Wireless neuromodulation bioelectronic device for vagal blockade

Abstract

The application discloses a wireless nerve regulation bioelectronic device for blocking vagus nerve. The electronic device is used in cooperation with a transmitting end and comprises a flexible substrate, a wireless energy supply coil, a receiving end modulation circuit, a microneedle conductive electrode and a biocompatible encapsulation layer. The wireless energy supply coil is arranged on the flexible substrate and is used for receiving wireless electromagnetic wave energy emitted by the transmitting end and converting the wireless electromagnetic wave energy into electric energy. One end of the receiving end modulation circuit is connected with the wireless energy supply coil, the receiving end modulation circuit modulates the electric energy generated by the wireless energy supply coil, and converts the electric energy signal into a low-frequency pulse electric stimulation signal. The other end of the receiving end modulation circuit is connected with the microneedle conductive electrode, and the microneedle conductive electrode is used for transmitting the low-frequency pulse electric stimulation signal to the microneedle conductive electrode. The microneedle conductive electrode is used for conducting the low-frequency pulse electric stimulation signal to a target position. The biocompatible encapsulation layer is used for encapsulating other components except the microneedle conductive electrode. The electronic device can be used for treating pancreatic cancer.

Description

Technical Field

[0001] This invention belongs to the field of biomedical engineering devices, specifically relating to a wireless neuromodulation bioelectronic device for blocking the vagus nerve and its construction method. Background Technology

[0002] Because pancreatic cancer often presents with few or no early symptoms, most patients are diagnosed at an advanced stage. At this point, the only way for patients to achieve long-term survival is through radical resection combined with systemic chemotherapy, but the five-year survival rate remains only 8%. Therefore, to address the current bottleneck in the treatment of malignant pancreatic cancer, it is crucial to develop innovative systemic treatment strategies in addition to surgery.

[0003] Recent studies have revealed abnormal vagal nerve activity in a mouse model of pancreatic cancer. The hepatic branch of the vagus nerve exhibits an abnormal pattern of "increased noise and decreased single-peak amplitude," and enhanced activation of neurons in the dorsal motor nucleus of the vagus nerve is observed. This result suggests that vagal nerve dysfunction may be involved in the progression of pancreatic cancer. Cutting-edge research indicates that vagal nerve blockade can inhibit the growth of advanced pancreatic cancer and prolong survival. Methods proposed include direct physical transection of the right cervical vagus nerve in mice, neurotoxin chemical blockade, and percutaneous / subcutaneous electrical nerve stimulation to effectively block abnormal nerve activity. Therefore, vagal nerve blockade may become a novel treatment strategy for advanced pancreatic cancer.

[0004] Vagus nerve neuromodulation offers a physical method to "reset" aberrant signal transduction along the axis. The vagus nerve plays a crucial role in maintaining homeostasis in peripheral and central metabolic pathways, and its downstream peripheral parasympathetic nervous system is a bidirectional electro- and chemical signaling pathway that regulates immune activation. Studies have shown that electromodulation of the vagus nerve system has a direct innervation effect on the liver and pancreas. Electromodulation techniques, represented by percutaneous modulation, can directly act on the nerve through implanted electrodes or devices, but these have limitations such as large surgical trauma, high difficulty, slow recovery, and the need for a second surgery to remove the device after treatment. However, wearable electrodes or devices, applied directly to the skin, can effectively achieve percutaneous neuromodulation, thus effectively overcoming dependence on invasive surgical implants. Therefore, percutaneous electrical nerve stimulation (TENS) for vagus nerve modulation may become a promising physical therapy option for cancer. However, existing transcutaneous electrical nerve stimulation devices have limitations such as complex and cumbersome structure (TW110124033), separate wired connection (CN113289246A), reliance on traditional power modules (CN121714838A), and difficulty in achieving lightweight devices (CN121868711A). Summary of the Invention

[0005] This invention provides a wireless neuromodulation bioelectronic device for blocking the vagus nerve, which can be used to treat pancreatic cancer. This wireless neuromodulation bioelectronic device features electromagnetic field wireless power conversion and modulation, and minimizes interface impedance to improve electrical signal transmission efficiency. This invention employs the concept of integrated bioelectronics to optimize the transmission efficiency of electrical stimulation signals between the skin barrier and intrinsic nerves, and verifies the effect of electrical stimulation driving a wireless magnetic field to block the vagus nerve, modulating immunomodulation combined with chemotherapy drugs to inhibit tumors. The implementation of this invention will provide a systemic physical therapy strategy for the clinical treatment of advanced pancreatic cancer.

[0006] This invention is achieved using the following technical solution:

[0007] A wireless neuromodulation bioelectronic device for blocking the vagus nerve integrates a flexible substrate, a wireless power coil, a receiver modulation circuit, microneedle conductive electrodes, and a biocompatible encapsulation layer. Used in conjunction with a transmitter that generates a variable magnetic field in a specific area, the device generates an electrical stimulation signal when near the magnetic field. This signal can effectively block abnormal vagal nerve activity, activate immune remodeling homeostasis, and, in combination with chemotherapy drugs, inhibit pancreatic tumor growth. This wireless neuromodulation bioelectronic device has clinical potential for vagal nerve blockade in the treatment of pancreatic cancer.

[0008] This invention provides a wireless neuromodulation bioelectronic device for blocking the vagus nerve. It can inhibit the development of malignant pancreatic cancer by transcutaneously blocking abnormal cervical nerve activity through the generated electrical stimulation nerve modulation signal. The device comprises a wireless power supply coil mounted on a flexible substrate to receive tunable radio electromagnetic wave energy and convert it into electrical energy. One end of the receiving modulation circuit is connected to the wireless power supply coil, modulating the generated electrical energy and converting the electrical signal into a low-frequency pulsed electrical stimulation signal, specifically 1-30 Hz. The other end of the receiving modulation circuit is connected to a microneedle conductive electrode to transmit the low-frequency pulsed electrical stimulation signal to the microneedle conductive electrode. The microneedle conductive electrode is specifically a hydrogel microneedle containing a dual-network conductive material (reduced graphene oxide and silver nanowires), used to conduct the low-frequency pulsed electrical stimulation signal to the target location, and can be inserted into the skin to improve signal transmission efficiency. The biocompatible encapsulation layer includes an elastic biocompatible upper encapsulation layer and an elastic biocompatible lower encapsulation layer for encapsulating other components.

[0009] In the above technical solution, the wireless power supply coil further comprises a planar wiring structure, specifically a two-layer structure. The bottom layer is a copper layer, and the top layer is a gold layer. The copper layer serves as a connecting layer to fix the gold layer onto a flexible substrate. The copper layer has a thickness of approximately 30-50 micrometers and a line width of approximately 50-100 micrometers. The gold layer has a thickness of approximately 1-3 nanometers and a line width of 50-100 micrometers. The wiring spirals are neatly arranged, with a spacing of approximately 50-200 micrometers between the lines. The coil has approximately 7-10 turns, with an inner diameter of approximately 8-12 millimeters and an outer diameter of approximately 15-20 millimeters. The wireless power supply coil can convert a specific alternating magnetic field signal modulated by the transmitter into a specific alternating electrical signal based on the principle of electromagnetic induction.

[0010] Furthermore, the receiving modulation circuit specifically consists of three surface-mount diodes (SOD-523 package, 1N5819WT) and two surface-mount capacitors (0402 package, 80-150 pF). The three surface-mount diodes are connected in series and form a series structure with one of the surface-mount capacitors. The two extended ends of the surface-mount capacitor are connected to the wireless power supply coil. The series structure and the other surface-mount capacitor form a parallel structure. The two extended ends of the surface-mount capacitor are the output terminals of the receiving modulation circuit. The receiving modulation circuit rectifies the specific alternating electrical signal in the wireless power supply coil into a specific DC output. Therefore, this receiving modulation circuit can be used to convert the alternating signal into a low-frequency pulse electrical stimulation signal for nerve electrical stimulation.

[0011] Furthermore, the low-frequency pulsed electrical stimulation signal generated by the receiving modulation circuit is transmitted to the vagus nerve in the neck through microneedle conductive electrodes that are inserted into and adhere to the skin surface, thereby achieving nerve signal blocking. The microneedle conductive electrode is a microneedle array structure, specifically comprising multiple arrayed frustum-shaped cone-shaped snap-fit ​​structures. The cone tips can be used to pierce the skin. This structural design minimizes interface impedance and improves the transmission efficiency of electrical signals. The specific dimensions of each microneedle are: the lower diameter of the frustum is approximately 300-400 micrometers, the upper diameter is approximately 200-300 micrometers, and the height is approximately 200-400 micrometers; the base diameter of the cone is approximately 300-400 micrometers, and the height is approximately 700-1000 micrometers. In the microneedle conductive electrode, the number of microneedles per 1 to 4 square centimeters is approximately between 10*10 and 20*20.

[0012] Furthermore, the mass percentage of the dual-network conductive material in the microneedle conductive electrode is 10-20%, wherein the mass ratio of the reduced graphene oxide to the silver nanowires is 1:1 to 1:2.

[0013] Furthermore, the biocompatible encapsulation layer is made of polydimethylsiloxane or skin-friendly silicone. Biocompatible encapsulation is performed on the parts that adhere to the skin surface, as well as the exposed wireless receiving coil and receiver modulation circuit, thereby improving the stability and safety of the device during use.

[0014] Furthermore, the wireless neuromodulation bioelectronic device for blocking the vagus nerve in this application is ultra-thin, transparent, and flexible, allowing it to adhere well to the skin surface. Combined with a polyurethane medical film, the device can be fixed at the stimulation point to prevent displacement. This wireless neuromodulation bioelectronic device can effectively provide transcutaneous electrical nerve stimulation for blocking abnormal vagus nerve activity in malignant pancreatic cancer.

[0015] This invention also provides a method for constructing a wireless neural modulation bioelectronic device, the method specifically including the following steps:

[0016] Step 1: Fabricate wireless power coils and circuit solder joints on a flexible substrate using micro-nano fabrication technology;

[0017] Flexible films such as PI, PET, PDMS and PMMA are selected as flexible substrates;

[0018] First, the flexible substrate is subjected to plasma cleaning;

[0019] Then, photolithography, development, and surface treatment are performed on the flexible substrate surface; the specific method is as follows:

[0020] By using magnetron sputtering to deposit a film on the surface of a flexible substrate, removing excess metal, and leaving patterned metal lines, a wireless power coil and circuit solder joints can be obtained.

[0021] The wireless power coil consists of two layers: a copper layer at the bottom and a gold layer at the top. The copper layer is approximately 30-50 micrometers thick with a line width of approximately 50-100 micrometers, while the gold layer is approximately 1-3 nanometers thick with a line width of 50-100 micrometers. The wiring is arranged in neat spirals, and the coil has approximately 7-10 turns.

[0022] Step 2: Repeat the above steps to prepare a flexible double-sided board. Prepare electrode pre-reserved sites on the other side of the flexible substrate for connecting microneedle conductive electrodes.

[0023] Step 3: Fabrication of the receiver modulation circuit:

[0024] Electronic components (including surface mount diodes and surface mount capacitors) are soldered to circuit solder joints using a low-temperature soldering process. The surface mount diodes and surface mount capacitors together constitute the receiving end modulation circuit. Specifically, three surface mount diodes are connected in series and form a series structure with one of the surface mount capacitors. The series structure and the other surface mount capacitor form a parallel structure.

[0025] Step 4: Fabrication process of the upper and lower layers of the flexible biocompatible encapsulation:

[0026] Polydimethylsiloxane (PDMS), which has excellent light transmittance, flexibility, and chemical inertness, is used for encapsulation. PDMS and a crosslinking agent are mixed at a mass ratio of 10:1 to 10:2, and degassed to obtain a PDMS precursor. The PDMS precursor is spin-coated onto the upper and lower surfaces of the device obtained in step 3, cured, and then subjected to plasma treatment to obtain the elastic and biocompatible encapsulation upper and lower layers. Before spin-coating the PDMS precursor, a release film is used to cover the electrode pre-reserved sites. Finally, the release film is peeled off to expose the electrode pre-reserved sites.

[0027] Step 5: Finally, prepare and assemble the microneedle conductive electrode;

[0028] Highly conductive reduced graphene oxide was prepared by reducing 10-20 mL of graphene oxide aqueous solution (concentration of 1-2 mg / mL) with 1-2 g of ascorbic acid at a certain temperature (60-90℃).

[0029] A conductive double-network solution was formed by incorporating reduced graphene oxide and silver nanowires into a hydrogel material. The hydrogel material was prepared using a mixed solution of PVA and PVP, with PVA comprising 10-20 wt% of the mixed solution and a PVP to PVA mass ratio of 1:1 to 1:2. The mass ratio of reduced graphene oxide to silver nanowires was between 1:1 and 1:2, and the total mass percentage of reduced graphene oxide and silver nanowires in the conductive double-network solution was 10-20%.

[0030] Microneedle conductive electrodes were prepared using a template method. The specific method was as follows: a conductive double-network solution was poured into a mold, vacuum-treated for 5-10 minutes, cured at 45-60℃ for 2-4 hours, and then demolded to obtain the microneedle conductive electrode. The microneedle conductive electrode was specifically a microneedle array structure, including multiple arrayed frustum-shaped cone-shaped snap-fit ​​structures. Based on this, the mold structure was also designed as a microneedle array structure. The mold preparation method was as follows: first, a snap-fit ​​structure including multiple arrayed frustum-shaped cone-shaped structures was prepared using brass (the number of microneedles per 1 to 4 square centimeters was approximately between 10*10-20*20, and the dimensions of each microneedle were: the diameter of the lower end of the frustum was 300-400 micrometers, the diameter of the upper end was 200-300 micrometers, and the height was 200-400 micrometers; the diameter of the bottom surface of the cone was 300-400 micrometers, and the height was 700-1000 micrometers). Then, PDMS is used for mold making to obtain a PDMS concave mold, which is the final mold that can be used directly. The specific dimensions of the mold can be selected according to the needs.

[0031] Then, the obtained microneedle conductive electrodes are cut into microneedle conductive electrodes with a needle body number of 3*3 to 5*5. Then, conductive carbon cloth double-sided tape (i.e. conductive adhesive tape layer) is used to fix the cut microneedle conductive electrodes to the electrode reserved sites; finally, wireless neural modulation bioelectronic device is obtained.

[0032] The aforementioned wireless neuromodulation bioelectronic device can inhibit the progression of pancreatic cancer through neuromodulation. Combined with clinical chemotherapy, it is expected to prolong the survival of patients with malignant pancreatic cancer and improve their quality of life. Future development of smart healthcare systems could establish radio-physical field wards based on this device, allowing patients to receive cancer treatment simply by wearing the device in their rooms, thus improving treatment adherence and quality of life.

[0033] The beneficial effects of this invention are as follows:

[0034] This invention provides a wireless neuromodulation bioelectronic device for blocking the vagus nerve, which can be used to treat pancreatic cancer.

[0035] This invention is guided by the exploration of systemic treatment methods for malignant tumors that are difficult to surgically remove. It develops a systematic method for intervening in vagus nerve activity with physical therapy, using the regulation of vagus nerve activity to activate immunity, delay the progression of malignant tumors, and improve patient survival. It provides a wireless neuromodulation bioelectronic device that blocks the vagus nerve to inhibit the progression of pancreatic cancer.

[0036] This invention aims to address the abnormal vagal nerve activity in a mouse model of malignant pancreatic cancer by using bioelectronic technology to perform percutaneous vagal nerve blockade. Specifically, a wireless power supply and control scheme for a wireless neuromodulation bioelectronic device was established. Utilizing the principle of electromagnetic induction and bioelectronic technology, pulsed electricity is transmitted percutaneously to the nerve to block abnormal vagal nerve activity, thus establishing a foundation for physical therapy. With the primary objective of blocking the vagus nerve through electrical stimulation, a wireless power supply coil is used to achieve wireless power supply / control. A dual-network conductive snap-fit ​​(frustum-supported cone) microneedle array electrode is constructed to overcome interfacial impedance, improve signal transmission efficiency, and effectively block the vagus nerve, inhibiting the progression of pancreatic cancer.

[0037] This invention explores the use of physical intervention to inhibit the excitability of neural activity based on the neural-cancer-immune linkage mechanism, clarifies the therapeutic effect of the device, and can further clarify the physical regulation nature of wireless neural modulation bioelectronic devices in further research. Attached Figure Description

[0038] Figure 1Structure of a wireless neuromodulation bioelectronic device for blocking the vagus nerve. 1. Wireless neuromodulation bioelectronic device for blocking the vagus nerve; 2. Elastic biocompatible upper package; 3. Receiver modulation circuit; 4. Wireless power supply coil; 5. Flexible substrate; 6. Elastic biocompatible lower package; 7. Conductive adhesive tape layer; 8. Microneedle conductive electrode.

[0039] Figure 2 Application modes of wireless neuromodulation bioelectronic devices for blocking the vagus nerve.

[0040] Figure 3 Schematic diagram of wireless power supply and control.

[0041] Figure 4 Electrical properties of a wireless neuromodulation bioelectronic device for blocking the vagus nerve. (1) Modulated voltage signal; (2) Modulated current signal.

[0042] Figure 5 Neuromodulation effect of percutaneous electrical nerve stimulation. (1) Bright field and fluorescence images of primary neurons; fluorescence images show the change in calcium ion fluorescence imaging intensity with different stimulation time under the regulation of electrical signals; under the regulation of low frequency electrical signals, the calcium ion concentration of neurons decreases (the fluorescence in the imaging neurons is weakened); (2) Real-time recording of neural electrical signals and analysis and statistics of neural action potentials.

[0043] Figure 6 Wireless neuromodulation bioelectronic devices for blocking the vagus nerve inhibit pancreatic cancer progression. (1) Schematic diagram of the establishment of a mouse model of pancreatic cancer in situ (KPC), the interaction between the vagus nerve and pancreatic cancer, and the inhibition of tumor growth by blocking abnormal vagus nerve activity through electrical stimulation; (2) Survival curves of four groups of mice (control group, ES group, Gem. group and ES & Gem. combined treatment group) after one treatment cycle; (3) In vivo fluorescence imaging of tumor changes in four groups of mice during treatment; (4) Tumor images of four groups of mice after one treatment cycle; (5) Normalized tumor weight of four groups of mice.

[0044] Figure 7 Microscopic morphology of the microneedle conductive electrode. Detailed Implementation

[0045] The technical solution of the present invention will be further described in detail below with reference to the accompanying drawings and specific embodiments.

[0046] This invention provides a wireless neuromodulation bioelectronic device for blocking the vagus nerve, a method for its construction, and an application of vagus nerve blockade in the treatment of pancreatic cancer.

[0047] A method for constructing a wireless neuromodulation bioelectronic device for blocking the vagus nerve, specifically including the following steps:

[0048] Step 1: Fabricate wireless power coils and circuit solder joints on a flexible substrate using micro-nano fabrication technology;

[0049] Flexible films (such as PI, PET, PDMS, and PMMA) are selected as flexible substrates; then, the flexible substrates are plasma cleaned; next, photolithography, development, and surface treatment are performed on the surface of the flexible substrates.

[0050] A film is deposited on the surface of a flexible substrate using magnetron sputtering to remove excess metal and leave patterned metal lines, namely wireless power coils and circuit solder joints.

[0051] The wireless power coil consists of two layers: a copper layer at the bottom and a gold layer at the top. The copper layer is approximately 30-50 micrometers thick with a line width of approximately 50-100 micrometers, while the gold layer is approximately 1-3 nanometers thick with a line width of 50-100 micrometers. The wiring is arranged in neat spirals, and the coil has approximately 7-10 turns.

[0052] Step 2: Repeat the above steps to prepare a flexible double-sided board. Prepare electrode pre-reserved sites on the other side of the flexible substrate for connecting microneedle conductive electrodes.

[0053] Step 3: Fabrication of the receiver modulation circuit:

[0054] Electronic components (including surface mount diodes and surface mount capacitors) are soldered to circuit solder joints using a low-temperature soldering process. The surface mount diodes and surface mount capacitors together constitute the receiving end modulation circuit. Specifically, three surface mount diodes are connected in series and form a series structure with one of the surface mount capacitors. The series structure and the other surface mount capacitor form a parallel structure.

[0055] Step 4: Fabrication process of the upper and lower layers of the flexible biocompatible encapsulation:

[0056] Polydimethylsiloxane (PDMS), which has excellent light transmittance, flexibility, and chemical inertness, is used for encapsulation. PDMS and a crosslinking agent are mixed in a mass ratio between 10:1 and 10:2, and degassed to obtain a PDMS precursor. The PDMS precursor is spin-coated onto the upper and lower surfaces of the device obtained in step 3, cured, and then subjected to plasma treatment to obtain the elastic and biocompatible encapsulation upper and lower layers. Before spin-coating the PDMS precursor, a release film is used to cover the electrode pre-reserved sites. Finally, the release film is peeled off to expose the electrode pre-reserved sites.

[0057] Step 5: Finally, prepare and assemble the microneedle conductive electrode;

[0058] Highly conductive reduced graphene oxide was prepared by reducing 10-20 mL of graphene oxide aqueous solution (concentration of 1-2 mg / mL) with 1-2 g of ascorbic acid at a certain temperature (60-90℃).

[0059] A conductive double-network solution was formed by incorporating reduced graphene oxide and silver nanowires into a hydrogel material. The hydrogel material was prepared using a mixed solution of PVA and PVP, with PVA and PVP comprising 10-20 wt% of the mixed solution and a PVP:PVA mass ratio of 1:1 to 1:2. The reduced graphene oxide and silver nanowires comprised 10-20% of the conductive double-network solution, with a mass ratio of 1:1 to 1:2.

[0060] The microneedle conductive electrode was fabricated using a template method. The specific method is as follows: First, the mold was prepared. The microneedle conductive electrode is a microneedle array structure, including multiple arrayed frustum-shaped cone-shaped interlocking structures (the lower diameter of the frustum is approximately 300-400 micrometers, the upper diameter is approximately 200-300 micrometers, and the height is approximately 200-400 micrometers; the diameter of the base of the cone is approximately 300-400 micrometers, the height is approximately 700-1000 micrometers, and the front-to-back spacing of the needle tips is approximately 700-1000 micrometers). Brass was used to fabricate the interlocking structures comprising multiple arrayed frustum-shaped cone-shaped structures (each 1 to 4 square meters). The number of microneedles per square centimeter is approximately between 10*10 and 20*20. PDMS is then used for molding to obtain a PDMS concave mold. Next, a conductive double-network solution is poured into the PDMS concave mold, vacuum-treated for 5-10 minutes, and cured at 45-60℃ for 2-4 hours. After demolding, the conductive microneedle electrodes are obtained. Microneedle conductive electrodes with 3*3 to 5*5 needles are cut and set aside. Then, conductive carbon cloth double-sided adhesive (i.e., conductive adhesive tape layer) is used to fix the microneedle conductive electrodes to the pre-reserved electrode sites. Finally, a wireless neural modulation bioelectronic device is obtained.

[0061] Example 1

[0062] See Figure 1The wireless neuromodulation bioelectronic device 1 for blocking the vagus nerve integrates the following components: a biocompatible encapsulation layer, including an elastic biocompatible upper encapsulation layer 2 and an elastic biocompatible lower encapsulation layer 6, used to biocompatiblely encapsulate the parts attached to the skin surface and other exposed parts to reduce the risk of inflammation and ensure stability and safety during use; a wireless power supply coil 4 attached to a flexible substrate 5, which can receive modulated radio electromagnetic wave energy and convert it into electrical energy; a receiver modulation circuit 3, used to convert the electrical energy signal into a low-frequency pulse electrical stimulation signal; and a microneedle conductive electrode 8 containing a dual-network conductive material (reduced graphene and silver nanowires) fixed to the electrode reserved site on the flexible substrate 5 by a conductive adhesive tape layer 7, wherein the microneedle conductive electrode 8 can be inserted into the skin to improve signal transmission efficiency.

[0063] The wireless power supply coil 4 has a planar wiring structure, which is specifically a two-layer structure. The bottom layer is a copper layer and the top layer is a gold layer. The copper layer serves as a connecting layer to fix the gold layer onto a flexible substrate. The copper layer has a thickness of approximately 30-50 micrometers and a line width of approximately 50-100 micrometers. The gold layer has a thickness of approximately 1-3 nanometers and a line width of 50-100 micrometers. The wiring spirals are neatly arranged, with a spacing of approximately 50-200 micrometers between the lines. The coil has approximately 7-10 turns, with an inner diameter of approximately 8-12 millimeters and an outer diameter of approximately 15-20 millimeters.

[0064] The wireless neuromodulation bioelectronic device 1 for blocking the vagus nerve works in conjunction with the transmitter, utilizing the principle of radio electromagnetic induction to achieve mutual isolation between power supply and consumption. After a programmable electrical signal is input, the radio transmitting coil of the transmitter generates a variable magnetic field around it. When the coil of the receiving device (i.e., the wireless power supply coil 4) approaches the variable magnetic field, it induces an alternating magnetic field and generates an alternating current signal. The circuit arranged in the bioelectronic device (i.e., the receiver modulation circuit 3) can rectify the alternating current into a direct current signal in real time. The output signal of the receiver modulation circuit can be arbitrarily adjusted by setting the parameters of the transmitter. In this embodiment, the receiver modulation circuit 3 rectifies the induced current into a pulse signal for neuromodulation (frequency: 3-5 Hz, current intensity: 5-10 mA, pulse width: 100-200 ms). To minimize interfacial impedance, the microneedle conductive electrode 8 integrates a dual conductive network of reduced graphene oxide and silver nanowires, effectively reducing resistivity and increasing conductivity. Structurally, the electrode is designed as a micron-sized needle, which can effectively penetrate the stratum corneum, overcome the skin barrier, reduce skin interfacial impedance, and achieve efficient local electrical signal transmission. Polydimethylsiloxane or skin-friendly silicone is used for biocompatible encapsulation of the parts adhering to the skin surface, as well as the exposed wireless power coil 4 and receiver modulation circuit 3, improving the stability and safety of the device during use.

[0065] Example 2

[0066] In the context of malignant tumors that are difficult to surgically remove, this invention provides a wireless neuromodulation bioelectronic device that uses physical therapy to intervene in vagus nerve activity. This device generates an electrical stimulation nerve modulation signal in a variable magnetic field, which transcutaneously blocks abnormal cervical nerve activity in a living organism, thereby inhibiting the progression of malignant pancreatic cancer.

[0067] Example 3

[0068] See Figure 3 This is a schematic diagram of wireless power transmission technology. A transmitter can be constructed using a signal generator, a signal amplifier, and a radio transmitting coil. The transmitter modulates the electromagnetic waves with the required parameters and forms a therapeutic magnetic field within a designated area. In the wireless neuromodulation bioelectronic device 1 for blocking the vagus nerve of this application, the wireless power supply coil 4 and the receiver modulation circuit 3 together constitute the receiver, which can convert alternating magnetic field signals into low-frequency pulsed electrical stimulation signals in real time within a magnetic field.

[0069] Specifically, the modulated signal from the signal generator is amplified by the signal amplifier and applied to the radio transmitting coil. The variable magnetic field signal generated by the radio transmitting coil forms a local therapeutic magnetic field in the air. The wireless power supply coil 4 can sense the magnetic field and generate an alternating current. The electrical signal is converted into a low-frequency pulse electrical stimulation signal by the modulation circuit at the back end (i.e., the receiving end modulation circuit 3). Finally, the low-frequency pulse electrical stimulation signal (through the microneedle conductive electrode 8) is applied to the vagus nerve to block its abnormal changes.

[0070] The wireless power supply coil 4 is integrated with the receiver modulation circuit 3, which can convert the modulated signal into a pulse square wave electrical signal in real time (frequency 5 Hz, pulse width 100 ms, voltage approximately 1.2 V). Figure 4 In (1), the current is about 10 mA (e.g.) Figure 4 (2)

[0071] Example 4

[0072] To assess the effects of neurally modulated electrical stimulation signal parameters on neurons, primary vagal tubercle neurons for imaging were cultured in a medium loaded with calcium ion indicators, and transient changes in calcium ion concentration within the imaging target region were observed. After low-frequency pulsed electrical stimulation, changes in fluorescence intensity within the visual field were suppressed, indicating a decrease in the average calcium ion concentration in the neurons (e.g., ...). Figure 5 (1)). Simultaneously, electrophysiological monitoring was performed on the dorsal vagal nucleus region of mice. It was observed that the nerve signal was inhibited after low-frequency pulse electrical stimulation, and statistical results showed a decrease in nerve action potentials (e.g., ...). Figure 5(2)). The above in vitro and in vivo results all demonstrate that electrical stimulation has an inhibitory effect on neuronal activity.

[0073] Example 5

[0074] See Figure 6 In a pancreatic cancer (KPC) mouse model, the hepatic branch of the vagus nerve exhibited an abnormal signal pattern of "increased noise and decreased single-peak amplitude," with enhanced activation of its dorsal motor nucleus neurons, suggesting that vagal nerve dysfunction may be involved in pancreatic cancer progression. To investigate the relationship between pancreatic cancer and neural activity, an orthotopic pancreatic cancer mouse model (KPC) was established, and vagal nerve block was performed to detect changes in the immune environment during pancreatic cancer development. Figure 6 (1) is a schematic diagram of the process of using biomedical electronic devices to block abnormal vagal nerve activity and thus affect the development of pancreatic cancer. First, on day 0, pancreatic cancer (KPC-Luc) cells were inoculated into the pancreas of mice. On day 7, the growth of the tumor was determined by in vivo imaging technology. All mice were randomly divided into four groups (blank control group: Control, electrical stimulation group: ES, gemcitabine group: Gem., and combined treatment group: ES & Gem.). On day 8, the first treatment began. The control group received no treatment. The neurostimulation group received 30 minutes of neurostimulation (3-5 Hz, 1-10 mA, 100-200 ms) with a wireless neuromodulation bioelectronic device attached to the mouse neck. The gemcitabine group received intraperitoneal chemotherapy (30-50 mg / kg, twice a week). The combined treatment group received 30 minutes of neurostimulation (3-5 Hz, 1-10 mA, 100-200 ms) with the device attached to the mouse neck, while simultaneously receiving intraperitoneal chemotherapy (30-50 mg / kg on days 8 and 12). Treatment continued for one week. Figure 6 (2) shows the monitoring results of mouse survival curves after one cycle of treatment was stopped. Except for the control group, the survival time of mice in other groups was prolonged, with the combined treatment showing the best effect. During the treatment, in vivo imaging technology was used to clarify the growth of tumors and the treatment effect. Figure 6 Image (3) shows in vivo bioluminescence imaging of four groups of mice, comparing tumor growth before and after treatment. Finally, the mice were euthanized to detect / observe the treatment results. Figure 6 Image (4) shows optical images of tumor size in four groups of mice. Figure 6 (5) shows the statistical results of tumor weight. The above results confirm that the combined treatment group has the best treatment effect.

[0075] Example 6

[0076] See Figure 7This is a microscopic morphological diagram of a microneedle conductive electrode. Specifically, the microneedle conductive electrode is a microneedle array structure, comprising multiple arrayed frustum-shaped cone-shaped snap-fit ​​structures. For example... Figure 7 On the left side, the dimensions of the microneedle (i.e., the snap-fit ​​structure of a frustum supporting a cone) in the microneedle conductive electrode 8 are as follows: the lower diameter of the frustum is approximately 300-400 micrometers, the upper diameter is approximately 200-300 micrometers, and the height is approximately 200-400 micrometers; the diameter of the base of the cone is approximately 300-400 micrometers, and the height is approximately 700-1000 micrometers. The microneedle conductive electrode 8 can be inserted into the skin through the cone. Figure 7 On the right side, the number of microneedles per 1 to 4 square centimeters is approximately between 10*10 and 20*20.

[0077] The above biological experimental results demonstrate the clinical potential of wireless neuromodulation bioelectronic devices for blocking the vagus nerve in the treatment of pancreatic cancer.

Claims

1. A wireless neuromodulation bioelectronic device for blocking the vagus nerve, used in conjunction with a transmitter, characterized in that, The device includes a flexible substrate, a wireless power supply coil, a receiver modulation circuit, microneedle conductive electrodes, and a biocompatible encapsulation layer. The wireless power supply coil is disposed on the flexible substrate and is used to receive radio electromagnetic wave energy emitted by the transmitter and convert it into electrical energy. One end of the receiver modulation circuit is connected to the wireless power supply coil, modulates the generated electrical energy, and converts the electrical energy signal into a low-frequency pulsed electrical stimulation signal. The other end of the receiver modulation circuit is connected to the microneedle conductive electrodes and is used to transmit the low-frequency pulsed electrical stimulation signal to the microneedle conductive electrodes. The microneedle conductive electrode is used to transmit the low-frequency pulsed electrical stimulation signal to the target location; the biocompatible encapsulation layer includes an elastic biocompatible encapsulation upper layer and an elastic biocompatible encapsulation lower layer, used to encapsulate other components except for the microneedle conductive electrode; The microneedle conductive electrode is specifically a hydrogel microneedle containing a dual-network conductive material, which is specifically a graphene oxide and silver nanowires. The microneedle conductive electrode is specifically a microneedle array structure, including several arrayed frustum-shaped cone-shaped snap-fit ​​structures.

2. The wireless neuromodulation bioelectronic device for blocking the vagus nerve according to claim 1, characterized in that, The mass percentage of the dual-network conductive material in the hydrogel microneedles is 10-20%, and the mass ratio of the reduced graphene oxide to the silver nanowires is 1:1 to 1:

2.

3. The wireless neuromodulation bioelectronic device for blocking the vagus nerve according to claim 1, characterized in that, The flexible substrate is specifically made of any one of PI, PET, PDMS and PMMA.

4. The wireless neuromodulation bioelectronic device for blocking the vagus nerve according to claim 1, characterized in that, The biocompatible encapsulation layer is made of polydimethylsiloxane or skin-friendly silicone.

5. A wireless neuromodulation bioelectronic device for blocking the vagus nerve according to claim 1, characterized in that, The receiver modulation circuit includes three surface-mount diodes and two surface-mount capacitors. The three diodes are connected in series with one of the surface-mount capacitors to form a series structure. The extended end of the surface-mount capacitor is connected to the wireless power supply coil. The series structure and the other surface-mount capacitor form a parallel structure. The two extended ends of the surface-mount capacitor are the output terminals of the receiver modulation circuit.

6. A wireless neuromodulation bioelectronic device for blocking the vagus nerve according to claim 1, characterized in that, The wireless power supply coil has a planar wiring structure, which is specifically a two-layer structure. The bottom layer is a copper layer and the top layer is a gold layer. The copper layer serves as a connecting layer to fix the gold layer onto a flexible substrate. The copper layer has a thickness of 30-50 micrometers and a line width of 50-100 micrometers, while the gold layer has a thickness of 1-3 nanometers and a line width of 50-100 micrometers. The wiring spirals are arranged neatly, and the coil has 7-10 turns.

7. A wireless neuromodulation bioelectronic device for blocking the vagus nerve according to claim 1, characterized in that, The lower end of the frustum has a diameter of 300-400 micrometers, the upper end has a diameter of 200-300 micrometers, and the height is 200-400 micrometers; the base of the cone has a diameter of 300-400 micrometers and a height of 700-1000 micrometers.

8. The method for constructing a wireless neuromodulation bioelectronic device for blocking the vagus nerve as described in any one of claims 1-7, characterized in that, Includes the following steps: Step 1: Fabricate the wireless power supply coil and circuit solder joints on a flexible substrate using micro-nano fabrication technology; the specific method is as follows: A film is deposited on the surface of a flexible substrate using magnetron sputtering to remove excess metal and leave patterned metal lines, which are the wireless power coil and circuit solder joints. Step 2: Repeat step 1 to prepare a flexible double-sided panel, and prepare electrode pre-reserved sites on the other side of the flexible substrate; Step 3: Solder the electronic components to the circuit solder joints using a low-temperature soldering process. The electronic components include three surface mount diodes and two surface mount capacitors. The three surface mount diodes and two surface mount capacitors together constitute the receiver modulation circuit. Step 4: Mix PDMS and crosslinking agent at a mass ratio of 10:1-2, and degas to obtain PDMS precursor; spin-coat the PDMS precursor onto the upper and lower surfaces of the device obtained in Step 3, cure and then perform plasma treatment to obtain the upper and lower layers of elastic biocompatible encapsulation. Step 5: Fabrication and assembly of microneedle conductive electrodes; Graphene oxide was prepared by reducing an aqueous solution of graphene oxide with ascorbic acid at a temperature of 60-90℃. Redox graphene and silver nanowires are added to hydrogel materials to form a conductive double network solution; The conductive double network solution is poured into a mold, vacuum treated for 5-10 minutes, cured at 45-60℃ for 2-4 hours, and then demolded to obtain a microneedle conductive electrode. Then, the conductive electrodes of the microneedles are fixed to the electrode pre-reserved sites using conductive carbon cloth double-sided adhesive; finally, a wireless neural modulation bioelectronic device is obtained.

9. The method for constructing a wireless neuromodulation bioelectronic device for blocking the vagus nerve as described in claim 8, characterized in that, In step 5, 1-2 g of ascorbic acid is reacted with 10-20 mL of an aqueous solution of graphene oxide at a concentration of 1-2 mg / mL.

10. The method for constructing a wireless neuromodulation bioelectronic device for blocking the vagus nerve as described in claim 8, characterized in that, The hydrogel material is specifically prepared from a mixed solution of PVA and PVP, wherein PVA accounts for 10-20 wt% of the mixed solution, and the mass ratio of PVP to PVA is 1:1-2.

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