A gel material with high adhesion, antibacterial properties and conductive stability, and preparation method and application thereof

Abstract

A gel material with high adhesion, antibacterial properties and conductive stability, as well as a preparation method and application thereof. The present invention belongs to the field of flexible bioelectronic materials. The purpose of the present invention is to provide a gel material with high adhesion, antibacterial properties and conductive stability, as well as a preparation method and application thereof. The present invention enhances the strength of the gel by introducing borax into the existing three-dimensional network hydrogel structure and multiple dynamic interactions between PVA and borax, and due to the conductivity of the ions, the conductivity of the entire gel after treatment is also significantly improved. The material prepared by the present invention has similar softness to that of tissue, strong adhesion, high antibacterial properties and stable conductivity; and its preparation is simple, the method is controllable, and it is convenient for large-scale and customized production; the raw materials used are convenient and easy to obtain, green and environmentally friendly, and the prepared samples have excellent biocompatibility.

Description

Technical Field

[0001] The present invention belongs to the field of flexible bioelectronic materials, and specifically relates to a gel material with high adhesion and antibacterial properties and conductive stability, and a preparation method and application thereof. Background Art

[0002] In recent years, bioelectronic systems that collect and transmit various physiological signals in different parts of the human body (such as the skin, brain, and heart) have received great attention, especially implantable electronic devices that come into contact with biological tissues and can provide high-performance electronic recording. Existing artificial electronic devices mainly use silicon and metal, and compared with dynamic, soft, and wet tissues, electronic devices exhibit almost opposite properties. The obvious modulus difference poses a major challenge to achieving seamless, conformal connections, and imperfect adhesion can easily lead to tissue damage and scar formation, increase the interface impedance between electronics and target organs, and reduce or completely lose the reliability and accuracy of signal transmission; in addition, for biosensing, it is very important that the surface of implantable bioelectrodes has the ability to prevent the growth and reproduction of harmful bacteria. The colonies on the surface will not only induce infection, but also impair the sensitivity of sensing electrical signals.

[0003] Adhesive hydrogels have been widely studied and explored in bioelectronics. They have strong and stable adhesion to highly deformed tissues, which meets the basic conditions for electronic devices to effectively capture and transmit signals. Although a lot of efforts have been made to design multifunctional adhesive hydrogels to meet bioelectronic applications, it still needs to overcome many obstacles, such as the difficulty in achieving combined properties including conductivity, antibacterial properties, and high transparency, which are usually mutually exclusive. The development and research of flexible bioelectronic materials with comprehensive performance that meet practical applications remains a long-standing and urgent problem. Therefore, it is urgent and necessary to develop a flexible bioelectronic material that can simultaneously achieve a modulus that matches the tissue, high adhesion to the tissue, and can resist external environmental factors such as dryness, cold and bacteria, while maintaining high-quality physiological signal collection capabilities.

[0004] Polyvinyl alcohol (PVA) has excellent biocompatibility, non-toxicity and water solubility, making it easy to make into hydrogels. Currently, existing PVA hydrogels with high adhesion and conductivity are usually made by directly mixing polyvinyl alcohol and borax solution, and relying on the dynamic borate bonds formed between the two to form a gel product. Due to the presence of hydroxyl groups on the PVA chain, it is very sensitive to borax and will cross-link quickly. At the same time, borax provides boric acid and tetrahydroxyborate ions after hydrolysis. The tetrahydroxyborate ions react with the nucleophilic diols of PVA to cause reversible cross-linking. However, this method has the following disadvantages: 1) Directly adding borax to the PVA solution will immediately form a white gel that cannot be dissolved even if stirred continuously for 24 hours (see Figure 1a). 2) If the amount of borax added is reduced, although the white gel will gradually redissolve in the solution under continuous stirring, if the amount of borax added is too small (only 5.8x10 -2 wt%), the weak mechanical properties and stability of the borax are minimal and the effect of borax cannot be exerted (see Figure 1 b). Therefore, the existing method of directly adding borax solution into PVA has difficult-to-control reversible crosslinking and often requires long-term stirring, which limits its further application and makes industrial production impossible. Summary of the invention

[0005] In order to solve the above technical problems, the present invention provides a gel material having both high adhesion and antibacterial properties and conductive stability, and a preparation method and application thereof.

[0006] One of the purposes of the present invention is to provide a method for preparing a gel material having both high adhesion and antibacterial properties and conductive stability, the preparation method being carried out according to the following steps:

[0007] The hydrogel with a three-dimensional network is immersed in a borax solution for 4-6 times for a total immersion time of 24-48 hours, and then placed in an oven at 25° C. until the thickness recovers to the initial hydrogel thickness.

[0008] It is further defined that the concentration of the borax solution is 0.08-0.12 mol / L.

[0009] Further defined, the preparation method of the hydrogel having a three-dimensional network is as follows:

[0010] S1: adding acrylic acid and acrylic acid-N-succinimidyl ester to a glycerol / water co-solvent, and then adding a polyvinyl alcohol solution to obtain a mixed solution;

[0011] S2: Add BIS and α-ketoglutaric acid to the mixed solution, and obtain a hydrogel with a three-dimensional network through UV-induced polymerization.

[0012] It is further defined that the mass ratio of acrylic acid to acrylic acid-N-succinimidyl ester in S1 is (10-18):1.

[0013] It is further defined that the mass ratio of glycerol to water in the glycerol / water co-solvent in S1 is (0.5-2):1.

[0014] It is further defined that the mass ratio of acrylic acid to glycerol / water co-solvent in S1 is (0.3-0.5):1.

[0015] It is further defined that the concentration of the polyvinyl alcohol solution in S1 is 10-20 wt %.

[0016] It is further defined that the mass ratio of polyvinyl alcohol in S1 to water in the glycerol / water co-solvent is (0.15-1):1.

[0017] It is further defined that the mass of BIS in S2 is 0.09-0.13% of the total mass of acrylic acid and N-succinimidyl acrylate.

[0018] It is further defined that the mass of α-ketoglutaric acid in S2 is 0.3-0.46% of the total mass of acrylic acid and N-succinimidyl acrylate.

[0019] It is further defined that the UV-induced polymerization in S2 is 5-25 min.

[0020] Further defined, S2 also includes washing the obtained hydrogel to remove some unpolymerized monomers, and then placing it in an oven at 25° C. for 4-8 hours to remove moisture introduced by washing.

[0021] The second object of the present invention is to provide a gel material prepared by the above preparation method which has both high adhesion and antibacterial properties and conductive stability.

[0022] It is further defined that the wet adhesion strength of the gel material is ≥ 70 kPa, the antibacterial rate is as high as 99.9%, and the conductivity change rate after 90 days is less than 0.01%.

[0023] The third object of the present invention is to provide a gel material prepared by the above-mentioned preparation method, which has both high adhesion and antibacterial properties and conductive stability and is applied in the field of human health monitoring and neuromodulation.

[0024] A fourth object of the present invention is to provide a flexible epidermal sensor, which is made of the above-mentioned gel material with high adhesion and antibacterial properties and conductive stability.

[0025] A fifth object of the present invention is to provide a bioelectrode, which comprises the above-mentioned gel material having both high adhesion and antibacterial properties and conductive stability.

[0026] Compared with the prior art, the present invention has the following significant effects:

[0027] The adhesive antibacterial flexible bioelectronic device material prepared by the present invention has similar softness to tissue, strong adhesion, high antibacterial property and stable conductivity, and has the following specific advantages:

[0028] (1) The present invention uses preformed PVA gel as raw material and utilizes the swelling properties of the gel to introduce borax into the hydrogel network, which not only avoids the problem of uncontrollable gelation of PVA and borax, but also enhances the gel strength after treatment through multiple dynamic interactions between PVA and borax. In addition, the ions produced by the hydrolysis of borax also significantly improve the overall conductivity of the hydrogel after treatment.

[0029] (2) The preparation of the present invention is simple, the method is controllable, and it is convenient for large-scale and customized production; the raw materials used are easily available, green and environmentally friendly, and the prepared samples have excellent biocompatibility.

[0030] (3) The excellent wet tissue adhesion strength of the gel material of the present invention is mainly attributed to the covalent and / or non-covalent reactions between the hydrogel and various matrices. Specifically, once the hydrogel comes into contact with the wet tissue, the hydration barrier is adsorbed and removed by many hydrophilic groups within a few seconds, while the internal hydrogel almost maintains its original state. At the same time, a physical interaction is formed between the hydrogel and the tissue surface, which has the effect of instant adhesion. As the adhesion time increases, the amide bond between the NHS of polyacrylic acid-N-succinimidyl ester and the amine group on the tissue surface forms a covalent crosslink, thereby providing stable and firm adhesion. Inside the hydrogel, the covalent crosslinking network between the tissue surface and the hydrogel effectively transmits stress, and there are a large number of dynamic non-covalent interactions (such as: PVA and borax) and physical entanglements (such as: PVA-PVA) inside the hydrogel as energy dissipation phases, and the two interact with each other, so that the overall adhesion strength increases.

[0031] (4) The human epidermal sensor prepared by the present invention can monitor human movement in real time and give corresponding feedback, and has high sensitivity, rapid response and signal reliability; in addition, the bioelectrode assembled based on the present invention achieves efficient neuromodulation under low current stimulation of the sciatic nerve of mice. In summary, the present invention demonstrates its application prospects in the fields of human health monitoring, tissue engineering and bioelectrodes. BRIEF DESCRIPTION OF THE DRAWINGS

[0032] Figure 1 ab are photos of PVA directly adding borax in the background technology;

[0033] Figure 2 This is an example diagram of a gel material with high adhesion, antibacterial properties and conductive stability obtained in an embodiment of the present invention stretched 10 times its original length;

[0034] Figure 3 This is a diagram showing the adhesion effect of the gel material with high adhesion and antibacterial properties and conductive stability on different materials, which is prepared in an embodiment of the present invention;

[0035] Figure 4This is an electron microscope image of the adhesion interface between the gel material with high adhesion and antibacterial properties and conductive stability and wet pig skin prepared in an embodiment of the present invention;

[0036] Figure 5 This is a graph showing the adhesion performance test results of the gel material with high adhesion, antibacterial properties and conductive stability prepared in an embodiment of the present invention;

[0037] Figure 6a This is a graph showing the antibacterial performance of a gel material having high adhesion, antibacterial properties, and conductive stability, prepared in an embodiment of the present invention;

[0038] Figure 6b This is a graph showing the antibacterial performance of the hydrogel obtained in Example S2 of the present invention;

[0039] Figure 7 This is a graph showing the change in conductivity of the gel material having high adhesion and antibacterial properties and conductive stability prepared in an embodiment of the present invention;

[0040] Figure 8 This is a graph showing the test results of the biocompatibility of the gel material with high adhesion and antibacterial properties and conductive stability prepared in an embodiment of the present invention;

[0041] Fig. 9 This is a graph showing the response time of a gel material with high adhesion and antibacterial properties and conductive stability prepared in an embodiment of the present invention as an epidermal strain sensor;

[0042] Fig.10 This is a graph showing the test results of the strain sensing performance of the gel material with high adhesion, antibacterial properties and conductive stability prepared in an embodiment of the present invention;

[0043] Fig.11 This is a graph showing the electrical stimulation response when the gel material with high adhesion and antibacterial properties and conductive stability prepared in an embodiment of the present invention is used as a bioelectrode. DETAILED DESCRIPTION

[0044] In order to make the purpose, technical solution and advantages of the present invention more clearly understood, the present invention is further described in detail below in conjunction with the embodiments. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not used to limit the present invention.

[0045] The experimental methods used in the following examples are conventional methods unless otherwise specified. The materials, reagents, methods and instruments used are conventional materials, reagents, methods and instruments in the art unless otherwise specified, and can be obtained through commercial channels by those skilled in the art.

[0046] The terms "comprising," "including," "having," "containing," or any other variations thereof, as used in the following examples, are intended to cover a non-exclusive inclusion. For example, a composition, step, method, article, or apparatus comprising the listed elements is not necessarily limited to only those elements, but may include other elements not expressly listed or inherent to such composition, step, method, article, or apparatus.

[0047] When equivalent, concentration or other value or parameter is represented by the range limited by range, preferred range or a series of upper preferred value and lower preferred value, this should be understood as specifically disclosing all ranges formed by any pairing of any upper range limit or preferred value and any lower range limit or preferred value, regardless of whether the scope is disclosed separately. For example, when disclosing range "1 to 5", described range should be interpreted as including range "1 to 4", "1 to 3", "1 to 2", "1 to 2 and 4 to 5", "1 to 3 and 5" etc. When numerical range is described in this article, unless otherwise stated, the scope is intended to include its end value and all integers and fractions within the scope. In the present application specification and claims, range limitation can be combined and / or interchanged, if these ranges are not otherwise stated, include all sub-ranges contained therein.

[0048] The indefinite articles "a" and "an" before the elements or components of the present invention have no limitation on the quantity requirements (i.e. the number of occurrences) of the elements or components. Therefore, "a" or "an" should be interpreted as including one or at least one, and the elements or components in the singular form also include the plural form, unless the quantity obviously refers to the singular form only.

[0049] Example:

[0050] The preparation method of a gel material having high adhesion and antibacterial properties and conductive stability in this embodiment is carried out by the following steps:

[0051] S1: 2.1 g of acrylic acid and 0.15 g of acrylic acid-N-succinimidyl ester were added to 5.52 g of glycerol / water co-solvent (glycerol: water (w:w) = 0.8:1), and then 0.5 mL of a 20 wt % polyvinyl alcohol solution was added, and the mixture was stirred at 40° C. for 10 min to obtain a mixed solution;

[0052] S2: 0.0021 g BIS and 0.008 g α-ketoglutaric acid were added to the mixed solution, and UV-induced polymerization was performed for 15 min to obtain a hydrogel with a thickness of 2 mm and a three-dimensional network. The hydrogel was then washed with deionized water to remove some unpolymerized monomers, and then placed in an oven at 25 ° C for 4 h to remove the moisture introduced by washing.

[0053] S3: The hydrogel with a three-dimensional network obtained in S2 was immersed in a borax solution with a concentration of 0.10 mol / L for a total of 5 times, each time for 5 hours, and the total immersion time was 25 hours. Deionized water was used to rinse between each immersion, and the next immersion was performed after rinsing. After the immersion was completed, it was placed in an oven at 25°C until the thickness recovered to 2 mm, thereby obtaining a gel material with high adhesion, antibacterial properties, and conductive stability.

[0054] Test 1:

[0055] The stretchability of the gel material with high adhesion and antibacterial properties and conductive stability prepared in the example was tested. The sample was stretched to 10 times its length on a universal stretching instrument. The results are as follows: Figure 2 As shown, from Figure 2 It can be seen that it did not break when stretched to 10 times its length, indicating that it has high stretchability and fully meets the requirements of wearable sensors.

[0056] Test 2:

[0057] The adhesion of the gel material with high adhesion antibacterial property and conductive stability prepared in the embodiment was tested, and the results are as follows: Figure 3 As shown, from Figure 3 It can be seen that the gel material with high adhesion and antibacterial properties and conductive stability prepared in the embodiment of the present invention has good adhesion properties for many common engineering materials and biological tissue materials in life.

[0058] Test three:

[0059] Figure 4 This is a cryo-scanning electron micrograph of the adhesion interface between the gel material with high adhesion antibacterial property and conductive stability prepared in the embodiment of the present invention and wet pig skin. Pig skin is used to simulate human tissue (the mechanical and physical properties are similar to those of human skin). Figure 4 It can be seen that the hydrogel-pigskin has seamless adhesion properties, which proves the reliability and effectiveness of the adhesion interface between the gel material with high adhesion antibacterial properties and conductive stability prepared in the embodiment of the present invention and the wet pigskin.

[0060] Test 4:

[0061] Interface shear strength test, the specific test steps are as follows:

[0062] The pig skin was cut into slices with a thickness of 2 mm, and washed with PBS buffer for 3 times. Then, the gel material with high adhesion and antibacterial properties and conductive stability prepared in the embodiment of the present invention was sandwiched between the wet pig skins and pressed for 3 minutes under gentle pressure.

[0063] The mechanical test was carried out in air at a test temperature of 25° C. and a constant tensile speed of 50 mm / min. Three samples in each group (n=3) were used for the adhesion test.

[0064] The results are as follows Figure 5 As shown, from Figure 5 It can be seen that the shear strength between the hydrogel and wet pig skin is 70 KPa, which proves the strong adhesion of the hydrogel to wet tissue.

[0065] Test 5:

[0066] The antibacterial performance is tested, the specific steps are as follows:

[0067] (1) Gram-positive bacteria (Staphylococcus aureus, ATCC6538) and Gram-negative bacteria (Escherichia coli, ATCC8739) were cultured in LB medium at 37°C overnight, the strains were collected by centrifugation, and diluted to 10% with PBS. 5 -10 6 CFU / mL.

[0068] (2) 100 mg of the gel material with high adhesion antibacterial property and conductive stability prepared in the example after UV sterilization and the hydrogel obtained in Example S2 without borax solution soaking were used as the control group. The two were added into a flask containing 10 mL of bacterial suspension, and the flask was placed in a shaking incubator at 37° C. for 4 hours. Then 100 μL of the suspension was taken out and mixed with 20 mL of agar medium. After the medium solidified, the plate was turned over and cultured for 18 hours, and the number of colonies was counted.

[0069] The results are as follows Figure 6a -b. As shown in Figure 6, after 18 hours of culture, many colonies were still formed in the borax-free treatment group, while almost no colonies were seen on the surface of the culture medium of the embodiment of the present invention. It can be seen that the antibacterial rate of the hydrogel against the two colonies is almost 99.99%, indicating the excellent antibacterial properties of the hydrogel.

[0070] Test six:

[0071] Figure 7 The conductivity change bar graph of the gel material with high adhesion and antibacterial properties and conductive stability prepared in the embodiment of the present invention from 0 to 90 days. Figure 7 It can be seen that the gel prepared by the present invention has stable conductivity, and the conductivity change in 90 days is less than 0.01%.

[0072] Test seven:

[0073] Cytotoxicity was tested, the specific steps are as follows:

[0074] (1) Mouse fibroblasts were cultured in DMEM medium (calf serum: sodium pyruvate: glutamine: non-essential amino acids in a ratio of 87:10:1:1:1) and 5% CO 2 , cultured in a 37°C constant temperature incubator.

[0075] (2) Take 20 mg of the gel sample of the present invention, sterilize it in a clean bench by ultraviolet irradiation for 30 min, add 10 ml of complete culture medium, and 5% CO 2 , extract in a 37℃ constant temperature incubator for 24h. After the extraction, take the supernatant and filter it with a 0.22μm filter membrane to sterilize it, and obtain a mother solution with a sample extraction concentration of 20mg / ml. Store it at 4℃ for later use and dilute it with complete culture medium according to the target concentration.

[0076] (3) Take mouse fibroblasts in the logarithmic growth cycle, count the cells, and adjust the cell concentration to 6x10 3 / well were seeded into 96-well plates, 5% CO 2 The cells were cultured overnight in a 37°C constant temperature incubator. No gel was added to the blank control group. After culturing for 24 h, 48 h, and 72 h, the culture medium was removed, each well was washed three times with PBS, and a culture medium containing 10% CCK-8 was added at 100 μL / well. The cells were incubated at 5% CO 2 , cultured in a 37°C constant temperature incubator for 2 hours, and the absorbance value at 450nm was detected by an enzyme marker. The intensity of fluorescence corresponded to the cell growth rate to feedback the cell viability.

[0077] The results are as follows Figure 8 As shown, from Figure 8 It can be seen that the relative cell survival rate of the gel sample group of the embodiment of the present invention on days 1-3 is almost 100%, showing no significant difference from the control group at any time point. It is confirmed that the hydrogel of the embodiment of the present invention has no harmful effect on cell viability and proliferation, meets the cytotoxicity requirements for application in biomaterials, and confirms its excellent biocompatibility.

[0078] Application Example 1: The gel material with high adhesion and antibacterial properties and conductive stability prepared in the embodiment is used as a strain sensor to test its epidermal sensing ability:

[0079] Fig. 9 The response sensitivity of the hydrogel strain sensor of the embodiment of the present invention is represented by its relative resistance change ΔR / R, which is defined as:

[0080] ΔR / R=(RR 0 ) / R 0 100%

[0081] Where R 0 and R is the resistance of the hydrogel before and after deformation.

[0082] Depend on Fig. 9 It can be seen that the hydrogel strain sensor of the embodiment of the present invention has a fast response time (421 ms) and a short recovery time (485 ms), and does not show hysteresis in the test, ensuring its feasibility in practical applications.

[0083] Fig.10 When the sensor is attached to the finger, as the finger bends at different angles (from 0°, 30°, 60° to 90°), the sensor can give corresponding feedback, and the corresponding resistance change also has a certain stability, indicating that the flexible epidermal sensor prepared based on the present invention has high reliability and excellent strain sensing performance.

[0084] Application Example 2: The gel material with high adhesion and antibacterial properties and conductive stability prepared in the embodiment is used as a biological electrode to test its nervous system regulation feedback ability. The specific test process is as follows:

[0085] (1) The ability of the prepared material to regulate feedback in the nervous system in vivo was studied using a rat model. The animals were anesthetized with isoflurane (1% isoflurane in oxygen) in an anesthesia chamber. A skin incision was made on the back of the paw to expose the hind limb muscles. The sciatic nerve was exposed by dissecting the lateral thigh muscles and biceps femoris.

[0086] (2) The gel material prepared in the embodiment was assembled into a composite electrode with a gold electrode, which was then sterilized by ultraviolet light and adhered to the exposed sciatic nerve fibers. Under the stimulation of 40 μA, the ankle joint of the mouse had a large change in movement angle.

[0087] The results are as follows Fig.11 As shown, it can be seen that the gel material prepared in the embodiment of the present invention has the ability to effectively transmit signals as a bioelectronic interface.

[0088] The above are only preferred specific embodiments of the present invention, which are all different implementations based on the overall concept of the present invention, and the protection scope of the present invention is not limited thereto. Any changes or substitutions that can be easily thought of by a person skilled in the art within the technical scope disclosed by the present invention should be included in the protection scope of the present invention. Therefore, the protection scope of the present invention should be based on the protection scope of the claims.

Claims

1. A method for preparing a gel material having both high adhesion and antibacterial properties and conductive stability. It is characterized in that Follow these steps: The hydrogel with a three-dimensional network is immersed in a borax solution for 4-6 times for a total of 24-48 hours, and then placed in a 25°C oven until the thickness is restored to the initial hydrogel thickness. The concentration of the borax solution is 0.1-0.12 mol / L. The antibacterial rate of the obtained gel material is as high as 99.9%, the conductivity change rate is less than 0.01% in 90 days, and the wet adhesion strength is ≥70 kPa; The steps of preparing the hydrogel having a three-dimensional network are as follows: S1: adding acrylic acid and acrylic acid-N-succinimidyl ester to a glycerol / water co-solvent, and then adding a polyvinyl alcohol solution to obtain a mixed solution; the mass ratio of acrylic acid to acrylic acid-N-succinimidyl ester is (10-18):1, the mass ratio of acrylic acid to the glycerol / water co-solvent is (0.3-0.5):1, and the mass ratio of polyvinyl alcohol to water in the glycerol / water co-solvent is (0.15-1):1; S2: BIS and α-ketoglutaric acid are added to the mixed solution, and a hydrogel with a three-dimensional network is obtained by UV-induced polymerization, wherein the mass of BIS is 0.09-0.13% of the total mass of acrylic acid and acrylate-N-succinimidyl ester, and the mass of α-ketoglutaric acid is 0.3-0.46% of the total mass of acrylic acid and acrylate-N-succinimidyl ester.

2. The method according to claim 1, It is characterized in that The mass ratio of glycerol to water in the glycerol / water co-solvent in S1 is (0.5-2):1, and the concentration of the polyvinyl alcohol solution is 10-20wt%.

3. The method according to claim 1, It is characterized in that The polymerization was induced by UV in S2 for 5-25 min.

4. The method according to claim 1, It is characterized in that S2 also includes washing the obtained hydrogel and then placing it in an oven at 25° C. for 4-8 hours.

5. The gel material having high adhesion and antibacterial properties and conductive stability obtained by the method according to claim 1.

6. A flexible epidermal sensor, It is characterized in that It is made of the gel material described in claim 5.

7. A bioelectrode, It is characterized in that It comprises the gel material as claimed in claim 5.

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