%, the material can generate a stable piezoelectric signal of approximately 150 mV. After 48 hours of liquid immersion, the area change rate of the hydrogel is controlled within 12%, demonstrating excellent anti-swelling properties. The material also exhibits self-healing properties and long-term cyclic sensing stability, fully meeting the special requirements of maintaining local homeostasis and signal transduction in moist infection environments.

[0081] The material prepared in this invention can be implanted into infected bone defect cavities such as periodontal pockets via injection or filling. After forming a gel in vivo, it generates a stable and conductive piezoelectric signal upon activation by external physiological stress or clinical ultrasound. Simultaneously, it synergistically releases magnesium ions and zinc components, effectively promoting osteogenic differentiation and achieving microenvironment regulation and antibacterial biofilm inhibition. This application can be used in conjunction with conventional debridement and systemic drug therapy.

[0082] For cases of infected alveolar bone defects, the material can also be directly applied to the repair of soft and hard tissue interfaces in the periodontal region or around implants, providing an innovative solution for bone regeneration treatment in complex oral environments.

[0083] The present invention will now be described in detail with reference to the accompanying drawings and specific embodiments. Any preparation methods, materials, structures, or compositional ratios not explicitly described in this technical solution are considered common technical features disclosed in the prior art.

[0084] Example 1

[0085] Preparation of heterojunctions and hydrogels with moderate sulfidation

[0086] See the schematic diagram of the overall preparation process. Figure 16 The specific steps are as follows:

[0087] 1. Preparation of zinc oxide / zinc sulfide heterojunctions

[0088] 0.10 g of zinc oxide nanoparticles were weighed and dispersed in 70 mL of deionized water. The mixture was ultrasonically stirred for 30 min to form a homogeneous suspension. 0.04 g of thioacetamide (C2H5NS) was added, and stirring continued for 30 min until completely dissolved. The mixture was transferred to a 100 mL stainless steel reactor and hydrothermally reacted at 180 °C for 24 h. The reaction product was centrifuged and washed (three times each with deionized water and ethanol), and then vacuum dried at 80 °C for 12 h. Finally, it was calcined at 400 °C for 2 h under an argon atmosphere to obtain a pale grayish-white powder, denoted as ZnO / ZnS-0.04.

[0089] 2. Synthesis of sodium carboxymethyl cellulose oxide

[0090] Dissolve 2 g of sodium carboxymethyl cellulose (CMC-Na) in 40 mL of water by stirring. Dissolve 1.1 g of sodium periodate (NaIO4) in 20 mL of water under light-protected conditions, stirring until completely dissolved. Slowly add the NaIO4 solution to the CMC-Na solution, then add 200 μL of hydrochloric acid (HCl), and stir at room temperature under light for 5 h. Add excess anhydrous ethanol to precipitate the product, collect by centrifugation, wash three times with ethanol, and dry overnight at 35 °C to obtain white oxidized sodium carboxymethyl cellulose (OCMC-Na) powder.

[0091] 3. Construction of piezoelectric hydrogels

[0092] Solution A preparation: Dissolve 0.294 g of trisodium citrate dihydrate (Na3Ct·2H2O) in 3.0 mL of deionized water, add 0.10 g of gelatin, and stir at 50 °C for 20 min.

[0093] Solution B preparation: Dissolve 0.08 g of magnesium chloride hexahydrate (MgCl2·6H2O) in 6.0 mL of deionized water, add 0.10 g of OCMC-Na and 0.04 g of ZnO / ZnS0.04 heterojunction, stir evenly at 60 °C, then slowly add 0.80 g of polyvinyl alcohol (PVA), and degas in an oil bath at 90 °C for 1 h.

[0094] Composite molding: Preheat solution A to 90 °C and hold for 10 min, then add solution B, stir at 90 °C for 20 min, ultrasonically degas for 15 min, and after molding, freeze at -20 °C for 24 h to form the final product.

[0095] Material proportioning and process parameters

[0096] Dry weight percentages: PVA≈59.9%, gelatin≈7.49%, OCMC-Na≈7.49%, ZnO / ZnS≈3%, MgCl2≈2.81%, Na3Ct≈19.32%.

[0097] Solution mixing temperature: 90 °C; freezing conditions: -20 °C × 24 h.

[0098] Example 2

[0099] Preparation of low sulfidation heterojunctions

[0100] Using the same process as in Example 1, only the amount of thioacetamide (C2H5NS) was adjusted to 0.02 g, while the other parameters remained unchanged, to obtain ZnO / ZnS-0.02 heterojunction material.

[0101] Example 3:

[0102] Preparation of high sulfidation heterojunctions

[0103] Experimental Example Description:

[0104] Based on the standard process of Example 1, the amount of thioacetamide (C2H5NS) was adjusted to 0.06 g, and other reaction conditions were completely consistent with those of Example 1, to obtain ZnO / ZnS-0.06 heterojunction material.

[0105] Comparative Example 1: POG (no heterojunction, no dual salt)

[0106] Solution A: Dissolve 0.10 g of gelatin in 3.0 mL of deionized water and stir at 50 °C for 20 min.

[0107] Solution B: Dissolve 0.10 g of OCMC-Na in 6.0 mL of deionized water and stir until homogeneous; slowly add 0.80 g of PVA and degas in a 90 °C oil bath for 1 h.

[0108] Compounding into gel: Preheat solution A to 90 °C for 10 min and then add it to solution B. Stir at 90 °C for 20 min; sonicate for 15 min to remove bubbles, pour into a mold, and freeze at -20 °C for 24 h to form the gel.

[0109] Note: Other conditions are the same as in Example 1, except that ZnO / ZnS, MgCl2, and Na3Ct are not added.

[0110] Comparative Example 2: POG-H (containing heterojunction, without dual salt)

[0111] Solution A: Dissolve 0.10 g of gelatin in 3.0 mL of deionized water and stir at 50 °C for 20 min.

[0112] Solution B: 0.10 g of OCMC-Na and ZnO / ZnS 0.04 Add 0.04 g to 6.0 mL of deionized water and stir well at 60 °C; slowly add 0.80 g of PVA and degas in an oil bath at 90 °C for 1 h.

[0113] Compounding into gel: Preheat solution A to 90 °C for 10 min and then add it to solution B. Stir at 90 °C for 20 min; sonicate for 15 min to remove bubbles, pour into a mold, and freeze at -20 °C for 24 h to form the gel.

[0114] Note: Other conditions are the same as in Example 1, except that MgCl2 and Na3Ct are not added.

[0115] Material characterization methods: XPS measurements were performed using a Thermo Scientific K-Alpha (USA). SEM imaging was performed using a ZEISS Sigma 300 (Germany), and TEM observation was performed using a JEOL JEM-F200 (Japan). KPFM (Kelvin probe force microscopy) was performed using an SCM-PIT-V2 probe. FTIR spectroscopy was acquired using a Thermo Fisher Scientific Nicoleti S20 (USA). All electrochemical data were acquired on a CH Instruments CHI760E electrochemical workstation. Electrochemical impedance spectroscopy (EIS) measurements were performed by clamping the hydrogel between two stainless steel electrodes at 10 °C. 6 -10-1 The test was conducted within the Hz frequency range with a 5 mV AC disturbance. The conductivity was calculated using the following formula:

[0116]

[0117] Where: σ: conductivity (S / cm); L: electrode spacing (cm); R: volume resistance obtained by EIS fitting (Ω); A: effective contact area between electrode and hydrogel (cm²) 2 )

[0118] Experimental Example 1:

[0119] To optimize the component ratio, ZnO / ZnS-x heterojunctions with different S source contents (x = 0.02, 0.04, 0.06, 0.08) were synthesized in Examples 1, 2, and 3. See attached... Figure 1 XPS results showed that the Zn 2p spectra of ZnO / ZnS with different composition ratios all exhibited two characteristic peaks. The peak position of ZnO / ZnS-0.04 shifted towards a lower binding energy compared to ZnO / ZnS-0.02. This is because S forms more oxygen vacancies when it substitutes O in situ at the interface, resulting in an increase in electrons around Zn and a decrease in binding energy. Conversely, the peak position of ZnO / ZnS-0.06 shifted back to a higher binding energy, indicating that as the ZnS content increases, the abundant S fills the oxygen vacancies, using its electronegativity to steal electrons from Zn, leading to an increase in binding energy. The O 1s spectrum showed that ZnO / ZnS-0.04 exhibited the highest oxygen vacancy ratio among all components, further corroborating the previous analysis.

[0120] Experimental Example 2:

[0121] The results are as follows Figure 2As shown: To further reveal the formation mechanism of the heterojunction, SEM results showed that a distinct coating layer existed on the surface of ZnO / ZnS-0.04. Zn was uniformly distributed in both the bulk phase and the coating layer, O was concentrated in the nanorod bulk phase, and S was mainly located in the outer layer, confirming the construction of the heterojunction structure. SEM images of ZnO / ZnS with different composition ratios showed that all materials maintained the nanorod shape of ZnO and formed a thin layer of ZnS on the surface. However, some uncovered areas could still be observed on the surface of ZnO / ZnS-0.02, indicating that ZnS did not effectively cover the surface; the surfaces of ZnO / ZnS-0.04 and ZnO / ZnS-0.06 were uniformly covered, with the latter being thicker than the former. The appropriate ZnS content is key to achieving effective piezoelectric enhancement: too little ZnS does not form an effective heterojunction interface, so it cannot effectively separate electrons inside ZnO, making it difficult to further alleviate the shielding effect; while too much ZnS not only fills the oxygen vacancies formed at the interface, but the excessively thick coating layer will also isolate the heterojunction interface inside the material, preventing the piezoelectric field of ZnO from functioning effectively.

[0122] Experimental Example 3:

[0123] like Figure 3 Mapping tests of the ZnO / ZnS heterojunctions show that the O element distribution on the surface of ZnO / ZnS-0.02 is very uniform, while the S element distribution is relatively sparse, indicating a low ZnS content. In ZnO / ZnS-0.06, the S element intensity is more pronounced, while the O element shows a lower intensity, indicating a higher ZnS thickness, which shields the piezoelectric field of the internal ZnO. In contrast, the surface of ZnO / ZnS-0.04 exhibits a uniform distribution of O and S elements, indicating the presence of a suitable and uniform ZnO / ZnS heterojunction on the surface.

[0124] Experimental Example 4:

[0125] like Figure 4 The high-resolution TEM image of the heterostructure bulk phase and the cladding layer interface shown reveals lattice fringes belonging to ZnO and ZnS, verifying the effective formation of the ZnO / ZnS-0.04 heterostructure interface.

[0126] Experimental Example 5:

[0127] like Figure 5 The piezoelectric response intensity of ZnO / ZnS-0.04, ZnO and ZnS was compared intuitively using PFM, and the results showed that ZnO / ZnS-0.04 had the highest piezoelectric response.

[0128] Experimental Example 6:

[0129] Appendix Figure 6Infrared spectroscopy revealed that the spectrum of POG-HC matched the characteristic peaks of PVA, Gel, and OCMC-Na, indicating the presence of a multi-network within the hydrogel. The partially oxidized OCMC-Na possesses both aldehyde and carboxyl groups, enabling it to interact with Mg... 2+ Coordination can also form Schiff base reversible bonds with gel, improving the stability of hydrogels in periodontal injections.

[0130] Experimental Example 7:

[0131] As attached Figure 7 SEM images of the hydrogel show that the POG-HC hydrogel exhibits a porous structure, which not only improves injection performance but also facilitates rapid ion transport within the polymer and the growth of osteoblasts. The dual-ion salt design enables Ct... 3- It can promote the cross-linking of some PVA chains through the "salting out" effect in Hofmeister theory, prevent the reduction of hydrogel gelation caused by the "salting solubility" effect of MgCl2, and regulate the effective mechanical strength of injection for periodontitis.

[0132] Experimental Example 8:

[0133] Appendix Figure 8 The results showed that POG-HC has excellent injectability, enabling non-invasive filling of periodontal lesions and avoiding the additional procedures and infection risks associated with implantation. Furthermore, due to the presence of reversible Schiff base bonds, POG-HC achieves effective self-healing, further ensuring its stability in practical applications.

[0134] Experimental Example 9:

[0135] Appendix Figure 9 The results showed that POG-HC maintained only 12% area change after 48 hours of swelling, which is much lower than the swelling of general hydrogels, indicating that it can maintain its shape well in the moist environment of the periodontal area.

[0136] Experimental Example 10:

[0137] Appendix Figure 10 The results showed that the conductivity of POG-HC was effectively improved after the addition of the dual-ionic salt system. EIS test results showed that, compared to POG (1.13 mS / cm⁻¹), the conductivity was significantly improved. -1 ) and POG-H (1.21 mS cm -1 The impedance of POG-HC is reduced to one-third of that of the former, and the corresponding ionic conductivity is as high as 3.82 mS / cm. -1 This demonstrates the significant improvement in conductivity resulting from the addition of ionic salts.

[0138] Experimental Example 11:

[0139] See appendix Figure 11 The results showed that the ultrasound (1 MHz, 0.5 W / cm²) was... 2 Under stimulation with a 20% duty cycle, POG-HC exhibited a voltage fluctuation of approximately 150mV, while POG-H showed only a weak voltage signal, and the curve of POG showed no fluctuation. This indicates that POG-HC can transmit piezoelectric signals to the lesion area with its excellent conductivity, which is beneficial for practical applications in the periodontal region.

[0140] Experimental Example 12:

[0141] Considering the repetitive chewing motion in the oral cavity, attached Figure 12 The results show that in long-cycle testing, after more than 1,000 stretching cycles, POG-HC can still maintain a stable resistance change signal curve, which also demonstrates its excellent stability in practical applications.

[0142] Experimental Example 13:

[0143] Experimental Methods: Before testing, all materials were soaked in 10% (v / v) penicillin-streptomycin solution for 24 h, then sterilized under UV light for 30 min, and washed multiple times with PBS. A hydrogel-cell co-culture model was established using Transwell culture plates. In short, periodontal ligament stem cell (PDLSC) cell suspensions (1 × 10⁻⁶) were used. 5 Cells / wells were seeded in the lower chamber, while hydrogels of different treatment groups were placed in the upper chamber. After co-culturing for 48 h, Calcein-AM / PI staining was performed according to the kit instructions. Cell morphology and fluorescence signals were observed using an inverted fluorescence microscope, where live cells showed green fluorescence and dead cells showed red fluorescence.

[0144] Appendix Figure 13 The results showed that after treatment with POG, POG-H, and POG-HC, both RAW264.7 mouse macrophage cell lines and PDLSC cells exhibited high survival rates. Live / Dead staining showed that all groups showed good survival status with no significant signs of cytotoxicity. Quantitative analysis further confirmed that there was no significant difference in cell activity among different groups (p > 0.05), indicating that the material system has good cell compatibility in vitro.

[0145] Experimental Example 14:

[0146] See appendix Figure 14POG-HC hydrogel samples (approximately 10 mm in diameter and 2 mm in thickness) were subcutaneously implanted in SD rats. Animals were sacrificed at weeks 1, 2, 3, and 4 post-surgery. After routine paraffin embedding, sections were prepared, and HE staining was performed to assess inflammatory cell infiltration, fibroblast response, and material degradation. Results showed that under physiological conditions, POG-HC hydrogel exhibited a gradual degradation trend subcutaneously, with no obvious fibrous encapsulation or foreign body reaction observed.

[0147] Experimental Example 15:

[0148] Experimental Methods: To evaluate the in vitro osteogenic potential of hydrogels, a hydrogel-cell co-culture system was established in 12-well plates. PDLSCs (5 × 10⁶ cells / well) were seeded in the 12-well plates. 4 Cells were cultured in a medium containing α-MEM (10 mM sodium β-glycerophosphate + 50 μg / mL ascorbic acid + 10 nM dexamethasone) and co-cultured with hydrogel. Once cells reached approximately 80% confluence, the medium was replaced with osteogenic induction medium (α-MEM + 10 mM sodium β-glycerophosphate + 50 μg / mL ascorbic acid + 10 nM dexamethasone), with medium changes every 3 days. During induction, cells were subjected to daily ultrasound stimulation (1 MHz, 0.5 W / cm²). 2 (20% duty cycle, 15 min). ALP detection (day 7): Stain with BCIP / NBT kit, wash with distilled water; observe staining intensity under a microscope. Measure OD405 using an ALP quantification kit to characterize ALP activity. Alizarin Red staining (day 21): Remove culture medium, fix for 20 min, wash 3 times with PBS; add alizarin red staining solution at room temperature for 30 min, wash with water and image. Subsequently, extract the bound dye with 10% hexadecylpyridine chloride (CPC) solution, shake at room temperature for 20 min, and measure OD562 at 562 nm to quantify the degree of calcification.

[0149] Appendix Figure 15 The results showed that, without exogenous growth factor stimulation, POG-HC continuously released a micro-electric field under ultrasound excitation, significantly inducing osteogenic phenotypic transformation of PDLSCs. On day 7, alkaline phosphatase (ALP) activity staining showed that the POG-HC group exhibited deeper staining, indicating significantly enhanced ALP activity; the absorbance at 405 nm was approximately 2.3 times that of the control group. On day 21, Alizarin Red (ARS) staining further verified its mineralization ability; the POG-HC group showed dense calcium nodule deposition, with a significant increase in OD@562nm, indicating good induction ability in the early and mid-stages of osteogenic formation.

[0150] The above description of the embodiments is provided to enable those skilled in the art to understand and use the invention. It will be apparent to those skilled in the art that various modifications can be made to these embodiments, and the general principles described herein can be applied to other embodiments without inventive effort. Therefore, the present invention is not limited to the above embodiments, and any improvements and modifications made by those skilled in the art based on the disclosure of the present invention without departing from the scope of the invention should be within the protection scope of the present invention.

Claims

1. A heterojunction-reinforced injectable piezoelectric hydrogel, characterized in that, It consists of the following components by weight percentage: 45% to 75% polyvinyl alcohol, 3% to 15% sodium carboxymethyl cellulose oxide, 3% to 15% gelatin, 1% to 10% zinc oxide / zinc sulfide heterojunction nanophase, 2% to 15% magnesium chloride, and 5% to 35% trisodium citrate. The zinc oxide / zinc sulfide heterojunction nanophase is a functional nanomaterial prepared by hydrothermal synthesis and chemical vapor deposition calcination. In the heterojunction-reinforced injectable piezoelectric hydrogel, the zinc oxide / zinc sulfide heterojunction nanophase forms a type II band and a built-in electric field at the interface, driving charge separation and utilizing oxygen vacancies to enhance the piezoelectric response. The wet ionic conductivity of the hydrogel is not less than 3.82 mS·cm. -1 It can output a piezoelectric signal of up to 150 mV under ultrasonic stimulation.

2. The heterojunction-reinforced injectable piezoelectric hydrogel according to claim 1, characterized in that, The porous structure of the hydrogel is achieved through the dual cross-linking of polyvinyl alcohol and sodium carboxymethyl cellulose oxide-gelatin network. Trisodium citrate promotes the cross-linking of polyvinyl alcohol segments through the salting-out effect, and magnesium chloride binds to the carboxyl groups of sodium carboxymethyl cellulose oxide through coordination bonds to form a dynamic reversible network. This ensures that the hydrogel's area expansion rate does not exceed 12% after 48 hours of immersion in physiological saline and that it possesses self-healing properties.

3. A method for preparing a heterojunction-reinforced injectable piezoelectric hydrogel as described in claim 1 or 2, characterized in that, Includes the following steps: S1. Preparation of solution A: Dissolve trisodium citrate in water, add gelatin, stir, and then pour into solution A; S2. Preparation of solution B: Dissolve magnesium chloride in water, add sodium carboxymethyl cellulose oxide and zinc oxide / zinc sulfide heterostructure nanophase, stir evenly, then add polyvinyl alcohol, heat in an oil bath and degas and cool to obtain solution B; S3. After heating solution A, add it to solution B, stir, degas by ultrasonication, mold, freeze-dry to obtain a heterostructure-reinforced injectable piezoelectric hydrogel.

4. The method for preparing a heterojunction-reinforced injectable piezoelectric hydrogel according to claim 3, characterized in that, In S1, the specific process for preparing solution A includes: First, dissolve trisodium citrate in deionized water, then add gelatin at 50°C and stir continuously for 20 minutes to obtain solution A.

5. The method for preparing a heterojunction-reinforced injectable piezoelectric hydrogel according to claim 3, characterized in that, In S2, the specific process for preparing solution B includes: First, magnesium chloride was dissolved in deionized water, then sodium carboxymethyl cellulose oxide and zinc oxide / zinc sulfide heterostructure nanophase were added, and the mixture was stirred at 60°C until homogeneous. Then, polyvinyl alcohol was added, and the mixture was heated in an oil bath at 90°C for 1 hour. Finally, the mixture was degassed and cooled to room temperature to obtain solution B.

6. The method for preparing a heterojunction-reinforced injectable piezoelectric hydrogel according to claim 3, characterized in that, In S3, the specific process includes: First, heat solution A to 90°C and keep it warm for 10 minutes. Then add it to solution B and stir at 90°C for 20 minutes to achieve thorough mixing. Next, sonicate for 15 minutes to remove air bubbles. Then pour it into a mold and freeze at -20°C for 24 hours to form a heterostructure-reinforced injectable piezoelectric hydrogel.

7. The method for preparing a heterojunction-reinforced injectable piezoelectric hydrogel according to claim 3, characterized in that, In the zinc oxide / zinc sulfide heterostructure nanophase, zinc sulfide is generated in situ on the surface of zinc oxide through a hydrothermal reaction of thioacetamide at 180°C, forming a coating layer structure, and the mass ratio of thioacetamide to zinc oxide is 0.2:1 to 1:

1. After the zinc oxide / zinc sulfide heterojunction nanophase was calcined at 400°C in an argon atmosphere for 2 hours, the oxygen vacancy ratio at its interface was characterized by XPS, showing a shift in binding energy.

8. The method for preparing a heterojunction-reinforced injectable piezoelectric hydrogel according to claim 3, characterized in that, In S1, the mass-to-volume ratio of trisodium citrate to water is from 0.022 g / mL to 0.16 g / mL, and the mass-to-volume ratio of gelatin to water is from 0.013 g / mL to 0.067 g / mL; In S2, the mass-to-volume ratio of magnesium chloride to water is 0.0045 g / mL to 0.033 g / mL, the mass-to-volume ratio of sodium carboxymethyl cellulose oxide to water is 0.0067 g / mL to 0.033 g / mL, the mass-to-volume ratio of zinc oxide / zinc sulfide heterojunction nanophase to water is 0.0022 g / mL to 0.022 g / mL, and the mass-to-volume ratio of polyvinyl alcohol to water is 0.1 g / mL to 0.17 g / mL. In S3, the volume ratio of solution A to solution B is 1:1.5 to 1:

3.

9. An application of the heterojunction-reinforced injectable piezoelectric hydrogel as described in claim 1 or 2, characterized in that, It is used in the preparation of drugs for treating bone defects related to periodontitis.

10. The application of the heterojunction-reinforced injectable piezoelectric hydrogel according to claim 9, characterized in that, The heterojunction-reinforced injectable piezoelectric hydrogel can generate piezoelectric signals under exogenous ultrasound stimulation. These piezoelectric signals, in conjunction with the release of magnesium and zinc ions, promote the enhancement of osteoblast alkaline phosphatase activity and induce calcium nodule deposition.

Images