Conductive hydrogel for jaw defect repair and application thereof

Abstract

The invention belongs to the technical field of hydrogel, and particularly relates to conductive hydrogel for jaw defect repair, which is prepared from methylacryloyl polysaccharide, an ionic liquid monomer and a conductive polymer material through ultraviolet light crosslinking under the action of a crosslinking agent and a photoinitiator, the hydrogel contains, by mass, 1.0%-5% of methylacryloyl polysaccharide and 0.1%-0.5% of a photoinitiator, and the volume fractions of an ionic liquid monomer, a conductive polymer material and a cross-linking agent are 1.0%-10%, 1%-20% and 0.5%-1% respectively. The mechanical property and the stability of the conductive hydrogel are enhanced, and attachment, growth and expansion of cells are facilitated. The modification also improves ion exchange at the interface of the cells and the material, and promotes the mineralization process, so that firmer bone tissues are formed, and the repair of jaw defects is facilitated; electrical stimulation is applied through the conductive network, a bio-electricity signal is simulated, proliferation and differentiation of osteoblasts are enhanced, and bone tissue regeneration is promoted.

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 an application 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 bone repair capacity 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 one's 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 the body's own functions and promote the regeneration of periodontal tissues, is a hot topic in the current research on jaw 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 tissues, but also accelerate cell proliferation and tissue healing due to their electrical conductivity. They have significant application potential, especially in the repair process of nerve 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 unsatisfactory conductivity, insufficient mechanical strength, and stability in complex biological environments needs to be improved.

[0004] Methacryloyl polysaccharides are obtained by chemically modifying natural polysaccharide molecules by introducing methacryloyl groups. This material combines the advantages of polysaccharides, such as good biocompatibility, low immunogenicity and biodegradability, while obtaining adjustable mechanical properties through cross-linking reactions. The applications of methacryloyl polysaccharides in the biomedical field include tissue engineering scaffolds, drug delivery systems, biosensors, wound dressings, etc. Due to its natural origin, methacryloyl polysaccharides have good biodegradability and biocompatibility, can provide support for the repair of jaw defects, and promote the attachment and growth of osteoblasts and periodontal ligament stem cells.

[0005] Ionic liquid monomers refer to monomer molecules with the characteristics of ionic liquids. Common examples include 1-vinyl-3-methylimidazolium bis(trifluoromethanesulfonyl)imide. These monomers have significant advantages in enhancing the conductivity of materials. Because they not only have excellent ionic conductivity, but also can form a conductive polymer network through polymerization, thus playing a key role in materials such as hydrogels. Introducing ionic liquid monomers can not only enhance the conductivity of hydrogels, but also improve their stability, making the materials more adaptable in the biological environment. In addition, they also show a positive role in electrostimulation-induced bone repair.

[0006] Conductive polymers show great application potential in the field of osteogenesis, mainly including types such as polypyrrole (PPy), polyaniline (PANI), poly(3,4-ethylenedioxythiophene) (PEDOT), and polythiophene. They have excellent biocompatibility and conductivity, and can promote bone tissue regeneration through electrostimulation. Currently, there are various applications, such as polypyrrole scaffolds combined with hydroxyapatite for accelerating bone healing, polyaniline scaffolds composite with gelatin for bone defect repair, PEDOT-based intelligent implant devices for bone healing monitoring, and conductive polymer osteogenesis scaffolds fabricated using 3D printing technology. The diverse applications of these materials provide innovative solutions for bone regeneration and repair.

[0007] The synergistic effect of these three components can provide an efficient conductive hydrogel material for jaw 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 jaw defect repair. The hydrogel is prepared by ultraviolet cross-linking of methacrylated polysaccharide, ionic liquid monomer, and conductive polymer material under the action of a cross-linking agent and a photoinitiator. Based on the excellent biocompatibility of methacrylated polysaccharide, the present invention comprehensively utilizes the high conductivity characteristics of the conductive polymer material and the ionic liquid monomer. The mass fractions of methacrylated polysaccharide and photoinitiator in the hydrogel are 1.0% - 5% and 0.1% - 0.5% respectively, and the volume fractions of ionic liquid monomer, conductive polymer material, and cross-linking agent are 1.0% - 10%, 1% - 20%, and 0.5% - 1%.

[0009] Preferably, the methacrylated polysaccharide is one or more of methacrylated chitosan, methacrylated sodium alginate, methacrylated carboxymethyl chitosan, methacrylated hyaluronic acid, and methacrylated 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:poly(styrenesulfonic acid), polyaniline:camphorsulfonic acid, polypyrrole:dodecylbenzenesulfonic acid, and poly(3-hexylthiophene):[6,6]-phenyl-C61-butyric acid methyl ester).

[0012] Preferably, the crosslinking agent is one or more of polyethylene glycol diacrylate, N,N'-methylenebisacrylamide, diglycerol dimethacrylate, divinyl acrylate, divinylacrylic 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, diphenylacetone, 2,2-dimethyl-2-phenylpropiophenone, and 1,2-diphenyl-2-styrylacetone.

[0014] Preferably, the mass fractions of methacrylated polysaccharide and photoinitiator in the hydrogel are 1.5% and 0.45% respectively, and the volume fractions of the ionic liquid monomer, conductive polymer material, and crosslinking agent are 10%, 15%, and 1.5%.

[0015] Preferably, the specific preparation steps of the hydrogel are as follows: add methacrylated polysaccharide, conductive polymer material, crosslinking agent, and photoinitiator to a PBS solution, stir magnetically at room temperature, and then crosslink 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 crosslinking time of the ultraviolet light is 5 s to 300 s.

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

[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] Preferably, the bone tissue is the jaw bone.

[0020] Compared with the prior art, the main advantages of the present invention are as follows: 1. The methacrylated polysaccharide used in the conductive hydrogel of the present invention has excellent biocompatibility and biodegradability, gradually degrades in vivo, and produces very few toxic reactions. Through methacrylation modification, its mechanical properties and stability are enhanced, which is beneficial to cell attachment, growth and expansion. This modification also improves ion exchange at the cell-material interface, promotes the mineralization process, thereby forming stronger bone tissue, and helps to repair jaw bone defects.

[0021] 2. The conductive polymer materials used in the conductive hydrogel of the present invention, such as poly(3,4-ethylenedioxythiophene) (PEDOT) and polythiophene, etc., have excellent electrical conductivity, biocompatibility and high surface area, which helps to improve the overall electrical conductivity performance of the hydrogel. During the repair process of jaw bone defects, the conductive hydrogel applies electrical stimulation through its conductive network, simulates bioelectric signals, enhances the proliferation and differentiation of osteoblasts, and promotes bone tissue regeneration.

[0022] 3. In the conductive hydrogel of the present invention, the mass ratio of methacrylated polysaccharide, ionic liquid monomer and conductive polymer can be flexibly adjusted according to specific requirements. For example, increasing the proportion of the conductive polymer material can enhance the electrical conductivity performance, while increasing the proportion of methacrylated polysaccharide can improve the mechanical strength and toughness of the hydrogel. Such tunability enables the material to provide personalized repair solutions for different types of jaw bone defects.

[0023] 4. By adding ionic liquid monomers to the conductive hydrogel of the present invention, the mechanical properties of the hydrogel are significantly enhanced. The hardness, compressive strength and stability of these materials are improved, ensuring a more lasting support effect of the hydrogel during the repair process. At the same time, the high stability of the added conductive polymer ensures the long-term application of the hydrogel in the biological environment, is not easily degraded, can effectively provide the mechanical support required for the bone defect site, and avoids collapse or deformation during the repair process.

[0024] The concept, specific structure and technical effects of the present invention will be further described below in conjunction with the 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 conductive hydrogel.

[0026] Figure 2is the gelation photograph of the methacrylated carboxymethyl chitosan / 1-vinyl-3-butylimidazolium tetrafluoroborate / poly(3,4-ethylenedioxythiophene):poly(styrenesulfonic acid) conductive hydrogel.

[0027] Figure 3 is the stress-strain curve of the methacrylated carboxymethyl chitosan / 1-vinyl-3-butylimidazolium tetrafluoroborate / poly(3,4-ethylenedioxythiophene):poly(styrenesulfonic acid) conductive hydrogel.

[0028] Figure 4 is the photograph of the lit small light bulb by the connected circuit of the methacrylated carboxymethyl chitosan / 1-vinyl-3-butylimidazolium tetrafluoroborate / poly(3,4-ethylenedioxythiophene):poly(styrenesulfonic acid) conductive hydrogel.

[0029] Figure 5 is the resistance change curve of the methacrylated carboxymethyl chitosan / 1-vinyl-3-butylimidazolium tetrafluoroborate / poly(3,4-ethylenedioxythiophene):poly(styrenesulfonic acid) conductive hydrogel for monitoring the bending of a human finger.

[0030] Figure 6 is the micro-CT image of the jaw bone after the repair of jaw bone defect using the methacrylated carboxymethyl chitosan / 1-vinyl-3-butylimidazolium tetrafluoroborate / poly(3,4-ethylenedioxythiophene):poly(styrenesulfonic acid) conductive hydrogel.

[0031] Figure 7 is the statistical chart of the new bone volume fraction after 4 weeks and 12 weeks of jaw bone defect repair using the methacrylated carboxymethyl chitosan / 1-vinyl-3-butylimidazolium tetrafluoroborate / poly(3,4-ethylenedioxythiophene):poly(styrenesulfonic acid) conductive hydrogel. Detailed implementation mode

[0032] The present invention will be described in detail below in conjunction with 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. The materials, reagents, etc. used in the following embodiments can be obtained from commercial channels unless otherwise specified.

[0033] Example 1 Methacrylated carboxymethyl chitosan / 1-vinyl-3-butylimidazolium tetrafluoroborate / poly(3,4-ethylenedioxythiophene):poly(styrenesulfonic acid) conductive hydrogel

[0034] (I) Preparation of the methacrylated carboxymethyl chitosan / 1-vinyl-3-butylimidazolium tetrafluoroborate / poly(3,4-ethylenedioxythiophene):poly(styrenesulfonic acid) conductive hydrogel.

[0035] 15 mg of methacrylated carboxymethyl chitosan was added to 1 mL of deionized water, and magnetically stirred at room temperature for 3 h at a rotation speed of 500 rpm. Then, 100 μL of 1-butyl-3-methylimidazolium tetrafluoroborate and 150 μL of PEDOT:PSS were added, and ultrasonicated at 60 kHz for 30 min. After homogenization, 15 μL of polyethylene glycol diacrylate and 4.5 mg of 2-hydroxy-4-(2-hydroxyethoxy)-2-methylpropiophenone were added, and cross-linked with ultraviolet light at a wavelength of 465 nm and a power of 30 W for 30 s to obtain a methacrylated carboxymethyl chitosan / 1-vinyl-3-butylimidazolium tetrafluoroborate / poly(3,4-ethylenedioxythiophene):poly(styrenesulfonate) conductive hydrogel (PCV hydrogel group). At the same time, two kinds of gels were prepared as controls, a hydrogel without 1-vinyl-3-butylimidazolium tetrafluoroborate (CV hydrogel group), and a hydrogel without methacrylated carboxymethyl chitosan / 1-vinyl-3-butylimidazolium tetrafluoroborate (C hydrogel group).

[0036] (II) Characterization of methacrylated carboxymethyl chitosan / 1-vinyl-3-butylimidazolium tetrafluoroborate / poly(3,4-ethylenedioxythiophene):poly(styrenesulfonate) conductive hydrogel.

[0037] (A) Gelation experiment detection of hydrogel: As Figure 2 shown, after the hydrogel was formed, the glass bottle was placed upside down and tilted, and no liquid flowed down, indicating that the hydrogel was successfully formed.

[0038] (B) Compression performance analysis: The stress-strain curve of the hydrogel was constructed by compressing the hydrogel with a mechanical testing machine. As Figure 3 shown, the hydrogel had good elasticity and compressibility.

[0039] (C) Small light bulb power-on experiment: The small light bulb, hydrogel and wire were connected in series. As Figure 4 shown, the small light bulb emitted light, indicating that the circuit was connected and the hydrogel had conductivity.

[0040] (D) Human activity detection experiment: The hydrogel was attached to the finger joints, back of the hand and arm of the human body. As Figure 5 shown, when the finger was bent and the back of the hand and arm moved, the resistance of the hydrogel changed significantly, indicating that the hydrogel had good electrical response.

[0041] (E) Jaw bone repair experiment of hydrogel: A periodontal bone defect with a size of 5 * 3 mm was created on the buccal root surface of the first molar in rats. The group without any measures was used as the blank control group (Con group), the hydrogel without conductive polymer material was used as the hydrogel group (CV hydrogel group), and the hydrogel with conductive polymer material was used as the conductive hydrogel group (PCV hydrogel group). A capacitive electric field of 100 mV / mm, 75 Hz, and a duty cycle of 80% was applied to all three groups. After 4 weeks of repair, as Figure 6 shown, the repair effects of the hydrogel group and the conductive hydrogel group were significantly better than those of the control group, and microCT of the conductive hydrogel group showed a smaller bone defect area.

[0042] (F) Statistics of bone mineral density BMD were carried out for the jaw bone repair situation: As Figure 7 shown, at 4 weeks, the newly formed bone in the control group was only 0.419 ± 0.05 g / cm2, which was significantly lower than 0.720 ± 0.07 g / cm2 in the hydrogel group and 0.801 ± 0.08 g / cm2 in the conductive hydrogel group. It indicates that the methacrylated carboxymethyl chitosan / 1-vinyl-3-butylimidazolium tetrafluoroborate / poly(3,4-ethylenedioxythiophene):poly(styrenesulfonic acid) conductive hydrogel accelerates the repair and regeneration of periodontal bone defects in rats.

[0043] 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 according to 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 based on the concept of the present invention through logical analysis, reasoning, or limited experiments should be within the protection scope determined by the claims.

Claims

1. A conductive hydrogel for repairing jawbone defects, which is prepared by ultraviolet cross-linking of methacrylated polysaccharide, ionic liquid monomer and conductive polymer material under the action of a cross-linking agent and a photoinitiator. The mass fractions of methacrylated polysaccharide and photoinitiator in the hydrogel are 1.0% - 5% and 0.1% - 0.5% respectively, and the volume fractions of ionic liquid monomer, conductive polymer material and cross-linking agent are 1.0% - 10%, 1% - 20% and 0.5% - 1%.

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

3. The conductive hydrogel according to claim 1, wherein 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.

4. The conductive hydrogel according to claim 1, wherein The conductive polymer material is one or more of poly(3,4-ethylenedioxythiophene):poly(styrenesulfonic acid), polyaniline:poly(styrenesulfonic acid), polyaniline:camphorsulfonic acid, polypyrrole:dodecylbenzenesulfonic acid and poly(3-hexylthiophene):[6,6]-phenyl-C61-butyric acid methyl ester).

5. The electro-conductive hydrogel according to claim 1, wherein The cross-linking agent is one or more of polyethylene glycol diacrylate, N,N'-methylenebisacrylamide, diglycerol dimethacrylate, divinyl acrylate, divinyl acrylic acid and bisacrylamide.

6. The conductive hydrogel according to claim 1, wherein, The photoinitiator is one or more of 2-hydroxy-2-methyl-1-[4-(2-hydroxyethoxy)phenyl]-1-propanone, lithium phenyl-2,4,6-trimethylbenzoylphosphinate, diphenylacetone, 2-dimethyl-2-phenylpropiophenone and 1,2-diphenyl-2-styrylacetone.

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

8. The conductive hydrogel according to claim 1, wherein The specific preparation steps of the hydrogel are as follows: add methacrylated polysaccharide, conductive polymer material, cross-linking agent and photoinitiator into PBS solution, stir magnetically at room temperature, and then cross-link the mixture under ultraviolet light to form a conductive hydrogel.

9. The electrically conductive hydrogel according to claim 8, wherein, The wavelength of the ultraviolet light is 365nm, 395nm or 405nm, the power of the ultraviolet light is 5W - 6000W, the cross-linking time of the ultraviolet light is 5s - 300s, the magnetic stirring time is 0.5h - 10h, and the speed regulation of the magnetic stirring is 300rpm - 1500rpm.

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

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