A Conductive Hydrogel for Skull Defect Repair and Its Application

Abstract

The present invention belongs to the technical field of hydrogels. Specifically, it relates to a conductive hydrogel for skull defect repair, which is prepared by polymerizing methacrylated polysaccharide, ionic liquid monomer and two-dimensional titanium-based conductive material under the action of an initiator and a promoter. The mass fractions of methacrylated polysaccharide, ionic liquid monomer, two-dimensional titanium-based conductive material and initiator in the hydrogel are 1.0% - 5.0%, 1.0% - 10%, 0.1% - 5.0% and 0.1% - 2.0% respectively, and the volume fraction of the promoter is 0.05% - 1.0%. The methacrylated polysaccharide used in the conductive hydrogel of the present invention has good biocompatibility and biodegradability, and can be gradually degraded in vivo without producing toxic reactions; the two-dimensional titanium-based conductive material used has excellent electrical conductivity and high surface area, which improves the overall electrical conductivity of the hydrogel, and promotes the proliferation and differentiation of osteocytes and accelerates the regeneration and healing of bone tissue by providing weak electrical stimulation.

Description

Technical Field

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

[0002] Skull defect refers to the partial absence or damage of the skull caused by trauma, disease or congenital reasons, which seriously affects the physiological functions, appearance and quality of life of patients. Traditional skull repair methods mainly rely on metal or plastic prostheses, but these repair materials usually lack biocompatibility, tissue repair function and good mechanical properties. In addition, metal prostheses may lead to postoperative infections, rejection reactions and poor biocompatibility. Therefore, the development of materials with good biocompatibility, mechanical properties, and the ability to support bone tissue repair and regeneration is a current research hotspot in skull defect repair.

[0003] In recent years, conductive hydrogels, as a new type of intelligent material, have shown great application potential in the biomedical field, especially in tissue engineering and wound repair. Conductive hydrogels can not only simulate the physical properties of human tissues, but also promote cell growth and tissue repair through their conductive properties. They have important application values, especially in the repair of tissues such as nerves and muscles that require electrical stimulation. However, existing conductive hydrogels still face some technical problems, such as insufficient conductivity, poor mechanical properties, and stability problems in complex biological environments.

[0004] Methacrylated polysaccharides are a class of natural polysaccharides modified by methacrylation reactions, such as methacrylated chitosan, sodium alginate, etc. Such materials play a role in enhancing the mechanical properties and improving the biocompatibility of hydrogels. Due to their natural origin, methacrylated polysaccharides have good biodegradability and biocompatibility, can provide support for skull defect repair, and promote cell attachment and growth.

[0005] Ionic liquid monomers refer to monomer molecules with ionic liquid characteristics, and common ones include 1-vinyl-3-methylimidazolium bis(trifluoromethanesulfonyl)imide, etc. These monomers have excellent conductivity and can effectively improve the conductive properties of hydrogels. The addition 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 and contributing to electrostimulation-induced bone repair.

[0006] Two-dimensional titanium-based conductive materials, such as titanium nitride, titanium carbide, etc., have excellent conductivity and good biocompatibility. Adding these materials to conductive hydrogels can greatly improve the conductive properties of the materials, promote cell growth and tissue repair. In addition, the high surface area and excellent mechanical properties of titanium-based conductive materials enable them to provide better mechanical support in skull defect repair and contribute to bone tissue regeneration.

[0007] The synergistic effect of these three components can provide an efficient conductive hydrogel material for skull 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 hydrogel for promoting skull defect repair with high-efficient conductive characteristics. The hydrogel is prepared by polymerization of methacrylated polysaccharide, ionic liquid monomer and two-dimensional titanium-based conductive material under the action of an initiator and an accelerator. Based on the excellent biocompatibility of methacrylated polysaccharide, the present invention comprehensively utilizes the high conductive characteristics of two-dimensional titanium-based conductive material and ionic liquid monomer. The mass fractions of methacrylated polysaccharide, ionic liquid monomer, two-dimensional titanium-based conductive material and initiator in the hydrogel are 1.0% - 5.0%, 1.0% - 10%, 0.1% - 5.0% and 0.1% - 2.0% respectively, and the volume fraction of the accelerator is 0.05% - 1.0%.

[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 two-dimensional titanium-based conductive material is one or more of titanium nitride, titanium carbide, titanium carbonitride, titanium boride and titanium sulfide.

[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 polysaccharide, ionic liquid monomer, two-dimensional titanium-based conductive material and initiator in the hydrogel are 1.5% - 4.0%, 4.0% - 5.0%, 0.5% - 1.0% and 0.1% - 2.0% respectively, and the volume fraction of the accelerator is 0.1% - 0.3%.

[0015] Preferably, the mass fractions of the methacrylated polysaccharide, ionic liquid monomer, two-dimensional titanium-based conductive material and initiator in the hydrogel are 2.0%, 5.0%, 0.5% - 1.0% and 0.1% - 2.0% respectively, and the volume fraction of the accelerator is 0.1% - 0.3%.

[0016] Preferably, the specific preparation steps of the hydrogel are as follows: Add methacrylated polysaccharide to deionized water, and after dissolving by magnetic stirring, add ionic liquid monomer and two-dimensional titanium-based conductive material. After ultrasonic treatment, add initiator, and after mixing, add accelerator, and let it stand at room temperature for polymerization to form a hydrogel.

[0017] Preferably, the time of the magnetic stirring is 2h - 12h; the rotation speed of the magnetic stirring is 500rpm - 2000rpm.

[0018] Preferably, the ultrasonic frequency is 20 kHz - 100 kHz, and the ultrasonic time is 5min - 120min.

[0019] 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.

[0020] Preferably, the bone tissue is the skull.

[0021] Compared with the prior art, the main advantages of the present invention are as follows:

[0022] 1. The methacrylated polysaccharide used in the conductive hydrogel of the present invention has good biocompatibility and biodegradability, and can be gradually degraded in vivo without producing toxic reactions. Through methacrylation modification, its mechanical properties and stability are enhanced, which is beneficial to cell attachment, growth and expansion, helps to repair skull defects, and reduces postoperative complications.

[0023] 2. The ionic liquid monomer used in the conductive hydrogel of the present invention has excellent electrical conductivity, which can enhance the electrical conductivity of the hydrogel; and further using two-dimensional titanium-based conductive materials such as titanium nitride and titanium carbide with excellent electrical conductivity and high surface area helps to further improve the overall electrical conductivity of the hydrogel. During the repair of skull defects, the conductive hydrogel can provide weak electrical stimulation, promote the proliferation and differentiation of osteocytes, and accelerate the regeneration and healing of bone tissue, especially playing a positive role in nerve-guided repair.

[0024] 3. The high stability of the two-dimensional titanium-based material added to the conductive hydrogel of the present invention ensures the long-term application of the hydrogel in the biological environment, is not easily degraded, can effectively provide the mechanical support required at the bone defect site, and avoids collapse or deformation during the repair process.

[0025] 4. In the conductive hydrogel of the present invention, the mass ratio of methacrylated polysaccharide, ionic liquid monomer and two-dimensional titanium-based conductive material can be flexibly adjusted according to specific requirements. For example, increasing the proportion of the titanium-based conductive material can enhance the conductivity performance, while increasing the proportion of methacrylated polysaccharide can improve the mechanical strength and toughness of the hydrogel. This tunability enables the material to provide personalized repair solutions for different types of skull defects.

[0026] 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, features and effects of the present invention. Description of the Drawings

[0027] Figure 1 is the preparation flow chart of the conductive hydrogel.

[0028] Figure 2 is the gelation photo of methacrylated carboxymethyl chitosan / 1-allyl-3-methylimidazolium bis(trifluoromethanesulfonyl)imide / titanium carbide conductive hydrogel.

[0029] Figure 3 is the stress-strain curve and elastic modulus of conductive hydrogels constructed with different materials; Figure 3 where A in is the stress-strain curve, Figure 3 and B in is the elastic modulus.

[0030] Figure 4 is the photo of the connected circuit of methacrylated carboxymethyl chitosan / 1-allyl-3-methylimidazolium bis(trifluoromethanesulfonyl)imide / titanium carbide conductive hydrogel making the small light bulb emit light.

[0031] Figure 5 is the conductivity result graph of conductive hydrogels constructed with different materials.

[0032] Figure 6 is the resistance change curve of methacrylated carboxymethyl chitosan / 1-allyl-3-methylimidazolium bis(trifluoromethanesulfonyl)imide / titanium carbide conductive hydrogel for monitoring human activities such as swallowing and finger bending.

[0033] Figure 7 is the skull micro-CT image of methacrylated carboxymethyl chitosan / 1-allyl-3-methylimidazolium bis(trifluoromethanesulfonyl)imide / titanium carbide conductive hydrogel after skull defect repair.

[0034] Figure 8 is the statistical graph of the new bone volume fraction of methacrylated carboxymethyl chitosan / 1-allyl-3-methylimidazolium bis(trifluoromethanesulfonyl)imide / titanium carbide conductive hydrogel 4 weeks and 8 weeks after skull defect repair. Detailed Embodiments

[0035] 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.

[0036] Example 1 Methacrylated Carboxymethyl Chitosan / 1-Allyl-3-Methylimidazolium Bis(trifluoromethanesulfonyl) Imide / Titanium Carbide Conductive Hydrogel

[0037] (I) Preparation of Methacrylated Carboxymethyl Chitosan / 1-Allyl-3-Methylimidazolium Bis(trifluoromethanesulfonyl) Imide / Titanium Carbide Conductive Hydrogel

[0038] Add 20 mg of methacrylated carboxymethyl chitosan to 1 mL of deionized water, and stir magnetically at room temperature at 500 rpm for 3 h. Then add 50 mg of 1-allyl-3-methylimidazolium bis(trifluoromethanesulfonyl) imide and 5 mg of titanium carbide, and ultrasonicate at 60 kHz for 30 min. After adding 5 mg of ammonium persulfate and mixing evenly, add 3 μL of tetramethylethylenediamine to accelerate the polymerization reaction to obtain methacrylated carboxymethyl chitosan / 1-allyl-3-methylimidazolium bis(trifluoromethanesulfonyl) imide / titanium carbide conductive hydrogel.

[0039] (II) Characterization of Methacrylated Carboxymethyl Chitosan / 1-Allyl-3-Methylimidazolium Bis(trifluoromethanesulfonyl) Imide / Titanium Carbide Conductive Hydrogel

[0040] Construct hydrogels of methacrylated carboxymethyl chitosan and methacrylated carboxymethyl chitosan / 1-allyl-3-methylimidazolium bis(trifluoromethanesulfonyl) imide hydrogel by a method similar to that of Example 1 as controls, and label the hydrogel of methacrylated carboxymethyl chitosan, methacrylated carboxymethyl chitosan / 1-allyl-3-methylimidazolium bis(trifluoromethanesulfonyl) imide hydrogel, and methacrylated carboxymethyl chitosan / 1-allyl-3-methylimidazolium bis(trifluoromethanesulfonyl) imide / titanium carbide conductive hydrogel as (1), (2), and (3), respectively.

[0041] (A) Hydrogel Gelation Experiment Detection: As Figure 2 shown, after the hydrogel gels, place the glass bottle upside down and tilted, and no liquid flows down, indicating that the hydrogel has successfully gelled.

[0042] (B) Compression Property Analysis: Construct the stress-strain curve of the hydrogel by compressing the hydrogel with a mechanical testing machine. As Figure 3As shown in A and B, the hydrogel has good elasticity and compressibility. At the same time, it can be found that the elastic modulus of the methacrylated carboxymethyl chitosan / 1-allyl-3-methylimidazolium bis(trifluoromethanesulfonyl)imide / titanium carbide conductive hydrogel (3) is significantly higher than that of the methacrylated carboxymethyl chitosan / 1-allyl-3-methylimidazolium bis(trifluoromethanesulfonyl)imide hydrogel (2), indicating that the addition of titanium carbide enhances the mechanical properties of the hydrogel.

[0043] (C) Small light bulb power-on experiment: Connect the small light bulb, hydrogel and wire in series. As Figure 4 shown, the small light bulb emits light, indicating that the circuit is connected and the hydrogel has conductivity. Further detect the conductivity of the methacrylated carboxymethyl chitosan hydrogel (1), methacrylated carboxymethyl chitosan / 1-allyl-3-methylimidazolium bis(trifluoromethanesulfonyl)imide hydrogel (2) and methacrylated carboxymethyl chitosan / 1-allyl-3-methylimidazolium bis(trifluoromethanesulfonyl)imide / titanium carbide conductive hydrogel (3). As Figure 5 shown, the addition of liquid monomer after gelation with ice and the addition of titanium carbide both significantly enhance the conductivity of the hydrogel.

[0044] (D) Human activity detection experiment: Attach the hydrogel to the human larynx and finger joints. As Figure 6 shown, when swallowing in the larynx and bending the fingers, the resistance of the hydrogel changes significantly, indicating that the hydrogel has good electrical response.

[0045] (E) Hydrogel skull repair experiment: Create a 4-mm diameter non-healing skull defect in C57 mice, and use the hydrogel for repair (gel group). Use the group without any measures as the control group (Con group), and use the hydrogel and apply a capacitive electric field of 100 mV / mm, 75 Hz, and a duty cycle of 80% as the hydrogel combined electric field group (gel+EF group). After 4 weeks and 8 weeks of repair, as Figure 7 shown, the repair level of the hydrogel repair group is higher than that of the control group, and the repair effect of the combined electric field group is better.

[0046] (F) For the skull repair situation, conduct statistics on the new bone volume fraction (BV / TV): As Figure 8As shown, at 4 weeks, the newly formed bone in the control group was only 1.26 ± 0.86%, significantly lower than 7.51 ± 0.56% in the hydrogel group and 9.15 ± 0.70% in the hydrogel combined with electric field group; at 8 weeks, the newly formed bone in the control group was 2.77 ± 1.11%, still significantly lower than 10.25 ± 1.34% in the hydrogel group and 15.95 ± 3.27% in the hydrogel combined with electric field group. It indicates that the methacrylated carboxymethyl chitosan / 1-allyl-3-methylimidazolium bis(trifluoromethanesulfonyl)imide / titanium carbide conductive hydrogel accelerates the repair of non-healing skull defects in mice, and the repair effect is further accelerated under electric field stimulation.

[0047] Example 2 Preparation of methacrylated chitosan / 1-allyl-3-butylimidazolium bis(trifluoromethanesulfonyl)imide / titanium nitride conductive hydrogel

[0048] Add 30 mg of methacrylated chitosan to 2 mL of deionized water, magnetically stir at room temperature at 1000 rpm for 5 h, add 80 mg of 1-allyl-3-butylimidazolium bis(trifluoromethanesulfonyl)imide and 20 mg of titanium nitride, ultrasonicate at 80 kHz for 60 min, add 10 mg of potassium persulfate and mix well, then add 5 μL of triethylamine to accelerate the polymerization reaction to obtain methacrylated chitosan / 1-allyl-3-butylimidazolium bis(trifluoromethanesulfonyl)imide / titanium nitride conductive hydrogel.

[0049] Example 3 Preparation of methacrylated carboxymethyl alginate / 1-allyl-3-methylimidazolium chloride / titanium carbonitride conductive hydrogel

[0050] Add 15 mg of methacrylated alginate to 1 mL of deionized water, magnetically stir at room temperature at 800 rpm for 4 h, add 40 mg of 1-allyl-3-methylimidazolium chloride and 8 mg of titanium carbonitride, ultrasonicate at 40 kHz for 40 min, add 4 mg of ammonium persulfate and mix well, then add 2 μL of diethylamine to accelerate the polymerization reaction to obtain methacrylated carboxymethyl alginate / 1-allyl-3-methylimidazolium chloride / titanium carbonitride conductive hydrogel.

[0051] Example 4 Preparation of methacrylated dextran / 1-vinyl-3-methylimidazolium bis(trifluoromethanesulfonyl)imide / titanium boride conductive hydrogel

[0052] 80 mg of methacrylated carboxymethyl chitosan was added to 2 mL of deionized water, and magnetically stirred at room temperature for 2 h at a speed of 600 rpm. 160 mg of 1-vinyl-3-methylimidazolium bis(trifluoromethanesulfonyl)imide, 10 mg of titanium boride were added, and sonicated at 55 kHz for 50 min. After adding 5 mg of azobisisobutyronitrile and mixing evenly, 2 μL of tetramethylethylenediamine was added to accelerate the polymerization reaction, and a methacrylated dextran / 1-vinyl-3-methylimidazolium bis(trifluoromethanesulfonyl)imide / titanium boride conductive hydrogel was obtained.

[0053] 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 based on the concept of the present invention through logical analysis, reasoning or limited experiments on the basis of the prior art should be within the protection scope determined by the claims.

Claims

1. A conductive hydrogel for skull defect repair, which is prepared by polymerizing methacrylated polysaccharide, ionic liquid monomer and two-dimensional titanium-based conductive material under the action of an initiator and an accelerator. The mass fractions of methacrylated polysaccharide, ionic liquid monomer, two-dimensional titanium-based conductive material and initiator in the hydrogel are 1.5% - 4.0%, 4.0% - 5.0%, 0.5% - 1.0% and 0.1% - 2.0% respectively, and the volume fraction of the accelerator is 0.1% - 0.3%. The methacrylated polysaccharide is methacrylated chitosan; the ionic liquid monomer is 1-allyl-3-methylimidazolium bis(trifluoromethanesulfonyl)imide; the two-dimensional titanium-based conductive material is one or more of titanium nitride, titanium carbide, titanium carbonitride, titanium boride and titanium sulfide. The initiator is one or more of ammonium persulfate, sodium persulfate and potassium persulfate. The accelerator is one or more of tetramethylethylenediamine, triethylamine and diethylamine. The specific preparation steps of the hydrogel are as follows: add methacrylated polysaccharide into deionized water, dissolve it by magnetic stirring, then add the ionic liquid monomer and two-dimensional titanium-based conductive material, add the initiator after ultrasonic treatment, mix well and then add the accelerator, and let it stand at room temperature for polymerization to form the hydrogel.

2. The conductive hydrogel according to claim 1, wherein The mass fractions of methacrylated polysaccharide, ionic liquid monomer, two-dimensional titanium-based conductive material and initiator in the hydrogel are 2.0%, 5.0%, 0.5% - 1.0% and 0.1% - 2.0% respectively, and the volume fraction of the accelerator is 0.1% - 0.3%.

3. The conductive hydrogel according to claim 1, wherein The time of magnetic stirring is 2h - 12h; the rotation speed of magnetic stirring is 500rpm - 2000rpm.

4. The conductive hydrogel according to claim 1, characterized in that, The ultrasonic frequency is 20 kHz - 100 kHz, and the ultrasonic time is 5min - 120min.

5. Use of the hydrogel according to any one of claims 1 - 4 in the preparation of bone tissue regeneration materials.

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