Implantable and tissue-adhesive full-hydrogel battery, electrical stimulation device, preparation method and application of electrical stimulation device in heart rate management

Abstract

The invention discloses an implantable and tissue-adhesive full-hydrogel battery, an electrical stimulation device, a preparation method and application of the electrical stimulation device in heart rate management, and belongs to the technical field of functional polymer materials. The method comprises the following steps: coating an anode active material and a cathode active material on the same side surface of the same PSA / PEDOT: PSS conductive hydrogel flexible substrate in parallel to form a hydrogel anode and a hydrogel cathode, and placing the anode and the cathode on the same side surface of the same hydrogel electrolyte to form an ion path; the conductive hydrogel between the anode and the cathode is used as a flexible resistor to form an electronic conductive path, and then the upper surface of the flexible resistor and the lower surface of the hydrogel electrolyte are wrapped by a flexible coating layer to obtain the implantable and tissue adhesion type electrical stimulation device. The current is conducted to myocardial cells from the hydrogel electrolyte in the form of ions, rhythm control is carried out by utilizing bioelectricity generated by the directional ion current, the electrical activity of biological tissues is regulated and controlled, and then a physiological or therapeutic effect is initiated.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of functional polymer materials, and particularly relates to an implantable and tissue-adhesive all-aqueous gel battery and an electric stimulation device, a preparation method and application thereof in heart rate management. BACKGROUND

[0002] Abnormal heart rate (including tachycardia, bradycardia, arrhythmia, etc.) is one of the core manifestations of cardiovascular diseases, which may cause myocardial infarction, heart failure and even sudden death and other fatal complications. Precise heart rate regulation is crucial for maintaining cardiovascular function. Emerging bioelectronic intervention, with electric stimulation as the core, has become an important direction for the treatment of arrhythmia due to its advantages of being safer, more sustainable and more intelligent.

[0003] In the past few decades, the commonly used heart rate management strategy in clinical practice is centered on cardiac implantable electronic devices, including implantable cardiac pacemakers, implantable cardioverter-defibrillators, etc., supplemented by drug therapy and external electric defibrillation. Although drug therapy is convenient to operate, it has the disadvantages of slow onset, large individual differences, long-term use of which may cause drug resistance and liver and kidney function damage; external electric defibrillation equipment is only suitable for emergency rescue scenes and cannot meet the daily management needs of patients with chronic heart rate abnormalities. The traditional cardiac implantable electronic device, as the mainstream solution, can achieve continuous heart rate regulation, but has many technical bottlenecks that are difficult to overcome: first, the cardiac implantable electronic device is usually powered by a rigid battery, which needs to be matched with a separate pacing lead to deliver the stimulation signal, and usually relies on surgical implantation methods such as suture fixation or direct insertion into the heart cavity. This process may cause great risk of myocardial laceration, perforation and bleeding, and may also cause complications such as electrode displacement and lead breakage after surgery; second, the size and rigidity of the device not only limit the patient's freedom of movement and reduce the long-term wearing comfort, but also easily cause adverse immune reactions such as inflammation caused by foreign body rejection.

[0004] As a precise and efficient heart rate control method, electrical stimulation can regulate the activity of ion channels in myocardial cells and improve the balance of autonomic nerves through specific parameters of electrical signals, so as to achieve heart rate correction. It has the advantages of rapid response, small side effects, precise control, etc. and has become a research hotspot in the field of heart rate management. In recent years, implantable and tissue-adhesive electrical stimulation devices have gradually emerged. The core idea is to achieve local electrotherapy through soft mechanical coupling and effective electrical transmission. The bioelectronic device based on tissue-mimicking hydrogel is expected to realize seamless fixation through the bio-hydrogel interface (adhesion strength up to 50 kPa) by matching the mechanical modulus of the heart tissue (about 10 kPa), significantly reducing the foreign body reaction while ensuring long-term function in the physiological environment. Although there are studies introducing battery-driven electronic rhythm management solutions (such as micro-soft lithium-ion droplet batteries for tissue stimulation and millimeter MG-MoO3 batteries for temporary cardiac pacing), it is still a core challenge to achieve reliable and long-term integration with the dynamic contracting heart tissue in the body. The existing hydrogel-based devices have poor stability in multi-layer interfaces (hydrogel cathode, electrolyte, anode connection), are prone to performance degradation and impedance fluctuations, leading to unpredictable stimulation parameters, and have not achieved the combination of lead-free, non-invasive, and bioadhesion, tissue-like properties, making it difficult to meet the dual needs of safety and long-term in clinical practice. Therefore, developing flexible bioadhesive electrical stimulation devices with high output stability, dynamic mechanical compliance, immunocompatibility, and self-powered ability has become a key direction to break through the limitations of existing heart rate management technology.

[0005] In view of the above problems, we describe in this application an implantable and tissue-adhesive all-hydrogel battery for heart rate management. The innovation of adhesive hydrogel material provides an ideal solution for this demand. The new dynamic supramolecular hydrogel (such as poly(acrylic acid) / [2-(methacryloyloxy)ethyl]dimethyl-(3-sulfopropyl)ammonium hydroxide / N-hydroxysuccinimidyl acrylate (PSA) hydrogel) not only has similar mechanical flexibility and water content to human soft tissue, but also realizes strong adhesion of the electrode-electrolyte (adhesion energy > 200 J m⁻²), which can be seamlessly integrated with biological tissue and directly attached to the myocardium without surgical fixation, avoiding secondary damage; its porous structure can absorb tissue exudate, maintain a local moist microenvironment, reduce signal attenuation at the electrode-tissue interface, and good biocompatibility can significantly inhibit the immune response; by introducing poly(3,4-ethylenedioxythiophene)-poly(styrenesulfonate) (PEDOT:PSS) into the new dynamic supramolecular hydrogel PSA to improve electronic conductivity, combined with an active carbon cathode and a nano-zinc sheet anode, and an electrolyte containing zinc salt (Zn(OTf3)2), an implantable and tissue-adhesive all-hydrogel battery (HZB) can be constructed. The implantable and tissue-adhesive all-hydrogel battery (HZB) formed by the present application can provide stable in vivo voltage output (0.90~1.17V) for up to 14 days, and the discharge of the battery can enhance myocardial cell contraction and promote cell junction protein expression, achieving low-energy defibrillation and rapid pacing, and enabling an in vitro rat heart to restore sinus rhythm within 5~10 seconds during arrhythmia. SUMMARY

[0006] The purpose of the present application is to provide an implantable and tissue-adhesive all-hydrogel battery and an electrical stimulation device, a preparation method and its application in heart rate management. The present application first prepares a PSA adhesive hydrogel precursor solution and a PSA / PEDOT:PSS conductive hydrogel, then uses the PSA / PEDOT:PSS conductive hydrogel as the hydrogel base of the bio-battery, and casts the anhydrous ethanol dispersion containing zinc nanosheets and active carbon active materials respectively onto the PSA / PEDOT:PSS conductive hydrogel to prepare a hydrogel anode and a hydrogel cathode; then dissolves Zn(OTf3)2 in the PSA adhesive hydrogel precursor solution to prepare a hydrogel electrolyte; finally, the flexible coating layer, the hydrogel anode and the hydrogel cathode, and the hydrogel electrolyte are sequentially assembled to form an implantable and tissue-adhesive all-hydrogel battery (HZB).

[0007] 1. Preparation of an implantable and tissue-adhesive all-hydrogel battery: (1) Preparation of PSA adhesive hydrogel and PSA / PEDOT:PSS conductive hydrogel The acrylic acid, 2-(methacryloyloxy)ethyl-dimethyl-(3-sulfopropyl) ammonium hydrochloride, succinimide, β-cyclodextrin / N-[2-(3,4-dihydroxyphenyl)ethyl]-2-methacrylamide supramolecular crosslinking agent and lithium-based phenyl (2,4,6-trimethylbenzoyl) phosphate photoinitiator are dissolved in deionized water to obtain a PSA adhesive hydrogel precursor solution; it is carefully injected into a tetrafluoroethylene mold, and then the adsorbed air in the precursor solution is removed by nitrogen blowing, and a PSA adhesive hydrogel is obtained after ultraviolet curing; The acrylic acid, 2-(methacryloyloxy)ethyl-dimethyl-(3-sulfopropyl) ammonium hydrochloride, succinimide, β-cyclodextrin / N-[2-(3,4-dihydroxyphenyl)ethyl]-2-methacrylamide supramolecular crosslinking agent and lithium-based phenyl (2,4,6-trimethylbenzoyl) phosphate photoinitiator are dissolved in 1~1.3wt% PEDOT:PSS aqueous dispersion system to obtain a PSA / PEDOT: PSS conductive hydrogel precursor solution; it is carefully injected into a tetrafluoroethylene mold, and then the adsorbed air in the precursor solution is removed by nitrogen blowing, and a PSA / PEDOT: PSS conductive hydrogel as a flexible substrate is obtained after ultraviolet curing; 1~1.3wt% of the PEDOT:PSS aqueous dispersion system, the concentration of acrylic acid is 15~25wt%, the concentration of 2-(methacryloyloxy)ethyl-dimethyl-(3-sulfopropyl) ammonium hydrochloride is 35~45wt%, the concentration of succinimide is 5~10wt%, the concentration of β-cyclodextrin / N-[2-(3,4-dihydroxyphenyl)ethyl]-2-methacrylamide supramolecular crosslinking agent (1 β-cyclodextrin corresponds to 2 DMA) supramolecular crosslinking agent is 2~5mol%, and the concentration of photoinitiator is 0.02~0.05mol%; (2) Preparation of implantable and tissue-adhesive all-hydrogel batteries Dissolve Zn(OTf3)2 in the PSA adhesive hydrogel precursor solution, and the final concentration of Zn(OTf3)2 is 2~4M; carefully inject it into a tetrafluoroethylene mold, then use nitrogen blowing to eliminate bubbles, and a hydrogel electrolyte is obtained after ultraviolet curing; The active material mixture of zinc nanosheet, acetylene black and polytetrafluoroethylene is dispersed in anhydrous ethanol, and the anode active material is obtained by ultrasonic treatment for 20-40 seconds, and then is drop-coated on a PSA / PEDOT: PSS conductive hydrogel flexible substrate to form a hydrogel anode; the active material mixture of activated carbon, acetylene black and polytetrafluoroethylene is dispersed in anhydrous ethanol, and the cathode active material is obtained by ultrasonic treatment for 20-40 seconds, and then is drop-coated on another PSA / PEDOT: PSS conductive hydrogel flexible substrate to form a hydrogel cathode; the mass ratio of zinc nanosheet or activated carbon, acetylene black and polytetrafluoroethylene is 16:3:1, and the concentration of the active material mixture in anhydrous ethanol is 80-120 mg / mL; The obtained hydrogel anode and hydrogel cathode are concentrated under reduced pressure to remove ethanol, and then the same size hydrogel anode and hydrogel cathode are respectively placed on the upper and lower surfaces of the same hydrogel electrolyte, so that the anode active material and the cathode active material are respectively in contact with the upper and lower surfaces of the hydrogel electrolyte, and the outer surfaces of the two PSA / PEDOT: PSS conductive hydrogel flexible substrates are wrapped with a flexible coating layer (polyurethane film) after being pressed for 3-8 min, thereby obtaining a layered implantable and tissue-adhesive full hydrogel battery; the battery can be used for wearable electronic devices or occasions requiring deformation of the battery; 2. Preparation of implantable and tissue-adhesive electric stimulation device and heart attachment and management of heart rate: (1) Preparation of implantable and tissue-adhesive electric stimulation device The active material mixture of zinc nanosheet, acetylene black and polytetrafluoroethylene is dispersed in anhydrous ethanol, and the anode active material is obtained by ultrasonic treatment for 20-40 seconds; the active material mixture of activated carbon, acetylene black and polytetrafluoroethylene is dispersed in anhydrous ethanol, and the cathode active material is obtained by ultrasonic treatment for 20-40 seconds; the anode active material and the cathode active material are coated on the same side surface of the same PSA / PEDOT: PSS conductive hydrogel flexible substrate in parallel to form a hydrogel anode and a hydrogel cathode, and then the hydrogel anode and the hydrogel cathode are placed on the same side surface of the same hydrogel electrolyte to form an ion passage; the PSA / PEDOT: PSS conductive hydrogel between the hydrogel anode and the hydrogel cathode serves as a flexible resistor to form an electronic conduction passage, and the electronic conduction passage and the ion passage form a complete loop; the upper surface of the flexible resistor and the lower surface of the hydrogel electrolyte are wrapped with a flexible coating layer (polyurethane film, 10 mm x 10 mm), thereby obtaining an implantable and tissue-adhesive electric stimulation device; Due to the potential difference between the anode active material and the cathode active material, the ions with different charges in the hydrogel electrolyte will move in opposite directions to generate an electric current, which will be used for electrical stimulation of the attached tissue, regulating the electrical activity of the biological tissue, and then inducing physiological or therapeutic effects. (2) Implantable and tissue-adhesive electrical stimulation device for heart rate management The SD rat is anesthetized by tracheal intubation with 1.5-3.0 v / v% isoflurane and mechanically ventilated; then an incision is made on the midline of the sternum of the SD rat to enter the thoracic cavity, and a rib spreader is used to enlarge the incision to expose the heart of the SD rat; then the implantable and tissue-adhesive electrical stimulation device of the application is attached to the ventricle-atrium junction of the heart, and the current transmission channel of the electrical stimulation device is "hydrogel electrolyte-myocardial tissue", which relies on the direct adhesion of the ion conductive properties of the hydrogel electrolyte to the tissue, and the tight adhesion of the hydrogel electrolyte side to the myocardial tissue through hydrogen bonds, electrostatic interaction and covalent bonds (without air gap), the current is directly conducted from the hydrogel electrolyte to the myocardial cells in the form of ions, and the biological electricity generated by the directional ion flow is used for rhythm control, thereby completing the heart rate management. BRIEF DESCRIPTION OF DRAWINGS

[0008] Figure 1 : The synthesis route of the implantable and tissue-adhesive full hydrogel battery (HZB) prepared by the application; Figure 2 : The correlation column chart of the hydrogel electrode and the hydrogel electrolyte prepared by the application under different material concentrations and the viability of myocardial cells; Figure 3 : The correlation column chart of the hydrogel electrode and the hydrogel electrolyte prepared by the application under different material concentrations and the viability of fibroblasts; Figure 4 : The influence column chart of the different treatment groups (control group CTR, electrode, electrolyte, HZB) prepared by the application on the optical density (Optical density) of H9C2 myocardial cells and NIH3T3 fibroblasts at 490 nm; Figure 5 : The actual picture of the PSA adhesive hydrogel prepared by the application adhered to different organs of mice; Figure 6 : The peeling force curve of the PSA adhesive hydrogel prepared by the application combined with different organs of mice; Figure 7 : The shear force curve of the PSA adhesive hydrogel prepared by the application combined with different organs of mice; Figure 8 : Column chart of fracture toughness and adhesion strength of the PSA adhesive hydrogel prepared by the present application combined on different organs of mice; Figure 9 : (a) is a structural schematic diagram of the implantable and tissue-adhesive electric stimulation device prepared by the present application; (b) is a structural schematic diagram of the implantable and tissue-adhesive full hydrogel battery (HZB) prepared by the present application; Figure 10 : A physical diagram of the implantable and tissue-adhesive full hydrogel battery prepared by the present application; Figure 11 : A cyclic voltammetry performance diagram of the implantable and tissue-adhesive full hydrogel battery prepared by the present application; Figure 12 : A diagram showing the relationship between the rate performance and the coulombic efficiency of the implantable and tissue-adhesive full hydrogel battery prepared by the present application and the cycle number; Figure 13 : Electrochemical impedance spectroscopy performance of the flexible electrode material of the implantable and tissue-adhesive full hydrogel battery prepared by the present application after different deformations (stretching, bending, twisting) and 1000 deformation cycles; Figure 14 : Charge and discharge performance of the implantable and tissue-adhesive full hydrogel battery prepared by the present application after different deformations (initial, stretching, bending, twisting) and 1000 deformation cycles; Figure 15 : Changes of the cycle performance and the coulombic efficiency of the implantable and tissue-adhesive full hydrogel battery prepared by the present application at a current density of 5 A / g with the cycle number; Figure 16 : A schematic diagram of the implantable and tissue-adhesive electric stimulation device prepared by the present application for treating heart rate of mice; Figure 17 : A schematic diagram of the electrotherapy (30 μA) atrioventricular block and typical electrocardiogram trajectory of the electric stimulation device prepared by the present application for rat heart; Figure 18 : A typical electrocardiogram trajectory diagram of the electric stimulation device prepared by the present application for rat heart at a low-energy electric defibrillation (200 μA); wherein the abscissa represents the recording time, and the ordinate is the electrocardiogram signal changing with time, which shows the normal electrocardiogram signal from the beginning, the electrocardiogram disorder signal after applying external interference, and the electrocardiogram signal after heart rate management.

[0009] As Figure 1The preparation process of HZB is shown in the figure. Zn(OTf3)2 is added to the PSA adhesive hydrogel precursor solution, and the hydrogel electrolyte is formed after UV curing. The PSA / PEDOT:PSS conductive hydrogel precursor solution is treated by UV light, and then the active material containing activated carbon / zinc nanosheet is dropped to form the hydrogel electrode. The hydrogel electrolyte and the hydrogel electrode are assembled into HZB, and finally the stretching is used to verify whether the layers of the full gel battery are tightly combined. As Figure 2 shown, in order to prove the biocompatibility of the hydrogel electrode and the hydrogel electrolyte to H9C2 myocardial cells, 1g of sterilized hydrogel electrode and hydrogel electrolyte were respectively soaked in 10% fetal bovine serum (10mL) DMEM medium for 72h to obtain hydrogel extract. H9C2 myocardial cells were incubated with hydrogel extract (concentration 0.02~0.1 g mL -1 ) in a 96-well plate at 37℃, 5% CO2 humidified environment. The cell viability was detected by MTT method, and the optical density was measured at 490nm. It can be seen that the cell viability is maintained above 90%, indicating that the hydrogel electrode and the hydrogel electrolyte have no obvious toxicity to H9C2 myocardial cells at the test concentration.

[0010] As Figure 3 shown, in order to prove the biocompatibility of the hydrogel electrode and the hydrogel electrolyte to NIH3T3 fibroblasts, the same method was used to verify the biocompatibility, and the cell viability was maintained above 90%, indicating that the hydrogel electrode and the hydrogel electrolyte had no obvious toxicity to NIH3T3 fibroblasts at the test concentration.

[0011] As Figure 4 shown, the cell optical density (490nm) detection histogram was used to evaluate the biocompatibility of the hydrogel battery (HZB) and its components (hydrogel electrode, hydrogel electrolyte) to two kinds of cells (H9C2 myocardial cells, NIH3T3 fibroblasts), and CTR was the control group containing only the corresponding cells. In all groups (CTR, electrode, electrolyte, HZB), the optical density values of H9C2 and NIH3T3 cells were in the range of 0.3~0.45, and the numerical difference between groups was small. It is proved that HZB and its components (hydrogel electrode, hydrogel electrolyte) have no significant inhibitory effect on the proliferation / survival of H9C2 and NIH3T3 cells.

[0012] As Figure 5As shown, in order to prove the adhesion effect of PSA adhesive hydrogel on different tissues, the figure shows the adhesion effect of PSA adhesive hydrogel on five kinds of organ tissues (heart, liver, spleen, lung, kidney), and it can be seen from the figure that effective adhesion is achieved on the surface of the tissues, which shows that it has good adhesion ability to various in-vivo tissues.

[0013] As shown in Figure 6 , the adhesion between PSA adhesive hydrogel and tissue was evaluated by using 180-degree peeling test after the rectangular hydrogel sample (10x30x2mm) was adhered to the tissue, and it can be seen that the PSA adhesive hydrogel showed strong adhesion effect on multiple mouse organs.

[0014] As shown in Figure 7 , the adhesion of PSA adhesive hydrogel was evaluated by using a gap shear test on a universal testing machine at a speed of 20mm / min. The PSA adhesive hydrogel was clamped between the sections of different mouse organs, and the adhesion width was 0.8cm. The measurement results show a standard shear adhesion curve, indicating that the PSA adhesive hydrogel has sufficient adhesion with the tissue.

[0015] As shown in Figure 8 , the interfacial adhesion of PSA adhesive hydrogel was quantitatively evaluated by standard peeling test and lap shear test, and the interfacial toughness and shear adhesion strength of different tissues were calculated. Due to the lack of micro / nano-scale topography of the stratum corneum (these structures can enhance intermolecular interactions), the toughness of PSA adhesive hydrogel on dry or mucus-covered organs is lower than that on the skin. However, PSA adhesive hydrogel achieves a high interfacial toughness of up to 330J m -2 , which is attributed to the high energy dissipation achieved by the dynamic supramolecular cross-linked network. The shear adhesion strength of PSA adhesive hydrogel on biological tissues reaches 180kPa. These high adhesion values can be attributed to multi-scale synergistic effects, including supramolecular interconnection, intermolecular forces (hydrogen bonds, electrostatic interactions), and covalent bonds.

[0016] As shown in Figure 9 (a), the PSA / PEDOT:PSS conductive hydrogel serves as a flexible resistor (size: 7mmx7mmx0.5mm), and the upper surface of the PSA / PEDOT:PSS conductive hydrogel and the lower surface of the hydrogel electrolyte (size: 7mmx7mmx0.5mm) are encapsulated by polyurethane to protect the internal structure; the flexible resistor is one of the key components to realize the function of electrical stimulation, and the hydrogel anode (containing zinc nanosheets) and the hydrogel cathode (containing activated carbon) are drop-casted on the lower surface of the flexible resistor in parallel to each other, which enables the device to generate sustained electrical stimulation; as shown in Figure 9As shown in (b), when the battery discharges, the battery releases energy through a load connected to an external circuit. Current flows from the positive electrode (zinc nanosheets) to the negative electrode (activated carbon), and electrons flow from the negative electrode to the positive electrode. At the positive electrode, zinc ions recombine with electrons to form metal oxides. The zinc metal or zinc powder at the negative electrode is converted back into zinc ions. This process continues until the zinc ions are completely transferred or the zinc material at the negative electrode is exhausted.

[0017] like Figure 10 The image shows the front and back views of the implantable and tissue-adhesive hydrogel battery (HZB). The layered structure of the battery results in a length and width of less than 1 cm and a thickness of only about 2.5 mm, reducing the feeling of a foreign body in the body.

[0018] like Figure 11 As shown, in the range of 1~10mV S -1 In the low scan rate range, the HZB CV curves of the supramolecularly cross-linked electrode-electrolyte interface (SEEI) exhibit a clear trend of current response changing with scan rate and potential. As the scan rate increases from 1 mV / s... -1 Increase to 10mV S -1 The absolute value of the current peak gradually increases, and the shape of the curve exhibits characteristics of both surface reactions (such as a relatively clear trend in current change) and the influence of diffusion processes (such as the continuous change of current with potential and scan rate). This indicates that the electrochemical reaction process is a mixture of surface and diffusion-controlled processes. This mixed control mechanism suggests that both rapid electron transfer steps at the electrode surface and diffusion steps of ions within the electrolyte or electrode material exist in the reaction, jointly dominating the kinetics of the electrochemical reaction.

[0019] like Figure 12 The figure shows the rate performance of HZB at 0.5A g. -1 At a current density, HZB exhibits approximately 239 mAh g. -1 Its high specific capacity and consistently high coulombic efficiency (above 99%) indicate excellent charge reversibility and minimal side reactions during charge-discharge at this rate. The results were obtained from tests at different current densities (0.5, 1, 2, 3, 5 A g). -1 The curves show that as the current density increases, the specific capacity decreases, but when the current density returns to 0.5 A / g... -1 At that time, the specific capacity can be recovered well, further demonstrating the advantages of HZB in rate performance and cycle stability.

[0020] like Figure 13As shown, the impedance characteristics of the material are displayed in its initial state and after 1000 cycles of stretching, bending, and torsion. The RCT value of SEEI is approximately 102 Ω, indicating excellent interfacial contact and stability. This also corroborates the influence of interfacial contact and stability on charge transfer resistance; the better the interfacial contact and the better the stability, the lower the charge transfer resistance and the higher the charge transport efficiency. As can be seen from the figure, the impedance curves (Z' is the real impedance, Z'' is the imaginary impedance) under different deformation states show very little change, indicating that the interfacial impedance remains stable under dynamic deformation. This demonstrates the advantages of the dynamic bonding within the hydrogel battery—it possesses mechanical elasticity against interlayer separation in a dynamic environment within the cell, thereby helping to reduce ion migration barriers, improve charge transport efficiency, and enhance fatigue resistance.

[0021] like Figure 14 As shown in the figure, the electrochemical performance of SEEI-based HZB is presented in its initial state and after 1000 cycles of 180° bending, 20% stretching, and 90° twisting. The figure shows that the charge-discharge curves under different deformation states almost completely overlap, indicating that the constant current charge-discharge performance of SEEI-based HZB remains unchanged after numerous repeated deformations. This demonstrates its excellent cycle stability and interfacial stability, proving that the dynamic bonding within the hydrogel battery effectively maintains interfacial performance and ensures stable electrochemical behavior even under repeated mechanical deformation.

[0022] like Figure 15 As shown, the cycling performance of the SEEI system battery is demonstrated. The SEEI charging capacity remains stable at approximately 90 mAh / g over 2000 cycles, exhibiting excellent cycle stability. Although the SEEI discharging capacity decreases somewhat, it ultimately remains around 90 mAh / g, with a capacity retention rate of 99%. The coulombic efficiency remains close to 100% throughout the cycle, indicating that the SEEI system has excellent charge reversibility and very few side reactions during charging and discharging.

[0023] like Figure 16 As shown, in vivo studies were conducted to further verify the potential of the HZB electrotherapy device in regulating cardiac arrhythmias. The figure illustrates the process of inducing atrioventricular block and ventricular fibrillation in rats through drug injection and electrical stimulation. Atrioventricular block, caused by the interruption of impulse transmission from the atria to the ventricles, impairs cardiac output and is typically treated with electrical stimulation. Intraperitoneal injection of diltiazem (50 mg dissolved in 1 mL of saline) inhibited sinoatrial node activity, reducing the heart rate from 380 bpm to 180 bpm. To verify the cardiac stimulation capability, the implantable and tissue-adhesive electrical stimulation devices prepared in this invention were attached to the cardiac surface for stimulation.

[0024] like Figure 17As shown, the ECG leads were first connected to the forelimb and left hindlimb for real-time monitoring. After attaching to the surface of the heart, HZB delivered a sustained electrical stimulation (30 mA) with therapeutic significance, which relieved the atrioventricular block and restored the spontaneous heart rhythm within seconds, with a heart rate of 420 beats / min. These results demonstrate that HZB, as a biocompatible and anti-injury electrical therapeutic device, can be used to treat cardiac conduction disorders and prevent bradycardia.

[0025] As shown, ventricular fibrillation is caused by abnormal excitation of multiple ectopic pacemakers in the ventricular myocardium and accumulation of electrical signals in the loop, which will trigger extremely chaotic electrical activity and eventually lead to the loss of effective cardiac pumping function. Ventricular fibrillation was induced by high-frequency current stimulation (10 mA, 4000 Hz). After confirming the onset of ventricular fibrillation by ECG, HZB was attached to the surface of the heart and stable electrical stimulation (200 mA) was started. This quickly terminated the ventricular fibrillation and restored normal sinus rhythm within seconds. If no intervention is made, ventricular fibrillation will develop into cardiac arrest. These results demonstrate that HZB can provide stable and tissue-integrated electrical therapy under dynamic physiological conditions, overcoming the rigid, invasive fixation method and biocompatibility issues of traditional cardiac implantable electronic devices, while ensuring long-term biological safety. Figure 18 As shown, ventricular fibrillation is caused by abnormal excitation of multiple ectopic pacemakers in the ventricular myocardium and accumulation of electrical signals in the loop, which will trigger extremely chaotic electrical activity and eventually lead to the loss of effective cardiac pumping function. Ventricular fibrillation was induced by high-frequency current stimulation (10 mA, 4000 Hz). After confirming the onset of ventricular fibrillation by ECG, HZB was attached to the surface of the heart and stable electrical stimulation (200 mA) was started. This quickly terminated the ventricular fibrillation and restored normal sinus rhythm within seconds. If no intervention is made, ventricular fibrillation will develop into cardiac arrest. These results demonstrate that HZB can provide stable and tissue-integrated electrical therapy under dynamic physiological conditions, overcoming the rigid, invasive fixation method and biocompatibility issues of traditional cardiac implantable electronic devices, while ensuring long-term biological safety. DETAILED DESCRIPTION

[0026] Example 1: 1. Preparation of implantable and tissue-adhesive all-hydrogel battery: (1) Preparation of PSA adhesive hydrogel and PSA / PEDOT:PSS conductive hydrogel Dissolve 2 g of acrylic acid, 4 g of 2-(methacryloyloxy)ethyl-dimethyl-(3-sulfopropyl) ammonium hydrochloride, 0.8 g of succinimide, 0.286 g of β-cyclodextrin / DMA (1 β-cyclodextrin corresponds to 2 DMA) supramolecular crosslinking agent, and 0.008 g of photoinitiator (lithium-based phenyl (2,4,6-trimethylbenzoyl) phosphate) in 2.906 g of deionized water to obtain a PSA adhesive hydrogel precursor solution; then remove the adsorbed air in the precursor solution by nitrogen purging for 15 minutes, then carefully inject into a tetrafluoroethylene mold and cure under 365 nm ultraviolet light for 25 minutes to obtain a PSA adhesive hydrogel; 2 g of acrylic acid, 4 g of 2-(methacryloyloxy)ethyl-dimethyl-(3-sulfopropyl) ammonium hydrochloride, 0.8 g of succinimide, 0.286 g of β-cyclodextrin / DMA (1 β-cyclodextrin corresponds to 2 DMA) supramolecular crosslinking agent and 0.008 g of photoinitiator (lithium-based phenyl (2,4,6-trimethylbenzoyl) phosphate) were dissolved in 2.906 g of 1 wt% PEDOT:PSS aqueous dispersion system to obtain a PSA / PEDOT:PSS conductive hydrogel precursor solution; the adsorbed air in the precursor solution was removed by nitrogen blowing for 15 minutes, and then carefully injected into a tetrafluoroethylene mold, and then cured by 365 nm ultraviolet light for 25 minutes to obtain a PSA / PEDOT:PSS conductive hydrogel as a flexible substrate; In the 1 wt% PEDOT:PSS aqueous dispersion system, the concentration of acrylic acid is 20 wt%, the concentration of 2-(methacryloyloxy)ethyl-dimethyl-(3-sulfopropyl) ammonium hydrochloride is 40 wt%, the concentration of succinimide is 8 wt%, the concentration of β-cyclodextrin / DMA (1 β-cyclodextrin corresponds to 2 DMA) supramolecular crosslinking agent is 3 mol%, and the concentration of photoinitiator is 0.03 mol%; (2) Preparation of implantable and tissue-adhesive all-hydrogel battery Zn(OTf3)2 was dissolved in the PSA adhesive hydrogel precursor solution with a final concentration of 3M; then nitrogen was blown to eliminate air bubbles, and a hydrogel electrolyte was obtained after ultraviolet curing; An active material mixture composed of 48 mg of zinc nanosheets, 9 mg of acetylene black, and 3 mg of polytetrafluoroethylene was dispersed in anhydrous ethanol, and ultrasonic treatment was performed for 30 seconds to obtain an anode active material; the obtained anode active material was then drop-coated on one PSA / PEDOT:PSS conductive hydrogel to form a hydrogel anode (i.e., the hydrogel anode is composed of a PSA / PEDOT:PSS conductive hydrogel flexible substrate and anode active material); an active material mixture composed of 48 mg of activated carbon, 9 mg of acetylene black, and 3 mg of polytetrafluoroethylene was dispersed in anhydrous ethanol, and ultrasonic treatment was performed for 30 seconds to obtain a cathode active material; the obtained cathode active material was then drop-coated on another PSA / PEDOT:PSS conductive hydrogel to form a hydrogel cathode (i.e., the hydrogel cathode is composed of a PSA / PEDOT:PSS conductive hydrogel flexible substrate and a cathode active material); the mass ratio of zinc nanosheets or activated carbon, acetylene black, and polytetrafluoroethylene is 16:3:1, and the concentration of the active material mixture in anhydrous ethanol is 100 mg / mL; The obtained hydrogel anode and hydrogel cathode were concentrated under reduced pressure to remove ethanol, and then hydrogel anodes and hydrogel cathodes with the same size (7 mm x 7 mm x 1 mm) were respectively placed on the upper and lower surfaces of the same hydrogel electrolyte (7 mm x 7 mm x 0.5 mm), so that the anode active material and the cathode active material were respectively in contact with the upper and lower surfaces of the hydrogel electrolyte. After pressing for 5 min, the outer surface of the two PSA / PEDOT: PSS conductive hydrogel flexible substrates was wrapped with a flexible coating layer (polyurethane film, 10 mm x 10 mm), thereby obtaining a layered implantable and tissue-adhesive all-hydrogel battery; 2. Preparation of implantable and tissue-adhesive electric stimulation device and heart attachment and management of heart rate: (1) Preparation of implantable and tissue-adhesive electric stimulation device The obtained implantable and tissue-adhesive all-hydrogel battery (HZB) constitutes an implantable and tissue-adhesive electric stimulation device for heart rate management: An active material mixture composed of 48 mg of zinc nanosheets, 9 mg of acetylene black, and 3 mg of polytetrafluoroethylene was dispersed in anhydrous ethanol, and ultrasonic treatment was performed for 30 seconds to obtain an anode active material; an active material mixture composed of 48 mg of activated carbon, 9 mg of acetylene black, and 3 mg of polytetrafluoroethylene was dispersed in anhydrous ethanol, and ultrasonic treatment was performed for 30 seconds to obtain a cathode active material; the anode active material and the cathode active material were applied in parallel on the same side surface of the same PSA / PEDOT: PSS conductive hydrogel (7 mm x 7 mm x 0.5 mm) to form a hydrogel anode and a hydrogel cathode (7 mm long, 2.5 mm wide, and a distance of 2 mm between the anode and the cathode); the hydrogel anode and the hydrogel cathode were placed on the same side surface of the same hydrogel electrolyte (7 mm x 7 mm x 0.5 mm) to form an ion channel; the PSA / PEDOT: PSS conductive hydrogel between the hydrogel anode and the hydrogel cathode served as a flexible resistor to form an electronic conduction channel; the upper surface of the flexible resistor and the lower surface of the hydrogel electrolyte were wrapped with a flexible coating layer (polyurethane film, 10 mm x 10 mm), thereby obtaining an implantable and tissue-adhesive electric stimulation device.

[0027] (2) Implantable and tissue-adhesive electric stimulation device for heart attachment and management of heart rate Rhythm control and defibrillation of rat heart in vivo and ECG monitoring: SD rats were anesthetized by tracheal intubation with 2 v / v% isoflurane and mechanically ventilated; then a cut was made in the SD rat's sternum midline to access the chest cavity and a rib spreader was used to enlarge the cut to expose the SD rat's heart; then the implantable and tissue-adhesive electric stimulation device of the present application was attached to the ventricle-atrium junction of the heart, the current transmission channel of the electric stimulation device was "hydrogel electrolyte-myocardial tissue", the core relied on the ion conductive properties of the hydrogel electrolyte and the direct adhesive contact with the tissue, the hydrogel electrolyte side was tightly adhered to the myocardial tissue by hydrogen bonds, electrostatic interactions and covalent bonds (without air gap), the electric current was directly conducted from the hydrogel electrolyte to the myocardial cells in the form of ions, and the bioelectricity generated by the directional ion flow was used for rhythm control.

[0028] Diltiazem (200 mg / mL) was injected intraperitoneally to induce bradycardia. The implantable and tissue-adhesive electric stimulation device was attached to the ventricle-atrium junction of the heart for rhythm control. Throughout the experiment, real-time ECG signals were used to monitor heart rate. In order to induce cardiac fibrillation, high-frequency electric stimulation (10 mA, 4000 HZ) was applied to the heart to trigger ventricular arrhythmia. As soon as the ECG signal confirmed the start of fibrillation, the electric stimulation was stopped, and high-frequency rhythm control was performed. Subsequently, the implantable and tissue-adhesive electric stimulation device prepared by the present application was connected to the heart to perform electric shock defibrillation.

Claims

1. A method for preparing an implantable and tissue-adhesive all-hydrogel battery, comprising the following steps: (1) Preparation of PSA-adhesive hydrogel and PSA / PEDOT:PSS conductive hydrogel Dissolve acrylic acid, 2-(methacryloyloxy)ethyl-dimethyl-(3-sulfopropyl) ammonium hydrochloride, succinimide, β-cyclodextrin / N-[2-(3,4-dihydroxyphenyl)ethyl]-2-methacrylamide supramolecular cross-linking agent and lithium-based phenyl (2,4,6-trimethylbenzoyl) phosphate photoinitiator in deionized water to obtain a PSA-adhesive hydrogel precursor solution; Acrylic acid, 2-(methacryloyloxy)ethyl-dimethyl-(3-sulfopropyl) ammonium hydrochloride, succinimide, β-cyclodextrin / N-[2-(3,4-dihydroxyphenyl)ethyl]-2-methacrylamide supramolecular crosslinking agent and lithium-based phenyl (2,4,6-trimethylbenzoyl) phosphate ester photoinitiator are dissolved in a 1~1.3wt% PEDOT:PSS aqueous dispersion system to obtain a PSA / PEDOT:PSS conductive hydrogel precursor solution; Carefully inject it into a tetrafluoroethylene mold, then remove the adsorbed air in the precursor solution by nitrogen blowing, and obtain a PSA / PEDOT:PSS conductive hydrogel as a flexible substrate after ultraviolet curing; (2) Preparation of an implantable and tissue-adhesive all-hydrogel battery Dissolve Zn(OTf3)2 in the PSA-adhesive hydrogel precursor solution, and the final concentration of Zn(OTf3)2 is 2-4 M; inject it into a tetrafluoroethylene mold, then blow nitrogen to eliminate air bubbles, and obtain a hydrogel electrolyte after ultraviolet curing; Disperse the active material mixture composed of zinc nanosheets, acetylene black and polytetrafluoroethylene in anhydrous ethanol, and ultrasonically treat for 20-40 seconds to obtain an anode active material, then drop coat the obtained anode active material on one PSA / PEDOT:PSS conductive hydrogel to form a hydrogel anode; disperse the active material mixture composed of activated carbon, acetylene black and polytetrafluoroethylene in anhydrous ethanol, and ultrasonically treat for 20-40 seconds to obtain a cathode active material, then drop coat the obtained cathode active material on another PSA / PEDOT:PSS conductive hydrogel to form a hydrogel cathode; the mass ratio of zinc nanosheets or activated carbon, acetylene black and polytetrafluoroethylene is 16:3:1, and the concentration of the active material mixture in anhydrous ethanol is 80-120 mg / mL; Concentrate the obtained hydrogel anode and hydrogel cathode under reduced pressure to remove ethanol, then place the hydrogel anode and the hydrogel cathode with the same size on the upper and lower surfaces of the same hydrogel electrolyte respectively, so that the anode active material and the cathode active material are in contact with the upper and lower surfaces of the hydrogel electrolyte respectively, and then wrap the outer surfaces of the two PSA / PEDOT:PSS conductive hydrogel flexible substrates with a flexible coating layer after pressing for 3-8 min, thereby obtaining a layered implantable and tissue-adhesive all-hydrogel battery.

2. The method of claim 1, wherein the implantable and tissue-adhesive all-hydrogel battery is prepared by: In the 1-1.3 wt% PEDOT:PSS aqueous dispersion system of step (1), the concentration of acrylic acid is 15-25 wt%, the concentration of 2-(methacryloyloxy)ethyl-dimethyl-(3-sulfopropyl) ammonium hydrochloride is 35-45 wt%, the concentration of succinimide is 5-10 wt%, the concentration of the supramolecular cross-linking agent is 2-5 mol%, and the concentration of the photoinitiator is 0.02-0.05 mol%.

3. The method of claim 1, wherein the implantable and tissue-adhesive all-hydrogel battery is prepared by: The flexible coating layer in step (2) is a polyurethane film.

4. An implantable and tissue-adhesive all-aqueous hydrogel battery, characterized by: is prepared by the preparation method of claim 1, 2 or 3.

5. A method for preparing an implantable and tissue-adhesive electrostimulation device, comprising the following steps: (1) Preparation of PSA adhesive hydrogel and PSA / PEDOT:PSS conductive hydrogel Dissolve acrylic acid, 2-(methacryloyloxy)ethyl-dimethyl-(3-sulfopropyl) ammonium hydrochloride, succinimide, β-cyclodextrin / N-[2-(3,4-dihydroxyphenyl)ethyl]-2-methacrylamide supramolecular crosslinking agent and lithium-based phenyl (2,4,6-trimethylbenzoyl) phosphate ester photoinitiator in deionized water to obtain a PSA adhesive hydrogel precursor solution; Acrylic acid, 2-(methacryloyloxy)ethyl-dimethyl-(3-sulfopropyl) ammonium hydrochloride, succinimide, β-cyclodextrin / N-[2-(3,4-dihydroxyphenyl)ethyl]-2-methacrylamide supramolecular crosslinking agent and lithium-based phenyl (2,4,6-trimethylbenzoyl) phosphate ester photoinitiator are dissolved in a 1~1.3wt% PEDOT:PSS aqueous dispersion system to obtain a PSA / PEDOT:PSS conductive hydrogel precursor solution; Carefully inject it into a tetrafluoroethylene mold, and then remove the adsorbed air in the precursor solution by nitrogen blowing. After UV curing, a PSA / PEDOT:PSS conductive hydrogel as a flexible substrate is obtained; (2) Preparation of an implantable and tissue-adhesive electrostimulation device Dissolve Zn(OTf3)2 in the PSA adhesive hydrogel precursor solution, and the final concentration of Zn(OTf3)2 is 2-4 M; Carefully inject it into a tetrafluoroethylene mold, and then use nitrogen blowing to eliminate air bubbles. After UV curing, a hydrogel electrolyte is obtained; Disperse the active material mixture composed of zinc nanosheets, acetylene black and polytetrafluoroethylene in anhydrous ethanol, and ultrasonically treat for 20-40 seconds to obtain an anode active material; disperse the active material mixture composed of activated carbon, acetylene black and polytetrafluoroethylene in anhydrous ethanol, and ultrasonically treat for 20-40 seconds to obtain a cathode active material; coat the anode active material and the cathode active material on the same side surface of the same PSA / PEDOT:PSS conductive hydrogel in parallel to each other to form a hydrogel anode and a hydrogel cathode, and then place the hydrogel anode and the hydrogel cathode on the same side surface of the same hydrogel electrolyte to form an ion channel; the PSA / PEDOT:PSS conductive hydrogel between the hydrogel anode and the hydrogel cathode serves as a flexible resistor to form an electronic conductive channel, and the electronic conductive channel and the ion channel form a complete loop, and then the upper surface of the flexible resistor and the lower surface of the hydrogel electrolyte are wrapped with a flexible coating layer, thereby obtaining an implantable and tissue-adhesive electrostimulation device.

6. The method for preparing an implantable and tissue-adhesive electrical stimulation device as described in claim 5, characterized in that: In the 1-1.3 wt% PEDOT:PSS aqueous dispersion system of step (1), the concentration of acrylic acid is 15-25 wt%, the concentration of 2-(methacryloyloxy)ethyl-dimethyl-(3-sulfopropyl) ammonium hydrochloride is 35-45 wt%, the concentration of succinimide is 5-10 wt%, the concentration of the supramolecular crosslinking agent is 2-5 mol%, and the concentration of the photoinitiator is 0.02-0.05 mol%.

7. The method for preparing an implantable and tissue-adhesive electrical stimulation device as described in claim 5, characterized in that: The flexible coating layer in step (2) is a polyurethane film.

8. An implantable and tissue-adherent electrical stimulation device, characterized by: is prepared by the preparation method of claim 5, 6 or 7.

9. Use of an implantable and tissue-adherent electro-stimulation device according to claim 8 for heart rate management, characterized in that: SD rats are anesthetized by tracheal intubation using 1.5-3.0 v / v% isoflurane and mechanically ventilated; then an incision is made on the midline of the sternum of the SD rat to access the thoracic cavity, and a rib spreader is used to enlarge the incision to expose the heart of the SD rat; then the implantable and tissue-adhesive electric stimulation device is attached to the ventricle-atrium junction of the heart, and the electric current is directly conducted from the hydrogel electrolyte to the myocardial cells in the form of ions, and the bioelectricity generated by the directional ion flow is used for rhythm control, thereby completing heart rate management.

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