Ultrasound-responsive piezoelectric ionic hydrogels and applications thereof

Abstract

The application provides an ultrasonic response piezoelectric ionic hydrogel and application thereof, and the hydrogel is formed by cross-linking and solidification of a precursor solution under ultraviolet irradiation; components of the precursor solution include a photosensitive polymer, an ionic polymer, a photoinitiator and a solvent; the photosensitive polymer includes any one or a combination of at least two of polyether F127 diacrylate, polyhydroxyethyl methacrylate, polyethylene glycol dimethyl acrylate, methacrylated gelatin or methacrylated collagen; and the ionic polymer includes any one or a combination of at least two of epsilon-polylysine, polyethyleneimine hydrochloride, polyallylamine hydrochloride, polyquaternary ammonium salt-10 or cationic guar gum. The application uses ultrasonic waves as an external remote driving signal to non-invasively and painlessly activate the piezoelectric ionic effect of the hydrogel, generate detectable periodic voltage and current signals in the hydrogel, and has excellent treatment effect on acne and infected wound repair.

Description

Technical Field

[0001] This invention belongs to the field of biomaterials technology, specifically relating to an ultrasonically responsive piezoelectric ion hydrogel and its applications. Background Technology

[0002] Acne is a chronic inflammatory skin disease affecting the pilosebaceous unit (pilosebaceous unit) and sebaceous glands, with an extremely high incidence. Its mechanism involves abnormal sebaceous gland secretion and excessive proliferation of microorganisms, primarily Propionibacterium acnes, along with an inflammatory cascade. Moderate to severe cases often result in permanent scarring. Currently, clinical treatment heavily relies on topical or oral antibiotics, but long-term use has led to increasingly serious bacterial resistance, with resistance rates exceeding 50% in many parts of the world. Antibiotic overuse has become a major bottleneck restricting acne treatment. Furthermore, infected wounds are also a challenging clinical problem. Pathogens, such as Staphylococcus aureus, readily form dense biofilm barriers on wound surfaces. Protected by this barrier, bacteria can be thousands of times more resistant to antibiotics than planktonic bacteria, leading to recurrent infections and prolonged healing. Traditional dressings have limited effectiveness against biofilms, and some metallic antibacterial agents are cytotoxic, which can actually hinder the healing process of normal tissue.

[0003] In the treatment of acne and infected skin wounds, in-situ micro-electric field stimulation has been proven to effectively promote tissue repair. However, traditional piezoelectric hydrogels typically rely on doped inorganic piezoelectric ceramic nanoparticles or rigid lattice polymers to achieve polarization-based electrostatic generation. These traditional materials, dependent on electron binding and dipole moment changes, usually have a mechanical modulus far exceeding that of human soft tissue, easily causing foreign body rejection. More importantly, the non-degradable inorganic nanocomponents pose a long-term risk of cumulative toxicity in vivo. In contrast, piezoelectric ionic hydrogels offer a novel passive electrical stimulation mechanism that better suits the moist physiological environment of the human body. As an emerging bioelectrically active material, piezoelectric ionic hydrogels can induce internal ion differential migration through mechanical deformation to generate endogenous electrical signals, achieving passive electromechanical conversion. However, existing piezoelectric ionic hydrogels heavily rely on direct macroscopic physical pressure or stretching for activation. For sensitive facial acne and fragile infected wounds, directly applying mechanical force not only causes severe pain but also leads to secondary tearing and ulceration of the wound and the spread of deep infection, greatly limiting their practical application in the field of dermatology. Ultrasound, as a non-invasive physical intervention method, has excellent tissue penetration. Although existing technologies utilize ultrasound to drive inorganic piezoelectric nanoparticles (such as BaTiO3) for antibacterial purposes, these inorganic nanomaterials have extremely poor biodegradability and pose a risk of long-term cumulative biotoxicity, making it difficult to meet the safety requirements for clinical translation.

[0004] In summary, there is currently a lack of an innovative system that combines the following characteristics: (1) It is composed entirely of biocompatible pure polymers, ensuring excellent in vivo degradation and biosafety; (2) It can remotely and non-invasively activate the piezoelectric ion effect through ultrasound, perfectly avoiding secondary damage caused by direct physical pressure on the affected area; (3) It has the ability to kill deep pathogens specifically without antibiotic mechanisms, and can promote tissue regeneration in conjunction with endogenous micro-electric fields, truly achieving the synergistic repair effect of "first non-invasive sterilization, then targeted healing". Summary of the Invention

[0005] To address the shortcomings of existing technologies, the present invention aims to provide an ultrasound-responsive piezoelectric ion hydrogel and its applications. The present invention utilizes ultrasound as an external remote driving signal to non-invasively and painlessly activate the piezoelectric ion effect of the hydrogel, generating detectable periodic voltage and current signals within the hydrogel, which has excellent therapeutic effects on acne and the repair of infected wounds.

[0006] To achieve this objective, the present invention employs the following technical solution: In a first aspect, the present invention provides an ultrasonically responsive piezoelectric ion hydrogel, wherein the hydrogel is formed by cross-linking and curing a precursor solution under ultraviolet irradiation; The precursor solution comprises a photosensitive polymer, an ionic polymer, a photoinitiator, and a solvent; The photosensitive polymer includes any one or a combination of at least two of the following: polyether F127 diacrylate, polyhydroxyethyl methacrylate, polyethylene glycol dimethacrylate, methacrylamide gelatin, or methacrylamide collagen. The ionic polymer includes any one or a combination of at least two of ε-polylysine, polyethyleneimine hydrochloride, polyallylamine hydrochloride, polyquaternium-10, or cationic guar gum.

[0007] This invention utilizes ultrasound as an external remote driving signal to replace the traditional direct mechanical squeezing method. It can non-invasively and painlessly activate the piezoelectric ion effect of hydrogel, generating detectable periodic voltage and current signals inside the hydrogel, thereby inhibiting bacterial proliferation, promoting skin cell proliferation and migration, and realizing the "sound-electric-chemical" transformation. It has excellent therapeutic effects on acne and infected wound repair.

[0008] This invention is based on the piezoelectric ion effect in a hydrated environment. A three-dimensional cross-linked network containing fixed positive charges undergoes anion migration in response to ultrasound, establishing a transient potential difference within the gel and generating detectable voltage and current signals. This mechanism completely eliminates rigid conductive phases and nanoparticles, exhibiting excellent biocompatibility and high tissue mechanical compatibility. For highly pain-sensitive facial acne and fragile infected wounds, it avoids the severe pain, secondary wound tearing, and spread of deep inflammation caused by direct physical pressure.

[0009] Preferably, the photoinitiator comprises any one or a combination of at least two of 2-hydroxy-4'-(2-hydroxyethoxy)-2-methylphenylacetone, phenyl-2,4,6-trimethylbenzoylphosphinic acid lithium, or 2,2'-azobis(2-methyl-N-(2-hydroxyethyl)propionamide).

[0010] Preferably, the solvent includes water or a phosphate buffer solution.

[0011] Preferably, the concentration of the photosensitive polymer in the precursor solution is 5-30% (w / v).

[0012] The specific point values ​​in the range of 5 to 30 can be 5, 8, 10, 12, 15, 17, 20, 23, 25, 28, or 30, etc.

[0013] Preferably, the concentration of the ionic polymer in the precursor solution is 1-5% (w / v).

[0014] The specific point values ​​from 1 to 5 can be 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, or 5, etc.

[0015] Preferably, the concentration of the photoinitiator in the precursor solution is 0.05~0.5% (w / v).

[0016] The specific point values ​​in the range of 0.05 to 0.5 can be 0.05, 0.1, 0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, or 0.5, etc.

[0017] Preferably, the photosensitive polymer includes poly(hydroxyethyl methacrylate), polyethylene glycol dimethacrylate, and methacrylamide gelatin.

[0018] In this invention, poly(hydroxyethyl methacrylate), polyethylene glycol dimethacrylate, and methacrylamide gelatin have a synergistic effect. Based on the polymer network formed by the three, a transient potential difference is generated under ultrasonic stimulation, which significantly inhibits bacterial proliferation and promotes the proliferation and migration of skin cells.

[0019] Preferably, the mass ratio of poly(hydroxyethyl methacrylate), polyethylene glycol dimethacrylate, and methacrylamide gelatin is (1~10):(1~10):(1~10).

[0020] The specific point value in the first 1~10 can be 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9 or 10, etc.

[0021] The specific point values ​​in the second set of 1 to 10 can be 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, or 10, etc.

[0022] The specific point value in the third range of 1 to 10 can be 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, or 10, etc.

[0023] Preferably, the ionic polymer comprises polyethyleneimine hydrochloride and / or polyallylamine hydrochloride.

[0024] In this invention, polyethyleneimine hydrochloride and polyallylamine hydrochloride are more effective than other ionic polymers. Based on the polymer network formed by them, a transient potential difference is generated under ultrasonic stimulation, which significantly inhibits bacterial proliferation and promotes the proliferation and migration of skin cells.

[0025] Preferably, the wavelength of the ultraviolet light is 320~400 nm, and the irradiation time is 5~60 s.

[0026] The specific point values ​​in the range of 320 to 400 can be 320, 365, 380, or 400, etc.

[0027] The specific point values ​​in the range of 5 to 50 can be 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, or 60, etc.

[0028] Preferably, the hydrogel generates electrical signals through ultrasonic stimulation.

[0029] Preferably, the power density of the ultrasound is 0.05~1.5 W / cm². 2 The frequency is 0.5~2 MHz.

[0030] The specific point values ​​in the range of 0.05 to 1.5 can be 0.05, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, or 1.5, etc.

[0031] The specific point values ​​in the range of 0.5 to 2 can be 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9 or 2, etc.

[0032] Preferably, the power density of the ultrasound is 0.1~1 W / cm². 2 The frequency is 0.8~1.5 MHz.

[0033] The specific point values ​​in the range of 0.1 to 1 can be 0.1, 0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 0.55, 0.6, 0.65, 0.7, 0.75, 0.8, 0.85, 0.9, 0.95, or 1, etc.

[0034] The specific point values ​​in the range of 0.8 to 1.5 can be 0.8, 0.85, 0.9, 0.95, 1, 1.05, 1.1, 1.15, 1.2, 1.25, 1.3, 1.35, 1.4, 1.45, or 1.5, etc.

[0035] Other specific point values ​​within the range of the above values ​​can be selected, and will not be elaborated on here.

[0036] In a second aspect, the present invention provides the use of the hydrogel as described in the first aspect in the preparation of antibacterial agents.

[0037] Thirdly, the present invention provides the use of the hydrogel as described in the first aspect in the preparation of acne inhibitors.

[0038] Fourthly, the present invention provides the use of the hydrogel as described in the first aspect in the preparation of infectious wound dressings.

[0039] Compared with the prior art, the present invention has the following beneficial effects: This invention utilizes ultrasound as an external, remote driving signal, replacing traditional direct mechanical compression. It non-invasively and painlessly activates the piezoelectric ion effect of hydrogels, generating detectable periodic voltage and current signals within the hydrogel. This inhibits bacterial proliferation and promotes skin cell proliferation and migration, achieving a "sound-electro-chemical" transformation. It exhibits excellent therapeutic effects for acne and infected wound repair. Completely eliminating rigid conductive phases and nanoparticles, it boasts excellent biocompatibility and high tissue mechanical compatibility. For facial acne and fragile infected wounds, which are extremely sensitive to pain, it avoids the severe pain, secondary wound tearing, and spread of deep inflammation caused by direct physical compression.

[0040] (1) Ultrasound-driven piezoelectric ion effect: When ultrasound penetrates the skin tissue and acts on the hydrogel, it generates periodic micro-compression-stretching deformation of the hydrogel through acoustic radiation force and micro-acoustic flow. During this deformation process, the fixed positive charge in the gel cannot move, while the free anions undergo differential directional migration under the pressure gradient, generating periodic ion current and voltage signals at the macroscopic level (piezoelectric ion effect).

[0041] (2) Contact antibacterial effect of ionic polymers: High-density cationic segments are electrostatically attracted to the negatively charged cell membrane of bacteria, physically disrupting the integrity of the cell membrane and producing a broad-spectrum antibacterial effect (Staphylococcus aureus, Escherichia coli, Propionibacterium acnes), without producing drug resistance.

[0042] (3) Synergistic effect of sound and electricity in antibacterial treatment: The ultrasonic cavitation effect increases the permeability of bacterial cell membranes, while the microcurrent generated by piezoelectric ions further interferes with the transmembrane potential of bacteria, thus synergistically improving the killing efficiency against stubborn infections and deep bacteria.

[0043] (4) Micro electric field promotes skin cell proliferation and migration: Endogenous micro electric field promotes the migration and proliferation of skin cells (HaCaT cells, HSF cells) through electrochemotaxis, accelerating wound closure and tissue repair. Attached Figure Description

[0044] Figure 1 The graphs show the voltage and current signals generated by the hydrogels prepared in Examples 1-3 under the same ultrasonic parameters. Figure 2 The voltage and current signals generated by the hydrogel prepared in Example 1 under different ultrasonic parameters are shown in the diagram. Figure 3 The tensile and compressive mechanical test diagrams are shown for the hydrogels prepared in Examples 1-3. Figure 4 Scanning electron microscope image of Staphylococcus aureus, Propionibacterium acnes and the ultrasonic-responsive piezoelectric ion hydrogel of Example 1 after co-incubation; Figure 5 This is a wound healing diagram of a full-thickness skin infection model on the back of C57BL / 6 mice treated with ultrasound-responsive piezoelectric ion hydrogel 14 days after the model was created. Figure 6 This is a skin repair image of a C57BL / 6 mouse dorsal acne model after 5 days of treatment with ultrasound-responsive piezoelectric ion hydrogel, as described in Example 1. Detailed Implementation

[0045] To further illustrate the technical means and effects of the present invention, the following describes the technical solution of the present invention in conjunction with preferred embodiments of the present invention. However, the present invention is not limited to the scope of the embodiments.

[0046] Where specific techniques or conditions are not specified in the examples, they shall be performed in accordance with the techniques or conditions described in the literature in this field, or in accordance with the product instructions. Reagents or instruments whose manufacturers are not specified are all conventional products that can be purchased through legitimate channels.

[0047] The sources of materials used in the following specific embodiments are as follows: Example 1 This embodiment provides a hydrogel, the preparation method of which includes: 0.3 g PHEMA, 0.4 g PEGDM, and 0.3 g GelMA were dissolved in 10 mL PBS solution. While stirring continuously, 0.3 g polyethyleneimine hydrochloride was added, and the mixture was stirred at 4°C for 2 h until completely dissolved. Then, 20 mg Irgacure 2959 was added in the dark, and the mixture was stirred for 30 min to obtain a precursor solution (3% ionic polymer concentration). The precursor solution was evacuated to remove internal air bubbles, and then irradiated under a 365 nm UV lamp for 20 s for photocuring to obtain a hydrogel.

[0048] Example 2 This embodiment provides a hydrogel, the preparation method of which includes: 1 g PHEMA, 1 g PEGDM, and 1 g GelMA were dissolved in 10 mL PBS solution. 0.2 g polyethyleneimine hydrochloride was added under continuous stirring, and the mixture was stirred at 4°C for 2 h until completely dissolved. Then, 5 mg LAP was added in the dark, and the mixture was stirred for 30 min to obtain a precursor solution (2% ionic polymer concentration). The precursor solution was evacuated to remove internal air bubbles, and then photocured under a 365 nm UV lamp for 15 s to obtain a hydrogel.

[0049] Example 3 This embodiment provides a hydrogel, the preparation method of which includes: 0.2 g PHEMA, 0.2 g PEGDM, and 0.1 g GelMA were dissolved in 10 mL PBS solution. While stirring continuously, 0.1 g polyethyleneimine hydrochloride was added, and the mixture was stirred at 4°C for 2 h until completely dissolved. Then, 50 mg VA-086 was added in the dark, and the mixture was stirred for 30 min to obtain a precursor solution (1% ionic polymer concentration). The precursor solution was evacuated to remove internal air bubbles, and then photocured under a 365 nm UV lamp for 25 s to obtain a hydrogel.

[0050] Example 4 This embodiment provides a hydrogel that differs from Example 1 only in that PHEMA is not added, and its reduced amount is proportionally allocated to PEGDM and GelMA, while the other raw materials and steps remain unchanged.

[0051] Example 5 This embodiment provides a hydrogel that differs from Example 1 only in that: PEGDM is not added, and its reduced amount is proportionally allocated to PHEMA and GelMA, while the other raw materials and steps remain unchanged.

[0052] Example 6 This embodiment provides a hydrogel that differs from Example 1 only in that: GelMA is not added, and its reduced amount is proportionally allocated to PHEMA and PEGDM, while the other raw materials and steps remain unchanged.

[0053] Example 7 This embodiment provides a hydrogel that differs from Example 1 only in that “GelMA, PHEMA and PEGDM” are replaced with “F127DA” in the same total amount, while the other raw materials and steps remain unchanged.

[0054] Example 8 This embodiment provides a hydrogel that differs from Example 1 only in that "polyethyleneimine hydrochloride" is replaced with an equal amount of "polyallylamine hydrochloride", while the other raw materials and steps remain unchanged.

[0055] Example 9 This embodiment provides a hydrogel that differs from Example 1 only in that "polyethyleneimine hydrochloride" is replaced with an equal amount of "polyquaternium-10", while the other raw materials and steps remain unchanged.

[0056] Example 10 This embodiment provides a hydrogel that differs from Example 1 only in that "polyethyleneimine hydrochloride" is replaced with an equal amount of "cationic guar gum", while the other raw materials and steps remain unchanged.

[0057] Example 11 This embodiment provides a hydrogel that differs from Example 1 only in that "polyethyleneimine hydrochloride" is replaced with an equal amount of "ε-polylysine", while the other raw materials and steps remain unchanged.

[0058] Comparative Example 1 This comparative example provides a hydrogel, the preparation method of which includes: 0.3 g PHEMA, 0.4 g PEGDM, and 0.3 g GelMA were dissolved in 10 mL PBS solution. 20 mg Irgacure 2959 was added in the dark, and the mixture was stirred for 30 min to obtain a precursor solution (0% ionic polymer concentration). The precursor solution was then vacuum-sealed to remove internal air bubbles, and then irradiated under a 365 nm UV lamp for 20 s for photocuring to obtain a hydrogel.

[0059] Test Example 1 The hydrogels prepared in Examples 1-3 were placed under the same ultrasonic parameters (1 MHz; 1 W / cm). 2 To stimulate: such as Figure 1As shown, the hydrogels prepared in Examples 1-3 can all generate stable periodic voltage and current signals. With the increase of ionic polymer concentration (1-3%), the density of fixed positive charge inside the gel increases, and the peak output voltage and current significantly improve.

[0060] Test Example 2 The hydrogel prepared in Example 1 was subjected to different ultrasonic parameters (1 MHz; 0.1 W / cm). 2 0.5 W / cm 2 1 W / cm 2 To stimulate: such as Figure 2 As shown, without any macroscopic physical compression, the peak values ​​of the open-circuit voltage and short-circuit current output by the hydrogel increase stepwise with the increase of ultrasound power. This not only confirms the high efficiency of ultrasound mechanical wave-driven electromechanical conversion, but also proves that ultrasound power can be used as a precise parameter for clinically regulating the intensity of in-situ electrical signals.

[0061] Test Example 3 Tensile and compressive mechanical tests were conducted on the hydrogels (ionic polymer concentration 0-3%) prepared in Examples 1-3 and Comparative Example 1: Figure 3 As shown, each group of hydrogels exhibits certain mechanical properties, but significant differences exist between different formulations. In the compression test, the hydrogel prepared in Example 2 showed the highest compressive stress, while that in Example 3 showed the lowest. In the tensile test, the hydrogel prepared in Example 2 showed the highest tensile strength but lower fracture strain, while the hydrogel prepared in Example 3 showed lower tensile strength but higher fracture strain. The hydrogel prepared in Example 1, on the other hand, demonstrated a good balance between strength and ductility. These results indicate that the mechanical properties of hydrogels can be effectively adjusted by controlling the content of the matrix polymer and the amount of ionic polymer introduced.

[0062] Test Example 4 In vitro antibacterial experiments were conducted against typical pathogens causing skin infections (Staphylococcus aureus and Propionibacterium acnes). (1) Examples 1-11: 5 mL 1×10 6 Add hydrogels (10 mm in diameter and 2 mm in thickness) from Examples 1-11 to CFU / mL bacterial suspension, and incubate at 37°C for 24 h, during which time 1 MHz and 1 W / cm² hydrogels are applied. 2 Ultrasound stimulation for 10 minutes; (2) Blank group: 5 mL 1×10 6 No hydrogel was added to the CFU / mL bacterial culture, and it was incubated at 37°C for 24 h without ultrasonic stimulation. (3) Control group 1: 5 mL 1×10 6The bacterial culture at CFU / mL was incubated at 37°C for 24 h without the addition of hydrogel, during which 1 MHz and 1 W / cm² hydrogel were applied. 2 Ultrasound stimulation for 10 minutes; (4) Control group 2: 5 mL 1×10 6 The hydrogel (10 mm in diameter and 2 mm in thickness) from Example 1 was added to the CFU / mL bacterial culture and incubated at 37°C for 24 h without ultrasonic stimulation. (5) Control group 3: 5 mL 1×10 6 Add the hydrogel (10 mm in diameter and 2 mm in thickness) from Example 1 to the CFU / mL bacterial culture, and incubate at 37°C for 24 h, during which mechanical compression stimulation of 1 N and 1 Hz is applied for 10 min.

[0063] The scanning electron microscope results of the bacteria after 24 hours of incubation are as follows: Figure 4 As shown: In the blank group, the bacterial surfaces were all smooth and plump, and the cell membranes were intact, indicating that simple ultrasonic stimulation could not destroy the bacterial structure. In control group 2, some bacteria showed wrinkling and slight indentation on their surfaces, proving that free cationic segments exerted preliminary physical pull on the bacterial membrane through electrostatic adsorption. In Example 1, the bacteria underwent large-scale rupture, with severe cell membrane perforation and a large amount of intracellular material leaking out, completely destroying the inherent morphology of the bacteria. This microscopic morphology confirms that the piezoelectric ion microcurrent generated by ultrasound drive severely interfered with the transmembrane potential of the bacteria, forming a powerful "sound-electro-chemical" synergistic bactericidal effect with the electrostatic membrane-breaking effect of ionic polymers. It has a broad-spectrum and devastating physical killing effect on both superficial Staphylococcus aureus and deep anaerobic Propionibacterium acnes. The degree of bacterial rupture in control group 3 was much lower than that in Example 1, further confirming the advantages of ultrasonic stimulation over mechanical stimulation.

[0064] Compared to the control group, the antibacterial rates of each treatment were calculated, and the results are shown in Table 1. As shown in Control Group 3, this invention utilizes ultrasound as an external remote driving signal to replace traditional direct mechanical extrusion, resulting in better bacterial inhibition. As shown in Example 7, photosensitive polymers affect the charge distribution in the hydrogel skeleton, thus influencing the bacterial inhibition effect. As shown in Examples 4-6, poly(hydroxyethyl methacrylate), polyethylene glycol dimethacrylate, and methacrylamide gelatin have a synergistic effect; the polymer network formed by these three compounds generates a transient potential difference under ultrasonic stimulation, resulting in better bacterial inhibition. As shown in Examples 8-11, polyethyleneimine hydrochloride and polyallylamine hydrochloride exhibit better bacterial inhibition effects compared to other ionic polymers.

[0065] Table 1 Test Example 5 In vitro scratch healing experiments were conducted on human immortalized keratinocytes (HaCaT cells) and human skin fibroblasts (HSF cells). The initial cell scratch width was 1 mm. Hydrogels were placed in cell co-incubation chambers, and cell migration rate was calculated based on scratch width after 48 h. (1) Examples 1-11: Hydrogels (10 mm in diameter and 2 mm in thickness) from Examples 1-11 were added to the cell scratch model and incubated at 37°C for 48 h, during which time 1 MHz and 1 W / cm² were applied. 2 Ultrasound stimulation for 10 minutes; (2) Blank group: No hydrogel was added to the cell scratch model, and the cells were incubated at 37°C for 48 h without ultrasonic stimulation; (3) Control group 1: No hydrogel was added to the cell scratch model. The cells were incubated at 37°C for 48 h, during which time 1 MHz and 1 W / cm² hydrogel were applied. 2 Ultrasound stimulation for 10 minutes; (4) Control group 2: The hydrogel of Example 1 (10 mm in diameter and 2 mm in thickness) was added to the cell scratch model and incubated at 37°C for 48 h without ultrasonic stimulation; (5) Control group 3: The hydrogel of Example 1 (10 mm in diameter and 2 mm in thickness) was added to the cell scratch model and incubated at 37°C for 48 h, during which mechanical compression stimulation of 1 N and 1 Hz was applied for 10 min.

[0066] Compared to the control group, the cell migration rates under each treatment were calculated, and the results are shown in Table 2. Control groups 1 and 2 show that simply applying ultrasound or hydrogel materials is insufficient to maximize cell activation. Only the piezoelectric ion micro-field converted from the micromechanical force of ultrasound can strongly activate the directional migration and proliferation network of epidermal and dermal cells through electrochemipulative effects. Control group 3 shows that this invention utilizes ultrasound as an external remote driving signal to replace traditional direct mechanical extrusion, resulting in a better cell migration-promoting effect. Example 7 shows that photosensitive polymers affect the charge distribution in the hydrogel framework, thus affecting the cell migration-promoting effect. Examples 4-6 show that poly(hydroxyethyl methacrylate), polyethylene glycol dimethacrylate, and methacrylamide gelatin have a synergistic effect. Based on the polymer network formed by these three substances, a transient potential difference is generated under ultrasound stimulation, resulting in a better cell migration-promoting effect. Examples 8-11 show that polyethyleneimine hydrochloride and polyallylamine hydrochloride promote cell migration better than other ionic polymers.

[0067] Table 2 Test Example 6 A full-thickness skin infection model was established on the back of BALB / c mice. A circular full-thickness skin wound with a diameter of approximately 1 cm was prepared on the back of the mice, and Staphylococcus aureus (1×10⁻⁶) was inoculated into the wound. 8 Establish an infection model using CFU / animal: (1) Example 1: Apply hydrogel of Example 1 (10 mm in diameter and 2 mm in thickness) above the wound, and apply 1 MHz, 1 W / cm² solution daily. 2 Ultrasound stimulation for 10 minutes; (2) Blank group: No hydrogel was applied above the wound, and no ultrasound stimulation was applied; (3) Control group 2: Hydrogel of Example 1 (10 mm in diameter and 2 mm in thickness) was applied over the wound, and no ultrasound stimulation was applied; (4) Control group 3: The hydrogel of Example 1 (10 mm in diameter and 2 mm in thickness) was applied above the wound and mechanical compression stimulation of 1N and 1 Hz was applied for 10 min daily.

[0068] Wound healing was evaluated at 1, 3, 7, and 14 days later, and the results were as follows: Figure 5 It can be seen that, compared with the traditional mechanical stimulation of control group 3, the wound healing rate of Example 1 is higher and the newly formed epithelium is smooth and intact. The wound of control group 2 still shows obvious scab formation and delayed inflammation, which confirms the powerful synergistic regeneration effect of the piezoelectric ion current excited by ultrasound microstrain and the physical membrane destruction by cations.

[0069] Test Example 7 BALB / c mice were subcutaneously injected with Propionibacterium acnes (1×10⁻⁶) on their backs. 8 Establish an acne model using CFU / unit: (1) Example 1: Apply the hydrogel of Example 1 (10 mm in diameter and 2 mm in thickness) to the acne area, and apply 1 MHz, 1 W / cm² solution daily. 2 Ultrasound stimulation for 10 minutes; (2) Blank group: No hydrogel was applied to the acne area, and no ultrasound stimulation was applied; (3) Control group 2: Hydrogel of Example 1 (10 mm in diameter and 2 mm in thickness) was applied to the acne area, and no ultrasonic stimulation was applied; (4) Control group 3: The hydrogel of Example 1 (10 mm in diameter and 2 mm in thickness) was applied to the acne area and mechanical compression stimulation of 1 N and 1 Hz was applied for 10 min daily.

[0070] Skin repair was evaluated after 1 day, 3 days, and 7 days, and the results were as follows: Figure 6It can be seen that, compared with the traditional mechanical stimulation of control group 3, the area of ​​redness and swelling on the back of the mice in Example 1 was drastically reduced, the macroscopic inflammatory nodules and redness and swelling symptoms were almost completely subsided, and the skin appearance was basically restored to normal. This not only suggests that the ultrasound-driven "sound-electric" effect can effectively penetrate the epidermal barrier and directly target deep pathogens, but also proves that this synergistic therapy can effectively cut off the inflammatory cascade of acne within a very short 5-day cycle, and has excellent rapid repair capabilities.

[0071] In addition, after the treatment cycle, heart, liver, spleen, lung, and kidney organs of mice were extracted for blinded HE staining analysis. The results showed that no pathological abnormalities were observed in the organ tissue sections of all treatment groups, and no systemic toxicity characteristics such as microvascular congestion, necrosis, or fibrosis were observed. This confirms that the all-polymer piezoelectric ion hydrogel system has high safety in vivo metabolism.

[0072] This invention illustrates an ultrasonically responsive piezoelectric ionic hydrogel and its applications through the above embodiments. However, this invention is not limited to the above embodiments, meaning that this invention does not necessarily rely on the above embodiments for implementation. Those skilled in the art should understand that any improvements to this invention, equivalent substitutions of the raw materials in the product of this invention, additions of auxiliary components, and selection of specific methods, all fall within the protection and disclosure scope of this invention.

[0073] The preferred embodiments of the present invention have been described in detail above. However, the present invention is not limited to the specific details in the above embodiments. Within the scope of the technical concept of the present invention, various simple modifications can be made to the technical solution of the present invention, and these simple modifications all fall within the protection scope of the present invention.

[0074] It should also be noted that the various specific technical features described in the above specific embodiments can be combined in any suitable manner without contradiction. In order to avoid unnecessary repetition, the present invention will not describe the various possible combinations separately.

Claims

1. An ultrasonically responsive piezoelectric ionic hydrogel, characterized in that, The hydrogel is formed by cross-linking and curing of a precursor solution under ultraviolet irradiation; The precursor solution comprises a photosensitive polymer, an ionic polymer, a photoinitiator, and a solvent; The photosensitive polymer includes any one or a combination of at least two of the following: polyether F127 diacrylate, polyhydroxyethyl methacrylate, polyethylene glycol dimethacrylate, methacrylamide gelatin, or methacrylamide collagen. The ionic polymer includes any one or a combination of at least two of ε-polylysine, polyethyleneimine hydrochloride, polyallylamine hydrochloride, polyquaternium-10, or cationic guar gum.

2. The hydrogel according to claim 1, characterized in that, The photoinitiator includes any one or a combination of at least two of 2-hydroxy-4'-(2-hydroxyethoxy)-2-methylphenylacetone, phenyl-2,4,6-trimethylbenzoylphosphine lithium, or 2,2'-azobis(2-methyl-N-(2-hydroxyethyl)propionamide); Preferably, the solvent includes water or a phosphate buffer solution.

3. The hydrogel according to claim 1 or 2, characterized in that, The concentration of the photosensitive polymer in the precursor solution is 5-30% (w / v); Preferably, the concentration of the ionic polymer in the precursor solution is 1-5% (w / v); Preferably, the concentration of the photoinitiator in the precursor solution is 0.05~0.5% (w / v).

4. The hydrogel according to any one of claims 1 to 3, characterized in that, The photosensitive polymers include polyhydroxyethyl methacrylate, polyethylene glycol dimethacrylate, and methacrylamide gelatin. Preferably, the mass ratio of poly(hydroxyethyl methacrylate), polyethylene glycol dimethacrylate, and methacrylamide gelatin is (1~10):(1~10):(1~10).

5. The hydrogel according to any one of claims 1 to 4, characterized in that, The ionic polymers include polyethyleneimine hydrochloride and / or polyallylamine hydrochloride.

6. The hydrogel according to any one of claims 1 to 5, characterized in that, The wavelength of the ultraviolet light is 320~400 nm, and the irradiation time is 5~60 s.

7. The hydrogel according to any one of claims 1 to 6, characterized in that, The hydrogel generates electrical signals through ultrasonic stimulation; Preferably, the power density of the ultrasound is 0.05~1.5 W / cm². 2 The frequency is 0.5~2 MHz.

8. The use of the hydrogel according to any one of claims 1 to 7 in the preparation of antibacterial agents.

9. The use of the hydrogel according to any one of claims 1 to 7 in the preparation of acne inhibitors.

10. The use of the hydrogel according to any one of claims 1 to 7 in the preparation of infectious wound dressings.

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