A composite electrode for vagus nerve stimulation, its preparation method and application

Abstract

A composite electrode for vagus nerve stimulation of the ear, its preparation method, and its application are disclosed, relating to the field of medical materials technology. The electrode comprises a conductive membrane prepared by vacuum filtration of a composite conductive ink. The composite conductive ink comprises PEDOT:PSS and dopamine hydrochloride intercalated within a single layer of MXene nanomaterials. The preparation process of the single-layer MXene nanomaterials involves dissolving LiF in HCl, adding Ti3AlC2 powder, continuously stirring, centrifuging to discard the supernatant, washing the precipitate until the pH of the supernatant reaches 5-6, collecting the precipitate, adding deionized water to the precipitate, sonicating in an ice-water bath to obtain a dispersion, centrifuging to collect the supernatant, and freeze-drying. This invention also provides a percutaneous vagus nerve stimulator incorporating this electrode, which can be used to prepare devices for treating epilepsy or neuromodulation devices for improving anxiety / sleep disorders.

Description

Technical Field

[0001] This invention relates to the field of medical materials technology, specifically to a composite electrode for vagus nerve stimulation of the ear, its preparation method, and its application. Background Technology

[0002] Percutaneous vagus nerve stimulation (taVNS) is a non-invasive neuromodulation technique that activates the nucleus tractus solitarius-locus coeruleus pathway by stimulating the afferent branches of the vagus nerve in the concha of the ear, thereby regulating neurotransmitter release and modulating the body's autonomic nervous activity. It has shown broad clinical application prospects in the treatment of neurological diseases such as epilepsy, insomnia, and depression.

[0003] Currently, taVNS devices primarily use traditional metallic materials such as Ag / AgCl and stainless steel as electrode materials. These materials have several significant drawbacks: First, their rigid structure makes it difficult to conformally fit the complex curves of the ear, leading to electrode displacement and poor contact with prolonged use. This can cause unstable stimulation currents and skin irritation, allergies, and other discomfort, severely impacting user experience and treatment adherence. Second, the conductive layer of traditional electrodes has weak interfacial bonding with the substrate, making them prone to delamination and detachment during repeated bending and long-term use. Third, their limited electrochemical performance and insufficient charge injection capacity hinder efficient and stable neuromodulation, limiting their widespread application in clinical and everyday settings.

[0004] In recent years, two-dimensional carbon material MXene has attracted widespread attention in the field of flexible electronic devices due to its excellent conductivity, hydrophilicity, and biocompatibility. However, single-layer MXene materials are prone to ineffective stacking between layers during film formation, disrupting the continuity of the conductive network and leading to decreased conductivity and stability. Simultaneously, the active Ti atoms on the MXene surface are easily oxidized, resulting in gradual performance degradation over long-term use, making it difficult to meet the long-term stability requirements of medical electrodes. Research shows that introducing conductive polymers and antioxidant molecules between monolayer MXene layers can effectively improve its interfacial stability and antioxidant properties, optimize the internal structure of the material, and enhance the electrochemical performance and skin adhesion of the electrode.

[0005] Based on this, the present invention proposes a percutaneous ear vagus nerve stimulator with a metal substrate and a composite MXene conductive layer, aiming to solve the above-mentioned technical problems of existing taVNS electrodes, achieve efficient, stable and comfortable neuromodulation, and meet the needs of clinical and daily applications. Summary of the Invention

[0006] This invention proposes a composite electrode for vagus nerve stimulation, its preparation method, and its application.

[0007] The specific technical solution of the present invention is as follows: A composite electrode for vagus nerve stimulation includes a metal substrate and a composite conductive film disposed on the metal substrate. The composite conductive film is prepared by vacuum filtration of composite conductive ink. The composite conductive ink comprises a single layer of MXene nanomaterials, PEDOT:PSS, and dopamine hydrochloride; the PEDOT:PSS and dopamine hydrochloride are intercalated between the layers of the single layer of MXene nanomaterials. The mass ratio of the monolayer MXene nanomaterial to PEDOT:PSS is 2~4:1, and the mass ratio of the monolayer MXene nanomaterial to dopamine hydrochloride is 30~50:1. The monolayer MXene nanomaterial was prepared by the following process: LiF was dissolved in HCl to obtain an etching solution, and Ti3AlC2 powder was added. The mixture was stirred continuously to obtain a reaction mixture. Transfer the reaction mixture to a centrifuge tube, centrifuge and discard the supernatant. Wash the precipitate with HCl solution and deionized water in sequence until the pH of the supernatant reaches 5-6, and collect the precipitate. Deionized water was added to the precipitate, and the mixture was ultrasonically treated in an ice-water bath to obtain a dispersion. The dispersion was centrifuged, the supernatant was collected, and the mixture was freeze-dried to obtain a single-layer MXene nanomaterial.

[0008] Preferably, the monolayer MXene nanomaterial is prepared by the following process: A monolayer MXene nanomaterial was prepared into an aqueous dispersion of 2-3 mg / ml and stirred thoroughly for 1-2 h. A PEDOT:PSS aqueous dispersion of 10-15 mg / ml was added to the MXene aqueous dispersion at a mass ratio of 2-4:1, and stirred at 200-300 rpm for 1-2 h to obtain a PEDOT:PSS intercalated MXene dispersion. A dopamine hydrochloride aqueous solution of 2 mg / ml was added to the above dispersion at a mass ratio of dopamine hydrochloride to MXene of 1:30-50, and stirred for 0.5-1 h to obtain the MXene composite conductive ink.

[0009] Preferably, the preparation of the composite electrode includes the following steps: (1) The above-mentioned MXene composite conductive ink is vacuum filtered to form a composite membrane on the filter membrane; (2) The composite membrane is vacuum dried at 25~45 °C for 2~4 h; (3) The dried composite membrane is peeled off from the filter membrane to obtain the MXene composite conductive membrane; (4) Coat the surface of the metal substrate with conductive silver paste, and then cover the metal substrate with the MXene composite conductive film. Seal and dry at room temperature for 2-4 hours to obtain the MXene composite electrode.

[0010] Preferably, the monolayer MXene nanomaterial and PEDOT:PSS are respectively configured into aqueous dispersions and stirred thoroughly; the monolayer MXene aqueous dispersion and the PEDOT:PSS aqueous dispersion are mixed and stirred to obtain a PEDOT:PSS intercalated MXene dispersion; then, an aqueous solution of dopamine hydrochloride is added and stirred to obtain a composite conductive ink based on MXene.

[0011] Preferably, the thickness of the metal substrate is 0.2~0.3 mm; and the thickness of the composite conductive film is 0.2~0.3 mm.

[0012] Preferably, the metal substrate is selected from stainless steel foil, copper foil, or titanium foil; the surface of the metal substrate is provided with a metal interface for connecting metal wires.

[0013] The present invention also provides a method for preparing the above-mentioned composite electrode for vagus nerve stimulation, characterized by comprising the following steps: The composite conductive ink was vacuum filtered into a film, vacuum dried, and then peeled off to obtain the MXene composite conductive film. The conductive film is fixed onto a metal substrate using conductive silver paste and then dried to obtain a composite electrode based on MXene.

[0014] The present invention also provides a percutaneous ear vagus nerve stimulator, comprising a stimulator body, electrodes disposed on the surface of the stimulator body, and wires disposed inside the stimulator body; The stimulator body is an in-ear headphone-style body whose shape is adapted to the human concha and cymba conchae. The stimulator body has two stimulation sites, which are used to cover the concha cavity and the cymba conchae, respectively; The electrode is the composite electrode used for vagus nerve stimulation, which includes a separately configured cavum concha stimulating electrode and cymba concha stimulating electrode. The wires are used to connect the corresponding electrodes and stimulation sites.

[0015] Preferably, the stimulator body is made of PEEK (polyether ether ketone) material or PC / ABS alloy (made of polycarbonate and ABS resin blend); the lead wire is made of silver-plated copper wire, and the surface of the lead wire is coated with PTFE nanoparticles, and the outer sheath of the lead wire is made of medical TPU material.

[0016] Preferably, it also includes a main control unit connected to the stimulator body. The main control unit has a UI interactive interface and multiple built-in stimulation levels, including a basic treatment level, a cognitive enhancement level, an emergency inhibition level, a mild treatment level, an intensive treatment level, and a user-defined level.

[0017] The present invention also provides the application of the above-mentioned composite material electrode or transcutaneous vagus nerve stimulator in the preparation of a device for treating epilepsy or a neuromodulation device for improving anxiety / sleep disorders.

[0018] Compared with the prior art, the specific beneficial effects of the present invention are as follows: This invention intercalates and composites monolayer MXene with PEDOT:PSS, and introduces dopamine hydrochloride to form a ternary composite conductive ink. This composite structure effectively suppresses the ineffective stacking of MXene nanosheets, constructing a continuous three-dimensional conductive network, resulting in an electrode conductivity more than 5 times higher than that of pure MXene films. Simultaneously, dopamine hydrochloride significantly enhances the antioxidant capacity of MXene by forming N-Ti coordination bonds with Ti atoms on the MXene surface; after 1000 CV cycles, the capacitance retention rate remains at approximately 105%, greatly improving the long-term stability of the electrode. Furthermore, the introduction of dopamine improves the interfacial adhesion between the conductive film and the skin, ensuring the stability of current transmission during long-term wear.

[0019] This invention uses a metal foil of a certain thickness as the electrode substrate, and laminates an MXene composite conductive film of the same thickness onto its surface, achieving synergistic optimization of electrode flexibility and conductivity. This flexible electrode can closely conform to the complex curvature of the human ear, maintaining stable skin contact during long-term wear, effectively avoiding the problems of easy detachment and large electrical signal fluctuations associated with traditional rigid electrodes. Heart rate variability testing verified that when using the electrodes of this invention for taVNS, volunteers showed a significant increase in high-frequency power (HF) and pRR50, indicating that vagal nerve activity was effectively enhanced and the stimulation effect was reliable and stable.

[0020] This invention employs an in-ear headphone-style main body design adapted to the human concha and cymba conchae, with an independent cymba conchae stimulation electrode extending from the rear of the stimulator. This achieves multi-point, wide-range synergistic stimulation of vagal nerve afferent fibers in the conchae region. Compared to traditional single-point stimulation electrodes, this design can more comprehensively activate the vagal nerve pathway, significantly improving the treatment effect of epilepsy and the overall effects of sleep and mood regulation. Short-term sleep quality experiments show that after using the electrodes of this invention for electrical stimulation, healthy volunteers experienced an increase in RMSSD (root mean square of the difference between adjacent normal sinus RR intervals), pNN50 (percentage of adjacent normal sinus RR interval differences greater than 50 ms), and SDNN (standard deviation of all normal sinus RR intervals) during sleep, and a decrease in average heart rate, indicating enhanced vagal nerve activity and a significant improvement in sleep structure.

[0021] The main control unit of this invention features six built-in stimulation modes: basic treatment, cognitive enhancement, emergency suppression, mild treatment, intensive treatment, and user-defined mode. These modes cover different stimulation frequencies, intensities, pulse widths, and durations. This design provides personalized neuromodulation solutions for different patient groups and application scenarios. It also combines the user experience of medical devices with that of everyday electronic devices, reducing patient resistance, improving treatment adherence, and extending epilepsy neuromodulation from hospitals to everyday home settings.

[0022] This invention provides a complete technical solution from conductive material synthesis and electrode design and fabrication to stimulator system integration. The fabricated MXene-based composite electrode possesses comprehensive advantages such as thinness, excellent conductivity, good biocompatibility, and stable stimulation effect, enabling efficient, stable, and comfortable transcutaneous vagus nerve stimulation. Experimental results in a rat model of epilepsy show that the electrode of this invention can effectively inhibit abnormal brain electrical activity during epileptic seizures and regulate autonomic nerve function, demonstrating significant therapeutic potential. This stimulator has the potential to become a non-innovative tool for the treatment of neurological diseases such as epilepsy, insomnia, and anxiety, possessing significant clinical translational value and broad application prospects. Attached Figure Description

[0023] Figure 1 This is a schematic diagram of the synthesis route of the conductive ink in Example 1; Figure 2 This is a schematic diagram of the fabrication route of the composite material electrode in Example 2; Figure 3 This is a low-temperature scanning electron microscope (LS-SEM) schematic diagram of the monolayer MXene nanosheets in Example 1 and the MP4A2 film in Example 2. Figure 4 X-ray diffraction patterns of the monolayer MXene nanosheets in Example 1 and the MP4A2 film in Example 2; Figure 5 XPS image of the MP4A2 film in Example 2; Figure 6 This is a comparison graph showing the conductivity of the MP4A2 membrane in Example 2 and the pure MXene membrane in Comparative Example 1. Figure 7 This is a design model diagram of the main body of the percutaneous ear vagus nerve stimulator in Example 3; Figure 8 This is a comparison graph showing the electrochemical performance of the MP4A2 membrane in Example 2 and the pure MXene membrane in Comparative Example 1. Figure 9 The results of heart rate variability analysis for percutaneous vagus nerve stimulation in Example 5; Figure 10 The results of the analysis on the improvement of sleep quality in healthy individuals by percutaneous vagus nerve stimulation in Example 5; Figure 11 The results of electroencephalogram (EEG) analysis and comparison between healthy rats and epileptic rats; Figure 12 The electroencephalogram (EEG) analysis results show the therapeutic effect of percutaneous vagus nerve stimulation on epileptic rats in Example 5. Figure 13 The electrocardiogram analysis results show the therapeutic effect of percutaneous auricular vagus nerve therapy on epileptic rats in Example 5. Detailed Implementation

[0024] To make the technical solutions of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings. It should be noted that the following embodiments are only used to better understand the technical solutions of the present invention and should not be construed as limiting the present invention.

[0025] Unless otherwise specified, all raw materials used in this invention are commercially available in the field.

[0026] The Chinese names and corresponding abbreviations of the raw materials used in specific embodiments of the present invention are as follows: Titanium aluminum carbide (MAX, Ti3AlC2), lithium fluoride (LiF), hydrochloric acid (HCl), poly(3,4-ethylenedioxythiophene)-poly(styrene sulfonic acid) (PEDOT:PSS), dopamine hydrochloride (DA), pentylenetetrazol (PTZ), PBS buffer (pH=7.2~7.4, 0.01M), cellulose acetate (CA) microporous filter membrane (50 mm × 0.22 μm), acetone (ACE).

[0027] Example 1. This embodiment provides a method for synthesizing MXene composite conductive ink. A schematic diagram of the synthesis route is shown below. Figure 1 The specific process is as follows: (1) Synthesis of monolayer MXene nanomaterials: LiF (1.5 g, 0.0578 mol, 1 eq) was dissolved in HCl solution (20 mL, 9 M, 0.225 mol, 3.9 eq) and stirred at room temperature for 0.5 h to obtain the etching solution; Ti3AlC2 powder (1.5 g, 2.33 mmol, 1 eq) was slowly added to the above etching solution, and the mixture was stirred continuously at 35 °C and 300 rpm for 36 h to obtain the reaction mixture. Transfer the reaction mixture to centrifuge tubes and centrifuge at 5000 rpm for 10 min, discarding the supernatant. Then, add 1 mol / L HCl solution to the precipitate and wash, centrifuging at 5000 rpm for 12 min. Repeat the centrifugation and washing process three times. Subsequently, wash with deionized water, repeating the washing process at 5000 rpm for 12 min until the pH of the supernatant reaches 5-6, and collect the precipitate. Deionized water was added to the precipitate, and the mixture was sonicated in an ice-water bath (40 kHz, 300 W) for 0.5 h to obtain a dispersion of exfoliated MXene nanosheets. The sonicated dispersion was centrifuged at 4500 rpm for 20 min, and the supernatant containing monolayer MXene nanosheets was collected. The collected upper clear liquid was freeze-dried for 24 h to obtain a single layer of MXene nanomaterials, which were then sealed and stored at 4 °C for use.

[0028] like Figure 1 As shown, the starting material is Ti3AlC2, which belongs to the typical MAX phase. The light blue MX layer in the figure is the Ti3C2 layer, which is the core framework retained after etching; the dark blue A layer is the aluminum atom layer, which is the part selectively dissolved and removed by HCl / LiF etching solution. The MX layer retains the excellent conductivity and mechanical properties of transition metal carbides, which is the basis for MXene as a conductive material.

[0029] (2) Synthesis of MXene-based composite conductive ink: Take 30 mg of the synthesized monolayer MXene nanomaterial and dissolve it in 15 ml of deionized water. Stir thoroughly at 200-300 rpm for 1-2 h at room temperature to obtain a 2 mg / ml MXene aqueous dispersion. Then add 0.5 ml of PEDOT:PSS aqueous solution (20 mg / ml) to the MXene aqueous dispersion and stir thoroughly at 200-300 rpm for 1-2 h at room temperature to obtain a PEDOT:PSS intercalated MXene dispersion. Prepare a 2 mg / ml dopamine hydrochloride aqueous solution and add 0.3 ml of dopamine hydrochloride aqueous solution to the above dispersion. Stir at 200-300 rpm for 0.5-1 h at room temperature to obtain the composite conductive ink.

[0030] Example 2. This embodiment provides a method for preparing an MXene composite electrode. A schematic diagram of the preparation route is shown below. Figure 2 The preparation method specifically includes: (1) The MXene composite conductive ink in Example 1 was ultrasonically treated (40 kHz, 300 W) for 5 min to make it more uniformly dispersed. Then, it was vacuum filtered on a cellulose acetate microporous filter membrane (50 mm × 0.22 μm) until the liquid was completely filtered to obtain a moist MXene composite conductive membrane; The moist MXene composite conductive membrane was vacuum dried at 40 °C for 4 h. After drying, it was placed in acetone solution to dissolve the CA microporous filter membrane. Then, the MXene composite conductive membrane after dissolving the CA microporous filter membrane was taken out and vacuum dried at 40 °C for 1 h to obtain the complete MXene composite conductive membrane, denoted as MP4A2 membrane.

[0031] (2) Apply a conductive silver paste with a thickness of about 0.1 mm to the metal substrate, and then cover the substrate with the MP4A2 film obtained in step (1). Dry at room temperature for 24 h to obtain the composite material electrode.

[0032] The monolayer MXene nanosheets prepared in Example 1 and the MP4A2 film prepared in Example 2 were observed by cryo-electron scanning microscopy, respectively. Figure 3 As shown, the top row shows a comparison of the cross-sectional SEM morphology, and the bottom row shows a comparison of the surface SEM morphology. Scanning electron microscopy reveals that the MP4A2 membrane has a more regular and orderly cross-section, with tighter interlayer spacing and a more uniform arrangement; the membrane surface is smoother, and the edges of the sheets are uniformly coated with PEDOT:PSS and dopamine, without obvious sharp protrusions or large pores. This indicates that PEDOT:PSS successfully intercalated between the MXene sheets, filling the interlayer gaps; the coordination effect of dopamine enhanced the bonding force between the sheets, making the stacking tighter; the adhesiveness of dopamine made the sheet bonding stronger, while also improving the interfacial adhesion between the membrane and human skin, ensuring stable current transmission during long-term wear.

[0033] X-ray diffraction analysis was performed on the monolayer MXene nanosheets prepared in Example 1 and the MP4A2 film prepared in Example 2, respectively. Figure 4 As shown, the characteristic peak 002 of the MP4A2 membrane shifts to the right, indicating a decrease in interlayer spacing. PEDOT:PSS intercalation fills the gaps between water molecules, while dopamine coordination further shortens the interlayer distance, resulting in a denser structure.

[0034] XPS tests were performed on the MP4A2 films prepared in Example 2, as follows: Figure 5As shown in the N 1s spectrum, an N-Ti peak appears at 396.5 eV, proving that the amino group of dopamine forms a coordination bond with the Ti on the MXene surface. In other words, dopamine is not a simple physical mixture, but rather it binds to MXene through chemical bonds, which not only enhances the interfacial binding force, but also stabilizes the active Ti atoms on the MXene surface and inhibits its oxidation.

[0035] Comparative Example 1. The preparation of a conventional pure MXene conductive film in this embodiment differs from that in Example 2 in that: Replace the MXene composite conductive ink in step (1) with a 2 mg / ml monolayer MXene aqueous dispersion, and follow the same steps as in Example 2 to obtain a pure MXene membrane without PEDOT:PSS and dopamine hydrochloride intercalation.

[0036] The conductivity of the films prepared in Example 2 and Comparative Example 1 was evaluated using a four-probe resistivity measurement system (FT-341, HOPTEC), and the results are as follows: Figure 6 As shown in the figure, the MP4A2 membrane has the highest conductivity. Compared with Comparative Example 1, the MP4A2 membrane after PEDOT:PSS and dopamine hydrochloride intercalation has a conductivity that is more than 5 times higher than that of the traditional pure MXene membrane.

[0037] Example 3. For reference Figure 7 The shape shown is used for the design and fabrication of a percutaneous ear vagus nerve stimulator, as detailed below: The stimulator body is designed to fit the concha and cymba conchae of the human ear. It adopts a similar in-ear headphone model. An additional electrode extends from the upper rear side of the body, bends and extends to the cymba conchae of the human ear, and opens at the concha and cymba conchae. Two stimulation sites are set. The opening at the conchae stimulation site is square and the opening at the cymba conchae stimulation site is rectangular. The MXene composite material electrode in Example 2 is respectively connected to the conchae stimulation electrode and the cymba conchae stimulation electrode. The wire inside the stimulator body connects to two stimulation sites, which are electrically connected to the concha cavity stimulation electrode and the concha cymba stimulation electrode, respectively. The stimulator body is sealed at the end with a rubber buckle and connected to an external main control unit that can output stimulation current at different levels.

[0038] Example 4. The main control unit for a percutaneous ear vagus nerve stimulator was designed and fabricated. The main control unit is required to output stimulation current at different levels, as detailed in the table below:

[0039] The waveform uses a bidirectional square wave, and bidirectional square wave current is output simultaneously on both electrodes.

[0040] UI design: Press and hold the power button for 3 seconds to turn on the device and enter the boot animation. After booting up, the six-grid main interface is displayed, with six levels: basic treatment, cognitive enhancement, emergency inhibition, mild treatment, intensive treatment, and user mode. Press the main button to switch the time dial. Taking the basic treatment at level 1 as an example, after selecting the level, you will be prompted to confirm the basic treatment intervention. There are two options: confirm and return. After confirming the treatment, the main interface will display "XX minutes countdown in basic treatment intervention". When selecting user mode, a parameter selection interface will appear. Users need to select the stimulation frequency (Hz) as 1, 4, 10, 15, 20, 25, 50, or 100; the stimulation intensity (mA) as 0.5, 1, 1.5, 2, 2.5, 3, 3.5, or 4; the pulse width (μs) as 100, 250, or 500; the on / off time (s / s) as 10 / 50, 20 / 40, 30 / 30, or 60 / 60; and the duration (h) as 0.25, 0.5, 0.75, or 1. After parameter selection, a prompt will appear to confirm the user mode intervention, with options to confirm or return. After confirming treatment, the main interface will display "XX minutes countdown in user mode intervention." Press and hold the main button for 3 seconds to power off. Press and hold the main button repeatedly to enter developer mode and display hardware information.

[0041] Example 5. This embodiment is used to verify the application of the MXene composite conductive film prepared in this application in transcutaneous ear vagus nerve stimulation. The following tests were performed: 1. Electrochemical performance testing of MXene composite conductive film: The interfacial electrochemical properties were analyzed using an electrochemical workstation (CHI 760E, CHInstruments) via electrochemical impedance spectroscopy (EIS), with a frequency scan range of 1 Hz to 100 kHz. Characterization was performed at 100 mV·s⁻¹ within a potential window of -0.6 to 0.6 V. -1 The capacitive behavior was evaluated at different scan rates. To characterize the capacitive behavior of the MXene composite conductive film at different scan rates, scan rates of 100, 50, 20, 10, 5, and 2 mV·s were performed within a potential window of -0.6 to 0.6 V. -1At different scan rates, CV tests were performed. To verify the electrochemical stability and antioxidant properties of the membrane, the MP4A2 membrane was subjected to 1000 CV cycles using an electrochemical workstation (CHI 760E, CHInstruments). The same tests were performed on the pure MXene conductive membrane, and the results were compared with those of the MP4A2 membrane. To verify the stimulatory effect of the membrane, the CSC value of the MP4A2 membrane was calculated using the chronovoltammetry method. The final results are as follows: Figure 8 As shown.

[0042] The CV cycle stability test results of the MP4A2 membrane and the pure MXene membrane are shown in Figures (a) and (b). The CV curves of the MP4A2 membrane before and after 1000 cycles almost completely overlap, with no significant decrease in curve shape, peak current, or capacitance. This indicates that the composite membrane maintains a stable electrode structure, active sites are not damaged, and electron transport channels are not blocked during long-term cycling, exhibiting excellent electrochemical cycle stability. In contrast, the current response of the pure MXene membrane gradually decreases with increasing cycle number, and the capacitance retention rate drops significantly after 1000 cycles. This is because the pure MXene membrane is prone to layer stacking and surface oxidation during cycling, leading to damage to the conductive network, reduction of active sites, and continuous performance degradation.

[0043] The capacitance retention results are shown in Figure (c). After 1000 cycles, the specific capacitance retention of the MP4A2 film remained at approximately 105%, an improvement likely related to electrode activation and interface contact optimization during cycling, with almost no performance degradation. In contrast, the specific capacitance retention of the pure MXene film continuously decreased from the initial 90%, remaining at only about 65% after 1000 cycles, indicating severe performance degradation. This directly demonstrates that the antioxidant modification of dopamine and the intercalation stabilizing effect of PEDOT:PSS effectively inhibited MXene oxidation and sheet collapse, significantly improving the cycle life of the electrode.

[0044] The rate performance test results are shown in Figures (f) and (g). The CV curves of the MP4A2 film at different scan rates all maintained a roughly rectangular shape with no obvious polarization distortion, even at 100mV. s -1Even at high scan rates, the composite film maintains a high current response and curve symmetry. This indicates that the composite film possesses excellent ion / electron transport kinetics. The continuous conductive network constructed by PEDOT:PSS and the improved interfacial wettability by dopamine ensure rapid charge transfer and ion diffusion at high scan rates. In contrast, the CV curve of the pure MXene film gradually deforms with increasing scan rate, and the current response decays significantly. At high scan rates, the curve deviates from the near-rectangular characteristic, and the polarization phenomenon intensifies. This is because the pure MXene film has tightly stacked layers, obstructing ion diffusion channels. At high scan rates, ions cannot quickly enter the interlayer, leading to a decrease in capacitance performance.

[0045] The initial CV performance comparison results are shown in (e). At the same scan rate, the area enclosed by the CV curves of the MP4A2 film is much larger than that of the pure MXene film, and the peak current is significantly higher. This indicates that the initial specific capacitance of the composite film is much better than that of the pure MXene film, which is attributed to the additional pseudocapacitive contribution provided by PEDOT:PSS and the full exposure of the active sites on the MXene surface after dopamine modification.

[0046] The results of the chronocurrent response test are shown in (d). The MP4A2 membrane exhibits a rapid and stable current response under pulsed voltage stimulation, with high overlap of current curves across multiple cycles and no significant drift or attenuation. This indicates that the composite membrane has low interfacial charge transfer impedance, fast current response speed, and good electrical stimulation signal transmission capability, making it suitable as a material for nerve electrical stimulation electrodes.

[0047] The capacitance-to-sense (CSC) comparison is shown in (h). At different scan rates, the CSC of the MP4A2 film is consistently significantly higher than that of the pure MXene film. While the CSC of the MP4A2 film decreases with increasing scan rate, the decrease is much smaller than that of the pure MXene film, and it maintains a high CSC value even at high scan rates. This directly demonstrates that the composite film possesses both high capacitance and excellent rate capability, enabling stable operation under electrical stimulation signals of different frequencies.

[0048] 2. Analysis of heart rate variability during transcutaneous vagus nerve stimulation: To evaluate the efficacy of MXene composite electrodes for percutaneous vagus nerve stimulation in the concha and cymba conchae of the human ear, 8–10 healthy volunteers were randomly selected for testing. Volunteers sat with their hands on their thighs at rest. Three hydrogel cardiac electrodes were placed 2 cm medial to the left wrist, 2 cm medial to the right wrist, and 2 cm superior to the medial aspect of the left ankle, connected using a three-lead configuration. Electrocardiogram (ECG) data were recorded for the first 5 minutes before stimulation. After recording, two MXene composite electrodes were placed in the cymba conchae and conchae of the left ear, respectively, connected externally. An external electrical stimulation power supply delivered a bidirectional square wave current pulse of 20 Hz, 1 mA, and 200 μs for 5 minutes, during which ECG data were recorded. After stimulation, the two MXene composite electrodes were removed, and ECG data were recorded again for the following 5 minutes. Subsequently, MATLAB programming was used to analyze 5-minute electrocardiogram data from three phases: pre-stimulation, during-stimulation, and post-stimulation. R-peaks were labeled, and the HF (ms) values ​​for each of the three phases were calculated. 2 The frequency domain indices of heart rate variability (HRV) were analyzed, including high-frequency power, LF / HF (low-frequency / high-frequency power ratio), RMSSD (root mean square of the difference between adjacent normal sinus RR intervals in ms), pNN50 (% of the percentage of adjacent normal sinus RR intervals with an absolute value greater than 50 ms), and SDNN (standard deviation of all normal sinus RR intervals in ms), and then compared. ECG data were processed using MAMLAB analysis, and the results are shown below. Figure 9 It can be seen that the high-frequency power (HF) and pRR50 increased significantly, while RMSSD and SDNN increased slightly. This indicates that the vagus nerve was significantly activated during electrical stimulation, and the autonomic nervous system balance shifted towards parasympathetic dominance, i.e., vagus nerve. The HF / PRN ratio is affected by both the sympathetic and vagus nerves, and its decrease indicates that vagus nerve activity was relatively enhanced, while sympathetic nerve activity was relatively inhibited.

[0049] 3. Analysis of the effect of transcutaneous vagus nerve stimulation on sleep quality in healthy individuals: To evaluate the effect of percutaneous vagus nerve stimulation (PVS) with MXene composite electrodes in the concha and cymba conchae of the human ear on improving sleep quality in volunteers, 8-10 healthy volunteers were randomly selected for the test. Before each volunteer went to sleep, two MXene composite electrodes were placed in the cymba conchae and conchae of the left ear, respectively, and then connected to external leads. An external electrical stimulation power supply delivered a bidirectional square wave current pulse of 20 Hz, 1 mA, and 200 μs for 30 minutes. A smart sleep monitoring device was worn on the wrist to monitor and record heart rate and electrocardiogram (ECG) information in real time during sleep. Data were collected one week before, during, and one week after stimulation. Analysis included heart rate and HF (ms) within 3 hours after sleep onset. 2 The following parameters were compared: high-frequency power, LF / HF (low-frequency / high-frequency power ratio), RMSSD (root mean square of the difference between adjacent normal sinus RR intervals in ms), pNN50 (% of the percentage of adjacent normal sinus RR intervals with an absolute value greater than 50 ms), and SDNN (standard deviation of all normal sinus RR intervals in ms). Data were analyzed using MATLAB, and the results are shown below. Figure 10 The decrease in average heart rate reflects better physiological recovery. The increase in RMSSD during sleep directly reflects enhanced vagal tone, and the significantly higher RMSSD during deep sleep compared to light sleep indicates improved sleep depth. Increased SDNN during stimulation indicates improved fine control of heart rate by the vagus nerve, suggesting a more stable sleep structure. The increase in HF during stimulation, consistent with the trend of RMSSD, further supports the conclusion of enhanced vagal tone and improved deep sleep quality.

[0050] 4. Analysis of the therapeutic effect of transcutaneous vagus nerve stimulation on epileptic rats: The therapeutic effect of MXene composite electrode stimulation on epilepsy symptoms in the left ear concha and cymba conchae of rats was evaluated. Epilepsy was modeled by intraperitoneal injection of PTZ (10 mg / ml) at 60 mg / kg into healthy rats (n=6).

[0051] (1) Electroencephalography (EEG) detection: Epilepsy rats underwent a 30-minute non-invasive EEG detection. After deep anesthesia induced by 2% isoflurane, needle electrodes were inserted subcutaneously into the anterior fontanelle of the rats, and simultaneously, needle electrodes were inserted subcutaneously above the temporalis muscles or neck muscles on both sides. A multi-channel neural acquisition system (RM6240EC, Chengdu Instrument Factory) was used to record the total electrical activity of the prefrontal cortex and surrounding extensive cortical areas. Brain signals in the epilepsy rats were recorded 30 minutes before stimulation. Then, two MXene composite material electrodes were placed in the cymba conchae and cavum conchae of the rats, respectively, and a 30-minute bidirectional square wave current pulse stimulation at 20 Hz, 1 mA, and 100 μs was applied, with brain signals recorded simultaneously for 30 minutes during stimulation. Brain signals were recorded 30 minutes after stimulation. The EEGs during, during, and after stimulation were analyzed, and EEG, time-spectrum, and average power spectrum were generated and compared to assess the therapeutic effect. Figure 12 As can be seen, the amplitude and frequency of spike waves in the original EEG decreased, and the high-frequency region in the time spectrum became significantly darker and bluer, indicating that abnormal high-frequency activity was inhibited during stimulation. This inhibitory effect persisted 20 minutes after the stimulation ended. Background noise decreased, the high-frequency region in the time spectrum remained predominantly blue, and there was no abnormal accumulation of high-frequency (Beta wave) energy in the average power spectrum. The overall spectral morphology was closer to the healthy "1 / f" characteristic (i.e., power naturally decays as frequency increases) than the "peak-like" aggregation seen in epileptic states. This suggests that transcutaneous vagus nerve stimulation had a certain inhibitory and therapeutic effect on the symptoms of epileptic rats.

[0052] (2) Electrocardiogram (ECG) detection: ECGs were performed on epileptic rats for 30 minutes. After deep anesthesia induced by 2% isoflurane, subcutaneous needle electrodes (3-5 mm deep) were inserted into the medial aspect of the right forelimb, right hindlimb, and left hindlimb of the rats. A three-lead connection was used to record the ECG signals of the epileptic rats. ECG signals were recorded for the first 30 minutes before stimulation. Then, two MXene composite material electrodes were placed in the sacrum and concha of the rats, respectively, and subjected to 30 minutes of bidirectional square wave current pulse stimulation at 20 Hz, 1 mA, and 100 μs. ECG signals were simultaneously recorded for 30 minutes during stimulation. Brain signals were recorded for 30 minutes after stimulation. The ECGs during, during, and after stimulation were analyzed, and EEG, time-spectrum, and average power spectrum were generated and compared to assess the therapeutic effect. Results are as follows: Figure 13As shown, the LF / HF ratio in the treatment group not only decreased but was even slightly lower than the healthy level; at the same time, the three indicators reflecting vagal nerve activity, SDNN, RMSSD and pNN5, all increased significantly and were slightly higher than those in the healthy control group.

[0053] Obviously, the above embodiments are merely illustrative examples for clear explanation and are not intended to limit the implementation. Those skilled in the art will recognize that other variations or modifications can be made based on the above description. It is neither necessary nor possible to exhaustively list all possible implementations here. However, obvious variations or modifications derived therefrom are still within the scope of protection of this invention.

Claims

1. A composite electrode for vagus nerve stimulation, characterized in that, Includes a metal substrate and a composite conductive film disposed on the metal substrate; The composite conductive film is prepared by vacuum filtration of composite conductive ink. The composite conductive ink comprises a single layer of MXene nanomaterials, PEDOT:PSS, and dopamine hydrochloride; the PEDOT:PSS and dopamine hydrochloride are intercalated between the layers of the single layer of MXene nanomaterials. The mass ratio of the monolayer MXene nanomaterial to PEDOT:PSS is 2~4:1, and the mass ratio of the monolayer MXene nanomaterial to dopamine hydrochloride is 30~50:

1. The monolayer MXene nanomaterial was prepared by the following process: LiF was dissolved in HCl to obtain an etching solution, and Ti3AlC2 powder was added. The mixture was stirred continuously to obtain a reaction mixture. Transfer the reaction mixture to a centrifuge tube, centrifuge and discard the supernatant. Wash the precipitate with HCl solution and deionized water in sequence until the pH of the supernatant reaches 5-6, and collect the precipitate. Deionized water was added to the precipitate, and the mixture was ultrasonically treated in an ice-water bath to obtain a dispersion. The dispersion was centrifuged, the supernatant was collected, and the mixture was freeze-dried to obtain a single-layer MXene nanomaterial.

2. The composite electrode for vagus nerve stimulation according to claim 1, characterized in that, Monolayer MXene nanomaterials and PEDOT:PSS were separately prepared into aqueous dispersions and stirred thoroughly. The monolayer MXene aqueous dispersion and the PEDOT:PSS aqueous dispersion were mixed and stirred to obtain a PEDOT:PSS intercalated MXene dispersion. Then, dopamine hydrochloride aqueous solution was added and stirred to obtain a composite conductive ink based on MXene.

3. The composite electrode for vagus nerve stimulation according to claim 1, characterized in that, The thickness of the metal substrate is 0.2~0.3 mm; the thickness of the composite conductive film is 0.2~0.3 mm.

4. The composite electrode for vagus nerve stimulation according to claim 1, characterized in that, The metal substrate is selected from stainless steel foil, copper foil, or titanium foil; the surface of the metal substrate is provided with a metal interface for connecting metal wires.

5. A method for preparing a composite electrode for vagus nerve stimulation according to any one of claims 1 to 4, characterized in that, Includes the following steps: The composite conductive ink was vacuum filtered into a film, vacuum dried, and then peeled off to obtain the MXene composite conductive film. The conductive film is fixed onto a metal substrate using conductive silver paste and then dried to obtain a composite electrode based on MXene.

6. A transcutaneous ear vagus nerve stimulator, characterized in that, It includes a stimulator body, electrodes disposed on the surface of the stimulator body, and wires disposed inside the stimulator body; The stimulator body is an in-ear headphone-style body whose shape is adapted to the human concha and cymba conchae. The stimulator body has two stimulation sites, which are used to cover the concha cavity and the cymba conchae, respectively; The electrode is a composite electrode for vagus nerve stimulation as described in any one of claims 1 to 4, comprising a separately configured cavum concha stimulating electrode and cymba concha stimulating electrode. The wires are used to connect the corresponding electrodes and stimulation sites.

7. The percutaneous ear vagus nerve stimulator according to claim 6, characterized in that, The stimulator body is made of PEEK material or PC / ABS alloy.

8. The percutaneous ear vagus nerve stimulator according to claim 6, characterized in that, It also includes a main control unit connected to the main body of the stimulator, the main control unit having a UI interactive interface and multiple built-in stimulation levels.

9. The use of a composite electrode for vagus nerve stimulation as described in any one of claims 1 to 4, or a percutaneous vagus nerve stimulator as described in any one of claims 6 to 8, in the preparation of a device for treating epilepsy or a neuromodulation device for improving anxiety / sleep disorders.

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