A fully degradable electrical stimulation system and preparation method thereof

Abstract

The present invention proposes a fully degradable electrical stimulation system, including a nanogenerator and an electrical stimulation electrode. The nanogenerator generates a continuous current and / or voltage through heartbeat, breathing, and body movement, and transmits it to the electrical stimulation electrode. The electrical stimulation electrode is fixed to the target position of the nerve, muscle, or bone in the body, and the electrical stimulation current and / or voltage is applied to the target position. The system of the present invention can release voltage, current, or electric field stimulation, solving the problem that the current electrical stimulation device needs battery power and the prognosis requires secondary surgery to remove it, so that the temporary medical device can be completely degraded in the body, alleviating the pain of the patient.

Description

Technical Field

[0001] The present invention belongs to the field of biomedicine, and in particular relates to a fully degradable electrical stimulation system. Background Art

[0002] Electrostimulation (ES) can regulate the bioelectric state by simulating the endogenous electric field, which can accelerate tissue repair, fracture healing, promote the regeneration of damaged nerves and prevent muscle atrophy. It is widely recognized as a promising non-drug treatment method in clinical practice and has been approved by the US Food and Drug Administration (FDA).

[0003] Pulsed electric fields of appropriate intensity and frequency can activate cell-related gene expression, promote the proliferation and differentiation of damaged tissue cells, and actively stimulate tissue regeneration. However, the electrical stimulation therapy used clinically relies on large and complex equipment, which relies on direct power supply from the mains frequency or battery drive. It has disadvantages such as inconvenience in carrying, battery energy depletion, and environmental pollution. The treatment process requires frequent visits to the doctor and is operated by professional doctors. In addition, existing electrical stimulation systems cannot be degraded and require additional surgery to remove, further limiting their potential in actual clinical applications.

[0004] Therefore, there is an urgent need to address a series of potential problems that limit the clinical transformation of electrical stimulation devices, such as their relatively large size, non-degradability, the need for secondary surgery to remove them, or the complex preparation process of external wireless power supply devices. Summary of the invention

[0005] In order to overcome the problems of the prior art, the present invention provides a fully degradable system that can be used for electrical stimulation therapy. The system has a simple structure, a wide range of materials, is biosafe, is easily flexible and miniaturized, and is directly powered by the mechanical movement of the body.

[0006] The present invention provides the following technical solutions:

[0007] A fully degradable electrical stimulation system includes a nanogenerator and an electrical stimulation electrode. The nanogenerator generates continuous current and / or voltage through heartbeat, breathing, and body movement, and transmits it to the electrical stimulation electrode. The electrical stimulation electrode is fixed to the target position of nerves, muscles, and bones in the body to apply the electrical stimulation current and / or voltage to the target position.

[0008] Furthermore, the nanogenerator is a friction nanogenerator, a piezoelectric nanogenerator or a piezoelectric-friction composite nanogenerator.

[0009] Furthermore, the friction nanogenerator comprises, from the inside to the outside, a first polymer elastic friction layer, a second polymer friction layer, a first metal layer, a second metal layer, and a packaging layer, the first polymer friction layer being an elastomeric friction layer and having a micro-nano structure on its inner surface, the first metal layer being attached to the outside of the first polymer elastic friction layer, the second metal layer being attached to the outside of the second polymer friction layer, an air layer being formed between the first polymer elastic friction layer and the second polymer friction layer, and the outermost layer being provided with a packaging layer;

[0010] The piezoelectric nanogenerator comprises, from the inside to the outside, a correspondingly arranged piezoelectric layer, a first metal electrode layer, a second metal electrode layer, and a packaging layer, wherein the first metal electrode layer and the second metal electrode layer are respectively attached to the upper and lower surfaces of the piezoelectric layer, and the outermost layer is provided with a packaging layer;

[0011] The piezoelectric-friction composite nanogenerator is composed of a first metal layer, a piezoelectric layer, a first polymer elastic friction layer, a second metal layer, a third metal layer, and a packaging layer arranged from the inside to the outside. The first polymer friction layer is an elastic friction layer and has a micro-nano structure on its inner surface. An air layer is formed between the first polymer elastic friction layer and the inner surface of the first metal layer. The inner and outer sides of the piezoelectric layer are respectively bonded to the first metal layer and the second metal layer. The other side of the first polymer elastic friction layer is in contact with the third metal layer. The outermost layer is encapsulated by the packaging layer.

[0012] Furthermore, the first polymer elastomer friction layer is one or more of hydrogel, polyurethane PU, polyglycerol sebacate PGS, polyoctanediol citrate POC, polyhydroxyalkanoate PHAs, and peptide bioelastomer, and has a thickness of 200-500 μm;

[0013] The second polymer friction layer is one or more of collagen, fibrin, silk, collagen, fibrin, silk, starch, alginate, chitin, hyaluronic acid derivatives, natural polyester, polylactic acid PLA, polyglycolic acid PGA, polylactic acid-glycolic acid copolymer PLGA, polycaprolactone PCL, polyvinyl alcohol PVA, polyethylene glycol PEG, regenerated cellulose, starch plastic, poly 3-hydroxybutyrate PHB, copolymer of 3-hydroxybutyrate and 3-hydroxyvalerate PHBV, copolymer of 3-hydroxybutyrate and 3-hydroxyhexanoate PHBH, with a thickness of 50-100 μm;

[0014] The metal layer is one or more of magnesium, iron, manganese, zinc, silicon, molybdenum, magnesium oxide, ferroferric oxide, manganese oxide, zinc oxide, silicon dioxide, molybdenum dioxide-based oxide, or AE21 magnesium alloy, Mg-Zr-Y alloy, and has a thickness of 20-500 nm;

[0015] The piezoelectric layer is one or more of poly (L-lactic acid) PLLA, glycine, collagen, fiber, chitin, and has a thickness of 20-200 μm;

[0016] The packaging layer material is a flexible insulating material of one or more of polylactic acid PLA, polyglycolic acid PGA, polylactic acid-glycolic acid copolymer PLGA, polycaprolactone PCL, polyethylene glycol PEG, polyvinyl alcohol PVA and polylactic acid-polyglycolic acid copolymer, with a thickness of 10-100 μm.

[0017] Furthermore, the electrical stimulation electrode is a needle-shaped electrode or a spiral electrode, the base layer is a wire base, the wire base is a degradable polymer line or a metal wire, a conductive layer is provided on the outside of the base layer, the conductive layer is a degradable metal, the encapsulation layer covers the conductive layer, both ends are exposed, the encapsulation layer is a degradable polymer, and the exposed wires at both ends are respectively connected to the nanogenerator and the target position.

[0018] Alternatively, the electrical stimulation electrode is a sheet electrode or a forked electrode, and the electrode includes a base layer, a conductive layer and a packaging layer. The base layer is a flexible film base, and the base layer material is a degradable polymer. The conductive layer is a degradable metal. The outermost side is provided with a packaging layer, and the packaging layer is a degradable polymer, which is connected to the nanogenerator and the target position respectively through external wires.

[0019] Further, the wire substrate is catgut, absorbable PLGA medical suture, PLA wire, magnesium wire, iron wire, molybdenum wire;

[0020] The conductive layer is a degradable metal such as magnesium, iron, manganese, zinc, silicon or molybdenum;

[0021] The encapsulation layer is based on polyvinyl alcohol, polyvinyl lactone, polylactic acid, polyhydroxybutyrate valerate, chitosan or sodium alginate.

[0022] A method for preparing a fully degradable electrical stimulation system comprises the following steps:

[0023] Step 1: taking degradable polylactic acid (PLA) particles, melting them at high temperature and placing them into a structural template to obtain a spiral conductor substrate;

[0024] Step 2: After the spiral conductor substrate is surface treated, a degradable metal is used as a target material, and magnetron sputtering is performed to form a 20-100 nm thick metal conductive layer in the spiral conductor substrate;

[0025] Step 3: Place the polylactic acid (PLA) solution in the 3D printed PVA groove, and peel off the polylactic acid (PLA) film after it is semi-dried. The polylactic acid (PLA) film is wrapped on the metal conductive layer, and bare wires are left at both ends of the spiral wire base;

[0026] Step 4: adding citric acid to 1,8-octanediol, melting the mixture at high temperature under nitrogen conditions, adding the prepolymer solution to the polydimethylsiloxane template of the micro-bowl structure, polymerizing under vacuum, and obtaining the first polymer elastic friction layer polyoctanediol citrate POC with a thickness of 200-500 μm;

[0027] Step 5: dissolving polylactic acid PLA in a chloroform solution, casting the solution on a glass plate, removing the remaining solvent, and obtaining a polylactic acid PLA film with a thickness of 50-100 μm to obtain a second polymer friction layer;

[0028] Step 6: Using magnetron sputtering technology, using degradable metal as a target, sputtering and depositing the degradable metal as a first metal layer on the first polymer elastic friction layer poly(octanediol citrate) POC, with a thickness of 20-500 nm; and depositing the degradable metal on one side of the second polymer friction layer poly(lactic acid) PLA as a second metal layer, with a thickness of 20-500 nm;

[0029] Step 7: Continue to form a film of polylactic acid (PLA) as a packaging layer on the outside of the first metal layer and the second metal layer, and assemble the layers using hot pressing technology.

[0030] By adopting the above technical solution, the present invention has the following beneficial effects:

[0031] (1) The present invention uses degradable materials as a substrate and prepares a fully degradable electrical stimulation system through micro-nano processing and flexible packaging. The system can release voltage or current stimulation, solving the problem that current electrical stimulation devices require battery power and require secondary surgery to remove. It allows temporary medical devices to be completely degraded in the body, alleviating the pain of patients.

[0032] (2) The electrical stimulation of the present invention acts on nerves, muscles, and bones in the form of an electric field to promote wound healing, bone repair, nerve damage repair, and functional reconstruction. It can be used for central nervous system injuries such as spinal cord, peripheral nerve injuries such as sciatic nerve, or muscles and bones. It is directly powered by the mechanical movement of the body and can be self-degraded in the body or absorbed and metabolized by the body. BRIEF DESCRIPTION OF THE DRAWINGS

[0033] Figure 1 This is a schematic diagram of the core structure of the friction nanogenerator in the present invention;

[0034] Figure 2 It is a schematic diagram of the core structure of the piezoelectric nanogenerator in the present invention;

[0035] Figure 3 This is a schematic diagram of the core structure of the piezoelectric-friction composite nanogenerator in the present invention;

[0036] Figure 4 It is a schematic diagram of the spiral electrode structure of the present invention;

[0037] Figure 5 is a schematic diagram of the interdigital electrode structure of the present invention;

[0038] Figure 6 is a schematic diagram of the system of the present invention applied to rats;

[0039] Figure 7 is a flow chart of the preparation of an implantable fully degradable electrical stimulation system in a specific embodiment of the present invention;

[0040] Figure 8 It is the output performance test result of the fully degradable electrical stimulation system;

[0041] Fig. 9 It is the degradation test result of the fully degradable electrical stimulation system;

[0042] Fig.10 It is a fully degradable electrical stimulation system that promotes wound healing results.

[0043] Description of Reference Numerals

[0044] 1. Nanogenerator, 2. Electrical stimulation electrode, 3. Vagus nerve, 4. Rat, 5. First polymer elastic friction layer, 6. Second polymer friction layer, 7. First metal layer, 8. Second metal layer, 9. Packaging layer, 10. Wire, 11. Piezoelectric layer, 12. Third metal electrode layer, 13. Base layer, 14. Conductive layer. DETAILED DESCRIPTION

[0045] In order to make the purpose, technical solution and advantages of the present invention more clearly understood, the present invention is further described in detail below in conjunction with the accompanying drawings and embodiments. It should be understood that the structural diagrams and specific embodiments described herein are only used to explain the present invention and are not used to limit the present invention.

[0046] Example 1

[0047] The present invention provides a fully degradable electrical stimulation system, comprising a nanogenerator 1 and an electrical stimulation electrode 2. The nanogenerator generates continuous current and / or voltage through heartbeat, breathing, and body movement, and transmits it to the electrical stimulation electrode. The electrical stimulation electrode is fixed to the target position of nerves, muscles, and bones in the body, and the electrical stimulation current and / or voltage is applied to the target position.

[0048] Electrical stimulation acts on nerves, muscles, and bones in the form of an electric field to promote wound healing, bone repair, nerve damage repair, and functional reconstruction. The present invention can be used for central nervous system injuries such as spinal cord, peripheral nerve injuries such as sciatic nerve, or muscles and bones. It is directly powered by the mechanical movement of the body and can be self-degraded in the body or absorbed and metabolized by the body.

[0049] Wherein, the nanogenerator is a friction nanogenerator, a piezoelectric nanogenerator or a piezoelectric-friction composite nanogenerator.

[0050] The principle of the triboelectric nanogenerator is the friction electrification and electrostatic induction effect. Under the drive of external force, the two friction layers come into contact with each other, and equal amounts of opposite charges are generated on the surface; when the external force is removed, the two layers of material separate, and the potential difference generated by the positive and negative charges drives the flow of electrons, generates current and realizes force-electricity conversion.

[0051] The nanogenerator can be a triboelectric nanogenerator, such as Figure 1 As shown, the friction nanogenerator comprises, from the inside to the outside, a first polymer elastic friction layer 5, a second polymer friction layer 6, a first metal layer 7, a second metal layer 8, and a packaging layer 9 which are arranged opposite to each other.

[0052] The first polymer friction layer is an elastomeric friction layer and has a micro-nano structure on its inner surface. An air layer is formed between the first polymer elastic friction layer and the inner surface of the second polymer friction layer. The first metal layer is attached to the outer side of the first polymer elastic friction layer, the second metal layer is attached to the outer side of the second polymer friction layer, and the outermost layer is provided with a packaging layer.

[0053] The working principle of the friction nanogenerator is the coupling of frictional electrification and electrostatic induction effect. For example, the friction nanogenerator is implanted in the heart and fits with the heart. The continuous beating of the heart can cause the first polymer elastic friction layer and the second polymer friction layer of the friction nanogenerator to periodically contact and separate. When the heart contracts, the first polymer elastic friction layer and the second polymer friction layer contact each other, and free electrons are generated between the surfaces of the two materials, and the electrons flow from the second polymer friction layer to the first polymer elastic friction layer. When the heart relaxes, the first polymer elastic friction layer and the second polymer friction layer separate from each other, resulting in an increase in the distance between the two materials, and electrons flow from the first polymer elastic friction layer to the second polymer friction layer. As the heart keeps beating, electrons circulate back and forth between the friction electric layers, so the friction nanogenerator generates output.

[0054] The nanogenerator can be a piezoelectric nanogenerator, such as Figure 2 As shown, the piezoelectric nanogenerator is composed of a correspondingly arranged piezoelectric layer 11, a first metal electrode layer 7, a second metal electrode layer 8, and a packaging layer 9 from the inside to the outside. The first and second metal electrode layers are respectively attached to the upper and lower surfaces of the piezoelectric layer, and the outermost layer is provided with a packaging layer. The working principle of the piezoelectric nanogenerator is the piezoelectric effect.

[0055] The piezoelectric nanogenerator is implanted in the heart and fits with the heart. The continuous beating of the heart can cause the piezoelectric nanogenerator to deform due to external force, and the surface of the piezoelectric layer material will produce positive and negative charge surfaces, which are called polar surfaces. The piezoelectric potential generated by these polar surfaces can be used to drive the movement of electrons in the external circuit, realize the conversion of mechanical energy into electrical energy, and the piezoelectric generator generates output to the outside.

[0056] The nanogenerator can be a piezoelectric-triboelectric composite nanogenerator, such as Figure 3 As shown, the piezoelectric-friction composite nanogenerator comprises, from the inside to the outside, a first metal layer 7, a first polymer elastic friction layer 5, a piezoelectric layer 11, a second metal layer 8, a third metal layer 12, and an encapsulation layer 9 which are arranged relatively one after another. The first polymer friction layer 5 is an elastomeric friction layer and a micro-nano structure is provided on the inner surface. An air layer is formed between the first polymer elastic friction layer 5 and the inner surface of the first metal layer 7. The inside and outside of the piezoelectric layer 11 are respectively bonded to the first metal layer 7 and the second metal layer 8. The other side of the first polymer elastic friction layer 5 is in contact with the third metal layer 12. The outermost layer is encapsulated by the encapsulation layer 9.

[0057] The working principle of the piezoelectric-friction composite nanogenerator is the coupling of friction electrification effect, electrostatic induction effect and piezoelectric effect. The device is implanted in the heart and generates output to the outside as the heart beats. When the device is subjected to heartbeat pressure, the first polymer elastic friction layer 5 and the first metal layer 6 contact each other. In this process, as the stress increases, the contact surface between the first polymer elastic friction layer 5 and the first metal layer 6 gradually increases. Subsequently, the stress applied to the piezoelectric material gradually increases. When the surface layer is in complete contact with the bottom layer, the piezoelectric and friction potentials both reach their maximum values. When the force is released, each layer returns to its original state, and electrons flow in the opposite direction under the action of piezoelectric and friction potentials. The repeated contact-separation allows the piezoelectric-friction composite nanogenerator to generate output to the outside.

[0058] The first high molecular weight elastic friction layer is one or more of hydrogel, polyurethane PU, polyglycerol sebacate PGS, polyoctanediol citrate POC, polyhydroxyalkanoate PHAs, and peptide bioelastomer, and has a thickness of 200-500 μm.

[0059] The second polymer friction layer is one or more of collagen, fibrin, silk, collagen, fibrin, silk, starch, alginate, chitin, hyaluronic acid derivatives, natural polyester, polylactic acid PLA, polyglycolic acid PGA, polylactic acid-glycolic acid copolymer PLGA, polycaprolactone PCL, polyvinyl alcohol PVA, polyethylene glycol PEG, regenerated cellulose, starch plastic, poly 3-hydroxybutyrate PHB, copolymer of 3-hydroxybutyrate and 3-hydroxyvalerate PHBV, copolymer of 3-hydroxybutyrate and 3-hydroxyhexanoate PHBH, with a thickness of 50-100 μm.

[0060] The metal layer is one or more of magnesium, iron, manganese, zinc, silicon, molybdenum, magnesium oxide, ferroferric oxide, manganese oxide, zinc oxide, silicon dioxide, molybdenum dioxide-based oxide, or AE21 magnesium alloy, Mg-Zr-Y alloy, and has a thickness of 20-500 nm;

[0061] The piezoelectric layer is one or more of poly (L-lactic acid) PLLA, glycine, collagen, fiber, chitin, and has a thickness of 20-200 μm;

[0062] The encapsulation layer material is a flexible insulating material of one or more of polylactic acid PLA, polyglycolic acid PGA, polylactic acid-glycolic acid copolymer PLGA, polycaprolactone PCL, polyethylene glycol PEG, polyvinyl alcohol PVA and polylactic acid-polyglycolic acid copolymer, with a thickness of 10-100 μm.

[0063] The electrical stimulation electrode is a needle electrode or a spiral electrode, the base layer is a wire base, the wire base is a degradable polymer line or a metal wire, a conductive layer is arranged on the outside of the base layer, the conductive layer is a degradable metal, the encapsulation layer covers the conductive layer, and both ends are exposed, the encapsulation layer is a degradable polymer, and the exposed wires at both ends are respectively connected to the nanogenerator and the target position.

[0064] Figure 4 The electrode shown is a spiral electrode, the base layer 13 is a wire base, the wire base is a degradable polymer wire, a conductive layer 14 is provided in the middle of the base layer, the conductive layer is a degradable metal, the encapsulation layer 9 covers the conductive layer, and both ends are exposed, the encapsulation layer is a degradable polymer, and the exposed wires at both ends are respectively connected to the nanogenerator and the target position.

[0065] Alternatively, the electrical stimulation electrode is a sheet electrode or a forked-finger electrode, and the electrode includes a base layer, a conductive layer and a packaging layer. The base layer is a flexible base, the conductive layer is a degradable metal, and the outermost layer is provided with a packaging layer, which is a degradable high molecular polymer and is connected to the nanogenerator and the target position respectively through external wires.

[0066] Figure 5The electrical stimulation electrode shown is a forked electrode, which includes a base layer, a conductive layer and a packaging layer. The base layer 13 is a flexible base, the conductive layer 14 is a degradable metal, and the outermost layer is provided with a packaging layer 9, which is a degradable high molecular polymer and is connected to the nanogenerator and the target position respectively through external wires.

[0067] The wire substrate can be catgut, absorbable PLGA medical suture, PLA wire, magnesium wire, iron wire, molybdenum wire. The conductive layer is a degradable metal of magnesium, iron, manganese, zinc, silicon or molybdenum. The encapsulation layer is polyvinyl alcohol, polygalactone, polylactic acid, polyhydroxybutyric acid valerate, chitosan or sodium alginate.

[0068] The system is directly powered by the body's movements such as breathing, pulse, and heartbeat, and can electrically stimulate nerves, muscles, bones and other tissues. After completing its mission, the system can be degraded and excreted from the body or absorbed by the body.

[0069] Example 2

[0070] The invention provides a method for preparing a fully degradable electrical stimulation system composed of a spiral electrode and a friction generator.

[0071] like Figure 7 As shown, a spiral electrode is prepared by taking polylactic acid PLA particles with a molecular weight of 20,000, melting them at 150° C., and placing them into a pre-prepared integrated structure template to obtain a spiral conductor substrate.

[0072] Treat with surface plasma for 5 minutes, rinse thoroughly with high-purity water and air dry under natural conditions. Place on an aluminum plate wrapped with flat aluminum foil while stretched straight. Place in a surface plasma resonance instrument and treat for 5 minutes in an oxygen atmosphere with a flow rate of 200-300sccm. After taking out, place the degradable polymer wire together with the aluminum foil on a sputtering substrate, use molybdenum Mo as the target material, and magnetron sputter at a power of 100W for 20 minutes. Repeat this process 3 times. A 20-100nm molybdenum Mo conductive layer is formed on the substrate.

[0073] The PLA particles were dissolved in chloroform solution by ultrasound at 25Hz and 100W for 30min, and the mass fraction of the PLA solution was 5%. 10mL of PLA solution was placed in the 18cm*5mm*3mm 3D printed PVA groove. When the PLA film was half dry, it was peeled off from the groove to obtain a 3mm thick PLA film. This process was repeated twice. The prepared degradable polymer wire was placed between two PLA films, with 1cm remaining at each end. The exposed wires at both ends were connected to the nanogenerator and the target position respectively. The middle was compacted and air-dried in a natural state to obtain an integrated degradable electrical stimulation wire wrapped with PLA, and the PLA was wrapped as an encapsulation layer.

[0074] Use a multimeter to verify the conductivity of the wire. Turn on the multimeter, adjust the multimeter to the ohm position, set it to the maximum range (infinity), connect the red and black terminals of the multimeter to one end of the red and black wires, respectively, and connect the other ends of the wires to the two ends of the prepared integrated electrical stimulation wire. The multimeter shows zero, proving that a degradable electrical stimulation electrode wire has been prepared.

[0075] A friction generator is prepared, which comprises, from the inside to the outside, a first polymer elastic friction layer of poly(octanediol citrate) POC, a second polymer friction layer of poly(lactic acid) PLA, a first metal layer of molybdenum, a second metal layer of molybdenum, and an encapsulation layer of poly(lactic acid) PLA.

[0076] Equimolar amounts of citric acid and 1,8-octanediol were added to a 250 mL solution in a three-necked round-bottom flask equipped with an inlet and outlet adapter. The mixture was stirred at 160-165°C in a silicone oil bath under nitrogen flow to melt the mixture. The system temperature was then lowered to 140°C and the mixture was stirred for another 1 hour. The prepolymer solution was added to a micro-bowl-structured polydimethylsiloxane template and polymerized at 80°C and 1 Pa in a vacuum for 1 day to generate a hemispherical array structured poly(octanediol citrate) POC degradable elastomer with a certain degree of cross-linking, wherein the hemispherical array structure is a micro-nano structure to increase the contact area of ​​the two friction layers, thereby obtaining the first polymer elastic friction layer poly(octanediol citrate) POC.

[0077] The second polymer friction layer polylactic acid PLA was synthesized. Polylactic acid PLA was dissolved in chloroform solution with a mass fraction of 5%. After sufficient stirring, it was cast on a glass plate with a diameter of 9 cm. The solution was air-dried for 12 hours and then heated in an oven for 12 hours to remove the remaining solvent. The thickness of the obtained polylactic acid PLA film was about 50-100 μm.

[0078] Using magnetron sputtering technology, with molybdenum Mo as the target material and a power of 100W, deposit on one side of the second polymer friction layer polylactic acid PLA for 20 minutes, and repeat this process 3 times. The deposited Mo is used as the second metal layer with a thickness of 20-500nm. The electrode layer Mo is sputtered and deposited on the first polymer elastic friction layer polyoctyl citrate POC as the first metal layer, with a power of 100W, a time of 30 minutes, and a thickness of 20-500nm.

[0079] Polylactic acid PLA is continuously formed on the outer sides of the first metal layer and the second metal layer as a packaging layer. The layers are assembled by hot pressing technology, with a hot pressing temperature of 100° C. and a time of 5 seconds.

[0080] Example 3

[0081] Test the output performance of the fully degradable electrical stimulation system when implanted in vivo and driven by the beating heart. Test the degradation performance of the fully degradable electrical stimulation system in vitro.

[0082] like Figure 8 As shown, the fully degradable electrical stimulation system was implanted outside the pericardium of SD rats, and the heartbeat was used to drive the fully degradable electrical stimulation system and generate pulse electrical stimulation. An oscilloscope (HDO6104) was used to test the electrical stimulation voltage generated by the fully degradable electrical stimulation system in vivo and its long-term stability when working in vivo (8a, d), and an electrometer (Keithley 6517B) was used to measure its in vivo output current and transferred charge (8b, c). Combined with a resistance box, the voltage and current parameters of the fully degradable electrical stimulation system under different load resistances were tested (8e, f). The output voltage was 10.5V, the output current was 2μA, and the transferred charge was 12nC. The fully degradable electrical stimulation system can work stably for 10 5 cycles, the equivalent resistance is 5*10 6 Ω.

[0083] The degradable behavior of the fully degradable electrical stimulation system was studied. The control group immersed the fully degradable electrical stimulation system in phosphate buffer solution (1×PBS). It was placed at 37°C for 21 days. Every 7 days, it was taken out of the PBS buffer solution, dried, and photographed. At 21 days, the entire system almost disappeared.

[0084] The results show that the electrical stimulation system can work stably over a long period of time in the body during the working cycle, and can degrade automatically after completing its working mission. The system can avoid the risk of secondary surgical removal, proving the feasibility of electrical stimulation therapy.

[0085] Example 4

[0086] The fully degradable electrical stimulation system of the present invention was applied to cells, demonstrating that the system can promote tissue repair and wound healing.

[0087] The interdigital electrodes of the fully degradable electrical stimulation system were placed at the bottom of the 6-well plate, with a width of 200 μm and a distance of 200 μm between the two parallel electrodes. L929 cells were cultured in the 6-well cell plate for 24 h and then stained with 1,1-dioctadecyl-3,3,3-tetramethylalkylcarbocyanine perchlorate (DiI) for 20 min. After removing the DiI dye, a 200 μm wide scratch parallel to the interdigital electrodes was made on the L929 cells with a pipette tip, and then different electric field stimulations were applied to the cells using the fully degradable electrical stimulation system.

[0088] The force applied to the fully degradable electrical stimulation system was similar to the force generated by heartbeat, and the duration of action was 72 hours. Cell migration was detected using a Lecia TCS SP8 confocal fluorescence microscope. Fig.10As shown, after 72 h, it was clearly observed that cells migrated across the scratches, and the scratches basically disappeared.

[0089] The results demonstrate that this system can promote cell migration and has great potential for use in tissue repair and wound healing.

[0090] The above-mentioned embodiments only express the implementation methods of the present invention, and the description thereof is relatively specific and detailed, but it cannot be understood as limiting the scope of the patent of the present invention. It should be pointed out that for ordinary technicians in this field, several modifications and improvements can be made without departing from the concept of the present invention, which all belong to the protection scope of the present invention. Therefore, the protection scope of the patent of the present invention shall be based on the attached claims.

Claims

1. A fully degradable electrical stimulation system, comprising a nanogenerator and an electrical stimulation electrode, characterized in that: The nanogenerator generates continuous current and / or voltage through heartbeat, breathing, and body movement, which is transmitted to the electrical stimulation electrode. The electrical stimulation electrode is fixed to the target position of nerves, muscles, and bones in the body to apply the electrical stimulation current and / or voltage to the target position; the nanogenerator is a friction nanogenerator; the friction nanogenerator is composed of a first polymer elastic friction layer, a second polymer friction layer, a first metal layer, a second metal layer, and an encapsulation layer arranged relatively from the inside to the outside, the first polymer elastic friction layer is an elastomeric friction layer and the inner surface is provided with a micro-nano structure, the first metal layer is attached to the outside of the first polymer elastic friction layer, the second metal layer is attached to the outside of the second polymer friction layer, an air layer is formed between the first polymer elastic friction layer and the second polymer friction layer, and the outermost layer is provided with an encapsulation layer; The first polymer elastic friction layer is one or more of hydrogel, polyurethane PU, polyglyceryl sebacate PGS, polyoctyl citrate POC, polyhydroxyalkanoate PHAs, and peptide bioelastomer, and has a thickness of 200-500 μm; The second polymer friction layer is one or more of collagen, fibrin, silk, starch, alginate, chitin, hyaluronic acid derivatives, natural polyester, polylactic acid PLA, polyglycolic acid PGA, polylactic acid-glycolic acid copolymer PLGA, polycaprolactone PCL, polyvinyl alcohol PVA, polyethylene glycol PEG, regenerated cellulose, starch plastic, poly 3-hydroxybutyrate PHB, copolymer of 3-hydroxybutyrate and 3-hydroxyvalerate PHBV, copolymer of 3-hydroxybutyrate and 3-hydroxyhexanoate PHBH, and has a thickness of 50-100 μm; The first metal layer and the second metal layer are one or more of magnesium, iron, manganese, zinc, silicon, molybdenum, magnesium oxide, ferroferric oxide, manganese oxide, zinc oxide, silicon dioxide, molybdenum dioxide-based oxide, AE21 magnesium alloy or Mg-Zr-Y alloy, and have a thickness of 20-500 nm; The material of the encapsulation layer is one or more flexible insulating materials selected from the group consisting of polylactic acid PLA, polyglycolic acid PGA, polylactic acid-glycolic acid copolymer PLGA, polycaprolactone PCL, polyethylene glycol PEG, polyvinyl alcohol PVA and polylactic acid-polyglycolic acid copolymer, with a thickness of 10-100 μm.

2. A fully degradable electrical stimulation system, comprising a nanogenerator and an electrical stimulation electrode, characterized in that: The nanogenerator generates continuous current and / or voltage through heartbeat, breathing, and body movement, and transmits it to the electrical stimulation electrode. The electrical stimulation electrode is fixed to the target position of nerves, muscles, and bones in the body, and the electrical stimulation current and / or voltage is applied to the target position. The nanogenerator is a piezoelectric nanogenerator, and the piezoelectric nanogenerator is composed of a correspondingly arranged piezoelectric layer, a first metal electrode layer, a second metal electrode layer, and a packaging layer from the inside to the outside. The first metal electrode layer and the second metal electrode layer are respectively attached to the upper and lower surfaces of the piezoelectric layer, and the outermost layer is provided with a packaging layer. The first metal electrode layer and the second metal electrode layer are one or more of magnesium, iron, manganese, zinc, silicon, molybdenum, magnesium oxide, ferroferric oxide, manganese oxide, zinc oxide, silicon dioxide, molybdenum dioxide-based oxide, AE21 magnesium alloy or Mg-Zr-Y alloy, and have a thickness of 20-500 nm; The piezoelectric layer is one or more of poly (L-lactic acid) PLLA, glycine, collagen, fiber, chitin, and has a thickness of 20-200 μm; The material of the encapsulation layer is one or more flexible insulating materials selected from the group consisting of polylactic acid PLA, polyglycolic acid PGA, polylactic acid-glycolic acid copolymer PLGA, polycaprolactone PCL, polyethylene glycol PEG, polyvinyl alcohol PVA and polylactic acid-polyglycolic acid copolymer, with a thickness of 10-100 μm.

3. A fully degradable electrical stimulation system, comprising a nanogenerator and an electrical stimulation electrode, characterized in that: The nanogenerator generates continuous current and / or voltage through heartbeat, breathing, and body movement, and transmits it to the electrical stimulation electrode. The electrical stimulation electrode is fixed to the target position of nerves, muscles, and bones in the body, and the electrical stimulation current and / or voltage is applied to the target position. The nanogenerator is a piezoelectric-friction composite nanogenerator. The piezoelectric-friction composite nanogenerator is composed of a first metal layer, a piezoelectric layer, a first polymer elastic friction layer, a second metal layer, a third metal layer, and a packaging layer, which are arranged relatively from the inside to the outside. The first polymer elastic friction layer is an elastomeric friction layer and has a micro-nano structure on its inner surface. An air layer is formed between the first polymer elastic friction layer and the inner surface of the first metal layer. The inner and outer sides of the piezoelectric layer are respectively bonded to the first metal layer and the second metal layer. The other side of the first polymer elastic friction layer is in contact with the third metal layer. The outermost layer is packaged by the packaging layer. The first polymer elastic friction layer is one or more of hydrogel, polyurethane PU, polyglyceryl sebacate PGS, polyoctyl citrate POC, polyhydroxyalkanoate PHAs, and peptide bioelastomer, and has a thickness of 200-500 μm; The first metal layer, the second metal layer and the third metal layer are one or more of magnesium, iron, manganese, zinc, silicon, molybdenum, magnesium oxide, ferroferric oxide, manganese oxide, zinc oxide, silicon dioxide, molybdenum dioxide-based oxide, AE21 magnesium alloy or Mg-Zr-Y alloy, and have a thickness of 20-500 nm; The piezoelectric layer is one or more of poly (L-lactic acid) PLLA, glycine, collagen, fiber, chitin, and has a thickness of 20-200 μm; The material of the encapsulation layer is one or more flexible insulating materials selected from the group consisting of polylactic acid PLA, polyglycolic acid PGA, polylactic acid-glycolic acid copolymer PLGA, polycaprolactone PCL, polyethylene glycol PEG, polyvinyl alcohol PVA and polylactic acid-polyglycolic acid copolymer, with a thickness of 10-100 μm.

4. The fully degradable electrical stimulation system according to any one of claims 1 to 3, characterized in that: The electrical stimulation electrode is a needle electrode or a spiral electrode, the base layer is a wire base, the wire base is a degradable polymer wire, a conductive layer is arranged outside the base layer, the conductive layer is a degradable metal, the encapsulation layer covers the conductive layer, both ends are exposed, the encapsulation layer is a degradable polymer, and the wires exposed at both ends are connected to the nanogenerator and the target position respectively; Alternatively, the electrical stimulation electrode is a sheet electrode or an interdigitated electrode, and the electrode includes a base layer, a conductive layer and a packaging layer. The base layer is a flexible film base, and the base layer material is a degradable polymer. The conductive layer is a degradable metal. The outermost side is provided with a packaging layer, and the packaging layer is a degradable polymer, which is connected to the nanogenerator and the target position respectively through external wires.

5. The fully degradable electrical stimulation system according to claim 4, characterized in that: The wire substrate is catgut, absorbable PLGA medical suture, PLA wire, magnesium wire, iron wire or molybdenum wire; The conductive layer is a degradable metal such as magnesium, iron, manganese, zinc, silicon or molybdenum; The encapsulation layer is polyvinyl alcohol, polygalactone, polylactic acid, polyhydroxybutyrate valerate, chitosan or sodium alginate.

6. A method for preparing the fully degradable electrical stimulation system according to any one of claims 1 to 3, characterized in that: The following steps are involved: Step 1: taking degradable polylactic acid (PLA) particles, melting them at high temperature and placing them into a structural template to obtain a spiral conductor substrate; Step 2: After the spiral conductor substrate is surface treated, a degradable metal is used as a target material, and magnetron sputtering is performed to form a 20-100 nm thick metal conductive layer in the spiral conductor substrate; Step 3: Place the polylactic acid (PLA) solution in the 3D printed PVA groove, and peel off the polylactic acid (PLA) film after it is semi-dried. The polylactic acid (PLA) film is wrapped on the metal conductive layer, and bare wires are left at both ends of the spiral wire base; Step 4: adding citric acid to 1,8-octanediol, melting the mixture at high temperature under nitrogen conditions, adding the prepolymer solution to the polydimethylsiloxane template of the micro-bowl structure, polymerizing under vacuum, and obtaining the first polymer elastic friction layer polyoctanediol citrate POC with a thickness of 200-500 μm; Step 5: dissolving polylactic acid PLA in a chloroform solution, casting on a glass plate, removing the remaining solvent, and obtaining a polylactic acid PLA film with a thickness of 50-100 μm to obtain a second polymer friction layer; Step 6: Using magnetron sputtering technology, using degradable metal as a target, sputtering and depositing the degradable metal as a first metal layer on the first polymer elastic friction layer poly(octanediol citrate) POC, with a thickness of 20-500 nm; and depositing the degradable metal as a second metal layer on the side of the second polymer friction layer poly(lactic acid) PLA, with a thickness of 20-500 nm; Step 7: Continue to form a film of polylactic acid (PLA) as a packaging layer on the outside of the first metal layer and the second metal layer, and assemble the layers using hot pressing technology.

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