Injection for producing radio stimulation and controlled release of NO and method for preparing the same

Abstract

The application discloses an injection for generating radio stimulation and controllable release of NO and a preparation method thereof, and comprises the following steps: dispersing piezoelectric nanoparticles in a Tris-HCl buffer solution, adding dopamine hydrochloride to perform a polymerization reaction, forming a polydopamine coating on the surface of the piezoelectric nanoparticles, and obtaining piezoelectric nanoparticles modified by polydopamine; adding an ultrasonic response nitric oxide donor solution, and obtaining piezoelectric nanoparticles modified by the nitric oxide donor after reaction; dispersing the piezoelectric nanoparticles modified by the nitric oxide donor in an injectable hydrogel carrier solution, and obtaining the injection for generating radio stimulation and controllable release of NO. The application modifies the nitric oxide donor on the surface of the piezoelectric nanoparticles based on the polydopamine coating, disperses the piezoelectric nanoparticles in the injectable hydrogel carrier solution, and synchronously generates a local electric field and controllable release of nitric oxide through non-invasive ultrasonic wireless driving, thereby synchronously realizing a double treatment function and synergistically promoting tissue repair.

Description

Technical Field

[0001] This invention relates to the field of biomedical technology, specifically to an injectable agent that generates radio stimulation and controlled release of NO, and its preparation method. Background Technology

[0002] Cardiovascular diseases (such as myocardial infarction and heart failure) and skin lesions (such as radiation ulcers and chronic wounds) are common and difficult-to-treat diseases in clinical practice. Their pathological mechanisms are complex and often accompanied by multiple problems such as electrophysiological disorders, excessive inflammatory response, and impaired angiogenesis. Traditional treatment methods such as drug therapy and surgical repair are difficult to improve multiple pathological aspects simultaneously, and their efficacy is limited.

[0003] Electrical stimulation, as a physical therapy method, can regulate cell proliferation, migration, and electrophysiological functions, showing great potential in cardiac repair and wound healing. However, traditional electrical stimulation relies on invasive electrode implantation, which can easily cause complications such as infection and tissue damage. In addition, the equipment is inconvenient to carry, seriously affecting the patient's quality of life.

[0004] Nitric oxide (NO) is a key signaling molecule that has the effects of dilating blood vessels, inhibiting inflammation, and promoting tissue repair. However, nitric oxide has a short half-life and is easily diffused. The release of traditional nitric oxide donors is uncontrollable, resulting in poor treatment effects and the risk of systemic side effects.

[0005] Injectable hydrogels, with their excellent tissue compatibility and minimally invasive therapeutic capabilities, have become an ideal choice for local drug delivery and cell carriers. However, existing injectable hydrogels lack the ability to simultaneously achieve electrical stimulation and controlled release of bioactive molecules, making it difficult to meet the repair needs of complex injury microenvironments.

[0006] Therefore, developing a non-invasive injectable hydrogel that simultaneously achieves radiofrequency stimulation and controlled release of nitric oxide is of great significance for improving the therapeutic effects of cardiac and skin injuries. Summary of the Invention

[0007] To address the shortcomings of existing technologies, this invention provides an injectable agent that generates radio stimulation and controls the release of nitric oxide, along with its preparation method. Based on a polydopamine coating, a nitric oxide donor is modified onto the surface of piezoelectric nanoparticles and dispersed in an injectable hydrogel carrier solution. Through non-invasive ultrasonic wireless driving, a local electric field can be generated simultaneously and nitric oxide can be released in a controlled manner, achieving dual therapeutic functions and synergistically promoting tissue repair.

[0008] To address the aforementioned technical problems, the first aspect of this invention provides a method for preparing an injectable substance that generates radio stimulation and controls the release of NO, comprising the following steps:

[0009] S1. Disperse piezoelectric nanoparticles in Tris-HCl (tris(hydroxymethyl)aminomethane) buffer solution, add dopamine hydrochloride to carry out polymerization reaction, form polydopamine coating on the surface of piezoelectric nanoparticles, and obtain polydopamine-modified piezoelectric nanoparticles.

[0010] S2. The polydopamine-modified piezoelectric nanoparticles are mixed with an ultrasonically responsive nitric oxide donor solution, and after the reaction, nitric oxide donor-modified piezoelectric nanoparticles are obtained.

[0011] S3. Disperse the nitric oxide donor-modified piezoelectric nanoparticles in an injectable hydrogel carrier solution to obtain an injectable preparation (injectable hydrogel) that generates radio stimulation and controlled NO release.

[0012] This invention modifies the surface of piezoelectric nanoparticles with nitric oxide donors via non-covalent or covalent bonds mediated by a polydopamine coating, and then disperses them in an injectable hydrogel carrier solution to obtain an injectable hydrogel. Through non-invasive ultrasonic wireless driving, a local electric field can be generated simultaneously and nitric oxide can be released in a controlled manner, thus achieving dual therapeutic functions and synergistically promoting tissue repair.

[0013] Furthermore, the piezoelectric nanoparticles are selected from sodium potassium niobate nanoparticles and / or barium titanate nanoparticles, with a particle size of 200-800 nm. Both types of piezoelectric nanoparticles possess excellent piezoelectric properties and biocompatibility, and can efficiently convert ultrasonic mechanical energy into electrical energy.

[0014] Furthermore, the nitric oxide donor is selected from one or more of N-nitroso-N-cyclohexylaniline (NCPA), S-nitroso-N-acetylpenicillamine (SNAP), diethyl azodicarboxylate, and N,N'-disec-butyl-N,N'-dinitroso-1,4-phenylenediamine (BNN6).

[0015] Furthermore, the injectable hydrogel carrier is selected from fish type I collagen or porcine decellularized matrix. The injectable hydrogel carrier rapidly gels upon ion-induced reaction at physiological temperature (37°C), exhibiting good injectability and tissue adhesion. Preferably, after injection, a further injection of 1 / 9 volume of 10X PBS (10x concentrated phosphate buffer) causes the mixture to rapidly gel in vivo, forming a stable composite hydrogel.

[0016] Furthermore, the mass ratio of the piezoelectric nanoparticles, dopamine hydrochloride, and nitric oxide donor is 1:(0.5-2):(0.01-0.1).

[0017] Furthermore, the concentration of the injectable hydrogel carrier solution is 0.5%-2% (w / v).

[0018] Furthermore, the concentration of the nitric oxide donor-modified piezoelectric nanoparticles dispersed in the injectable hydrogel carrier solution is 5-10 mg / mL.

[0019] Furthermore, a second aspect of the present invention provides an injectable preparation obtained by the preparation method described in the first aspect, which generates radio stimulation and controlled release of NO.

[0020] Furthermore, the injectable agent simultaneously achieves electrical stimulation and controlled NO release under ultrasonic wireless driving conditions. Preferably, the ultrasonic wireless driving parameters are: frequency 100-1000 kHz, voltage 1-10 V, pulse interval 10-30 ms, pulse period 100-3000 pulses, the electrical signal is amplified 80-120 times by a power amplifier before being input to the ultrasonic probe, the ultrasonic probe is positioned 2-8 cm away from the treatment site, stimulation is performed for 10-30 minutes daily, and continuous stimulation is performed for 7-28 days.

[0021] A third party to this invention provides the use of the injectable formulation described in the first aspect in the preparation of remedies for cardiovascular diseases and skin lesions.

[0022] The beneficial effects of this invention are:

[0023] This invention modifies the surface of piezoelectric nanoparticles with nitric oxide donors via non-covalent or covalent bonds mediated by a polydopamine coating, thereby increasing the specific surface area of ​​the nitric oxide donors and thus improving the efficiency of controlled nitric oxide release and the treatment cycle.

[0024] The injectable agent of this invention can simultaneously generate a local electric field and controllably release nitric oxide through non-invasive ultrasound wireless drive. Radio stimulation regulates cell electrophysiological functions and promotes nerve regeneration, while nitric oxide inhibits inflammatory responses and promotes angiogenesis. It synergistically improves the tissue repair microenvironment, achieving dual therapeutic functions simultaneously and synergistically promoting tissue repair. It does not require implanted electrodes or other devices, avoiding the infection risks and portability problems of traditional treatments, and is well tolerated by patients.

[0025] The piezoelectric nanoparticles and injectable hydrogel carriers of this invention are both non-biotoxic and do not cause significant organ damage after implantation in vivo, demonstrating high biosafety. The injectable form is suitable for minimally invasive injection at irregular injury sites and can be applied to the treatment of heart diseases such as myocardial infarction and heart failure, as well as skin diseases such as radiation ulcers and chronic wounds, showing high clinical application value. Attached Figure Description

[0026] To more clearly illustrate the technical solution of the present invention, the drawings used in the embodiments will be briefly introduced below. Obviously, the drawings described below are only embodiments of the present invention. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0027] Figure 1 This is a SEM image of the potassium sodium niobate nanoparticles obtained in Example 1 of the present invention;

[0028] Figure 2 This is a SEM image of the barium titanate nanoparticles obtained in Example 2 of the present invention;

[0029] Figure 3 This is Test Example 1 of the present invention, which describes the piezoelectric performance test characterization.

[0030] Figure 4 This is a comparison graph of the voltage output of different piezoelectric nanoparticles in Test Example 2 of the present invention;

[0031] Figure 5 This is the result of the nitric oxide release test in Test Example 3 of the present invention;

[0032] Figure 6 These are representative echocardiogram images of mice with myocardial infarction, Test Example 4 of this invention, 28 days after surgery;

[0033] Figure 7 This is a comparison chart of left ventricular ejection fraction and left ventricular fractional shortening rate on days 3, 7, and 28 after surgery in mice with myocardial infarction, as shown in Test Example 4 of this invention.

[0034] Figure 8 This is an immunofluorescence staining image of α-smooth muscle actin in the myocardial tissue of a mouse with myocardial infarction on day 28, which is test example 4 of the present invention.

[0035] Figure 9 yes Figure 8 Bar chart comparing neovascularization parameters among different groups; data are expressed as mean ± standard deviation, *p < 0.05, ***p < 0.001;

[0036] Figure 10 The images and ulcer scores of mice with radiation ulcers (Test Example 5 of this invention) at 5, 10, 15, and 20 days after treatment are shown in the figure. Data are expressed as mean ± standard deviation, ***p < 0.001.

[0037] Figure 11 This is a Masson staining image of skin tissue from a radiation-induced ulcer mouse, Test Example 5 of the present invention, 21 days after treatment;

[0038] Figure 12 yes Figure 11 Bar chart comparing the positive areas of *Pseudomonas aeruginosa* staining; data are expressed as mean ± standard deviation, *p < 0.05, **p < 0.01;

[0039] Figure 13 This is a schematic diagram of the preparation method of Embodiment 3 of the present invention. Detailed Implementation

[0040] The technical solution of the present invention will be clearly and completely described below with reference to specific embodiments. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0041] Example 1

[0042] This embodiment relates to a method for preparing potassium sodium niobate nanoparticles, comprising the following steps:

[0043] Niobium pentoxide (13.29 g), KCl (37.275 g), and K2CO3 (3.45 g) were mixed and ground, calcined at 1000℃ for 3 h, and then washed and dried after being soaked in 2 M HNO3 to remove impurities. The mixture was then mixed with Na2CO3 (3.35 g), NaCl (0.3 g), KCl (3.35 g), and K2CO3 (0.34 g), calcined at 850℃ for 10 min, washed, centrifuged, and dried at 60℃ for 24 h to obtain sodium potassium niobate nanoparticles. SEM analysis showed that the particle size was 300-600 nm, exhibiting a regular cubic morphology (see Figure 1).

[0044] Example 2

[0045] This embodiment relates to a method for preparing barium titanate nanoparticles, comprising the following steps:

[0046] Tetrabutyl titanate (10 mL) was dissolved in anhydrous ethanol (50 mL), and hydrochloric acid solution (1 mol / L) was slowly added dropwise under stirring to adjust the pH to 3.5, forming a titanium sol. Barium chloride (5 g) was dissolved in deionized water (20 mL) and slowly added to the titanium sol. After stirring for 2 h, the mixture was allowed to gel. The gel was dried at 80 °C for 12 h and calcined at 600 °C for 2 h to obtain barium titanate nanoparticles. SEM analysis showed that the particle size was 350-550 nm, with good crystallinity. Figure 2 .

[0047] Example 3

[0048] This embodiment relates to a method for preparing nitric oxide donor-modified piezoelectric nanoparticles, comprising the following steps:

[0049] Potassium sodium niobate nanoparticles (20 mg) prepared in Example 1 were dispersed in 20 mL of Tris-HCl buffer (10 mM, pH 8.5), and dopamine hydrochloride (20 mg) was added. After sonication for 30 min, the mixture was stirred at room temperature for 12 h. The polydopamine-modified potassium sodium niobate nanoparticles were collected by centrifugation. They were then dispersed in 10 mL of PBS solution, and NCPA (0.2 mg / mL) was added. The mixture was stirred in the dark for 24 h, centrifuged and washed three times, and then lyophilized to obtain potassium sodium niobate nanoparticles modified with an ultrasound-responsive nitric oxide donor. (Refer to Appendix) Figure 13 After subsequent injection, nitric oxide is released by generating an electric field driven by ultrasound.

[0050] Example 4

[0051] The difference between this embodiment and Example 3 is that the potassium sodium niobate nanoparticles prepared in Example 1 are replaced with barium titanate nanoparticles prepared in Example 2, while other steps and parameters remain unchanged, to obtain barium titanate nanoparticles modified with ultrasonically responsive nitric oxide donors.

[0052] Example 5

[0053] This embodiment relates to a method for preparing an injectable substance that generates radio stimulation and controlled release of NO, comprising the following steps:

[0054] The modified sodium potassium niobate nanoparticles obtained in Example 3 were dispersed at (5 mg / mL) in a 1% (w / v) aqueous solution of type I fish collagen to form a homogeneous injectable hydrogel.

[0055] Example 6

[0056] This embodiment relates to a method for preparing an injectable substance that generates radio stimulation and controlled release of NO, comprising the following steps:

[0057] The modified sodium barium titanate nanoparticles obtained in Example 4 were dispersed at (5 mg / mL) in a 1% (w / v) fish type I collagen solution to form a homogeneous injectable hydrogel.

[0058] Example 7

[0059] This embodiment relates to a method for preparing an injectable substance that generates radio stimulation and controlled release of NO, comprising the following steps:

[0060] (1) Referring to Example 3, NCPA was replaced with BNN6 to prepare sodium potassium niobate nanoparticles modified with ultrasonically responsive nitric oxide donors.

[0061] (2) Disperse the sodium potassium niobate nanoparticles modified with ultrasound-responsive nitric oxide donors obtained in step (1) in a 0.5% (w / v) fish collagen solution to prepare an injectable hydrogel.

[0062] Example 8

[0063] This embodiment relates to a method for preparing an injectable substance that generates radio stimulation and controlled release of NO, comprising the following steps:

[0064] Fresh porcine myocardial tissue was collected, the connective tissue was removed, and the tissue was chopped. The tissue was then shaken with 0.5% SDS (sodium dodecyl sulfate) solution at 4°C for 24 h, followed by decalcification with 0.5 M EDTA (ethylenediaminetetraacetic acid) solution at 4°C for 48 h. After repeated freeze-thaw cycles (-80°C / 37°C) three times, the tissue was digested with trypsin for 12 h, the precipitate was collected by centrifugation, and the precipitate was freeze-dried to obtain porcine decellularized matrix powder.

[0065] Porcine decellularized matrix powder was dissolved in deionized water to prepare a 1.5% (w / v, 1.5 g / 100 mL) hydrogel solution. Barium titanate nanoparticles with modified ultrasound-responsive nitric oxide donors (8 mg / mL) prepared in Example 4 were added and stirred evenly to obtain an injectable hydrogel (injection).

[0066] Comparative Example 1

[0067] Compared to Example 7, BNN6 was not modified with piezoelectric particles, and an injectable hydrogel was prepared by directly dispersing BNN6 in equal amounts in a 0.5% (w / v) fish collagen solution.

[0068] Comparative Example 2

[0069] The potassium sodium niobate nanoparticles obtained in Example 1 were dispersed directly in a 1% (w / v) fish type I collagen solution without modification to form a homogeneous injectable hydrogel.

[0070] Comparative Example 3

[0071] The barium titanate nanoparticles obtained in Example 2 were dispersed directly in 1.5% (w / v) porcine decellularized matrix hydrogel without modification to form a homogeneous injectable hydrogel.

[0072] Test Example 1: Piezoelectric Performance Test

[0073] The injectable hydrogel obtained in Example 5 was placed in a silicon mold, and an ultrasonic probe was placed 2 cm above the gel. The input voltage was 5V, 10V, and 15V peak-to-peak value, with a frequency of 800 kHz, a pulse interval of 10 ms, and a pulse period of 100. The electrical signal was amplified 35 times by a power amplifier before being input to the ultrasonic probe. The voltage signal generated by the hydrogel was recorded using a digital oscilloscope. The results are shown in Figure 3. The voltage generated by the injectable hydrogel was stable at 1.1-1.2 V, which is within the biosafety voltage range and can achieve effective radio stimulation.

[0074] Test Example 2: Comparison of Voltage Output of Different Piezoelectric Nanoparticles

[0075] The injectable hydrogels obtained in Example 5 (sodium potassium niobate) and Example 6 (barium titanate) were tested for voltage output under the same ultrasonic parameters (10Vpp, 800 kHz). The results are shown in Figure 4. The output voltage of the hydrogel modified with sodium potassium niobate nanoparticles in Example 5 was 1.15 ± 0.05 V, and the output voltage of the hydrogel modified with barium titanate nanoparticles in Example 6 was 1.08 ± 0.04 V. Both of them meet the requirements of radio stimulation.

[0076] Test Example 3: Nitric Oxide Release Test

[0077] The injectable hydrogels obtained in Example 7 and Comparative Example 1 were subjected to ultrasound (800 kHz, 10 V, 10 ms pulse, 3000 cycles) for 30 minutes daily, as per reference. Figure 5 In Example 7, BNN6 modification mixed with injectable hydrogel on the surface of nanoparticles still resulted in the detection of nitric oxide release after 28 days; in Comparative Example 1, BNN6 was directly mixed into injectable hydrogel, and no nitric oxide release was detected after 14 days.

[0078] Test Example 4: Treatment Experiment for Myocardial Infarction in Mice

[0079] A mouse model of myocardial infarction was established by permanently ligating the left anterior descending coronary artery. Mice were randomly divided into 5 groups (n=8): sham operation group, myocardial infarction group, myocardial infarction model mice injected only with the piezoelectric nitric oxide donor hydrogel prepared in Example 5, myocardial infarction model mice injected with the injectable piezoelectric hydrogel prepared in Comparative Example 2 + ultrasound stimulation group, and myocardial infarction model mice injected with the piezoelectric nitric oxide donor hydrogel prepared in Example 5 + ultrasound stimulation group. Ultrasound stimulation was performed starting on the second day after surgery, for 10 minutes daily (800 kHz, 10 V, 10 ms pulse, 100 cycles) for 28 consecutive days.

[0080] Echocardiography was performed at 3, 7, 14, and 28 days post-surgery. The results are shown in Figures 6-7. The left ventricular ejection fraction (LVEF) and left ventricular fractional shortening (LVFS) in the piezoelectric nitric oxide donor hydrogel + ultrasound stimulation group were significantly higher than those in other groups. At 28 days, the LVEF reached 56.36 ± 3.48%, significantly better than the myocardial infarction model group (34.76 ± 5.07%). (Reference) Figure 8-9 Immunofluorescence staining of α-smooth muscle actin showed that the density of neovascularization in the infarcted area was significantly increased in the piezoelectric nitric oxide donor hydrogel + ultrasound stimulation group, indicating that the injectable hydrogel can effectively improve cardiac function and inhibit ventricular remodeling in mice with myocardial infarction.

[0081] Test Example 5: Radiation Ulcer Treatment Experiment in Mice

[0082] A mouse radiation-induced ulcer model was established using local irradiation with a 45 Gy electron beam. Mice were randomly divided into 5 groups (n=5): a blank control group (no irradiation), a model control group (radiation-induced ulcer), a group with radiation-induced ulcers injected only with the injectable piezoelectric nitric oxide donor hydrogel prepared in Example 8, a group with radiation-induced ulcers injected with the injectable piezoelectric hydrogel prepared in Comparative Example 3 plus ultrasound stimulation, and a group with radiation-induced ulcers injected with the injectable piezoelectric nitric oxide donor hydrogel prepared in Example 8 plus ultrasound stimulation. The ultrasound stimulation conditions were as follows: starting on the second day after surgery, ultrasound stimulation was performed for 15 minutes daily (800 kHz, 10 V, 10 ms pulse, 3000 cycles) for 21 consecutive days.

[0083] Skin damage scores were recorded at 5, 10, 15, and 20 days post-treatment. The results are shown in Figure 10. The piezoelectric hydrogel + ultrasound group significantly improved skin damage scores, while the piezoelectric nitric oxide hydrogel + ultrasound group further reduced damage scores. (Reference) Figure 11-12 Masson staining showed that collagen deposition in the skin tissue of the KB-US group was uniform and the epidermal thickness returned to normal. DHE staining showed that the level of oxidative stress was significantly reduced, indicating that the injectable hydrogel can effectively promote the healing of radiation ulcers.

[0084] In summary, this invention modifies the surface of piezoelectric nanoparticles with nitric oxide donors via non-covalent or covalent bonds mediated by a polydopamine coating, increasing the specific surface area of ​​the nitric oxide donors and thus improving the efficiency of controlled nitric oxide release and the treatment cycle. The injectable solution, driven wirelessly by non-invasive ultrasound, can simultaneously generate a local electric field and controllably release nitric oxide. Radio stimulation regulates cellular electrophysiological functions and promotes nerve regeneration, while nitric oxide inhibits inflammatory responses and promotes angiogenesis, synergistically improving the tissue repair microenvironment and simultaneously achieving dual therapeutic functions. This synergistically promotes tissue repair without the need for implanted electrodes or other devices, avoiding the infection risks and portability issues of traditional treatments, and resulting in good patient tolerance. Both the piezoelectric nanoparticles and the injectable hydrogel carrier of this invention are non-toxic, causing no significant organ damage after implantation, demonstrating high biocompatibility. The injectable form is suitable for minimally invasive injection at irregular injury sites, and can be applied to the treatment of cardiac diseases such as myocardial infarction and heart failure, as well as skin diseases such as radiation ulcers and chronic wounds, demonstrating high clinical application value.

[0085] The present invention has been described in detail above with reference to specific embodiments and exemplary examples; however, these descriptions should not be construed as limiting the present invention. Those skilled in the art will understand that various equivalent substitutions, modifications, or improvements can be made to the technical solutions and embodiments of the present invention without departing from the spirit and scope of the invention, and all such modifications and improvements fall within the scope of the present invention. The scope of protection of the present invention is defined by the appended claims.

Claims

1. A method for preparing an injectable substance that generates radio stimulation and controlled release of NO, characterized in that, Includes the following steps: S1. Disperse piezoelectric nanoparticles in Tris-HCl buffer, add dopamine hydrochloride to carry out polymerization reaction, form polydopamine coating on the surface of piezoelectric nanoparticles, and collect the polydopamine-modified piezoelectric nanoparticles by centrifugation. S2. The polydopamine-modified piezoelectric nanoparticles are mixed with an ultrasonically responsive nitric oxide donor solution, and after the reaction, nitric oxide donor-modified piezoelectric nanoparticles are obtained. S3. The nitric oxide donor-modified piezoelectric nanoparticles are dispersed in an injectable hydrogel carrier solution to obtain an injectable that generates radio stimulation and controlled NO release.

2. The method for preparing the injectable substance that generates radio stimulation and controlled NO release as described in claim 1, characterized in that, The piezoelectric nanoparticles are selected from potassium sodium niobate nanoparticles and / or barium titanate nanoparticles, with a particle size of 200-800 nm.

3. The method for preparing the injectable substance that generates radio stimulation and controlled NO release as described in claim 1, characterized in that, The nitric oxide donor is selected from one or more of N-nitroso-N-cyclohexylaniline, S-nitroso-N-acetylpenicillamine, diethyl azodicarboxylate, and N,N'-disec-butyl-N,N'-dinitroso-1,4-phenylenediamine.

4. The method for preparing the injectable substance that generates radio stimulation and controlled NO release as described in claim 1, characterized in that, The injectable hydrogel carrier is selected from fish type I collagen or porcine decellularized matrix.

5. The method for preparing the injectable substance that generates radio stimulation and controlled NO release as described in claim 1, characterized in that, The mass ratio of the piezoelectric nanoparticles, dopamine hydrochloride, and nitric oxide donor is 1:(0.5-2):(0.01-0.1).

6. The method for preparing the injectable substance that generates radio stimulation and controlled NO release as described in claim 1, characterized in that, The concentration of the injectable hydrogel carrier solution is 0.5%-2% (w / v).

7. The method for preparing the injectable substance that generates radio stimulation and controlled NO release as described in claim 1, characterized in that, The concentration of the nitric oxide donor-modified piezoelectric nanoparticles dispersed in the injectable hydrogel carrier solution is 5-10 mg / mL.

8. An injectable preparation that generates radio stimulation and controlled release of NO, obtained by the preparation method according to any one of claims 1-7.

9. The injectable formulation for generating radio stimulation and controlled NO release as described in claim 8, characterized in that, The injectable solution achieves simultaneous electrical stimulation and controlled NO release under ultrasonic wireless driving conditions.

10. The use of the injectable formulation of claim 8 in the preparation of medicaments for the treatment of cardiovascular diseases and skin lesions.

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