Conductive hydrogel for repairing jaw defects and its application

Abstract

The present invention belongs to the technical field of hydrogels, and specifically relates to a conductive hydrogel for repairing jaw defects. The hydrogel is prepared by ultraviolet crosslinking of a methacryloylated polysaccharide, an ionic liquid monomer, and a conductive polymer material under the action of a crosslinker and a photoinitiator. The mass fractions of the methacryloylated polysaccharide and the photoinitiator in the hydrogel are 1.0% to 5% and 0.1% to 0.5%, respectively, and the volume fractions of the ionic liquid monomer, the conductive polymer material, and the crosslinker are 1.0% to 10%, 1% to 20%, and 0.5% to 1%. The conductive hydrogel of the present invention has enhanced mechanical properties and stability, which is conducive to cell attachment, growth, and expansion. This modification also improves ion exchange at the interface between cells and materials, promotes the mineralization process, and thus forms stronger bone tissue, which helps repair jaw defects. Electrical stimulation is applied through its conductive network to simulate bioelectric signals, enhance the proliferation and differentiation of osteoblasts, and promote bone tissue regeneration.

Description

Technical Field

[0001] The present invention belongs to the technical field of hydrogels, and in particular relates to a conductive hydrogel for repairing jaw defects and applications thereof. Background Art

[0002] Periodontitis is a worldwide epidemic inflammatory disease that leads to progressive destruction of periodontal tissues, including connective tissue attachments and alveolar bone. Periodontal bone destruction caused by periodontitis is considered to be one of the main causes of tooth loss, seriously affecting patients' chewing, pronunciation and aesthetic functions. However, existing treatments for periodontitis, including initial periodontal treatment, flap surgery and guided bone regeneration, can only control the progression of the disease, while the ability to repair bone is limited. In addition, the oral cavity has multiple functions. As the starting point of the digestive tract, it is in frequent contact with the external environment, which makes the oral environment complex and susceptible to invasion by various microorganisms, making it difficult to fully recover through its own abilities. Therefore, the development of materials with good biocompatibility, mechanical properties, and support for bone tissue repair and regeneration, to achieve the mobilization of body functions and promote the regeneration of periodontal tissue, is a hot topic in current research on mandibular defect repair.

[0003] In recent years, conductive hydrogels, as an innovative smart material, have shown broad application prospects in the biomedical field, especially in tissue engineering and wound repair. These materials can not only mimic the physical properties of human tissue, but also accelerate cell proliferation and tissue healing due to their electrical conductivity. They have significant application potential, especially in the repair process of neural tissue and muscle tissue that requires electrical signal stimulation. In addition, conductive hydrogels have broad application prospects in many fields such as biosensors, supercapacitors, and flexible wearable electronic devices, and are ideal materials for future flexible electronic devices. However, current conductive hydrogels still face several technical challenges, such as suboptimal conductivity, insufficient mechanical strength, and the need to improve their stability in complex biological environments.

[0004] Methacryl-coated polysaccharides are chemically modified by introducing methacryloyl groups into natural polysaccharide molecules. This material combines the advantages of polysaccharides, such as good biocompatibility, low immunogenicity, and biodegradability, while also achieving tunable mechanical properties through cross-linking reactions. Methacryl-coated polysaccharides have applications in biomedicine, including tissue engineering scaffolds, drug delivery systems, biosensors, and wound dressings. Due to their natural origin, methacryloyl-coated polysaccharides exhibit good biodegradability and biocompatibility, providing support for the repair of jaw defects while promoting the attachment and growth of osteoblasts and periodontal ligament stem cells.

[0005] Ionic liquid monomers refer to monomer molecules with ionic liquid properties. Common examples include 1-vinyl-3-methylimidazolium bis(trifluoromethanesulfonyl)imide salt. These monomers have significant advantages in improving the conductivity of materials because they not only have excellent ionic conductivity, but can also form conductive polymer networks through polymerization, thus playing a key role in materials such as hydrogels. The introduction of ionic liquid monomers can not only enhance the conductivity of hydrogels, but also improve their stability, making the materials more adaptable in biological environments. In addition, they also show a positive effect in bone repair induced by electrical stimulation.

[0006] Conductive polymers, primarily including polypyrrole (PPy), polyaniline (PANI), poly(3,4-ethylenedioxythiophene) (PEDOT), and polythiophene, show great potential in osteogenesis. These materials possess excellent biocompatibility and electrical conductivity, enabling them to promote bone regeneration through electrical stimulation. Currently, they have been used in a variety of applications, including polypyrrole scaffolds bonded with hydroxyapatite to accelerate bone healing, polyaniline scaffolds composited with gelatin for bone defect repair, PEDOT-based smart implants for bone healing monitoring, and conductive polymer osteogenic scaffolds fabricated using 3D printing technology. These diverse applications offer innovative solutions for bone regeneration and repair.

[0007] The synergistic effect of these three components can provide an efficient conductive hydrogel material for mandibular defect repair, which has biocompatibility, mechanical properties and electrical conductivity characteristics. Summary of the Invention

[0008] One of the objectives of the present invention is to provide a conductive hydrogel for repairing mandibular defects. The hydrogel is prepared by ultraviolet crosslinking of methacryloylated polysaccharide, ionic liquid monomer and conductive polymer material under the action of a crosslinker and a photoinitiator. The hydrogel of the present invention is based on the excellent biocompatibility of methacryloylated polysaccharide and comprehensively utilizes the high conductivity properties of conductive polymer material and ionic liquid monomer. The mass fractions of methacryloylated polysaccharide and photoinitiator in the hydrogel are 1.0% to 5% and 0.1% to 0.5%, respectively, and the volume fractions of ionic liquid monomer, conductive polymer material and crosslinker are 1.0% to 10%, 1% to 20% and 0.5% to 1%.

[0009] Preferably, the methacryloylated polysaccharide is one or more of methacryloylated chitosan, methacryloylated sodium alginate, methacryloylated carboxymethyl chitosan, methacryloylated hyaluronic acid and methacryloylated dextran.

[0010] Preferably, the ionic liquid monomer is one or more of 1-vinyl-3-methylimidazolium bis(trifluoromethanesulfonyl)imide, 1-vinyl-3-butylimidazolium bis(trifluoromethanesulfonyl)imide, 1-allyl-3-methylimidazolium bis(trifluoromethanesulfonyl)imide, 1-allyl-3-ethylimidazolium bis(trifluoromethanesulfonyl)imide, 1-allyl-3-butylimidazolium bis(trifluoromethanesulfonyl)imide, 1-allyl-3-methylimidazolium chloride and 1-allyl-3-ethylimidazolium chloride.

[0011] Preferably, the conductive polymer material is one or more of poly(3,4-ethylenedioxythiophene):poly(styrenesulfonic acid), polyaniline:polystyrenesulfonic acid, polyaniline:camphorsulfonic acid, polypyrrole:dodecylbenzenesulfonic acid and poly(3-hexylthiophene):[6,6]-phenyl-C61-butyric acid methyl ester).

[0012] Preferably, the cross-linking agent is one or more of polyethylene glycol diacrylate, N,N'-methylenebisacrylamide, diglycerol dimethacrylate, divinyl acrylate, divinyl acrylic acid and bisacrylamide.

[0013] Preferably, the photoinitiator is one or more of 2-hydroxy-2-methyl-1-[4-(2-hydroxyethoxy)phenyl]-1-propanone, lithium phenyl-2,4,6-trimethylbenzoylphosphinate, diphenylacetophenone, 2-dimethyl-2-phenylpropionylbenzene and 1,2-diphenyl-2-phenylvinyl acetone.

[0014] Preferably, the hydrogel contains methacryloyl polysaccharide and photoinitiator in mass fractions of 1.5% and 0.45% respectively, and the ionic liquid monomer, conductive polymer material and cross-linking agent in volume fractions of 10%, 15% and 1.5% respectively.

[0015] Preferably, the hydrogel is prepared by adding methacrylated polysaccharide, conductive polymer material, crosslinking agent and photoinitiator to PBS solution, stirring magnetically at room temperature, and crosslinking the mixture under ultraviolet light to form a conductive hydrogel.

[0016] Preferably, the wavelength of the ultraviolet light is 365 nm, 395 nm or 405 nm; the power of the ultraviolet light is 5 W to 6000 W; and the time of the ultraviolet light cross-linking is 5 s to 300 s.

[0017] Preferably, the magnetic stirring time is 0.5 h to 10 h, and the speed of the magnetic stirring is 300 rpm to 1500 rpm.

[0018] In another preferred embodiment of the present invention, the present invention further provides use of the hydrogel of the present invention in preparing bone tissue regeneration materials.

[0019] Preferably, the bone tissue is jawbone.

[0020] Compared with the prior art, the present invention has the following main advantages:

[0021] The methacryloylated polysaccharide used in the conductive hydrogel of this invention exhibits excellent biocompatibility and biodegradability, gradually degrading in vivo with minimal toxicity. The methacryloylation modification enhances its mechanical properties and stability, facilitating cell attachment, growth, and expansion. This modification also enhances ion exchange at the cell-material interface, promoting mineralization and ultimately forming stronger bone tissue, aiding in the repair of jaw defects.

[0022] 2. The conductive polymer materials used in the conductive hydrogel of this invention, such as poly(3,4-ethylenedioxythiophene) (PEDOT) and polythiophene, possess excellent conductivity, biocompatibility, and a high surface area, which contribute to the hydrogel's overall electrical conductivity. During the jaw defect repair process, the conductive hydrogel applies electrical stimulation through its conductive network, simulating bioelectrical signals, enhancing osteoblast proliferation and differentiation, and promoting bone tissue regeneration.

[0023] 3. In the conductive hydrogel of this invention, the mass ratio of the methacryloyl polysaccharide, ionic liquid monomer, and conductive polymer can be flexibly adjusted according to specific needs. For example, increasing the proportion of the conductive polymer can enhance electrical conductivity, while increasing the proportion of the methacryloyl polysaccharide can improve the hydrogel's mechanical strength and toughness. This adjustability enables the material to provide personalized repair solutions for different types of jaw defects.

[0024] 4. The conductive hydrogel of the present invention significantly enhances its mechanical properties by incorporating ionic liquid monomers. These materials have enhanced hardness, compressive strength, and stability, ensuring the hydrogel's supportive effect during the repair process is more durable. Furthermore, the high stability of the added conductive polymer ensures the hydrogel's long-term use in biological environments, making it less susceptible to degradation and effectively providing the mechanical support required for bone defects, preventing collapse or deformation during the repair process.

[0025] The concept, specific structure and technical effects of the present invention will be further described below in conjunction with the accompanying drawings to fully understand the purpose, characteristics and effects of the present invention. BRIEF DESCRIPTION OF THE DRAWINGS

[0026] Figure 1 This is a flow chart of the preparation of conductive hydrogel.

[0027] Figure 2This is a photograph of the gel formation of methacryloylated carboxymethyl chitosan / 1-vinyl-3-butylimidazole tetrafluoroborate / poly(3,4-ethylenedioxythiophene):poly(styrenesulfonic acid) conductive hydrogel.

[0028] Figure 3 Figure 2 is the stress-strain curve of methacryloyl carboxymethyl chitosan / 1-vinyl-3-butylimidazole tetrafluoroborate / poly(3,4-ethylenedioxythiophene):poly(styrenesulfonic acid) conductive hydrogel.

[0029] Figure 4 This is a photo of a small light bulb emitting light through a connected circuit of methacryloyl carboxymethyl chitosan / 1-vinyl-3-butylimidazole tetrafluoroborate / poly(3,4-ethylenedioxythiophene):poly(styrenesulfonic acid) conductive hydrogel.

[0030] Figure 5 The resistance change curve of methacryloyl carboxymethyl chitosan / 1-vinyl-3-butylimidazole tetrafluoroborate / poly(3,4-ethylenedioxythiophene):poly(styrenesulfonic acid) conductive hydrogel for monitoring the bending of human fingers.

[0031] Figure 6 Micro-CT image of the jaw after mandibular defect repair using methacryloyl carboxymethyl chitosan / 1-vinyl-3-butylimidazole tetrafluoroborate / poly(3,4-ethylenedioxythiophene):poly(styrenesulfonic acid) conductive hydrogel.

[0032] Figure 7 Statistical graph of new bone volume fraction after 4 and 12 weeks of mandibular defect repair using methacryloylated carboxymethyl chitosan / 1-vinyl-3-butylimidazole tetrafluoroborate / poly(3,4-ethylenedioxythiophene):poly(styrenesulfonic acid) conductive hydrogel. DETAILED DESCRIPTION

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

[0034] Example 1 Methacryloylation of carboxymethyl chitosan / 1-vinyl-3-butyl imidazole tetrafluoroborate / poly (3,4-ethylenedioxythiophene): poly (styrene sulfonic acid) conductive hydrogel

[0035] (a) Preparation of methacryloyl carboxymethyl chitosan / 1-vinyl-3-butylimidazole tetrafluoroborate / poly(3,4-ethylenedioxythiophene):poly(styrenesulfonic acid) conductive hydrogel.

[0036] 15 mg of methacryloylated carboxymethyl chitosan was added to 1 mL of deionized water and magnetically stirred at 500 rpm for 3 h at room temperature. Then, 100 μL of 1-butyl-3-methylimidazolium tetrafluoroborate and 150 μL of PEDOT:PSS were added. Ultrasonication at 60 kHz was performed for 30 min and homogenization was performed. Then, 15 μL of polyethylene glycol diacrylate and 4.5 mg of 2-hydroxy-4-(2-hydroxyethoxy)-2-methylpropiophenone were added. The mixture was cross-linked with UV light at 465 nm and 30 W for 30 s to obtain methacryloylated carboxymethyl chitosan / 1-vinyl-3-butylimidazolium tetrafluoroborate / poly(3,4-ethylenedioxythiophene):poly(styrenesulfonic acid) conductive hydrogel (PCV gel group). Two types of gels were prepared as controls: a hydrogel without 1-vinyl-3-butylimidazolium tetrafluoroborate (CV gel group) and a hydrogel without methacryloylated carboxymethyl chitosan / 1-vinyl-3-butylimidazolium tetrafluoroborate (C gel group).

[0037] (ii) Characterization of methacryloylated carboxymethyl chitosan / 1-vinyl-3-butylimidazole tetrafluoroborate / poly(3,4-ethylenedioxythiophene):poly(styrenesulfonic acid) conductive hydrogel.

[0038] (A) Hydrogel formation test: Figure 2 As shown, after the hydrogel is gelled, the glass bottle is placed upside down and tilted, and no liquid flows down, indicating that the hydrogel is successfully gelled.

[0039] (B) Compression performance analysis: The stress-strain curve of the hydrogel was constructed by compressing the hydrogel using a mechanical testing machine, e.g. Figure 3 As shown, the hydrogel has good elasticity and compressibility.

[0040] (C) Experiment of electrifying a small light bulb: Connect the small light bulb, hydrogel and wire in series, as shown in the following example: Figure 4 As shown, the small light bulb emits bright light, indicating that the circuit is connected and the hydrogel is conductive.

[0041] (D) Human activity detection experiment: The hydrogel is attached to the human finger joints, back of the hand and arm, such as Figure 5 As shown, the resistance of the hydrogel changes significantly when the fingers are bent and the back of the hand and arm move, indicating that the hydrogel has good electrical response.

[0042] (E) Hydrogel jaw repair experiment: A 5*3mm periodontal bone defect was created on the buccal root surface of the first molar of rats. A group without any treatment was used as the blank control group (Con group), a hydrogel without conductive polymer material was used as the gel group (CV gel group), and a hydrogel with conductive polymer material was used as the conductive gel group (PCV gel group). A capacitive electric field of 100mV / mm, 75Hz, and 80% duty cycle was applied to all three groups. After 4 weeks of repair, Figure 6 As shown in the figure, the repair effects of the gel group and the conductive gel group were significantly better than those of the control group, and the microCT of the conductive gel group showed a smaller bone defect area.

[0043] (F) According to the condition of jaw repair, the bone mineral density (BMD) is counted: Figure 7 As shown, at 4 weeks, the new bone mass in the control group was only 0.419±0.05 g / cm2, significantly lower than the 0.720±0.07 g / cm2 in the hydrogel group and the 0.801±0.08 g / cm2 in the conductive hydrogel group. This indicates that the methacryloylated carboxymethyl chitosan / 1-vinyl-3-butylimidazole tetrafluoroborate / poly(3,4-ethylenedioxythiophene):poly(styrenesulfonic acid) conductive hydrogel accelerates the repair and regeneration of periodontal bone defects in rats.

[0044] The preferred embodiments of the present invention have been described in detail above. It should be understood that numerous modifications and variations based on the concepts of the present invention are possible without inventive effort by those skilled in the art. Therefore, any technical solution that can be derived by one skilled in the art through logical analysis, reasoning, or limited experimentation based on the concepts of the present invention and the prior art should be within the scope of protection defined by the claims.

Claims

1. A conductive hydrogel for jaw defect repair, the hydrogel being prepared by ultraviolet crosslinking of a methacryloylated polysaccharide, an ionic liquid monomer, and a conductive polymer material under the action of a crosslinker and a photoinitiator. The mass fractions of the methacryloylated polysaccharide and the photoinitiator in the hydrogel are 1.0% to 5% and 0.1% to 0.5%, respectively, and the volume fractions of the ionic liquid monomer, the conductive polymer material, and the crosslinker are 1.0% to 10%, 1% to 20%, and 0.5% to 1%. The ionic liquid monomer is one or more of 1-vinyl-3-methylimidazolium bis(trifluoromethanesulfonyl)imide, 1-vinyl-3-butylimidazolium bis(trifluoromethanesulfonyl)imide, 1-allyl-3-methylimidazolium bis(trifluoromethanesulfonyl)imide, 1-allyl-3-ethylimidazolium bis(trifluoromethanesulfonyl)imide, 1-allyl-3-butylimidazolium bis(trifluoromethanesulfonyl)imide, 1-allyl-3-methylimidazolium chloride and 1-allyl-3-ethylimidazolium chloride; The conductive polymer material is one or more of poly(3,4-ethylenedioxythiophene):poly(styrene sulfonic acid), polyaniline:polystyrene sulfonic acid; The specific preparation steps of the hydrogel are: adding methacrylated polysaccharide, conductive polymer material, crosslinking agent and photoinitiator into PBS solution, stirring magnetically at room temperature, and crosslinking the mixture under ultraviolet light to form a conductive hydrogel.

2. The conductive hydrogel according to claim 1, wherein The methacryloyl polysaccharide is one or more of methacryloyl chitosan, methacryloyl sodium alginate, methacryloyl carboxymethyl chitosan, methacryloyl hyaluronic acid and methacryloyl dextran.

3. The conductive hydrogel according to claim 1, wherein The cross-linking agent is one or more of polyethylene glycol diacrylate, diglycerol dimethacrylate, divinyl acrylate and bisacrylamide.

4. The conductive hydrogel according to claim 1, wherein The cross-linking agent is N,N'-methylenebisacrylamide.

5. The conductive hydrogel according to claim 1, characterized in that The photoinitiator is one or more of 2-hydroxy-2-methyl-1-[4-(2-hydroxyethoxy)phenyl]-1-propanone, lithium phenyl-2,4,6-trimethylbenzoylphosphinate, diphenylacetophenone, 2-dimethyl-2-phenylpropionylbenzene and 1,2-diphenyl-2-phenylvinyl acetone.

6. The conductive hydrogel according to claim 1, characterized in that The hydrogel contains methacrylated polysaccharide and photoinitiator in mass fractions of 1.5% and 0.45% respectively, and ionic liquid monomer, conductive polymer material and cross-linking agent in volume fractions of 10%, 15% and 1.5% respectively.

7. The conductive hydrogel according to claim 1, characterized in that The wavelength of the ultraviolet light is 365nm, 395nm or 405nm, the power of the ultraviolet light is 5W to 6000W, the time of the ultraviolet cross-linking is 5s to 300s, the time of the magnetic stirring is 0.5h to 10h, and the speed adjustment of the magnetic stirring is 300rpm to 1500rpm.

8. Use of the conductive hydrogel according to any one of claims 1 to 7 in preparing bone tissue regeneration materials.

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