Biodegradable capacitive coupling nerve stimulator for inflammation radio therapy

Abstract

The invention discloses a biodegradable capacitance coupling nerve stimulator used for radio therapy inflammation, the capacitance coupling nerve stimulator comprises a nerve stimulation element and a packaging element, the packaging element is located on the surface of the nerve stimulation element, the packaging element is an elastomer SBPUE, and the packaging element is located on the surface of the nerve stimulation element. The preparation method of the elastomer SBPUE comprises the following steps: S1, mixing PCL and PTMEG in a container, heating the mixture in a vacuum oil bath at 100 DEG C to remove moisture, and then cooling to 70 DEG C; s2, dropwise adding isophorone diisocyanate dissolved in DMAc and DBTDL into the container, stirring in a nitrogen atmosphere, synthesizing a prepolymer, and cooling to room temperature; s3, adding dimethyl glyoxime dissolved in DMAc as a chain extender, and carrying out a sealed reaction; s4, after the reaction is completed, DMAc is added to adjust the concentration of a product to 30 wt%, and the elastomer SBPUE is obtained. Chronic electrical stimulation is carried out on vagus nerves in a young rat model, and successful application of the vagus nerves in electronic drug anti-inflammatory treatment of PIBD is proved.

Description

Technical Field

[0001] The invention belongs to the technical field of biomedical electronics medical instruments, and in particular relates to a biodegradable capacitive coupling nerve stimulator for radiofrequency therapy of inflammation. Background Art

[0002] Pediatric inflammatory bowel disease (PIBD), an immune-mediated gastrointestinal disease, is a difficult-to-treat disease with no effective treatment. The incidence of PIBD has been increasing, and children affected by the disease often face other complications such as growth failure, delayed puberty, psychological problems, and concerns about body image. Current drug and surgical treatments have limited efficacy, so finding more effective treatments is an ongoing challenge. Recently, bioelectronic device-based peripheral nerve stimulation electromedicine has been explored in preclinical studies for the treatment of difficult-to-treat metabolic and immune-mediated diseases. However, existing bioelectronic devices often involve non-biodegradable neural electrodes and bulky energy supply systems. These implanted non-biodegradable components, if subsequently removed, can cause severe tearing and perforation of neural tissue as it may be encapsulated by fibrotic tissue at the electrode-tissue interface, while leaving them in place may limit the child's neurodevelopment. Therefore, there is an urgent need to develop biodegradable electrotherapy devices, especially for growing pediatric patients, whose nerves are still developing and may increase in size.

[0003] The limitations of bulky battery-powered implants highlight the need for miniaturized, wirelessly powered bioelectronic devices. Recently, implantable flexible piezoelectric and triboelectric nanogenerators have been investigated for self-powered bioelectronics, harvesting energy from internal organ movements such as breathing, heartbeat, or muscle stretching. Precise control of stimulation parameters, including current density, pulse width, stimulation frequency, and treatment duration, has been achieved in battery-free, ultrasound-driven neurostimulators. Despite this, the development of biodegradable, ultrasound-driven, miniaturized nanogenerators with high current output for electrotherapy treatment remains a challenge. In addition, the current integration and packaging of powered nanogenerators, device wiring, and neural stimulation electrodes requires a complex and challenging multilayer stacking process. Developing a high-performance electrotherapy device that integrates biodegradable neural electrodes, device wiring, and wireless power transfer components is a daunting task that needs to be achieved through a simple all-in-one process.

[0004] Constructing robust neural interfaces is essential for reliable chronic neural stimulation during long-term electrotherapy, which is indeed challenging for commonly used mouse and rat models with tiny peripheral nerves. In the widely used cuff electrodes that wrap around the target peripheral nerve, the neural stimulation electrode is usually fixed by mechanical suturing. This approach often leads to stress compression and increased inflammation of the neural tissue. To alleviate the high stress compression on the peripheral nerve fibers during the cuff electrode anchoring process, researchers have recently investigated advanced fixation methods. For example, carefully designed mechanical structures, shape memory polymers, and mechanically adaptive hydrogels have been developed for precise fixation of cuff electrodes. Despite these new methods, designing multifunctional materials that can both stress-free fixation of neural electrodes and provide biodegradable properties for transient bioelectronics remains elusive. We envision that using a biodegradable elastomer with self-healing properties as an encapsulation layer for the neural electrode can address this challenge. The adhesive ability between the two elastomer interfaces can achieve effective and gentle fixation. Summary of the invention

[0005] In order to solve the deficiencies of the above-mentioned prior art, the present invention provides a biodegradable capacitively coupled neurostimulator (BCC neurostimulator) for radiotherapy of inflammation, which is successfully applied in the electronic medicine anti-inflammatory treatment of PIBD by chronic electrical stimulation of the vagus nerve in a juvenile rat model. The BCC neurostimulator provides electrical stimulation pulses by high-frequency electric field capacitive coupling between an implantable power receiving electrode and a wearable power transmitting electrode. In order to achieve the insulation and biocompatible sealed packaging of the device, the present invention has developed a self-healing biodegradable polyurethane elastomer (SBPUE). The self-healing adhesive properties of the polyurethane elastomer help to easily fix the neurostimulation electrode on the tiny vagus nerve in the rat model. The advantage of this simple capacitive coupling configuration is that it can integrate the neurostimulation electrode, the serpentine connecting wire, the power receiving electrode and the grounding electrode. The advantage of this simple capacitive coupling configuration is that the integrated integration of the neurostimulation electrode, the connecting wire, the power receiving electrode and the grounding electrode can be achieved by laser cutting a piece of molybdenum (Mo) foil. Our detailed investigation of the therapeutic efficacy and immune microenvironment demonstrates that programmable capacitively coupled electrical pulses can effectively modulate the vagus nerve for PIBD treatment by regulating the balance of intestinal immune cells, representing an important step toward wireless radiotherapy for dynamically developing pediatric patients.

[0006] In order to achieve the above purpose, this application adopts the following technical solutions:

[0007] A biodegradable capacitively coupled neurostimulator for radiotherapy of inflammation, the capacitively coupled neurostimulator comprising a neurostimulating element and a packaging element, the packaging element being located on the surface of the neurostimulating element, the packaging element being an elastomer SBPUE, and the preparation method of the elastomer SBPUE comprising the following steps:

[0008] S1: PCL and PTMEG were mixed in a container, the mixture was heated in an oil bath at 100°C under vacuum to remove moisture, and then cooled to 70°C;

[0009] S2: Isophorone diisocyanate and DBTDL dissolved in DMAc were added dropwise into a container and stirred under a nitrogen atmosphere to synthesize the prepolymer and then cooled to room temperature;

[0010] S3: adding dimethylglyoxime dissolved in DMAc as a chain extender to seal the reaction;

[0011] S4: After the reaction is completed, DMAc is added to adjust the concentration of the product to 30 wt %, thereby obtaining the elastomer SBPUE.

[0012] As one embodiment, the preparation method of the elastomer SBPUE comprises the following steps:

[0013] S1: PCL (14.5 g, 7.25 mmol) and PTMEG (7.25 g, 7.25 mmol) were placed in a container and mixed, and the mixture was heated in an oil bath at 100 °C under vacuum to remove moisture, and then cooled to 70 °C;

[0014] S2: Isophorone diisocyanate (6.77 g, 30.45 mmol) and DBTDL (0.050 g, 2000 ppm) dissolved in DMAc (5 mL) were added dropwise into a container and stirred under a nitrogen atmosphere. After the prepolymer was synthesized, it was cooled to room temperature;

[0015] S3: Dimethylglyoxime (1.683 g, 14.50 mmol) dissolved in DMAc (10 mL) was added as a chain extender and the reaction was sealed;

[0016] S4: After the reaction is completed, DMAc (30 mL) is added to adjust the concentration of the product to 30 wt %, thereby obtaining the elastomer SBPUE.

[0017] In the above technical solution, the neural stimulation element includes a power receiving electrode, a ground electrode, two neural stimulation electrodes and a serpentine connecting wire, wherein one of the neural stimulation electrodes is connected to the power receiving electrode via the serpentine connecting wire, and the other neural stimulation electrode is connected to the ground electrode via the serpentine connecting wire.

[0018] In the above technical solution, the power receiving electrode and the grounding electrode are circular, with diameters of 10 mm and 5 mm respectively, and they are connected to the nerve stimulation electrode through the serpentine connecting wire with a length of 10 mm and a width of 0.2 mm.

[0019] In the above technical solution, the nerve stimulation electrode is 0.1 mm wide and 5 mm long, and the gap between two nerve stimulation electrodes is 1 mm.

[0020] In the above technical solution, the nerve stimulation element is made of a laser-cut 20 μm thick Mo foil and is encapsulated with a 100 μm thick elastomer SBPUE.

[0021] In the above technical solution, the cut neural stimulation element is placed on the partially cured adhesive surface of the SBPUE substrate, thus completing the packaging.

[0022] In the above technical solution, both sides of the power receiving electrode are packaged, and only one side of the grounding electrode is packaged.

[0023] The beneficial effects of the present invention are:

[0024] The present invention has successfully developed a biodegradable capacitively coupled neurostimulator (BCC neurostimulator) for radiotherapy of inflammation, which has the characteristics of wireless power supply, battery-free and miniaturization, and is specifically used for electronic drug treatment of PIBD. The BCC neurostimulator adopts capacitively coupled wireless energy transmission technology to integrate the power receiving electrode, ground electrode, neurostimulation electrode and serpentine connecting wire into one, and is made using a simple laser cutting process. In addition, the self-healing properties of the SBPUE material rationally designed in the present invention not only ensure the seamless packaging of the implanted device, but also enable the neurostimulation electrode to be gently and effectively attached to the tiny peripheral nerves, ensuring a stable and stress-free neural interface. The BCC neurostimulator exhibits excellent stability and biodegradability, and can maintain electrical properties throughout the treatment period and then gradually degrade, thereby minimizing the risk of long-term tissue damage or immune response. In vivo experiments have shown that the BCC neurostimulator can achieve precise and efficient chronic biphasic electrical stimulation without the need for complex circuits. The device effectively regulates vagus nerve activity and reduces inflammation.

[0025] Clinical manifestations of PIBD children include diarrhea, blood in the stool, etc., often accompanied by growth and development disorders such as weight loss or slow growth. The surface of the intestinal mucosa shows rough and granular changes. Repeated chronic inflammation also causes the intestine to shorten and make the intestine look like a lead pipe. The innate and adaptive immunity of the intestine of PIBD mice is aggravated. The overactivation of the immune system leads to the destruction of the intestinal mucosal structure, inflammatory cell infiltration and crypt loss, and intestinal mucosal barrier damage. In addition, long-term and repeated chronic intestinal inflammation leads to abdominal adhesion, intestinal fibrosis and stiffness, and the colon is significantly shortened. The micro-VNS device was implanted into the left vagus nerve of 3-week-old SD mice and VNS (vagus nerve stimulation) was given for 20 minutes every day for 32 consecutive days, which effectively alleviated the growth and development disorders, intestinal pathological damage, intestinal inflammation, and increased intestinal epithelial permeability of PIBD mice. All of these prove the therapeutic effect of VNS (vagus nerve stimulation) on PIBD.

[0026] The therapeutic potential of the BCC neurostimulator in precision bioelectronic medicine, especially in pediatric patients, is critical for safety, biodegradability, and minimal invasiveness. This approach not only optimizes the therapeutic effect of chronic inflammatory diseases such as PIBD, but also enhances patient safety and comfort, paving the way for future advances in transient bioelectronics and precision medicine. BRIEF DESCRIPTION OF THE DRAWINGS

[0027] Figure 1 :Abnormal vagus nerve function in PIBD young mice.

[0028] Figure 2 : In vitro output performance of the BCC neurostimulator. Among them, a. The input voltage waveform of the power-transmitting gold foil electrode is designed for efficient wireless power transmission. b. The output voltage pulse generated by the power-receiving molybdenum foil electrode. c. The relationship between the open-circuit voltage and short-circuit current generated by the BCC neurostimulator and the input voltage. d. The stability of the output voltage generated by the molybdenum power receiving electrode during immersion in PBS at 37°C for 4 weeks. e. The output current of the molybdenum foil power receiving electrode when an input drive voltage of 4V (1Hz) is applied to the gold foil power transmitting electrode. f. The amplified output current waveform with an amplitude of about 250μA. g. The dependence of the open-circuit output voltage on the input voltage at different distances between the gold foil power transmitting electrode and the molybdenum foil power receiving electrode.

[0029] Figure 3 : Measurement and fitting of resistance, reactance and capacitance components at different frequencies. a. Relationship between frequency and resistance or inductive reactance of neural tissue (1 mm vagus nerve of rat), showing the decrease in resistance (red) and increase in reactance (green) at higher frequencies. b. Relationship between frequency and device capacitance (powered electrode with 1 cm diameter), showing the decrease in capacitance at higher frequencies.

[0030] Figure 4 : Dependence of output current on input voltage under different loads. Where, a. Output current of Mo power receiving electrode without reactance matching. b. Output current of Mo power receiving electrode with reactance matching (adding 1mH inductor in the power transmitter circuit). When the load resistance (2kΩ to 20kΩ) increases, the output current of Mo power receiving electrode decreases. After reactance matching, it can be close to about 250μA when the load resistance is about 10kΩ (impedance of neural tissue at 1MHz).

[0031] Figure 5 : Electrochemical properties of Mo neural stimulation electrodes. Among them, a, representative Bode plots of Mo electrodes and gold electrodes. b, representative CV curves of Mo electrodes and gold electrodes. c, representative CIC curves of Mo electrodes and gold electrodes with biphasic pulses (±0.5V, 1.5ms). d, impedance (1kHz) of Mo neural stimulation electrodes and gold neural stimulation electrodes (n=5). e, CSC characteristics of Mo neural stimulation electrodes and gold neural stimulation electrodes (n=5). f, CIC characteristics of Mo neural stimulation electrodes and gold neural stimulation electrodes (n=5). Compared with gold neural stimulation electrodes, the CSC and CIC characteristics of Mo neural stimulation electrodes are significantly improved, and the impedance is lower. g, long-term electrochemical performance monitoring of Mo neural stimulation electrodes immersed in PBS solution, the results show that Mo neural stimulation electrodes can ensure good electrochemical performance within 4 weeks (n=5). Figure 6 :Design and structural characterization of SBPUE. a. 1H NMR of the developed SBPUE confirms its successful synthesis. b. FT-IR spectrum of SBPUE shows functional groups corresponding to PCL and PTHF.

[0032] Figure 7 : Mechanical properties and self-healing characteristics of SBPUE. Among them, a, representative tensile stress-strain curve of SBPUE, which has a tissue-like tensile modulus of 34 kPa. b, representative load-displacement curve of SBPUE shows that SBPUE achieves rapid healing and complete healing within 120 minutes. c, when the healing time is extended to 120 minutes (n=5), the interface toughness between two healed SBPUE increases from 420.8±22.63J m-2 to 937±111.7J m-2. d, SBPUE peeling and tensile test image, two SBPUE films self-heal for 120 minutes, scale bar, 1 cm. e, optical microscope images of damaged and healed SBPUE films, scale bar: 100 μm. f, ultra-tensile response of SBPUE, linear strain is about 1500%. g, cyclic tensile curve of SBPUE at 20% strain shows residual strain of about 15%. There is no waiting time between two consecutive cyclic stretching (cycle 1-cycle 10).

[0033] Figure 8 : In vitro cytotoxicity test of BCC neurostimulator. Among them, a, CCK8 detection of cell viability of ND7 / 23 cells by BCC neurostimulant extract (n=5). b, CCK8 detection of cell viability of L929 cells by BCC neurostimulant extract (n=5). c, live-dead staining of ND7 / 23 and L939 cells by BCC neurostimulant extract. Scale bar, 100 μm. Data are expressed as mean ± SD in (a and b), first by one-way ANOVA and then by Tukey test. NS, not significant.

[0034] Fig. 9 : Biodegradability of BCC neurostimulator components. a. Weight changes of Mo and SBPUE films (immersed in 1× PBS at 37°C) indicate that they biodegrade slowly and thus can maintain their shape in the first month to match the disease treatment period (n=5). b. Comparison of images of each component before and after 1 month of in vitro degradation, scale bar, 5 mm. c. SEM image of Mo film after degradation. Scale bar, 50 μm.

[0035] Fig.10 : In vivo biocompatibility and transient performance of the BCC neurostimulator. Among them, a, photos of the BCC neurostimulator implantation process. The capacitively coupled power receiving electrode of the BCC neurostimulator was placed under the skin of the neck, and the neurostimulating electrode of the BCC neurostimulator was gently wrapped around the vagus nerve through the self-healing adhesive properties of BSPUE. b, complex action potential (CAP) evoked by the vagus nerve after neuromodulation using stimulation pulses generated by the wirelessly powered BCC neurostimulator. c, representative immunofluorescence photos of the vagus nerve in the BCC group and the sham group 4 weeks after implantation. Scale bar, 50 μm. d, normalized fluorescence intensity of neuronal nuclei (NeuN), tumor necrosis factor-α (TNF-α), and S100 calcium-binding protein B (S-100β) in the BCC group and the sham group (n=5). e, representative immunofluorescence photos of skin tissue in the BCC group and the sham group 4 weeks after implantation. Scale bar, 100 μm. f, Normalized fluorescence intensity of caspase-3 and TNF-α in the BCC group and sham group (n = 5). g, Images of implanted BCC neurostimulators showed that they maintained good shape within 4 weeks and completed most of the degradation process within 12 weeks. Data in (d, f) are presented as mean ± SD, first analyzed by one-way ANOVA and then by Tukey post hoc test. NS, not significant.

[0036] Fig.11: Histological analysis of major organs (n=6). H&E stained histological appearance of dissected heart, liver, spleen, lung, and kidney tissues from the VNS group and sham operation group. Scale bar, 100 μm.

[0037] Fig.12 : Photos of the wireless stimulation system. a. The external ground electrode is composed of a rectangular Mo with PU encapsulated on one side. b. The power transmitting electrode is composed of a gold foil with PU encapsulated on both sides. c. Image of the placement of the external wireless stimulation system. The external ground electrode and the implanted ground electrode are electrically connected to the skin tissue. And the power transmitting electrode is well aligned with the implanted power receiving electrode. Scale bar, 1 cm.

[0038] Fig.13 :Acute recordings after capacitive coupling stimulation. Among them, a. Compound action potential (CAP) of vagus nerve after capacitive coupling stimulation of rat vagus nerve. b. Compound muscle action potential (CMAP) caused by capacitive coupling stimulation of rat sciatic nerve. c. Gastrocnemius muscle tension caused by capacitive coupling stimulation of rat sciatic nerve. Changes in CAP, CMAP and gastrocnemius muscle tension verified the effectiveness of capacitive coupling stimulation on neuromodulation.

[0039] Fig.14 : Temperature changes caused by capacitive coupling effect. 20 minutes of capacitive coupling stimulation shows no obvious temperature increase. Scale bar, 1 cm.

[0040] Fig.15:BCC neurostimulator chronic vagus nerve stimulation electrotherapy for PIBD. a. Overall experimental schedule for in vivo experiments in the OXA-induced PIBD model. OXA (3%, 10 mg / kg dose) was administered by skin presensitization on day 1, and OXA (1%, 10 mg / kg dose) was administered three times by enema on days 6, 20, and 34. Rats in the VNS group were implanted with a BCC neurostimulator on day 1, and capacitively coupled wireless VNS was administered for 20 minutes every day from day 6 until the rats were killed. b / c. Average weight changes (b) and dynamic activity index (DAI) scores over time (c) calculated from different groups, indicating that capacitively coupled wireless VNS can alleviate weight loss and slow down the increase in DAI scores (n=5). d. Colon lengths of rats in the control, PIBD, and VNS groups indicate that capacitively coupled wireless VNS can inhibit the shortening of the colon (n=5). e. Colon mucosal injury index (CMDI) of rats in different groups showed that the PIBD group increased faster and the VNS group increased slower (n=5). f, photos of mesenteric lymph nodes, colon and colon mucosa of rats in different groups. g, colon inflammation-related histological scores (HIS) of rats in different groups showed that capacitive-coupled wireless VNS could significantly reduce inflammation of rat colon (n=5). h, H&E staining images of colon of rats in different groups showed that PIBD model could induce significant colon inflammation and injury, and capacitive-coupled wireless VNS could reduce such injury. i, intestinal TNF-α concentrations in different groups suggested that capacitive-coupled wireless VNS could reduce inflammation caused by OXA-induced PIBD (n=5). j, serum FITC-dextran concentrations in different groups suggested that capacitive-coupled wireless VNS could improve hyperpermeability enhancement caused by OXA-induced PIBD (n=5). Data are expressed as mean ± SD in (b, c, d, e, g, i, j), and one-way ANOVA was performed first, followed by Tukey post hoc test. *P≤0.05, ***P≤0.001. NS, not significant. DETAILED DESCRIPTION

[0041] In order to better illustrate the purpose, technical solutions and advantages of the present invention, the present invention will be further described below in conjunction with specific embodiments. The present invention can be implemented in many different forms and should not be construed as being limited to the embodiments set forth herein. On the contrary, these embodiments are provided so that this disclosure will be thorough and complete, and the concept of the present invention will be fully conveyed to those skilled in the art, and the present invention will only be limited by the claims.

[0042] Unless otherwise specified, various raw materials, reagents, instruments and equipment used in the present invention can be purchased from the market or prepared by existing methods.

[0043] 1. Experimental process

[0044] 1. Preparation of BCC neurostimulator

[0045] Biodegradable and self-healing elastomer (SBPUE) is used as an encapsulating element of the BCC neurostimulator to prevent it from direct contact with the surrounding biological fluids. The typical polymerization procedure of SBPUE is described as follows. PCL (14.5 g, 7.25 mmol) and PTMEG (7.25 g, 7.25 mmol) were placed in a dry glass container equipped with a mechanical stirrer. The mixture was heated in an oil bath at 100 ° C for 1 hour under vacuum to remove any moisture and then cooled to 70 ° C. Isophorone diisocyanate (6.77 g, 30.45 mmol) and DBTDL (0.050 g, 2000 ppm) dissolved in DMAc (5 mL) were added dropwise to the container and stirred for 2 hours under a nitrogen atmosphere. After the prepolymer was synthesized, the reactor was cooled to room temperature. Dimethylglyoxime (1.683 g, 14.50 mmol) dissolved in DMAc (10 mL) was then added as a chain extender. The reactor was sealed and the reaction was carried out for 12 hours. Finally, the concentration of the product was adjusted to 30 wt % by adding additional DMAc (30 mL) for further characterization.

[0046] The neurostimulation electrodes, serpentine connecting wires, power receiving electrodes, and ground electrodes of the BCC neurostimulator are made of laser-cut Mo foil (20 μm thick). They are designed by CAD, where the power receiving electrode and the ground electrode are circular with diameters of 10 mm and 5 mm, respectively. They are connected to the neurostimulation electrodes via serpentine wires that are 10 mm long and 0.2 mm wide. The neurostimulation electrodes are 0.1 mm wide and 5 mm long, and the gap between the two neurostimulation electrodes is 1 mm. A femtosecond laser (Suzhou Bailing Laser Co., Ltd., Axinite IR30) was used to cut the drawn pattern on the Mo foil. The laser parameters were set to a repetition rate of 1 kHz and a power of 1.5 W. The Mo foil was placed on the partially cured sticky surface of the SBPUE substrate. The uncured SBPUE coating ensures that the SBPUE film is firmly bonded to itself to form a top encapsulation layer. Both sides of the power receiving electrode are encapsulated, and only one side of the ground electrode is encapsulated.

[0047] 2. Chemical structure characterization

[0048] The chemical structure of SBPUE was studied using nuclear magnetic resonance spectrometer (NMR, AV400, Bruker, Switzerland) and Fourier transform infrared spectrometer (FTIR, Nicolet iS50R, USA).

[0049] 3. Electrochemical characterization

[0050] The electrochemical properties of the Mo neural stimulation electrodes in 1×PBS were characterized using a three-electrode system (including a working electrode (Mo electrode), a counter electrode (1×1 cm Pt sheet), and an Ag / AgCl reference electrode). In the electrochemical impedance spectroscopy, the measured frequency range was from 10 -1 to 10 5 Hz, using a 5 mV amplitude sine wave current and a DC potential of 0 V. Charge injection measurements were performed in 1 × PBS using biphasic pulses of 1.5 ms and ±0.5 V.

[0051] According to the measured charge injection curve, the charge injection density (Qinj) is calculated using formula (1):

[0052]

[0053] Where Qc represents the amount of charge passing through the cathode, Qa represents the amount of charge passing through the anode, and A represents the area of ​​the Mo electrode.

[0054] To measure the charge storage capacity (CSC), cyclic voltammetry was applied with a scan potential between -0.5 and 0.5 V and a scan rate of 100 mV s-1. CSC was calculated from the measured CV data using formula (2):

[0055]

[0056] where v is the scan rate, E1 and E2 are the potential windows, i is the current at each potential, and A is the area of ​​the electrode.

[0057] To evaluate the electrochemical stability, the Mo electrodes were immersed in 1×PBS (37°C) for 4 weeks. The charge injection, charge storage, and impedance characteristics of the Mo electrodes were evaluated every week.

[0058] 4. Mechanical and self-healing tests of SBPUE

[0059] A 30wt% SBPUE DMAc solution was loaded into a 27mm×5mm×2mm circular Teflon mold, and the mold was gradually heated from 40°C to 130°C within 24 hours and vacuum dried at 60°C for 12 hours to remove residual solvent until there were no bubbles in the sample. The mechanical properties were measured using a universal testing machine (CTM8000, manufactured by Xie Qiang Instrument). In order to measure the tensile properties of SBPUE, the stretching rate was 50mm·min-1. The elastic modulus of SBPUE was calculated from the slope of the linear part of the stress-strain curve. In the cyclic tensile test, SBPUE was stretched to 20% strain. The tensile test speed was 20mm·min-1, the compression speed was 5mm·min-1, and the number of cycles was 10.

[0060] The self-healing test was mainly evaluated by scratch recovery and mechanical property recovery at room temperature and for different time periods. The scratch recovery test was performed by scratching the clean film with an 18G needle. The scratches were crossed across another scratch in an oblique manner so that the change in scratch width can be easily tracked using an optical microscope. The recovery of mechanical properties was evaluated by tapping two separate cut samples by 2 mm (in axial tension) and pressing them under a plumb bob for a period of time at room temperature. The toughness of the tested samples was calculated by integrating the area under the stress-strain curve.

[0061] 5. Cytocompatibility test

[0062] The cell compatibility of SBPUE was tested by CCK-8 and live-dead cell staining using cells including L929, PC12 and ND7 / 23. The BCC neurostimulator was macerated in Dulbecco's modified Eagle's medium (DMEM) at 37°C for 24 hours to obtain an extract (100 mg BCC dissolved in 1 mL DMEM). Before use, 10% v / v fetal bovine serum and 100 U mL-1 penicillin-streptomycin were added to the BCC neurostimulator extract. The cells were seeded in 24-well tissue culture plates at a density of 3000, 2000 and 1500 per well, respectively, and incubated at 37°C, 5% CO2 for 1 day, 3 days and 5 days. Cell viability was quantitatively determined by CCK-8 assay. In addition, the cells were seeded in 6-well tissue culture plates at a density of 10,000, 6,000, and 6,000 per well, respectively, and cultured at 37°C, 5% CO2 for 1d, 3d, and 5d. Cell viability was assessed visually by live-dead staining and studied by fluorescence microscopy image analysis.

[0063] 6. Construction of capacitive coupling system

[0064] The entire coupling system consists of an internal (BCC neurostimulator) and an external wireless power supply part. A circular gold foil with a diameter of 10 mm (encapsulated on both sides) is used as the power transmitting electrode, and a small rectangular molybdenum sheet (encapsulated on one side) is used as the external grounding electrode. They are connected to the signal input terminal using an enameled copper wire with a diameter of 40 μm. The waveform is edited using ArbExpress software (Tektronix, USA) to generate a composite waveform composed of a sine wave (frequency of 1 MHz, amplitude of 0.4 V) and a trapezoidal wave. The edited waveform is input into a function generator (AFG3021C, Tektronix, USA), which is connected to a broadband amplifier (ATA-1200B, Aigtek, China), which outputs the signal to an external device.

[0065] 7. Measurement of open circuit voltage and short circuit current

[0066] The external ground electrode was aligned with the ground electrode of the BCC neurostimulator, and the power transmitting electrode was aligned with the power receiving electrode of the BCC neurostimulator. The power transmitting electrode was connected to the positive output of the broadband amplifier, and the ground electrode was connected to the negative output. The power receiving electrode of the BCC neurostimulator was connected to the positive probe of the digital oscilloscope, and the ground electrode was grounded. By adjusting the gain of the broadband amplifier, the input voltage was increased from 2.5V to 5V, and the open-circuit voltage of the coupling device at different input voltages was displayed on the digital oscilloscope. For the measurement of short-circuit current, the output of the current preamplifier (SR570, Stanford, USA) was connected to the digital oscilloscope through a BNC interface. The coupling device was then connected to the broadband amplifier output and the input of the current preamplifier. The function generator output voltage was increased from 2.5V to 5V, and the short-circuit current of the coupling device at different input voltages was displayed using a digital oscilloscope and a current preamplifier. The distance between the power transmitter gold foil and the power receiver molybdenum foil was changed by inserting tissues of different thicknesses between them. These tissues included 1 mm of rat skin, 2 mm of pectoralis muscle, 3 mm of stacked muscle and skin, 10 mm of gastrocnemius muscle, and 11 mm of stacked gastrocnemius muscle and skin.

[0067] 8. Impedance and load matching

[0068] The resistance and reactance of 1 cm long vagus nerve tissue at input signal frequencies of 50 Hz to 100 kHz were measured using a digital bridge (TH2830, Changzhou Tonghui Electronics Co., Ltd.), and the reactance at an operating frequency of 1 MHz was calculated by fitting the allometric function model. The appropriate inductance was selected for matching using formula (3):

[0069]

[0070] Where X is reactance, f is operating frequency, C is capacitance, and L is inductance.

[0071] The impedance of 1 cm long vagus nerve tissue at different frequencies was measured using a digital bridge, and then the allometric function model and formula (4) were fitted to calculate the resistance of 1 mm long vagus nerve tissue at an operating frequency of 1 MHz:

[0072]

[0073] Where R is the resistance, ρ is the material resistivity, L is the material length, and S is the cross-sectional area.

[0074] According to the calculated vagus nerve tissue resistance, a load resistance of 2 kΩ to 20 kΩ was selected for current measurement, and the output current values ​​under different loads with and without impedance matching were tested.

[0075] 9. Measurement of electrophysiological signals

[0076] The electrophysiological signals were collected using a biological signal acquisition and analysis system (BL-420N, Chengdu Taimeng Software Co., Ltd.). The left sciatic nerve was exposed, and the nerve electrode of the built-in device was wrapped around the sciatic nerve, and the working electrode and the ground electrode were buried subcutaneously. The needle was inserted into the left gastrocnemius muscle and connected to the signal input line of the biological signal acquisition and analysis system. The external device was fixed on the skin using medical ultrasonic coupling glue, aligned with the built-in device, and an input stimulation signal was applied to the external device. The changes in muscle action potential before and after stimulation were recorded. The left gastrocnemius tendon was then separated and connected to the tension sensor of the biological signal acquisition and analysis system with sutures. The input stimulation signal was applied to the external device, and the changes in muscle tension before and after stimulation were recorded. Next, the right vagus nerve was exposed, and the nerve electrode of the built-in device was wrapped around the vagus nerve, and the working electrode and the ground electrode were buried subcutaneously. The input stimulation signal was applied to the external device, and the changes in nerve action potential before and after stimulation were recorded.

[0077] 10. Intestinal permeability measurement

[0078] SD rats were fasted for 6 hours, and FITC-dextran (4kDa) was dissolved in pure water at a concentration of 50 mg mL-1. The solution was administered to whole body samples at a dose of 600 mg kg-1. Blood was collected into tubes 4 hours later and then centrifuged at 3000 rpm for 10 minutes to obtain the supernatant. The adsorption of FITC-dextran was measured at 520 nm.

[0079] 11. BCC implantation for long-term vagus nerve stimulation

[0080] In the VNS group, the left cervical vagus nerve of anesthetized rats was exposed by dissection for BCC implantation, and the generator was implanted directly into the skin of the neck. The vagus nerve was stimulated for 20 minutes daily with biphasic charge-balanced rectangular current pulses (power transmitter input of ±4 V, pulse width of 0.6 ms per phase, and stimulation frequency of 1 Hz) for 4 weeks. During the stimulation, the rats were anesthetized with isoflurane using an animal research anesthesia machine (R583S, RWD).

[0081] 12. Flow cytometer

[0082] The intestinal tissue was first rinsed with saline to remove clots and adhesions. The intestinal tissue was cut into 0.3 cm long segments, pre-digested, filtered, and mucus removed until the segments were clean. The obtained intestinal segments were further minced, digested, filtered, and rinsed with culture medium to prepare intestinal single-cell suspensions. The organ tissues were minced, filtered, and ground, then centrifuged to remove red blood cells and resuspended to prepare organ single-cell suspensions. The intestinal and other organ tissue suspensions were stained for FVS510 viability, FcγII and FcγIII receptor (FCR) blocking, surface marker (CD45, CD4, CD8) staining, and resuspended for CD4+ and CD8 + Flow cytometric analysis of T cells. For detection of Th1, Th17, and Treg, single cell suspensions were incubated with leukocyte activation cocktail in a humidified CO2 incubator at 37°C for 6 hours prior to staining with FVS510. After surface staining (CD45, CD4, TCRβ), cells were fixed and permeabilized with transcription factor buffer set, followed by intracellular staining (IFN-γ, IL-17, FOXP3).

[0083] 13. Histopathology and immunofluorescence examination

[0084] At 4 weeks after treatment, rat nerves, intestinal tissues, skin, heart, liver, spleen, lungs, and kidneys were fixed with 4% paraformaldehyde, dehydrated, and paraffin-embedded. These tissues were then sectioned and stained for HE histopathological analysis. Immunofluorescence staining of NeuN, TNF-α, and S100-β was used to evaluate damage and inflammation at the neural interface. Immunofluorescence staining of Caspase-3 and TNF-α was used to evaluate skin tissue damage and inflammation at the skin interface. CD68, CD103, MPO, CD3, CD19, and NKp46 were selected as specific markers for evaluating intestinal inflammation. More specifically, TCRβ and CD4 were selected to mark CD4+TCRβ+T cells, while INF-γ, IL-17, and FOXP3 were selected to mark Th1, Th17, and Treg cells, respectively. ImageJ software was used to analyze the fluorescence intensity of biomarkers.

[0085] 2. Experimental Results

[0086] 1. Structure and performance of BCC neurostimulator

[0087] A biodegradable capacitively coupled neurostimulator (BCC neurostimulator) was fabricated using a 20 μm thick Mo foil cut by a laser beam and encapsulated with a 100 μm thick SBPUE. After constructing a robust neural interface on the left cervical vagus nerve of SD rats using the self-healing adhesive properties of SBPUE, the soft BCC neurostimulator was implanted under the skin of the rat's neck. The BCC neurostimulator operates in a single capacitor power transfer configuration. The power amplifier transmits the high-frequency electric field to the wearable power transmitting electrode (Au foil encapsulated on both sides) placed on top of the neck skin. The implanted Mo power receiving electrode (1 cm in diameter, encapsulated on both sides) serves as a capacitively coupled power receiver. For electrical stimulation of the vagus nerve, one Mo neurostimulation electrode is connected to the Mo power receiving electrode, and the other Mo neurostimulation electrode is connected to the Mo ground electrode, which is encapsulated on one side. For capacitively coupled wireless power transfer, the wearable gold (Au) power transmitting electrode is aligned with the capacitively coupled power receiver Mo electrode, while both the wearable ground electrode (encapsulated on one side) and the implanted Mo ground electrode (encapsulated on one side) are electrically connected to the skin tissue ( Figure 1 a, b). Figure 1 In the paper, the high-frequency electric field capacitive coupling between the implanted BCC neurostimulator and the wearable power transmitter made of an insulating metal patch can generate an AC current due to the electrostatic induction effect.

[0088] Biphasic stimulation is crucial in biomedical stimulators because it utilizes a charge-balancing waveform to mitigate charge accumulation and avoid harmful electrochemical reactions at the electrode interface. Traditional wireless energy transfer methods, such as the photoelectric effect and inductive coupling, usually require complex circuits to achieve biphasic stimulation. However, by utilizing the electrostatic induction effect, a simple configuration of gold power transmitting electrodes and molybdenum power receiving electrodes can be used to coordinate with a precisely edited input voltage waveform to generate adjustable biphasic electrical pulses. The input voltage waveform is generated by a trapezoidal wave with a sinusoidal carrier waveform, and the edited waveform is used to generate biphasic rectangular pulses (±4V, 1Hz, 0.6ms per phase) with an interval of 0.15ms (between two phases) ( Figure 2 a). In response to the voltage input from the gold foil electrode of the wearable power transmitter, the molybdenum foil electrode of the power receiver in the BCCR neural stimulator efficiently outputs biphasic charge-balanced rectangular voltage pulses with an amplitude of approximately ±3.38V ( Figure 2 b), the corresponding output short-circuit current is about 250μA ( Figure 2 e, f). Figure 2 As shown in Figure 3, the short-circuit current and open-circuit voltage increase with increasing input voltage. Therefore, the desired output for neuromodulation can be obtained by adjusting the input voltage applied to the gold energy transmitter foil. In addition, the distance between the energy transmitter gold foil and the energy receiver molybdenum foil (controlled by changing the tissue with different thicknesses) has little effect on the capacitive coupling efficiency ( Figure 2g). The open circuit voltage showed long-term stability after being immersed in PBS at 37°C for 30 days, indicating that the capacitive coupling efficiency has the characteristics of long-term stability ( Figure 2 d).

[0089] In order to achieve maximum output at the power receiving end of the in vivo load (neurostimulation electrodes connected to the vagus nerve tissue), we further studied the impedance matching of the capacitive coupling system. This was achieved by measuring and fitting the resistance and reactance in the neural tissue and the capacitance of the capacitive coupling device at different frequencies ( Figure 3 ). According to the calculated parameters, a 1mH inductor is added to the wearable power transmitter circuit for reactance matching under high-frequency capacitive coupling conditions. Since the resonant frequency of the capacitive coupling system of the load simulating neural tissue is about 1MHz, a 1MHz sine wave with an amplitude of 0.4V is used as the carrier during waveform editing. Then, we studied the relationship between the output current of the Mo power receiving electrode and the load resistance under different input voltages when the carrier waveform frequency is 1MHz ( Figure 4 ). The output current of the Mo power receiving electrode decreases as the load resistance increases from 2kΩ to 20kΩ. By reactance matching, the output current can reach about 250μA when the load resistance is about 10kΩ, which corresponds to the impedance of the vagus nerve tissue at 1MHz. The output voltage traces with and without reactance matching are shown in Figure 4 As shown in Figure 2, the output voltage of the implantable power receiving device can be significantly improved by reactance matching. These results emphasize the importance of reactance matching between the power transmitter and the power receiver to ensure more efficient capacitive coupling.

[0090] We thoroughly investigated the electrochemical properties of biodegradable Mo neurostimulation electrodes to evaluate their neuromodulatory capabilities. For comparison, we also examined gold electrodes, which are widely used in bioelectronics. Compared with gold electrodes, Mo electrodes exhibit lower charge transfer resistance ( Figure 5 d), thereby reducing the impedance at the interface between the electrode and the neural tissue ( Figure 5 a). To determine the sensitivity to external electrical signals, the charge storage and exchange capacities were further examined. In the cyclic voltammetry (CV) curves, the Mo electrode showed a higher charge storage capacity than the Au electrode (0.22 ± 0.027 mC·cm-2; Figure 5 e and Figure 5 b) Larger capacitance (charge storage capacity; CSC) (3.93±1.06mC·cm-2). Under biphasic pulse (±0.5V, 1.5ms) electrical stimulation, the Mo electrode achieved a higher current density of ~500mA·cm-2 at a stimulation voltage of ±0.5V ( Figure 5c). The charge injection capacity (CIC) of the Mo electrode is 4.6±0.71mC·cm-2, which is much higher than that of the gold electrode (0.199±0.017mC·cm-2), indicating that the Mo electrode significantly improves the CIC of the neural stimulation electrode ( Figure 5 f). The long-term stability of the impedance, CSC, and CIC of the Mo electrode was then studied. The impedance of the Mo electrode showed a downward trend in the first 2 weeks and an upward trend in the second 2 weeks, while the CSC and CIC values ​​showed the opposite trend, first increasing and then decreasing ( Figure 5 g). Mo neurostimulation electrodes with enhanced electrochemical properties show the potential to support low-intensity and high-efficiency electrical stimulation for safe neuromodulation.

[0091] 2. Packaging and biocompatibility of BCC neurostimulator

[0092] In addition to the molybdenum (Mo) neurostimulation electrodes, Mo device wiring, and Mo power receiving electrodes, the device packaging layer is also a key component of the neurostimulator. In order to achieve rapid, room temperature, and seamless packaging of the BCC neurostimulator, we explored the rational synergistic molecular design of SBPUE. Specifically, the proposed SBPUE uses polycaprolactone (PCL) and polytetrahydrofuran (PTHF) as soft segments and dimethyl ethylene glycol oxime as hard segments ( Figure 6 ). The soft segment of SBPUE gives it low crystallinity, excellent stretchability, degradability, and good cell compatibility, while the hard segment enhances its toughness, fracture energy, and self-healing ability. Figure 2 The Fourier transform infrared (FTIR) spectrum of SBPUE in i confirmed the successful synthesis of SBPUE. -1 The peak at 1238 cm indicates the presence of ether functional groups, while the peak at 1238 cm -1 and 1732cm -1 The peaks at 2864 cm -1 and 3372cm -1 The peaks correspond to the stretching vibrations of -CH2-CH3 and NH. These findings are also supported by nuclear magnetic resonance (NMR) analysis ( Figure 6 ).

[0093] We further studied the mechanical properties and self-healing characteristics of the prepared SBPUE. SBPUE exhibited extremely high elasticity and could withstand a linear strain of approximately 1500% ( Figure 7 f), whose tensile modulus was measured to be 34 kPa (see Figure 7a). These results suggest weak intermolecular forces between molecular chains and enhanced stretchability, which is attributed to the mixed soft segments of PCL and PTHF. The elastic recovery hysteresis of SBPUE was evaluated by applying 20% ​​strain for 10 cycles. Although SBPUE did not show complete recovery, it recovered after the first loading-unloading cycle (see Figure 7 g), the residual strain is about 15%, and the tensile stress loss in subsequent cycles after the tensile stress returns to zero is slightly lower than in the previous cycles. This hysteresis is partly attributed to the energy dissipation caused by the dissociation of hydrogen bonds. In addition, SBPUE exhibits rapid self-healing properties due to the multiple hydrogen bonds in its structure. Scratches on the SBPUE film can heal within 120 minutes at room temperature ( Figure 7 d). Peel test of two self-healing SBPUE films showed strong adhesion (see Figure 7 b and e), 420.8 ± 22.63 J m-2 was measured after 10 minutes of self-healing time, and increased to 937 ± 111.7 J m-2 after 120 minutes of self-healing (see Figure 7 c) These results indicate that SBPUE achieves rapid and complete self-healing within 120 minutes, potentially enabling self-healing fixation of neural stimulation electrodes. This is expected to replace conventional mechanical suturing methods, ensuring stability and reducing potential tissue damage during fixation.

[0094] To verify the biocompatibility of the BCC neurostimulator, we performed CCK-8 assays and live-dead staining assays to evaluate its in vitro cytotoxicity. We cultured two neural cell lines (PC12 and ND7 / 23) and a mouse fibroblast cell line (L929) with BCC extracts for 5 days and used normal DMEM as a control group. The negative control group was also cultured with normal DMEM. The relative survival rate of cells cultured with BCC extracts was comparable to that of the control group (see Figure 8 a, b). In addition, there was no significant difference in cell morphology between the BCC extract group and the control group ( Figure 8 c) These results indicate that the BCC neurostimulator is non-cytotoxic.

[0095] In addition, we also studied the in vitro biodegradability of the components of the BCC neurostimulator, including Mo and SBPUE. The weight changes of the Mo and SBPUE films immersed in 1× PBS at 37°C showed that they could be slowly degraded (see Fig. 9 a), the shape was kept constant during the first month to match the disease treatment cycle (see Supplementary Fig. 9 b) During the entire degradation process of the Mo electrode, cracks, fragmentation and the formation of new cracks appeared (see Supplementary Fig. 9c). Therefore, the electrochemical surface area of ​​the electrode initially increases and then decreases. This fluctuation is also the reason why its electrochemical performance increases and then decreases accordingly (see Fig. 9 c).

[0096] 3. Functional characteristics of BCC neurostimulator in vivo

[0097] To characterize the function of the BCC neurostimulator in vivo, we investigated the immune response in neural and skin tissues. We focused on molybdenum (Mo) neurostimulating electrodes in contact with neural tissue and SBPUE-encapsulated Mo power receiving electrodes in contact with skin tissue, which were analyzed after implantation of the BCC neurostimulator (see Fig.10 a). Fig.10 As shown in Figure 2, no obvious inflammatory infiltration was observed in the BCC group compared with the control group. We used immunofluorescence to analyze the immune response and cell population changes in the vagus nerve tissue 4 weeks after implantation, labeling neuronal nuclei (NeuN), tumor necrosis factor-α (TNF-α), and S100 calcium-binding protein B (S-100β). There was no significant difference in the number of Schwann cells and neurons in the BCC group compared with the control group (see Figure 2). Fig.10 c). In addition, there was no significant difference in TNF-α expression between the BCC group and the control group, which is an important marker for evaluating immune response (see Fig.10 d) Similarly, implantation of the BCC neurostimulator did not induce a severe immune response in the skin tissue. Fig.10 As shown in e and f, there was no obvious inflammatory infiltration or tissue damage in the BCC group compared with the control group (TNF-α indicates inflammation, and Caspase-3 is associated with apoptosis and necrosis). These results indicate that the BCC neurostimulator has good biocompatibility and does not induce a significant immune response in vivo. In addition, the long-term in vivo implantation process showed that the BCC neurostimulator has good degradability, maintaining a good shape within 4 weeks and completing most of the degradation within 12 weeks (see Fig.10 g). This timeline is consistent with the preset disease treatment cycle, which enhances consistency. Moreover, the entire degradation process has no significant impact on the main organs of rats (see Fig.11 ).

[0098] 4. Electromedical therapy for PIBD using BCC neurostimulator

[0099] To investigate the feasibility of wireless capacitive coupling configuration for electropharmaceutical neuromodulation, we tested the BCC neurostimulator in a rat model, targeting the vagus and sciatic nerves. The capacitively coupled power supply electrodes consisted of a pair of soft, insulated molybdenum foils placed under the skin of the neck as power receiving electrodes (encapsulated on both sides) and ground electrodes (encapsulated on one side) (see Fig.10a). Above the skin of the neck, we placed a piece of gold foil as a power transmitting electrode (encapsulated on both sides) and a small external ground electrode (molybdenum sheet encapsulated on one side) ( Fig.12 a, b). The external ground electrode and the implanted ground electrode are both electrically connected to the skin tissue, and the external power transmitting electrode is aligned with the implanted power receiving electrode ( Fig.12 c) If Fig.10 As shown in b, capacitively coupled electrical stimulation pulses (power transmission input of ±4V, pulse width of 0.6ms per phase, stimulation frequency of 1Hz) can induce compound action potentials (CAP) of the vagus nerve during 20 minutes of electrical stimulation ( Fig.13 a) without significantly increasing the temperature ( Fig.14 ). Similarly, capacitively coupled electrical stimulation pulses can induce sciatic nerve responses characterized by compound muscle action potentials (CMAP) and changes in gastrocnemius muscle tension ( Fig.13 b,c).

[0100] Next, we conducted in vivo experiments in a rat model to investigate the therapeutic effects of capacitively coupled wireless electronic drug therapy on PIBD. The PIBD model was induced in 3-week-old rats by multiple OXA enemas (see Fig.15 a), on the first day, the vagus nerve stimulation (VNS) group was implanted with a BCC neurostimulator and received 20 minutes of capacitively coupled wireless electronic drug therapy daily (power transmission input was ±4V, pulse width was 0.6ms, and stimulation frequency per phase was 1Hz). The weight changes of the rats were monitored throughout the process. Since the rats used were in the growth and development period, even if the intestine was damaged by OXA, weight loss still occurred in the acute phase (1-3 days after oxazolidinone enema), but weight rebounded in the remission period. The weight loss of the PIBD group in the acute phase was significantly greater than that of the control group, while capacitively coupled wireless electronic drug therapy alleviated the weight loss of the VNS group (see Fig.15 b). Therefore, the percentage of weight loss is based on the average weight gain of the control group as a baseline, rather than an individual before-after comparison. The Disease Activity Index (DAI) score can be estimated based on weight, stool characteristics, and occult blood. Fig.15 As shown in (c), the DAI in the PIBD group was significantly higher than that in the control group due to weight loss, watery diarrhea, and bloody stools, while capacitively coupled wireless electronic drug treatment alleviated these symptoms.

[0101] Compared with the control group, the PIBD group had a shorter colon length and enlarged mesenteric lymph nodes with a beaded appearance (see Fig.15 d). There is obvious adhesion between the colon and the small intestine, the colon is severely congested and edematous, the intestinal wall is obviously stiff and thickened, and full-thickness necrosis and multiple ulcers can be seen in the distal colon (see Fig.15f). Compared with the PIBD group, the enlargement of mesenteric lymph nodes in the VNS group was milder. The colon mucosal injury index (CMDI) and inflammation-related histological score (HIS) in the PIBD and VNS groups were significantly higher than those in the control group. Fig.15 e and Fig.15 As shown in g, the CMDI and HIS of the VNS group were significantly lower than those of the PIBD group, and the results were statistically significant.

[0102] We also investigated the histological changes in the colon. The PIBD group showed obvious inflammatory cell infiltration. The proximal segment showed normal architecture and crypt morphology, with low-level inflammation and scattered infiltration of immune cells (see Fig.15 h,i). However, in the middle and distal parts of the colon, the morphology was significantly destroyed, the structure was unclear, the crypts were lost, transmural inflammation and goblet cells were absent. In the proximal and middle colon treated with the VNS group, the structure and crypt morphology were clear, and immune cells were scattered infiltrated, while the distal part showed severe inflammation, including transmural immune cell infiltration. At the same time, the changes in intestinal permeability and colon length after the PIBD model were further studied. The concentration of FITC-dextran in serum reflects the changes in intestinal permeability. PIBD leads to increased intestinal permeability and inflammation, while capacitively coupled wireless electronic drug treatment alleviates these pathological changes (see Fig.15 j).

[0103] Obviously, the above embodiments are merely examples for the purpose of clear explanation, and are not intended to limit the implementation methods. For those skilled in the art, other different forms of changes or modifications can be made based on the above description. It is not necessary and impossible to list all the implementation methods here. The obvious changes or modifications derived therefrom are still within the scope of protection of the invention.

Claims

1. A biodegradable capacitively coupled neurostimulator for radiotherapy of inflammation, characterized in that: The capacitive coupling neural stimulator comprises a neural stimulation element and a packaging element, wherein the packaging element is located on the surface of the neural stimulation element, and the packaging element is an elastomer SBPUE. The preparation method of the elastomer SBPUE comprises the following steps: S1: PCL and PTMEG were mixed in a container, the mixture was heated in an oil bath at 100°C under vacuum to remove moisture, and then cooled to 70°C; S2: Isophorone diisocyanate and DBTDL dissolved in DMAc were added dropwise into a container and stirred under a nitrogen atmosphere to synthesize a prepolymer and then cooled to room temperature; S3: adding dimethylglyoxime dissolved in DMAc as a chain extender to seal the reaction; S4: After the reaction is completed, DMAc is added to adjust the concentration of the product to 30 wt %, thereby obtaining the elastomer SBPUE.

2. The capacitively coupled neural stimulator according to claim 1, characterized in that: The neural stimulation element includes a power receiving electrode, a ground electrode, two neural stimulation electrodes and a serpentine connecting wire, wherein one of the neural stimulation electrodes is connected to the power receiving electrode via the serpentine connecting wire, and the other neural stimulation electrode is connected to the ground electrode via the serpentine connecting wire.

3. The capacitively coupled neural stimulator according to claim 2, characterized in that: The power receiving electrode and the grounding electrode are circular, with diameters of 10 mm and 5 mm respectively, and are connected to the nerve stimulation electrode via the serpentine connecting wire with a length of 10 mm and a width of 0.2 mm.

4. The capacitively coupled neural stimulator according to claim 2, characterized in that: The nerve stimulation electrode is 0.1 mm wide and 5 mm long, and the gap between two nerve stimulation electrodes is 1 mm.

5. The capacitively coupled neural stimulator according to claim 1, characterized in that: The neurostimulatory element was made of laser-cut 20 μm thick Mo foil and encapsulated with 100 μm thick SBPUE, the elastomer.

6. The capacitively coupled neural stimulator according to claim 5, characterized in that: The cut neural stimulation element is placed on the partially cured adhesive surface of the SBPUE substrate to complete the packaging.

7. The capacitively coupled neural stimulator according to claim 2, characterized in that: Both sides of the power receiving electrode are encapsulated, and only one side of the grounding electrode is encapsulated.

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