CN114870254A - Fully-degradable electrical stimulation system and preparation method thereof - Google Patents

Abstract

The invention provides a fully degradable electrical stimulation system which comprises a nano generator and an electrical stimulation electrode, wherein the nano generator generates continuous current and/or voltage through heartbeat, respiration and body movement and conducts the continuous current and/or voltage to the electrical stimulation electrode, the electrical stimulation electrode is fixed at a target position of nerves, muscles and bones in a body, and the electrical stimulation current and/or voltage acts on the target position. The system can release voltage, current or electric field stimulation, solves the problems that the current electric stimulation device needs energy supply of a battery and the prognosis needs secondary operation removal, ensures that the temporary medical device can be completely degraded in vivo, and relieves the pain of patients.

Description

Fully degradable electrical stimulation system and preparation method thereof

Technical Field

The invention belongs to the field of biological medical treatment, and particularly relates to a fully degradable electrical stimulation system.

Background

Electrical Stimulation (ES) can accelerate tissue repair, fracture healing, promote regeneration of damaged nerves, and prevent muscle atrophy, etc., by modulating bioelectrical states by simulating endogenous electric fields, is widely acknowledged in clinical practice as a promising non-Drug treatment method, and has been approved by the US Food and Drug Administration (FDA).

The pulse electric field with proper strength and frequency can activate the expression of cell related gene, promote the proliferation and differentiation of damaged tissue cell and stimulate the regeneration of tissue. However, the clinical electrical stimulation therapy depends on large and complex equipment, depends on the mains power frequency for direct power supply or battery driving, has the disadvantages of inconvenient carrying, battery energy exhaustion, environmental pollution and the like, and requires frequent treatment and operation by a professional doctor in the treatment process. Furthermore, existing electrical stimulation systems are not degradable and require additional surgical removal, further limiting their potential in practical clinical applications.

Therefore, at present, a series of potential problems limiting clinical transformation of the electrical stimulation device, such as relatively large volume, non-degradability, need of secondary operation extraction, or complex preparation process of an external wireless energy supply device, are urgently needed to be solved.

Disclosure of Invention

In order to overcome the problems in the prior art, the invention provides a fully degradable system for electrical stimulation treatment, which has the advantages of simple structure, wide material sources, biological safety, easy flexibility and miniaturization, and is directly powered by mechanical movement of an organism.

The invention provides the following technical scheme:

a full degradable electrical stimulation system comprises a nanometer generator and an electrical stimulation electrode, wherein the nanometer generator generates continuous current and/or voltage through heartbeat, respiration and body movement and conducts the continuous current and/or voltage to the electrical stimulation electrode, and the electrical stimulation electrode is fixed at a target position of nerves, muscles and bones in a body and acts the electrical stimulation current and/or voltage on the target position.

Further, the nano generator is a friction nano generator, a piezoelectric nano generator or a piezoelectric-friction composite nano generator.

Furthermore, the friction nano-generator is sequentially provided with a first polymer elastic friction layer, a second polymer friction layer, a first metal layer, a second metal layer and a packaging layer from inside to outside, wherein the first polymer friction layer is an elastomer friction layer, the inner surface of the first polymer friction layer is provided with a micro-nano structure, 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, an air layer interval is formed between the first polymer elastic friction layer and the second polymer friction layer, and the outermost layer is provided with the packaging layer;

the piezoelectric nano generator comprises a piezoelectric layer, a first metal electrode layer, a second metal electrode layer and a packaging layer which are correspondingly arranged from inside to outside in sequence, wherein the first metal electrode layer and the second metal electrode layer are respectively attached to the upper surface and the lower surface of the piezoelectric layer, and the packaging layer is arranged on the outermost layer;

the piezoelectric-friction composite nano generator sequentially comprises 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 from inside to outside, wherein the first metal layer, the piezoelectric layer, the first polymer elastic friction layer, the second metal layer, the third metal layer and the packaging layer are oppositely arranged. The first polymer friction layer is an elastomer friction layer, a micro-nano structure is arranged on the inner surface of the first polymer friction layer, an air layer interval is formed between the first polymer elastic friction layer and the inner surface of the first metal layer, the inner side and the outer side of the piezoelectric layer are respectively attached to the first metal layer and the second metal layer, the other side of the first polymer elastomer friction layer is in contact with the third metal layer, and the outermost layer is packaged through a packaging layer.

Further, the first polymer elastomer friction layer is one or more of hydrogel, polyurethane PU, poly-glycerol sebacate PGS, poly-octylene glycol citrate POC, polyhydroxyalkanoates PHAs and polypeptide biological elastomer, and the thickness is 200-500 μm;

the second high 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 plastics, poly (3-hydroxybutyrate) (PHB), copolymer PHBV of 3-hydroxybutyrate and 3-hydroxyvalerate, and copolymer PHBH of 3-hydroxybutyrate and 3-hydroxyhexanoate, and the thickness of the second high polymer friction layer is 50-100 mu m;

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 and Mg-Zr-Y alloy, and the thickness is 20-500 nm;

the piezoelectric layer is one or more of poly-L-lactic acid PLLA, glycine, collagen, fiber and chitin, and the thickness of the piezoelectric layer is 20-200 μm;

the packaging layer is made of one or more flexible insulating materials selected from 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, and has a thickness of 10-100 μm.

Further, the electrical stimulation electrode is a needle electrode or a spiral electrode, the substrate layer is a lead substrate, the lead substrate is a degradable high-molecular wire or a metal wire, a conductive layer is arranged on the outer side of the substrate layer, the conductive layer is degradable metal, the packaging layer covers the conductive layer, two ends of the packaging layer are exposed, the packaging layer is degradable high-molecular polymer, and leads exposed at two ends of the packaging layer are respectively connected with the nano-generator and the target position.

Or, the electric stimulation electrode is a sheet electrode and an interdigital electrode, the electrode comprises a basal layer, a conducting layer and a packaging layer, the basal layer is a flexible film substrate, the basal layer is made of degradable high polymer, the conducting layer is made of degradable metal, the packaging layer is arranged on the outermost side, the packaging layer is made of degradable high polymer, and the packaging layer is respectively connected with the nano generator and the target position through external leads.

Further, the lead substrate is catgut, absorbable PLGA medical suture, PLA thread, magnesium thread, iron wire and molybdenum wire;

the conducting layer is made of degradable metals such as magnesium, iron, manganese, zinc, silicon or molybdenum;

the packaging layer is polyvinyl alcohol, poly-caprolactone, polylactic acid, polyhydroxybutyrate valerate, chitosan or sodium alginate.

A method of making a fully degradable electrical stimulation system comprising the steps of:

taking degradable polylactic acid (PLA) particles, melting at high temperature, and then putting into a structural template to obtain a spiral wire substrate;

secondly, performing surface treatment on the spiral lead substrate, taking degradable metal as a target material, and performing magnetron sputtering to form a metal conducting layer with the thickness of 20-100nm in the spiral lead substrate;

placing a polylactic acid (PLA) solution in a PVA groove printed in 3D, and when the PLA film is half-dried and peeled, wrapping the PLA film on a metal conducting layer, and leaving exposed leads at two ends of a spiral lead substrate;

step four, adding citric acid into 1, 8-octanediol, melting the mixture at high temperature under the condition of nitrogen, adding the prepolymer solution into a polydimethylsiloxane template with a micro-bowl structure, and polymerizing under vacuum to prepare a first high-molecular elastic friction layer poly (octylene glycol citrate) POC with the thickness of 200-500 mu m;

step five, dissolving polylactic acid (PLA) in a chloroform solution, casting the solution on a glass plate, removing the residual solvent to obtain a polylactic acid (PLA) film with the thickness of 50-100 mu m, and preparing a second polymer friction layer;

sixthly, performing POC sputtering deposition on the degradable metal serving as a first metal layer with the thickness of 20-500nm by using a magnetron sputtering technology and taking the degradable metal as a target material on the first high-molecular elastic friction layer; depositing degradable metal as a second metal layer on one side of the second polymer friction layer, namely polylactic acid (PLA), wherein the thickness is 20-500 nm;

and seventhly, continuously forming films on the outer sides of the first metal layer and the second metal layer to form polylactic acid (PLA) serving as packaging layers, and assembling the layers by utilizing a hot pressing technology.

By adopting the technical scheme, the invention has the following beneficial effects:

(1) the fully degradable electrical stimulation system is prepared by using a degradable material as a substrate through micro-nano processing and flexible packaging. The system can release voltage or current stimulation, solves the problems that the current electrical stimulation device needs energy supply by a battery and the prognosis needs secondary operation removal, so that the temporary medical device can be completely degraded in vivo, and the pain of a patient is relieved.

(2) The electric stimulation of the invention acts on nerves, muscles and bones in the form of an electric field so as to achieve the aims of promoting wound healing, bone repair, nerve injury repair and function reconstruction. Can be used for treating central nerve injury such as spinal cord, peripheral nerve injury such as sciatic nerve or muscle and bone. The energy is directly supplied by the mechanical movement of the body, and can be degraded in the body or absorbed and metabolized by the body.

Drawings

FIG. 1 is a schematic diagram of the core structure of a triboelectric nanogenerator according to the invention;

FIG. 2 is a schematic diagram of the core structure of the piezoelectric nanogenerator according to the invention;

FIG. 3 is a schematic diagram of the core structure of the piezoelectric-friction composite nanogenerator according to the invention;

FIG. 4 is a schematic diagram of a helical electrode structure of the present invention;

FIG. 5 is a schematic diagram of an interdigital electrode configuration in accordance with the present invention;

FIG. 6 is a schematic diagram of the system of the present invention applied to a rat;

fig. 7 is a flow chart of the preparation of the implantable fully degradable electrical stimulation system in an embodiment of the present invention;

FIG. 8 shows the output performance test results of the fully degradable electrical stimulation system;

FIG. 9 is a result of a degradation experiment of a fully degradable electrical stimulation system;

fig. 10 is the result of the fully degradable electrical stimulation system promoting wound healing.

Description of the reference numerals

The nerve stimulation device comprises a 1 nanometer generator, 2 electrical stimulation electrodes, 3 vagus nerves, 4 rats, 5 first polymer elastic friction layers, 6 second polymer friction layers, 7 first metal layers, 8 second metal layers, 9 packaging layers, 10 leads, 11 piezoelectric layers, 12 third metal electrode layers, 13 basal layers and 14 conducting layers.

Detailed Description

In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention will be described in further detail with reference to the accompanying drawings and embodiments. It should be understood that the block diagrams and specific examples are set forth only for the purpose of illustrating the invention and are not to be construed as limiting the invention.

Example 1

The invention provides a fully degradable electrical stimulation system which comprises a nano generator 1 and an electrical stimulation electrode 2, wherein the nano generator generates continuous current and/or voltage through heartbeat, respiration and body movement and conducts the continuous current and/or voltage to the electrical stimulation electrode, the electrical stimulation electrode is fixed at a target position of nerves, muscles and bones in a body, and the electrical stimulation current and/or voltage acts on the target position.

The electric stimulation acts on nerves, muscles and bones in the form of an electric field so as to achieve the purposes of promoting wound healing, bone repair, nerve injury repair and function reconstruction. The invention can be used for central nerve injuries such as spinal cord, peripheral nerve injuries such as sciatic nerve or muscle and bone. The energy is directly supplied by the mechanical movement of the body, and can be degraded in the body or absorbed and metabolized by the body.

Wherein the nano generator is a friction nano generator, a piezoelectric nano generator or a piezoelectric-friction composite nano generator.

The principle of the friction nano generator is the friction electrification and the electrostatic induction effect. Under the drive of external force, the two friction layers are contacted with each other, and the surfaces generate the same amount of heterogeneous charges; when the external force is removed, the two layers of materials are separated, and the electric potential difference generated by the positive and negative charges drives electrons to flow, so that current is generated and force-electricity conversion is realized.

The nano-generator may be a friction nano-generator, as shown in fig. 1, the friction nano-generator includes, in order from inside to 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 an encapsulation layer 9, which are disposed oppositely.

The first polymer friction layer is an elastomer friction layer, the inner surface of the first polymer friction layer is provided with a micro-nano structure, an air layer interval 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.

The working principle of the friction nano generator is that friction plays a coupling role between electricity and electrostatic induction effect. For example, the friction nano-generator is implanted into the heart and attached to the heart, and the continuous beating of the heart can cause the first polymer elastic friction layer and the second polymer elastic friction layer of the friction nano-generator to periodically contact and separate. When the heart contracts, the first polymer elastic friction layer and the second polymer friction layer are contacted with each other, 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 are separated from each other, which results in the increase of 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 beats, electrons cyclically reciprocate between the triboelectric layers, thus rubbing the nanogenerator to produce an output.

The nano-generator can be a piezoelectric nano-generator, as shown in fig. 2, the piezoelectric nano-generator is sequentially provided with a piezoelectric layer 11, a first metal electrode layer 7, a second metal electrode layer 8 and an encapsulation layer 9, the first metal electrode layer and the second metal electrode layer are respectively attached to the upper surface and the lower surface of the piezoelectric layer, and the outermost layer is provided with the encapsulation layer. The working principle of the piezoelectric nano generator is piezoelectric effect.

The piezoelectric nano generator is implanted into the heart and attached to the heart, the piezoelectric nano generator can deform under the action of external force due to continuous beating of the heart, and positive and negative charge surfaces, namely polar surfaces, can be generated on the surface of the piezoelectric layer material. The piezoelectric potential generated by the polar surfaces can be used for driving electrons in an external circuit to move, so that the conversion from mechanical energy to electric energy is realized, and the piezoelectric generator generates output outwards.

The nano generator can be a piezoelectric-friction composite nano generator, as shown in fig. 3, the piezoelectric-friction composite nano generator is sequentially provided with 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 oppositely arranged from inside to outside, the first polymer friction layer 5 is an elastomer friction layer, the inner surface of the first polymer elastic friction layer is provided with a micro-nano structure, an air layer interval is formed between the first polymer elastic friction layer 5 and the inner surface of the first metal layer 7, the piezoelectric layer 11 is internally and externally attached to the first metal layer 7 and the second metal layer 8 respectively, the other side of the first polymer elastic friction layer 5 is in mutual contact with the third metal layer 12, and the outermost layer is encapsulated through the encapsulation layer 9.

The working principle of the piezoelectric-friction composite nano generator is that friction is coupled with the electric effect, the electrostatic induction effect and the piezoelectric effect. The device is implanted at the heart to produce an output as the heart beats. When the device is subjected to a heartbeat pressure, the first polymer elastic friction layer 5 and the first metal layer 6 are in contact with each other. In this process, the contact surface between the first polymeric elastic friction layer 5 and the first metal layer 6 gradually increases with the increase of the stress. Subsequently, the stress applied to the piezoelectric material gradually increases. Both the piezoelectric and triboelectric potentials reach a maximum when the surface layer is in full contact with the bottom layer. When the force is released, the layers return to their original state and electrons flow in opposite directions under the action of the piezoelectric and triboelectric potentials. The contact-separation is repeated, so that the piezoelectric-friction composite nano generator generates output outwards.

Wherein the first polymer elastomer friction layer is one or more of hydrogel, polyurethane PU, poly-sebacic acid glyceride PGS, poly-octyl glycol citrate POC, polyhydroxyalkanoates PHAs and polypeptide biological elastomer, and the thickness is 200-500 μm.

The second high molecular 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 plastics, poly (3-hydroxybutyrate) (PHB), Poly (PHBV) which is a copolymer of 3-hydroxybutyrate and 3-hydroxyvalerate, and Poly (PHBH) which is a copolymer of 3-hydroxybutyrate and 3-hydroxyhexanoate, and the thickness of the second high molecular friction layer is 50-100 mu m.

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 and Mg-Zr-Y alloy, and the thickness is 20-500 nm;

the piezoelectric layer is one or more of poly-L-lactic acid PLLA, glycine, collagen, fiber and chitin, and has a thickness of 20-200 μm;

the packaging layer is made of one or more flexible insulating materials selected from 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, and has a thickness of 10-100 μm.

The electric stimulation electrode is a needle electrode and a spiral electrode, the basal layer is a lead substrate, the lead substrate is a degradable high-molecular wire or a metal wire, a conductive layer is arranged on the outer side of the basal layer and is degradable metal, the packaging layer covers the conductive layer, two ends of the packaging layer are exposed, the packaging layer is a degradable high-molecular polymer, and leads with two exposed ends are respectively connected with the nano-generator and the target position.

The electrode shown in fig. 4 is a spiral electrode, the substrate layer 13 is a wire substrate, the wire substrate is a degradable polymer wire, the conductive layer 14 is arranged in the middle of the substrate layer, the conductive layer is a degradable metal, the packaging layer 9 coats the conductive layer, two ends of the conductive layer are exposed, the packaging layer is a degradable polymer, and the wires exposed at the two ends are respectively connected with the nano-generator and the target position.

Or the electric stimulation electrode is a sheet electrode and an interdigital electrode, the electrode comprises a basal layer, a conducting layer and a packaging layer, the basal layer is a flexible basal layer, the conducting layer is degradable metal, the packaging layer is arranged on the outermost side, the packaging layer is degradable high molecular polymer, and the packaging layer is respectively connected with the nanometer generator and the target position through external leads.

The electric stimulation electrode shown in fig. 5 is an interdigital electrode, the electrode comprises a substrate layer, a conductive layer and a packaging layer, the substrate layer 13 is a flexible substrate, the conductive layer 14 is degradable metal, the packaging layer 9 is arranged on the outermost side, and the packaging layer is degradable high polymer and is respectively connected with the nano-generator and the target position through external leads.

The lead substrate can be catgut, absorbable PLGA medical suture, PLA thread, magnesium thread, iron wire, molybdenum wire. The conducting layer is made of degradable metals such as magnesium, iron, manganese, zinc, silicon or molybdenum. The packaging layer is polyvinyl alcohol, poly-caprolactone, polylactic acid, polyhydroxy butyrate valerate, chitosan or sodium alginate.

The system is directly powered by organism movement such as respiration, pulse, heartbeat and the like, and can apply electric stimulation to tissues such as nerves, muscles, bones and the like, and the system can be automatically degraded and discharged out of the body or absorbed by the organism after finishing the work mission.

Example 2

The invention provides a preparation method of a fully degradable electrical stimulation system formed by a spiral electrode and a friction generator set.

As shown in fig. 7, a helical electrode is prepared, polylactic acid PLA particles with a molecular weight of 20000 are taken, melted at 150 ℃, and placed into a prepared integrated structure template to obtain a helical lead substrate.

Treating with surface plasma for 5min, washing with high-purity water, and air drying under natural condition. Placed on an aluminum plate wrapped with a flat aluminum foil under the condition of being stretched straight. Placing in a surface plasma resonance instrument, and treating for 5min under an oxygen atmosphere with a flow rate of 200-. After being taken out, the degradable polymer wire and the aluminum foil are placed on a sputtering substrate, the molybdenum Mo is taken as a target material, the magnetron sputtering is carried out for 20min under the power of 100W, and the process is repeated for 3 times. And forming a molybdenum Mo conducting layer with the thickness of 20-100nm on the substrate.

Dissolving polylactic acid PLA particles in a chloroform solution by 30min, 25Hz and 100W ultrasound, wherein the mass fraction of the polylactic acid PLA solution is 5%. And (3) placing 10mL of polylactic acid PLA solution in 18cm by 5mm by 3mm 3D printed PVA grooves, and peeling the polylactic acid PLA film from the grooves when the polylactic acid PLA film is semi-dried to obtain the polylactic acid PLA film with the thickness of 3 mm. This process was repeated twice. The prepared degradable polymer wire is placed between two polylactic acid PLA films, the two ends of the degradable polymer wire are respectively remained for 1cm, and the exposed wires at the two ends are respectively connected with a nano generator and a target position. Compacting the middle and air-drying the obtained product in a natural state to obtain the integrated degradable electrical stimulation lead wrapped by the polylactic acid PLA, wherein the polylactic acid PLA is wrapped into a packaging layer.

And (5) verifying the conduction condition of the lead by using a multimeter. Opening the universal meter, adjusting the universal meter to an ohmic gear, placing the universal meter at the maximum range (infinity), connecting the red and black terminals of the universal meter with one ends of the red and black wires of the universal meter respectively, connecting the other ends of the wires with two ends of the prepared integrated electrical stimulation wire respectively, and displaying that the number is zero by the universal meter, thereby proving that the degradable electrical stimulation electrode wire is prepared.

The friction generator is prepared by sequentially arranging a first high-molecular elastic friction layer poly (octylene glycol citrate) POC, a second high-molecular friction layer poly (lactic acid) PLA, a first metal layer molybdenum layer, a second metal layer molybdenum layer and an encapsulation layer poly (lactic acid) PLA from inside to outside.

Adding citric acid and 1, 8-octanediol in equimolar amounts into a three-neck round-bottom flask in 250mL of solution, preparing an inlet and an outlet adapter, stirring the mixture in a silicon oil bath under the condition of nitrogen flow at 165 ℃, melting the mixture, then cooling the system temperature to 140 ℃, stirring the mixture for 1h, adding the prepolymer solution into a polydimethylsiloxane template with a micro-bowl structure, and polymerizing the prepolymer solution for 1d under the vacuum of 80 ℃ and 1pa to generate a degradable poly (octyl glycol citrate) POC elastomer with a hemispherical array structure with a certain crosslinking degree, wherein the hemispherical array structure is a micro-nano structure, so as to increase the contact area of two friction layers and prepare the poly (octyl glycol citrate) POC with a first high-molecular elastic friction layer.

And (3) synthesizing polylactic acid (PLA) of the second high-molecular friction layer, wherein the PLA is dissolved in a chloroform solution, the mass fraction of the PLA is 5%, the PLA is fully stirred and then cast on a glass plate with the diameter of 9cm, the solution is air-dried for 12h, and then the PLA is placed in an oven to be heated for 12h to remove the residual solvent, and the thickness of the prepared PLA film is about 50-100 mu m.

By utilizing a magnetron sputtering technology, molybdenum Mo is used as a target material, 100W of power is used, the deposition is carried out for 20min on one side of the polylactic acid PLA of the second high polymer friction layer, and the process is repeated for 3 times. The deposited Mo is used as a second metal layer with the thickness of 20-500 nm. And (3) performing POC sputtering deposition on the first high-molecular elastic friction layer to obtain an electrode layer Mo as a first metal layer, wherein the power is 100W, the time is 30min, and the thickness is 20-500 nm.

And continuously forming a film of polylactic acid (PLA) on the outer sides of the first metal layer and the second metal layer to serve as a packaging layer. Assembling each layer by using a hot pressing technology, wherein the hot pressing temperature is 100 ℃, and the time is 5 s.

Example 3

The output performance of the fully degradable electrical stimulation system when implanted in vivo and driven by the heart beat was tested. And testing the degradation performance of the fully degradable electric stimulation system in vitro.

As shown in fig. 8, the fully degradable electrical stimulation system was implanted outside the pericardium of SD rats and was driven by heartbeat and generated pulsed electrical stimulation. The electric stimulation voltage generated in vivo by the fully degradable electric stimulation system and the long-range stability (8a, d) of the fully degradable electric stimulation system during in vivo work are tested by an oscilloscope (HDO6104), and the in vivo output current and the transferred charge quantity (8B, c) are measured by an electrometer (Keithley 6517B). And (3) testing voltage and current parameters (8e and f) of the fully degradable electrical stimulation system under different load resistances by combining a resistance box. The output voltage is 10.5V, the output current is 2 muA, the transferred charge amount is 12nC, and the fully degradable electrical stimulation system can stably work for 10 ⁵ One cycle, equivalent resistance of 5 x 10 ⁶ Ω。

The degradable behavior of the fully degradable electrical stimulation system was studied. The control group immersed the fully degradable electrical stimulation system in phosphate buffered saline (1 × PBS). The mixture was left at 37 ℃ for 21 d. Every 7d was removed from PBS buffer, dried, and photographed. 21d, the entire system almost disappears.

The result shows that the electric stimulation system can stably work in the body length range in the working period, and the work can be automatically degraded after the work mission is finished. The system can avoid the risk of secondary surgical removal, demonstrating the feasibility for electrical stimulation therapy.

Example 4

The application of the fully degradable electrical stimulation system in cells proves that the system can promote tissue repair and wound healing.

And an interdigital electrode of the fully degradable electric stimulation system is arranged at the bottom of the 6-hole plate, the width of the interdigital electrode is 200 mu m, and the distance between two parallel electrodes is 200 mu m. L929 cells were cultured in 6-well cell plates for 24h and then stained with 1, 1-octacosyl-3, 3, 3-tetramethylalkylcyanine perchlorate (DiI) for 20 min. After the DiI dye was removed, a scratch of 200 μm width parallel to the interdigital electrode was made on the L929 cell with a pipette tip, and then different electric field stimuli were applied to the cell using a fully degradable electrical stimulation system.

The acting force exerted on the fully degradable electric stimulation system is similar to the acting force generated by heartbeat, and the acting time is 72 h. Cell migration was detected using a Lecia TCS SP8 confocal fluorescence microscope. The results are shown in fig. 10, after 72h, it is clearly observed that the cells migrated across the scratch, and the scratch substantially disappeared.

The results demonstrate that the system can promote cell migration and has great potential for tissue repair and wound healing.

The above-mentioned embodiments only express the embodiments of the present invention, and the description thereof is more specific and detailed, but not construed as limiting the scope of the present invention. It should be noted that, for a person skilled in the art, several variations and modifications can be made without departing from the inventive concept, which falls within the scope of the present invention. Therefore, the protection scope of the present patent should be subject to the appended claims.

Claims (7)

1. A full degradable electric stimulation system comprises a nano generator and an electric stimulation electrode, and is characterized in that the nano generator generates continuous current and/or voltage through heartbeat, respiration and body movement and conducts the continuous current and/or voltage to the electric stimulation electrode, the electric stimulation electrode is fixed at a target position of nerves, muscles and bones in a body, and the electric stimulation current and/or voltage acts on the target position.

2. The fully degradable electrical stimulation system of claim 1, wherein the nano-generator is a triboelectric nano-generator, a piezoelectric nano-generator or a piezoelectric-triboelectric composite nano-generator.

3. The fully-degradable electrical stimulation system according to claim 2, wherein the friction nanogenerator comprises a first polymer elastic friction layer, a second polymer friction layer, a first metal layer, a second metal layer and an encapsulation layer which are arranged in sequence from inside to outside, wherein the first polymer elastic friction layer and the second polymer friction layer are arranged oppositely;

the piezoelectric nano generator comprises a piezoelectric layer, a first metal electrode layer, a second metal electrode layer and a packaging layer which are correspondingly arranged from inside to outside in sequence, wherein the first metal electrode layer and the second metal electrode layer are respectively attached to the upper surface and the lower surface of the piezoelectric layer, and the packaging layer is arranged on the outermost layer;

the piezoelectric-friction composite nano generator sequentially comprises 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 from inside to outside, wherein the first metal layer, the piezoelectric layer, the first polymer elastic friction layer, the second metal layer, the third metal layer and the packaging layer are oppositely arranged. The first polymer friction layer is an elastomer friction layer, a micro-nano structure is arranged on the inner surface of the first polymer friction layer, an air layer interval is formed between the first polymer elastic friction layer and the inner surface of the first metal layer, the inner side and the outer side of the piezoelectric layer are respectively attached to the first metal layer and the second metal layer, the other side of the first polymer elastomer friction layer is in contact with the third metal layer, and the outermost layer is packaged through a packaging layer.

4. The fully degradable electrical stimulation system of claim 3, wherein the first polymeric elastomer friction layer is one or more of hydrogel, polyurethane PU, poly-glycerol sebacate PGS, poly-capryl glycol citrate POC, poly-hydroxy fatty acid ester PHAs, and polypeptide bio-elastomer with a thickness of 200-500 μm;

the second high 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 plastics, poly (3-hydroxybutyrate) (PHB), a copolymer PHBV of 3-hydroxybutyrate and 3-hydroxyvalerate, and a copolymer PHBH of 3-hydroxybutyrate and 3-hydroxyhexanoate, and the thickness of the second high polymer friction layer is 50-100 mu m;

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 and Mg-Zr-Y alloy, and the thickness is 20-500 nm;

the piezoelectric layer is one or more of poly-L-lactic acid PLLA, glycine, collagen, fiber and chitin, and the thickness of the piezoelectric layer is 20-200 μm;

the packaging layer is made of one or more flexible insulating materials selected from 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, and has a thickness of 10-100 μm.

5. The fully degradable electrical stimulation system of claim 1, wherein the electrical stimulation electrode is a needle electrode or a spiral electrode, the substrate layer is a wire substrate, the wire substrate is a degradable polymer wire, a conductive layer is arranged outside the substrate layer, the conductive layer is a degradable metal, the packaging layer covers the conductive layer, two ends of the packaging layer are exposed, the packaging layer is a degradable polymer, and the wires exposed at two ends are respectively connected with the nano-generator and a target position;

or, the electric stimulation electrode is a sheet electrode and an interdigital electrode, the electrode comprises a basal layer, a conducting layer and a packaging layer, the basal layer is a flexible film substrate, the basal layer is made of degradable high polymer, the conducting layer is made of degradable metal, the packaging layer is arranged on the outermost side, the packaging layer is made of degradable high polymer, and the packaging layer is respectively connected with the nano generator and the target position through external leads.

6. The fully degradable electrical stimulation system of claim 5, wherein the lead substrate is catgut, absorbable PLGA medical suture, PLA thread, magnesium thread, iron wire, molybdenum wire;

the conducting layer is made of degradable metals such as magnesium, iron, manganese, zinc, silicon or molybdenum;

the packaging layer is polyvinyl alcohol, poly-caprolactone, polylactic acid, polyhydroxybutyrate valerate, chitosan or sodium alginate.

7. A method of preparing the fully degradable electrical stimulation system of claim 1 comprising the steps of:

taking degradable polylactic acid (PLA) particles, melting at high temperature, and then putting into a structural template to obtain a spiral wire substrate;

secondly, performing surface treatment on the spiral lead substrate, taking degradable metal as a target material, and performing magnetron sputtering to form a metal conducting layer with the thickness of 20-100nm in the spiral lead substrate;

placing a polylactic acid (PLA) solution in a PVA groove printed in 3D, and when the PLA film is half-dried and peeled, wrapping the PLA film on a metal conducting layer, and leaving exposed leads at two ends of a spiral lead substrate;

step four, adding citric acid into 1, 8-octanediol, melting the mixture at high temperature under the condition of nitrogen, adding the prepolymer solution into a polydimethylsiloxane template with a micro-bowl structure, and polymerizing under vacuum to prepare a first high-molecular elastic friction layer poly (octylene glycol citrate) POC with the thickness of 200-500 mu m;

step five, dissolving polylactic acid (PLA) in a chloroform solution, casting the solution on a glass plate, removing the residual solvent to obtain a polylactic acid (PLA) film with the thickness of 50-100 mu m, and preparing a second polymer friction layer;

sixthly, performing POC sputtering deposition on the degradable metal serving as a first metal layer with the thickness of 20-500nm by using a magnetron sputtering technology and taking the degradable metal as a target material on the first high-molecular elastic friction layer; depositing degradable metal as a second metal layer on one side of the second polymer friction layer, namely polylactic acid (PLA), wherein the thickness is 20-500 nm;

and seventhly, continuously forming films on the outer sides of the first metal layer and the second metal layer to form polylactic acid (PLA) serving as packaging layers, and assembling the layers by utilizing a hot pressing technology.

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