An ultrasonically driven implantable wireless radio stimulation device

Abstract

The application belongs to the field of biomedical engineering devices, and particularly relates to an ultrasonic driving implantable wireless electric stimulation device, which comprises a magnetic nanoparticle hydrogel microneedle unit, an in-vivo piezoelectric energy collector, an electric energy modulation circuit, a polypyrrole electrode electric stimulation unit, a flexible substrate layer and a biocompatible packaging layer. The device can receive external wireless ultrasonic energy, convert it into electric energy and then modulate it into an electric stimulation parameter signal; a patterned electrode transmits the stimulation signal to a tumor site for electric stimulation; under the regulation of an external magnetic field, the swellable hydrogel microneedle loads magnetic nanoparticles and delivers them to the tumor site. Electric stimulation combined with magnetic nanoparticles produces active oxygen through a Fenton reaction, directly inhibits tumor cells and regulates macrophage polarization through electric signals, thereby remodeling the immunosuppressive microenvironment of pancreatic cancer and providing a minimally invasive, efficient and safe comprehensive inhibition scheme for pancreatic cancer.

Description

Technical Field

[0001] This application belongs to the field of biomedical engineering devices, specifically relating to an ultrasound-driven implantable radio stimulation device. Background Technology

[0002] Traditional methods for inhibiting the proliferation of pancreatic cancer cells have significant limitations: 1) They are suitable for a small proportion of patients requiring surgical resection, and the recurrence rate is high; 2) Current first-line chemotherapy drugs are not very effective for advanced-stage patients, and the inhibition of tumor cell proliferation is accompanied by side effects such as bone marrow suppression; 3) Pancreatic cancer has an immunosuppressive microenvironment, resulting in minimal efficacy of immune checkpoint inhibitors such as PD-1 / PD-L1 inhibitors. Therefore, it is necessary to explore novel strategies for inhibiting the proliferation of pancreatic cancer cells, improve patient compliance, and address the side effects associated with clinical tumor cell proliferation inhibition.

[0003] Electrostimulation therapy (ESPT) is an emerging physical therapy. It inhibits tumor cell proliferation by interfering with mitosis and triggering apoptosis signaling pathways. EPT avoids chemotherapy resistance and is suitable for patients with advanced or resistant tumors. Although EPT has been partially applied clinically, it still faces challenges in inhibiting the proliferation of pancreatic cancer cells, such as the bulky size of the EPT equipment, complex wired connections, poor biocompatibility after implantation, and the lack of wireless EPT platforms specifically designed for inhibiting the proliferation of pancreatic cancer cells. Summary of the Invention

[0004] This application relates to an ultrasound-driven implantable radio-stimulation device, comprising a magnetic nanoparticle hydrogel microneedle unit, an in vivo piezoelectric energy harvester, an electrical modulation circuit, a polypyrrole electrode electrical stimulation unit, a flexible substrate layer, and a biocompatible encapsulation layer. The microneedle structure of the magnetic nanoparticle hydrogel microneedle unit enables the delivery of magnetic nanoparticles to the tumor site and allows it to adhere tightly to pancreatic tissue. The in vivo piezoelectric energy harvester converts external ultrasonic mechanical energy into electrical energy based on the piezoelectric effect, providing power to the entire device. The electrical modulation circuit modulates the alternating current signal collected by the in vivo piezoelectric energy harvester into a direct current electrical stimulation signal and transmits it to the electrical stimulation electrode unit. The polypyrrole electrode electrical stimulation unit delivers the electrical stimulation signal to the tumor region. The flexible substrate layer carries a metal layer and serves as a connection between the electrical stimulation unit and the circuit. The biocompatible encapsulation layer is used for encapsulating the electronic device.

[0005] In one embodiment, the magnetic nanoparticle hydrogel microneedle unit uses hydrogel as a carrier to load magnetic nanoparticles.

[0006] In one embodiment, the in-body piezoelectric energy harvester includes micron-sized lead zirconate titanate and coated electrodes with polarized ends. Alternatively, the in-body piezoelectric energy harvester includes piezoelectric ceramics such as lead zirconate titanate, barium titanate, and potassium sodium niobate, and coated electrodes with polarized ends.

[0007] In one embodiment, the power modulation circuit includes a bridge circuit and a voltage-regulating capacitor. Alternatively, the power modulation circuit may include a half-wave rectifier circuit, a full-wave rectifier circuit, and a bridge rectifier circuit, etc.

[0008] In one embodiment, the polypyrrole electrode electrostimulation unit includes depositing a biocompatible polypyrrole material on a metal electrode. Alternatively, the polypyrrole electrode electrostimulation unit includes polypyrrole, polyaniline, and poly(3,4-ethylenedioxythiophene):poly(styrenesulfonate), PEDOT:PSS, etc.

[0009] In one embodiment, the flexible substrate layer comprises a flexible transparent material, polydimethylsiloxane, and a polyester film. Alternatively, the flexible substrate layer may include polydimethylsiloxane (PDMS), polyethylene terephthalate (PET) film, polyimide (PI) film, and polymethyl methacrylate (PMMA) film, etc.

[0010] In one embodiment, perforations and cuts are made in a flexible substrate to form an integrated, cuff-like thin-film device that can be bent and looped onto pancreatic tumor tissue. Alternatively, perforations and cuts are made in a flexible substrate to form an integrated, snap-on or plug-in type thin-film device that can be bent and looped onto pancreatic tumor tissue.

[0011] In one embodiment, the magnetic nanoparticle hydrogel microneedle unit uses methacrylamide gelatin hydrogel as a carrier. Alternatively, the magnetic nanoparticle hydrogel microneedle unit uses polyvinyl alcohol (PVA), polyvinylpyrrolidone (PVP), and polyethylene glycol diacrylate (PEDGA) hydrogel as a carrier.

[0012] In one embodiment, a metal electrode is placed in a precursor solution containing a dopant and a pyrrole monomer; a platinum sheet, an Ag / AgCl electrode, and a platinum wire serve as the working electrode, a reference electrode, and a counter electrode, respectively; a biocompatible conductive polymer polypyrrole film is deposited on the metal electrode to form a polypyrrole electrode electrostimulation unit.

[0013] This application realizes a wireless implantable electronic medical device for inhibiting the proliferation of pancreatic cancer tumor cells, which has the following beneficial effects: (1) This application demonstrates the anti-tumor performance of a wireless implantable electronic medical device used to inhibit the proliferation of pancreatic cancer tumor cells; (2) This application realizes the deep energy harvesting, regulation and transfer in the body through the piezoelectric effect, eliminating technical difficulties such as external battery dependence and complex wired connection; (3) This application provides wireless power to the in vivo device through external ultrasound, and can also control the external ultrasound to achieve real-time wireless control of the in vivo device. The electrical stimulation parameters can be wirelessly controlled according to clinical guidance. (4) This application combines a cuff-type structural design with a hydrogel magnetic nanoparticle microneedle unit to adapt to the narrow and soft shape of the pancreas. Structurally, the device can be bent and looped onto the pancreatic tumor site. Drug delivery and fixation are achieved through the swellable hydrogel microneedle unit, thus realizing the biocompatibility and long-term stable fixation of the device. (5) The microneedle unit of this application can deliver magnetic nanoparticles to the tumor area in situ with precision, and the magnetic nanoparticles can be targeted and stacked by external magnetic field. (6) This application is encapsulated with biocompatible materials (PPy, PDMS and GelMA, etc.) and has excellent biocompatibility after implantation.

[0014] This application discloses an ultrasound-driven implantable radio-stimulation device that receives external wireless ultrasound energy, converts it into electrical energy, and modulates it into electrical stimulation parameter signals. Patterned electrodes transmit the stimulation signals to the tumor site for electrical stimulation. Under the control of an external magnetic field, swellable hydrogel microneedles load nanomagnetic nanoparticles and deliver them to the tumor site. The combination of electrical stimulation and magnetic nanoparticles generates reactive oxygen species through the Fenton reaction, directly killing tumor cells and regulating macrophage polarization through electrical signals, thus reshaping the immunosuppressive microenvironment of pancreatic cancer. This provides a minimally invasive, highly efficient, and safe comprehensive tumor cell proliferation inhibition strategy for pancreatic cancer. This device has significant clinical translational potential and can be extended to liver cancer, breast cancer, and ovarian cancer, among others. Attached Figure Description

[0015] The present application will be described in more detail below based on embodiments and with reference to the accompanying drawings. Wherein: Figure 1 A schematic diagram of an ultrasound-driven implantable radio-stimulation device is shown. Figure 2 A schematic diagram illustrating the application of ultrasound-driven implantable radio-stimulation devices is shown. Figure 3 Demonstrating the application of a prototype of an ultrasound-driven implantable radio stimulation device; Figure 4 Electrical performance of ultrasound-driven implantable radio-stimulation devices; Figure 5 To demonstrate the in vitro antitumor effect of ultrasound-driven implantable radiofrequency stimulation devices.

[0016] Figure label: 1-The overall device, 2-Magnetic nanoparticle hydrogel microneedle unit, 3-In vivo piezoelectric energy harvester, 4-Electrical energy modulation circuit, 5-Polypyrrole bioconductive material layer, 6-Patterned metal gold layer, 7-Patterned metal copper layer, 8-Flexible platform PET layer, 9-Biocompatible encapsulation layer. Detailed Implementation

[0017] The present application will now be further described in conjunction with the accompanying drawings.

[0018] The present application will be further described below through specific embodiments.

[0019] Example 1: In an ultrasound-driven implantable radio-stimulation device and its structure, such as Figure 1The magnetic nanoparticle microneedle unit uses gelatin methacryloyl (GelMA) hydrogel as a carrier. The microneedle structure enables precise delivery of nanoparticles and stable device attachment. The nanoparticle dosage can be adjusted as needed. The specific preparation method involves mixing 1-2 g of sponge-like solid GelMA with 20-40 mL of a 0.10-0.25% (w / v), i.e., 1.0-2.5 mg / mL, initiator standard solution in the dark. The mixture is dissolved by heating in a water bath in the dark, and then gelled by irradiation with an ultraviolet light source for 10-30 seconds. The gel strength can be controlled by adjusting the irradiation time and intensity. The in vivo piezoelectric energy harvester uses sintered piezoelectric ceramic as the core material. A micron-sized in vivo piezoelectric energy harvester is fabricated through physical cutting and electrode coating processes and connected to a flexible substrate platform. The power modulation circuit uses a classic bridge circuit to achieve quantitative output of the bipolar signal generated by the in vivo piezoelectric energy harvester. The device is then mounted on the flexible platform solder joints. Polypyrrole bioconductive material layer: Patterned metal electrodes are placed in a precursor solution containing a certain amount of dopants and pyrrole monomers, including sodium oxalate, naphthalenesulfonic acid, and camphorsulfonic acid. During electrochemical polymerization, platinum sheets, Ag / AgCl electrodes, and platinum wires serve as the working electrode, reference electrode, and counter electrode, respectively. A biocompatible conductive polymer polypyrrole (Ppy) film is deposited on the patterned metal electrodes. Patterned gold metal layer: The metal layer is deposited using magnetron sputtering. Patterned copper metal layer: The metal layer is deposited using magnetron sputtering, with copper serving as a connecting layer. Flexible substrate platform layer: Primarily composed of flexible transparent materials such as polydimethylsiloxane (PDMS) and polyester film (PET), this layer mainly supports the patterned metal layers as connections for the electrostimulation unit and circuit wiring. Biocompatible encapsulation layer: Polydimethylsiloxane (PDMS) is used for encapsulation. The elastomer and crosslinking agent are mixed at a mass ratio of 10:1 and then ultrasonically treated for 15 minutes to eliminate air bubbles to obtain a PDMS mixture. The mixture is then coated on the surface of the radio stimulation device and cured.

[0020] Figure 2To illustrate the application of ultrasound-driven implantable radio-stimulation devices, this paper uses the physical morphology of pancreatic tumors as an example to demonstrate the cuff-like physical structure of the device. Based on the anatomical characteristics of pancreatic tumors, a cuff-like device structure was designed. The radio-stimulation device is integrated in a two-dimensional plane, facilitating minimally invasive implantation. The two-dimensional to three-dimensional cuff design allows the device to be bent and fixed to the pancreatic cancer site. Programmable electrical energy is used to drive the ultrasound probe, generating programmable mechanical energy (ultrasound energy) to achieve wireless control of the electrostimulation physical therapy parameters. Simultaneously, a mechanical dynamics simulation model of wireless magnetic field traction of magnetic nanoparticles is established, and an imaging-assisted wireless power supply / control method for the implantable device is developed.

[0021] Figure 3 This is a prototype of an ultrasound-driven implantable radio-stimulation device, with the device looped around the pancreas. A partial view shows the device looped around tumor tissue. The application of the prototype to the pancreas and tumor tissue demonstrates the superior structural design of the device: nearly 80% of pancreatic ductal carcinomas occur in the pancreatic head, and the soft, narrow shape of the pancreas presents challenges for the fixation of implantable medical electronic devices. Therefore, this application designs a biocompatible device structure based on the physical characteristics of mouse pancreatic glands and pancreatic ductal carcinomas. The radio-stimulation device integrates a polypyrrole electrode electrical stimulation unit and a magnetic nanoparticle hydrogel microneedle unit. Simultaneously, considering the implantation surgery and fixation methods, the various functional units are integrated and distributed on the same two-dimensional plane, allowing the device to be implanted into the target area through a small incision. After implantation, the snap-on three-dimensional sleeve-like device loops around the cancerous area of ​​the mouse's pancreatic head, constructing a biocompatible implantable device.

[0022] Figure 4 To illustrate the electrical performance of ultrasound-driven implantable radio-frequency stimulation devices, we will take the DC stimulation parameters output by the device as an example: The in vivo piezoelectric energy harvester can convert ultrasound energy into electrical energy in real time through the piezoelectric effect, transforming bipolar mechanical waves into bipolar output electrical signals of the same frequency. Alternating current can be modulated into a unipolar output electrical signal through the energy management module. The device ultimately outputs a 1-2V DC voltage for treating pancreatic cancerous areas, achieving direct immune function regulation and promoting the immune modulation of tumor-associated macrophages.

[0023] Figure 5To illustrate the in vitro antitumor effect of ultrasound-driven implantable radio-stimulated devices, a pancreatic cancer cell model is used as an example for detailed explanation: KPC pancreatic cancer cells are a pancreatic cancer cell line developed from a transgenic mouse model (a specific combination of mutations in three key genes: Kras, P53, and Cre). KPC pancreatic cancer cells were injected into wells at doses of 10... 5 -2×10 5 The cells were seeded at a density of [number] cells / units in culture dishes and incubated under standard conditions for 24-48 hours. After incubation, the old culture medium was discarded and fresh culture medium was added. Then, an ultrasonically driven electrode was used to generate a stimulation signal, which, in conjunction with the magnetic nanoparticle microneedle unit, inhibited tumor cells. The ultrasonic conditions were [0.5-1 MHz, 1-2 W / cm²]. 2 Under the incubation conditions, each well was treated for 5-10 min, and then cultured for 24-48 h. The in vitro cell experiments were divided into four groups: a blank control group (Group 1), an electrostimulation group (Group 2), a magnetic nanoparticle group (Group 3), and a group combining electrostimulation with magnetic nanoparticles and tumor cell proliferation inhibition (Group 4). After 24 hours of incubation, cell viability was assessed using a kit, and UV absorbance was measured using a multi-mode microplate reader to evaluate the inhibitory effect of the ultrasound-driven implantable radiofrequency stimulation device on pancreatic cancer cells under in vitro culture conditions. Group 1 represents the cell proliferation of the blank control group; Group 2 represents the cell proliferation of the electrostimulation group alone; Group 3 represents the cell proliferation of the magnetic nanoparticle group alone; and Group 4 represents the cell proliferation of the mixed tumor cell proliferation inhibition group. Here, relative proliferation rate describes the fold or percentage change relative to the control group; it is a dimensionless quantity used to compare the promoting or inhibiting effects of different treatments on cell proliferation, and no units are required.

[0024] While this application has been described herein with reference to specific embodiments, it should be understood that these embodiments are merely examples of the principles and applications of this application. Therefore, it should be understood that many modifications can be made to the exemplary embodiments, and other arrangements can be designed without departing from the spirit and scope of this application as defined by the appended claims. It should be understood that different dependent claims and features described herein can be combined in ways different from those described in the original claims. It is also understood that features described in conjunction with individual embodiments can be used in other described embodiments.

Claims

1. An ultrasound-driven implantable radio-stimulation device, characterized in that, It includes a magnetic nanoparticle hydrogel microneedle unit, an in vivo piezoelectric energy harvester, an electrical energy modulation circuit, a polypyrrole electrode electrical stimulation unit, a flexible substrate layer, and a biocompatible encapsulation layer. The microneedle structure of the magnetic nanoparticle hydrogel microneedle unit can deliver magnetic nanoparticles to the tumor site and adhere tightly to the pancreatic tissue. The in vivo piezoelectric energy harvester converts external ultrasonic mechanical energy into electrical energy based on the piezoelectric effect, providing power for the entire device; The electrical energy modulation circuit modulates the alternating current signal collected by the piezoelectric energy harvester in the body into a direct current electrical stimulation signal, which is then transmitted to the electrical stimulation electrode unit. The polypyrrole electrode electrostimulation unit delivers electrical stimulation signals to the tumor area; A flexible substrate supports a metal layer, serving as a connection between the electrical stimulation unit and the circuitry. Biocompatible encapsulation layers are used for the encapsulation of electronic devices.

2. The ultrasound-driven implantable radio stimulation device according to claim 1, characterized in that, The magnetic nanoparticle hydrogel microneedle unit uses hydrogel as a carrier to load magnetic nanoparticles.

3. The ultrasound-driven implantable radio stimulation device according to claim 1, characterized in that, The in vivo piezoelectric energy harvester includes micron-sized lead zirconate titanate and coated electrodes with polarized surfaces at both ends.

4. The ultrasound-driven implantable radio stimulation device according to claim 1, characterized in that, The power modulation circuit includes a bridge circuit and a voltage-regulating capacitor.

5. The ultrasound-driven implantable radio stimulation device according to claim 1, characterized in that, The polypyrrole electrode electrostimulation unit comprises depositing a biocompatible polypyrrole material on a metal electrode.

6. The ultrasound-driven implantable radio stimulation device according to claim 1, characterized in that, The flexible substrate layer comprises flexible transparent materials polydimethylsiloxane and polyester film.

7. The ultrasound-driven implantable radio stimulation device according to claim 1, characterized in that, By drilling and cutting into a flexible substrate, an integrated cuff-like thin-film device is formed that can be bent and looped onto pancreatic tumor tissue.

8. The ultrasound-driven implantable radio stimulation device according to claim 1, characterized in that, The magnetic nanoparticle hydrogel microneedle unit uses methacrylamide gelatin hydrogel as a carrier.

9. The ultrasound-driven implantable radio stimulation device according to claim 1, characterized in that, A metal electrode is placed in a precursor solution containing dopants and pyrrole monomers. A platinum sheet, an Ag / AgCl electrode, and a platinum wire serve as the working electrode, a reference electrode, and a counter electrode, respectively. A biocompatible conductive polymer polypyrrole film is deposited on the metal electrode to form a polypyrrole electrode electrostimulation unit.

Images