Piezoelectric / conductive integrated hydrogel for jaw defect repair and application thereof

Abstract

The invention belongs to the technical field of hydrogel, and relates to piezoelectric / conductive integrated hydrogel for jaw defect repair, which is prepared from methylacryloyl protein, zwitterionic monomer and titanate piezoelectric particles through ultraviolet crosslinking under the action of a crosslinking agent and a photoinitiator, the hydrogel comprises, by mass, 1.0%-10% of methacrylated protein, 1.0%-10% of zwitterionic monomers, 1.0%-10% of titanate piezoelectric particles and 0.1%-5% of an initiator, and the volume fraction of an accelerant is 0.05%-1.0%. The hydrogel disclosed by the invention has excellent mechanical strength and certain flexibility, can realize piezoelectric and conductive functions of the hydrogel, can effectively promote proliferation, differentiation and mineralization of bone cells under the action of an electric field, accelerates bone tissue repair, and has a more remarkable bone regeneration effect compared with a non-electrical stimulation material in the prior art.

Description

Technical Field

[0001] The present invention belongs to the technical field of hydrogels, and specifically, relates to a piezoelectric / conductive integrated hydrogel for jaw defect repair and its application. Background Art

[0002] Periodontitis is an infectious disease that affects the periodontal ligament and alveolar bone, characterized by inflammation of the gingival tissue and loss of periodontal attachments and bone mass, which may ultimately lead to tooth loss. Traditional periodontitis treatment methods mainly focus on controlling soft tissue inflammation in the periodontal tissue, but there are certain difficulties in achieving the regeneration of periodontal hard tissue. A key goal of periodontal treatment is to promote the restoration of lost tissues to their original shape, structure, and function. Therefore, the development of a biocompatible material that can promote bone tissue repair has become the core focus of current medical and materials science research.

[0003] Piezoelectric / conductive materials have received extensive attention in the biomedical field, especially in osteogenic applications. These materials affect cell behavior, promote the proliferation and differentiation of osteocytes, and thus accelerate the osteogenic process by converting mechanical stimuli into electrical signals or through the action of an electric field. Hydrogels have been widely used in the fields of soft tissue repair and wound dressings due to their excellent biocompatibility, adjustable properties, and high water content. The integrated hydrogel combining piezoelectricity and conductivity can more effectively enhance the response of organisms to electrical stimulation, becoming an important direction for a new generation of bone repair materials. Piezoelectric materials can provide continuous electrical stimulation under non-invasive conditions, which is helpful for bone tissue repair.

[0004] Methacrylated proteins have been widely used in the field of biomedical materials in recent years due to their excellent biocompatibility and biodegradable properties. It performs outstandingly in tissue engineering, drug delivery, biosensors, and wound healing. Silk fibroin, collagen, and fibrin are common bio-protein materials. After methacrylation modification, the monomer compatibility and cross-linking performance of these protein materials are significantly enhanced, thus forming a more stable hydrogel system with excellent mechanical strength. Methacrylated proteins act as scaffolds in hydrogels, providing an ideal environment for cell growth and promoting cell adhesion, proliferation, and differentiation.

[0005] Amphoteric monomers are a class of molecules with two or more functional groups, which can include cationic and anionic groups, hydrophilic and hydrophobic groups. Amphoteric monomers exhibit unique functions and importance in a wide range of applications. Their self-assembly ability enables them to form ordered structures through intermolecular interactions, a property that is particularly suitable for the development of self-healing materials, allowing them to automatically repair when damaged. In addition, by adjusting the ratio of hydrophilic and hydrophobic groups in amphoteric monomers, the solubility and biocompatibility of materials can be effectively regulated, and their interfacial stability can be enhanced. More importantly, amphoteric monomers can significantly improve the ionic conductivity of materials, enabling them to sense and regulate bioelectric signals in the environment, which is crucial for the application of piezoelectric / conductive integrated hydrogels in bioelectric stimulation. Existing research has demonstrated that hydrogel materials containing zwitterionic monomers can activate intracellular signal pathways under the action of a local electric field, promoting bone tissue regeneration.

[0006] Titanate-based piezoelectric particles can generate significant charges when mechanical stress is applied or undergo observable mechanical deformation in an electric field, exhibiting excellent piezoelectric properties. This property can promote the migration of fibroblasts and macrophages, facilitating wound repair. Titanate-based piezoelectric materials can promote the proliferation and differentiation of stem cells through the dual stimulation of mechanical force and electrical signals, accelerating the healing rate of bone defects. Research has shown that the application of such materials in piezoelectric hydrogels can effectively simulate the electrical environment of natural bone tissue, thereby promoting bone tissue regeneration and repair. Therefore, titanate-based materials show significant application potential in the biomedical field, especially in bone repair and regenerative medicine.

[0007] By combining these hydrogels with good biocompatibility and titanate-based materials with dual mechanical and electrical stimulation, the piezoelectric / conductive hydrogel can not only meet the repair requirements in terms of biocompatibility and degradability, but also accelerate the bone repair process through its electrical properties, providing a new technical approach for the repair of jawbone defects. Summary of the Invention

[0008] One of the objectives of the present invention is to provide a piezoelectric / conductive integrated hydrogel with piezoelectric and conductive properties for promoting the repair of jawbone defects. The piezoelectric / conductive integrated hydrogel is prepared by ultraviolet cross-linking of methacrylated protein, zwitterionic monomer, and titanate-based piezoelectric particles under the action of a cross-linking agent and a photoinitiator. The mass fractions of methacrylated protein, zwitterionic monomer, titanate-based piezoelectric particles, and initiator in the hydrogel are 1.0% - 10%, 1.0% - 10%, 1.0% - 10%, and 0.1% - 5% respectively, and the volume fraction of the promoter is 0.05% - 1.0%. Based on the excellent biocompatibility of methacrylated protein, the hydrogel combines the piezoelectric effect of titanate-based piezoelectric particles and the conductive properties after polymerization of zwitterionic monomers.

[0009] Preferably, the methacrylated protein is one or more of methacrylated silk fibroin, methacrylated collagen, and methacrylated fibrin.

[0010] Preferably, the zwitterionic monomer is one or more of 2-methacryloyloxyethyl phosphorylcholine, 1-propylsulfonic acid-3-vinylimidazolium inner salt, 2-(methacryloyloxy)ethyl]dimethyl-(3-sulfopropyl), and 2-(methacryloyloxy)ethyl]dimethyl-(3-sulfopropyl) ammonium hydroxide.

[0011] Preferably, the titanate-based piezoelectric particles are one or more of barium titanate, strontium titanate, barium strontium titanate, and calcium barium titanate.

[0012] Preferably, the initiator is one or more of ammonium persulfate, sodium persulfate, potassium persulfate, and azobisisobutyronitrile.

[0013] Preferably, the accelerator is one or more of tetramethylethylenediamine, triethylamine, and diethylamine.

[0014] Preferably, the mass fractions of methacrylated protein, zwitterionic monomer, titanate-based piezoelectric particles, and initiator in the hydrogel are 8.0%, 10%, 5.0%, and 0.5% respectively, and the volume fraction of the accelerator is 0.3%.

[0015] Preferably, the specific preparation steps of the hydrogel are as follows: Add methacrylated protein to PBS solution, stir magnetically at room temperature, then add zwitterionic monomer and titanate-based piezoelectric particles, add the initiator after ultrasonic treatment, mix well and then add the accelerator, and let it stand at room temperature to polymerize to form a hydrogel.

[0016] Preferably, the time of magnetic stirring is 2 h to 12 h, and the rotation speed of magnetic stirring is 500 rpm to 2000 rpm.

[0017] Preferably, the ultrasonic frequency is 20 kHz to 100 kHz, and the ultrasonic time is 5 min to 120 min.

[0018] In another preferred embodiment of the present invention, the present invention also provides the application of the hydrogel of the present invention in the preparation of bone tissue regeneration materials.

[0019] Compared with the prior art, the main advantages of the present invention are: 1. The piezoelectric / conductive integrated hydrogel of the present invention combines zwitterionic monomers with titanate-based piezoelectric particles, enabling the piezoelectric and conductive functions of the hydrogel. Under the action of an electric field, it can effectively promote the proliferation, differentiation, and mineralization of osteoblasts, accelerate bone tissue repair, and has a more significant bone regeneration effect compared to non-electrically stimulated materials in the prior art.

[0020] 2. The combination of methacrylated protein and titanate-based piezoelectric particles in the piezoelectric / conductive integrated hydrogel of the present invention not only has excellent mechanical strength but also has a certain degree of flexibility. This characteristic makes it more suitable for repairing jawbone defects and reduces the risk of material rupture or deformation after surgery.

[0021] 3. The piezoelectric / conductive integrated hydrogel of the present invention combines the biocompatibility of biomaterials, the electric field stimulation of piezoelectric materials, and the function of zwitterionic monomers to regulate electrical properties, possessing multiple functions that traditional single-functional materials cannot provide. It provides more comprehensive support and more efficient healing effects during the bone repair process.

[0022] 4. The piezoelectric / conductive integrated hydrogel of the present invention combines the biocompatibility of biomaterials, the electric field stimulation of piezoelectric materials, and the function of zwitterionic monomers to regulate electrical properties, possessing multiple functions that traditional single-functional materials cannot provide. It provides more comprehensive support and more efficient healing effects during the bone repair process.

[0023] 5. Through a simplified cross-linking method and a low-temperature synthesis process, the hydrogel system of the present invention makes the production process more convenient and has a lower cost, with the potential to achieve large-scale production and promotion in clinical applications.

[0024] The following will further illustrate the concept, specific structure, and technical effects of the present invention with reference to the accompanying drawings to fully understand the purpose, features, and effects of the present invention. Description of the Drawings

[0025] Figure 1 is the preparation flow chart of the piezoelectric / conductive integrated hydrogel.

[0026] Figure 2 is the SEM image of the methacrylated gelatin / [2-(methacryloyloxy)ethyl]dimethyl-(3-sulfopropyl)ammonium hydroxide / barium titanate composite piezoelectric / conductive integrated hydrogel.

[0027] Figure 3 is the EDS image of the methacrylated gelatin / [2-(methacryloyloxy)ethyl]dimethyl-(3-sulfopropyl)ammonium hydroxide / barium titanate composite piezoelectric / conductive integrated hydrogel.

[0028] Figure 4XRD patterns of methacrylated gelatin / [2-(methacryloyloxy)ethyl]dimethyl-(3-sulfopropyl)ammonium hydroxide / barium titanate composite piezoelectric / conductive hydrogel and barium titanate.

[0029] Figure 5 Histogram of Young's modulus of methacrylated gelatin / [2-(methacryloyloxy)ethyl]dimethyl-(3-sulfopropyl)ammonium hydroxide / barium titanate composite piezoelectric / conductive hydrogel.

[0030] Figure 6 Open-circuit voltages generated by methacrylated gelatin / [2-(methacryloyloxy)ethyl]dimethyl-(3-sulfopropyl)ammonium hydroxide / barium titanate composite piezoelectric / conductive hydrogel at different compression amplitudes.

[0031] Figure 7 Micro-CT images of the jawbone after repair of jawbone defects using methacrylated gelatin / [2-(methacryloyloxy)ethyl]dimethyl-(3-sulfopropyl)ammonium hydroxide / barium titanate composite piezoelectric / conductive hydrogel.

[0032] Figure 8 Statistical chart of bone density after repair of jawbone defects using methacrylated gelatin / [2-(methacryloyloxy)ethyl]dimethyl-(3-sulfopropyl)ammonium hydroxide / barium titanate composite piezoelectric / conductive hydrogel. Detailed implementation mode

[0033] The present invention will be described in detail below with reference to the accompanying drawings and specific embodiments, but it should not be construed as a limitation of the present invention. Unless otherwise specified, the technical means used in the following embodiments are conventional means well known to those skilled in the art, and the materials, reagents, etc. used in the following embodiments can be obtained from commercial sources unless otherwise specified.

[0034] Example 1 Methacrylated gelatin / [2-(methacryloyloxy)ethyl]dimethyl-(3-sulfopropyl)ammonium hydroxide / barium titanate composite piezoelectric / conductive hydrogel

[0035] (I) Preparation of methacrylated gelatin / [2-(methacryloyloxy)ethyl]dimethyl-(3-sulfopropyl)ammonium hydroxide / barium titanate composite piezoelectric / conductive hydrogel.

[0036] 80 mg of methacrylated gelatin was added to 1 mL of deionized water, followed by the addition of 100 mg of 2-[(methacryloyloxy)ethyl]dimethyl-(3-sulfopropyl)ammonium hydroxide, 50 mg of BaTiO3 nanoparticles. After sonication at 60 kHz for 30 min, 5 mg of ammonium persulfate was added and mixed well, and then 3 μL of polyethylene glycol diacrylate was added to accelerate the polymerization reaction, resulting in a methacrylated gelatin / 2-[(methacryloyloxy)ethyl]dimethyl-(3-sulfopropyl)ammonium hydroxide / barium titanate composite piezoelectric / conductive integrated hydrogel.

[0037] (II) Characterization of the methacrylated gelatin / 2-[(methacryloyloxy)ethyl]dimethyl-(3-sulfopropyl)ammonium hydroxide / barium titanate composite piezoelectric / conductive integrated hydrogel.

[0038] (A) Analysis by scanning electron microscopy (SEM): The morphology of the hydrogel was observed under SEM. As Figure 2 shown, the hydrogel has a porous structure, which is beneficial for cell infiltration.

[0039] (B) Analysis by energy-dispersive X-ray spectroscopy (EDS): During the SEM imaging, energy-dispersive X-ray spectroscopy scanning was performed. As Figure 3 shown, the important elements of the hydrogel were analyzed. It contains nitrogen (N) from 2-[(methacryloyloxy)ethyl]dimethyl-(3-sulfopropyl)ammonium hydroxide, titanium (Ti) and barium (Ba) from barium titanate, indicating that 2-[(methacryloyloxy)ethyl]dimethyl-(3-sulfopropyl)ammonium hydroxide and barium titanate were successfully incorporated into the hydrogel.

[0040] (C) X-ray diffraction (XRD) analysis: X-ray diffraction analysis of the hydrogel and barium titanate was carried out using an X-ray diffractometer. Figure 4 The results show that the XRD pattern of the hydrogel contains the XRD diffraction characteristic peaks of barium titanate, indicating that barium titanate was successfully incorporated into the hydrogel.

[0041] (D) Compression property analysis: The Young's modulus of the hydrogel was calculated through compression experiments on a mechanical testing machine. As Figure 5 shown, the hydrogel modified with zwitterionic monomers has better elasticity and compressibility compared to the gelatin gel group, and the mechanical properties of the material are further enhanced after the addition of barium titanate.

[0042] (E) Compression property analysis: The open-circuit voltage of BaMGgel generated when compressed repeatedly at 5%, 10%, 20% or 30% at 1.1 Hz was measured using a digital multimeter. As Figure 6 shown, it shows that the hydrogel has compression properties.

[0043] (F) Mandibular repair experiment of hydrogel: A periodontal bone defect model with a size of 5*4 mm was created on the buccal side of the root of the first molar of SD rats. The group without any measures was used as the blank control group (Con group), the hydrogel without barium titanate material was used as the gelatin gel group (Ggel group), and the hydrogel with barium titanate material was used as the piezoelectric / conductive gel group (BaMGgel group). After 4 weeks of repair, as Figure 7 shown, the bone density of both the hydrogel group and the piezoelectric / conductive group was greater than that of the control group, and the bone defect area was smaller. The repair effect of the piezoelectric / conductive group was better.

[0044] (G) Statistics of bone mineral density (BMD) for the mandibular repair situation: As Figure 8 shown, the newly formed bone in the control group was only 0.44±0.05%, which was significantly lower than 0.65±0.07% in the gelatin hydrogel group and 0.74±0.11% in the piezoelectric / conductive group. It indicates that the methacrylated gelatin / [2-(methacryloyloxy)ethyl]dimethyl-(3-sulfopropyl)ammonium hydroxide / barium titanate composite piezoelectric / conductive integrated hydrogel accelerates the repair of periodontal bone defects and can have a therapeutic effect without electric field assistance.

[0045] The preferred specific embodiments of the present invention have been described in detail above. It should be understood that those of ordinary skill in the art can make many modifications and variations based on the concept of the present invention without creative labor. Therefore, all technical solutions that can be obtained by those skilled in the art in the technical field of the present invention through logical analysis, reasoning, or limited experiments based on the concept of the present invention on the basis of the existing technology shall fall within the protection scope determined by the claims.

Claims

1. A piezoelectric / conductive integrated hydrogel for jaw defect repair, which is prepared by ultraviolet cross-linking of methacrylated protein, zwitterionic monomer and titanate-based piezoelectric particles under the action of a cross-linking agent and a photoinitiator. The mass fractions of methacrylated protein, zwitterionic monomer, titanate-based piezoelectric particles and initiator in the hydrogel are 1.0% - 10%, 1.0% - 10%, 1.0% - 10% and 0.1% - 5% respectively, and the volume fraction of the accelerator is 0.05% - 1.0%.

2. The hydrogel according to claim 1, characterized in that, The methacrylated protein is one or more of methacrylated silk fibroin, methacrylated collagen and methacrylated fibrin.

3. The hydrogel according to claim 1, characterized in that, The zwitterionic monomer is one or more of 2-methacryloyloxyethyl phosphorylcholine, 1-propylsulfonic acid-3-vinylimidazolium inner salt, 2-(methacryloyloxy)ethyl]dimethyl-(3-sulfopropyl) and 2-(methacryloyloxy)ethyl]dimethyl-(3-sulfopropyl) ammonium hydroxide.

4. The hydrogel according to claim 1, characterized in that, The titanate-based piezoelectric particles are one or more of barium titanate, strontium titanate, barium strontium titanate and calcium barium titanate.

5. The hydrogel according to claim 1, wherein The initiator is one or more of ammonium persulfate, sodium persulfate, potassium persulfate and azobisisobutyronitrile.

6. The hydrogel according to claim 1, wherein The accelerator is one or more of tetramethylethylenediamine, triethylamine and diethylamine.

7. The hydrogel according to claim 1, wherein The mass fractions of methacrylated protein, zwitterionic monomer, titanate-based piezoelectric particles and initiator in the hydrogel are 8.0%, 10%, 5.0% and 0.5% respectively, and the volume fraction of the accelerator is 0.3%.

8. The hydrogel according to claim 1, characterized in that, The specific preparation steps of the hydrogel are as follows: Add methacrylated protein to PBS solution, stir magnetically at room temperature, then add zwitterionic monomer and titanate-based piezoelectric particles, add the initiator after ultrasonic treatment, mix well and then add the accelerator, and let it stand at room temperature to polymerize to form a hydrogel.

9. The hydrogel according to claim 8, characterized in that, The time of magnetic stirring is 2h - 12h, the rotation speed of magnetic stirring is 500rpm - 2000rpm, the ultrasonic frequency is 20kHz - 100 kHz, and the ultrasonic time is 5min - 120min.

10. Use of the hydrogel according to any one of claims 1 - 9 in the preparation of bone tissue regeneration materials.

Images