An implantable electrical stimulator for osteoarthritis treatment and a method of manufacturing the same

Abstract

The application discloses an implantable electric stimulator for treating osteoarthritis and a preparation method thereof. The implantable electric stimulator comprises a triboelectric packaging body, a first triboelectric layer and a second triboelectric layer enclosed in the packaging body; the first triboelectric layer comprises a first triboelectric layer and a first electrode layer arranged on the surface of the first triboelectric layer, and the surface of the first triboelectric layer away from the first electrode layer has a first nanostructure; the second triboelectric layer has the same structure as the first triboelectric layer; the first triboelectric layer and the second triboelectric layer are oppositely arranged on the side with the nanostructure, and the first nanostructure and the second nanostructure are separated by a flexible insulator to form a gap; a hydrogel adhesive film is attached to the upper surface of the triboelectric packaging body, and the first electrode layer and the second electrode layer are respectively electrically connected with the upper surface of the packaging body. The implantable electric stimulator can be used for in-vivo osteoarthritis treatment without additional power supply device, and the output voltage signal can be adjusted as required.

Description

Technical Field

[0001] This invention relates to an implantable electrical stimulator for the treatment of osteoarthritis and its preparation method, belonging to the field of medical devices. Background Technology

[0002] Osteoarthritis (OA) is a degenerative joint disease characterized by the degeneration of articular cartilage and secondary bone hyperplasia, leading to joint pain, swelling, and functional impairment, particularly affecting weight-bearing joints such as the knee and hip. Its pathogenesis is complex, involving multiple factors including genetics, age, sex, weight, joint injury, and inflammatory factors. Cartilage, as a vital structure within the joint, is crucial for maintaining joint function. However, due to the avascular nature of joints, the self-repair capacity of damaged cartilage is extremely limited. Traditional drug and physical therapies only provide palliative relief and cannot fundamentally resolve osteoarthritis; they can only alleviate pain and slow its progression. Therefore, promoting cartilage regeneration and repair is key to the treatment of osteoarthritis.

[0003] Cartilage itself is an electrically charged tissue exhibiting electromechanical properties. Movement and other weight-bearing activities cause mechanical deformation of the tissue, generating electrical signals through the flow of positively charged particles through the negatively charged cartilage ECM. These electrical signals are considered a crucial component of cartilage function; changes in the cartilage matrix occurring in osteoarthritis (OA) disrupt the physiological electric field required for normal matrix maintenance. External electrical stimulation (ES) can mimic the tissue's endogenous electrical signals, inducing compression and deformation, and restoring environmental homeostasis after injury or disease. Therefore, ES has been proposed as a tool for cartilage tissue engineering to improve the regeneration, mechanical properties, and other characteristics of engineered tissues. Existing studies have shown that electrical stimulation can enhance chondrocyte proliferation and anabolism, influence voltage-sensitive calcium ion channels, and positively impact cell proliferation and DNA synthesis. Appropriate electrical stimulation can also stimulate the expression of aggregated proteoglycan (ACAN) and type II collagen (COL2A1) mRNA in human OA cartilage explants and increase the production of proteoglycans and collagen. In conclusion, topical ES is a promising, non-invasive stimulation method for treating OA.

[0004] Traditional electrostimulation therapy utilizes external electrodes to directly discharge electricity into the wound area, followed by the use of conductive scaffolds integrated with the external electrodes to improve treatment quality. Additionally, some studies have placed conductive coils around cell culture systems to generate pulsed potentials non-invasively, mimicking natural electrical signals in the human body. However, external power sources and conductive connectors remain unavoidable. Recent advancements in smart materials allow for passive electrostimulation therapy with or without external stimulation. During walking, continuous relative motion occurs within joints, and triboelectric or piezoelectric materials can achieve self-powered therapy by utilizing passive biomechanical energy from the human body. However, current protocols for in vivo electrostimulation therapy for osteoarthritis lack clear guiding parameters and primarily rely on different piezoelectric materials. Highly biocompatible piezoelectric materials typically have relatively low piezoelectric coefficients, resulting in very limited output electrical signals.

[0005] Therefore, applying specific electrical stimulation to articular cartilage based on the principle of triboelectricity can promote cartilage regeneration and repair, showing great potential and application prospects for the regenerative treatment of osteoarthritis. Summary of the Invention

[0006] The purpose of this invention is to provide an implantable electrical stimulator for the treatment of osteoarthritis and its preparation method. The implantable electrical stimulator of this invention is based on the principle of triboelectricity, can be used for the treatment of osteoarthritis in vivo without the need for an additional power supply device, and the output voltage signal can be adjusted as needed.

[0007] In a first aspect, the present invention provides an implantable electrical stimulator, comprising: A triboelectric power generation package includes a package body and a first triboelectric electrode layer and a second triboelectric power generation layer encapsulated within the package body. The first triboelectric power generation layer includes a first friction layer and a first electrode layer disposed on the surface of the first friction layer, wherein the surface of the first friction layer away from the first electrode layer has a first nanostructure. The second triboelectric power generation layer includes a second friction layer and a second electrode layer disposed on the surface of the second friction layer, wherein the surface of the second friction layer away from the second electrode layer has a second nanostructure. The first and second friction layers are made of different materials and are both biodegradable. The sides of the first and second friction layers with nanostructures are arranged opposite each other, and a gap is formed between the first and second nanostructures by a flexible insulator. A hydrogel adhesive film is attached to the upper surface of the triboelectric encapsulation body, and the first electrode layer and the second electrode layer are electrically connected to electrodes disposed on the upper surface of the encapsulation body.

[0008] In the aforementioned implantable electrical stimulator, the first friction layer is made of polylactic acid-glycolic acid copolymer, and the second friction layer is made of polycaprolactone. The thicknesses of the first friction layer and the second friction layer are 50–100 μm, respectively.

[0009] In the aforementioned implantable electrical stimulator, both the first electrode layer and the second electrode layer are made of PEDOT:PSS. The thicknesses of the first electrode layer and the second electrode layer are 5 μm to 10 μm, respectively; The electrodes disposed on the upper surface of the package body include electrode A and electrode B, which are electrically connected to the first electrode layer and the second electrode layer, respectively. Both electrode A and electrode B are made of PEDOT:PSS. The thicknesses of electrode A and electrode B are 5 μm to 10 μm, respectively; The material of the connection circuit between the first electrode layer and the second electrode layer and the electrode A and the electrode B is PEDOT:PSS.

[0010] In the aforementioned implantable electrical stimulator, the flexible insulator is further arranged around the periphery between the first nanostructure and the second nanostructure to form the gap in the middle. The width of the flexible insulator is 1 / 20 to 1 / 10 of the width of the first friction layer or the second friction layer in the horizontal x or y direction; The thickness of the flexible insulator is 50–100 μm; The flexible insulator is made of a biodegradable flexible polymer that is different from the two friction layers, preferably polyvinyl alcohol.

[0011] In the aforementioned implantable electrical stimulator, the encapsulation body is further made of an insulating flexible polymer material, preferably a polylactic acid-glycolic acid copolymer.

[0012] In the aforementioned implantable electrical stimulator, the hydrogel adhesion membrane is further made of methacrylamide gelatin. The thickness of the hydrogel adhesion film is 0.5–1 mm.

[0013] In a second aspect, the present invention provides a method for preparing an implantable electrical stimulator as described in any of the preceding claims, comprising the following steps: S1. Prepare a first friction film and form a nanostructure on the surface of the first friction film. Deposit a first electrode on the side of the first friction film away from the nanostructure to obtain the first friction electrode layer. S2. Prepare a second friction film and form a nanostructure on the surface of the second friction film. Deposit a second electrode on the side of the second friction film away from the nanostructure to obtain the second friction electrode layer. S3. Prepare the flexible insulator and use the flexible insulator to separate the first triboelectric electrode layer and the second triboelectric electrode layer. Then, encapsulate the entire structure with an encapsulation layer on which a connection circuit is deposited and electrically connect the first electrode and the second electrode to the electrode provided on the upper surface of the encapsulation layer, thereby obtaining a triboelectric power generation encapsulation body. S4. The hydrogel is attached to the upper surface of the triboelectric encapsulation to obtain the implantable electrical stimulator for the treatment of osteoarthritis.

[0014] In the above-mentioned method for preparing an implantable electrical stimulator, the step of forming a nanostructure further includes: placing one side of the first friction film or the second friction film in a NaOH solution for reaction; preferably, the concentration of the NaOH solution is 2 mol / L and the reaction time is 30 minutes.

[0015] In the above-mentioned method for preparing an implantable electrostimulator, the method for preparing the encapsulation layer with the deposited connection circuit includes: using oxygen PLASMA to perform surface modification treatment on the upper surface of the encapsulation layer to introduce oxygen-containing hydrophilic groups, and then depositing a PEDOT:PSS thin film by spraying and patterning it with a 532nm laser to obtain an electrode pattern and connection circuit. The steps of bonding the hydrogel film include: using oxygen PLASMA to perform surface modification treatment on the upper surface of the encapsulation layer to introduce oxygen-containing hydrophilic groups, then casting the hydrogel onto the upper surface of the encapsulation layer, and achieving in-situ crosslinking through ultraviolet exposure.

[0016] Thirdly, the present invention provides the use of the implantable electrical stimulator described in any of the preceding claims or the implantable electrical stimulator prepared by the method described in any of the preceding claims in the preparation of products for treating osteoarthritis.

[0017] The present invention has the following beneficial effects: This invention allows for adjustment of the output voltage signal as needed. In practical applications, the device outputs a specific electrical stimulation parameter of 200mV / cm at a physiological frequency, which can simultaneously guide the migration and anabolism of chondrocytes, accelerating the regeneration of articular cartilage. For in vivo treatment, no additional power supply is required; bioenergy is converted into electrical energy. This invention involves a wide range of material selection, simple processing methods, and is easy to widely apply. The entire device is made of biocompatible and biodegradable material, which can slowly degrade in vivo, with an expected stable operating time of 3-4 weeks. The implantable electrical stimulator of this invention has certain peel strength and shear strength, meeting the needs of in vivo treatment. Attached Figure Description

[0018] Figure 1 is a schematic diagram of the implantable electrical stimulator for the treatment of osteoarthritis according to the present invention. Figure 1A - Cross-sectional view; Figure 1B-Top view.

[0019] Figure 2 This is a schematic diagram of the action site of the implantable electrical stimulator for the treatment of osteoarthritis according to the present invention.

[0020] Figure 3 This is a flowchart illustrating the manufacturing process of the implantable electrical stimulator for the treatment of osteoarthritis according to the present invention.

[0021] Figure 4 The images shown are SEM images of thin films with different surface structures in the embodiments of the present invention, namely untreated PCL (A) and PLGA (C) surfaces, and PCL (B) and PLGA (D) surfaces with nanostructures.

[0022] Figure 5 The curves represent the output voltages of thin films with different surface structures in the embodiments of the present invention. Curve A represents the output signal of PCL and PLGA without surface nanostructures, while curve B represents the corresponding output curve of PCL and PLGA with surface nanostructures.

[0023] Figure 6 This illustrates the change in the water contact angle of the thin film before and after Plasma treatment in this embodiment of the invention.

[0024] Figure 7 This is a photograph of an implantable electrical stimulator for the treatment of osteoarthritis, as described in an embodiment of the present invention.

[0025] Figure 8 This refers to the peel strength of the device on the tissue in the embodiments of the present invention.

[0026] Figure 9 This refers to the shear strength of the device against tissue in the embodiments of the present invention.

[0027] Figure 10 The results show the effects of the device on the expression of genes related to stem cell chondrogenic differentiation.

[0028] The labels in the diagram are as follows: 100 - Implantable electrical stimulator; 101 - Encapsulation body; 102 - First friction layer; 103 - First electrode layer; 104 - First nanostructure; 105 - Second friction layer; 106 - Second electrode layer; 107 - Second nanostructure; 108 - Flexible insulator; 109 - Hydrogel adhesion film; 110 - Connecting circuit; 111 - Electrode A; 112 - Electrode B; 200-Intra-articular cartilage. Detailed Implementation

[0029] To make the objectives, technical solutions, and advantages of this invention clearer, the technical solutions of the invention will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some, not all, of the embodiments of this invention. All other embodiments obtained by those skilled in the art based on the embodiments of this invention without creative effort are within the scope of protection of this invention.

[0030] Unless otherwise defined, the technical or scientific terms used in this invention shall have the ordinary meaning understood by one of ordinary skill in the art to which this invention pertains. The terms "first," "second," and similar terms used in this invention do not indicate any order, quantity, or importance, but are merely used to distinguish different components. Terms such as "comprising" or "including" mean that the element or object preceding the word encompasses the elements or objects listed following the word and their equivalents, without excluding other elements or objects.

[0031] In the description of this invention, it should be noted that the terms "upper", "lower", "horizontal", "vertical", etc., indicate the orientation or positional relationship based on the orientation or positional relationship shown in the accompanying drawings. They are only for the convenience of describing this invention and simplifying the description, and do not indicate or imply that the system or element referred to must have a specific orientation, or be constructed and operated in a specific orientation. Therefore, they should not be construed as limitations on this invention.

[0032] In the description of this invention, it should be noted that, unless otherwise explicitly specified and limited, the terms "assembly," "setup," and "connection" should be interpreted broadly. For example, they can refer to a fixed connection, a detachable connection, or an integral connection; they can refer to a mechanical connection or an electrical connection; they can refer to a direct connection or an indirect connection through an intermediate medium; and they can refer to the internal connection of two components. Those skilled in the art can understand the specific meaning of the above terms in this invention based on the specific circumstances.

[0033] As described in the background section, current passive electrical stimulation therapy devices mainly rely on piezoelectric materials. However, highly biocompatible piezoelectric materials typically have a relatively small piezoelectric coefficient, resulting in very limited output electrical signals. Therefore, this invention develops an implantable electrical stimulator based on the principle of triboelectricity to provide specific electrical stimulation to articular cartilage for the treatment of osteoarthritis. As shown in Figure 1, the present invention provides an implantable electrical stimulator for the treatment of osteoarthritis, comprising: a triboelectric encapsulation body, including an encapsulation body 101 and a first triboelectric electrode layer and a second triboelectric layer encapsulated within the encapsulation body 101; the first triboelectric layer includes a first triboelectric layer 102 and a first electrode layer 103 disposed on the surface of the first triboelectric layer (as shown in Figure 1, the first electrode layer 103 is located on the upper surface of the first triboelectric layer 102), and the surface of the first triboelectric layer 102 away from the first electrode layer 103 has a first nanostructure 104 (as shown in Figure 1, the first nanostructure 104 is located on the lower surface of the first triboelectric layer 102); the second triboelectric layer includes a second triboelectric layer 105 and a second electrode layer 106 disposed on the surface of the second triboelectric layer (as shown in Figure 1, the second electrode layer 106 is located on the lower surface of the second triboelectric layer 105). The second friction layer 105 has a second nanostructure 107 on the surface away from the second electrode layer 106 (as shown in Figure 1, the second nanostructure 107 is located on the upper surface of the second friction layer 105); the first friction layer 102 and the second friction layer 105 are made of different materials and are both biodegradable materials; the sides of the first friction layer 102 and the second friction layer 105 with nanostructures are arranged opposite each other (as shown in Figure 1, the first nanostructure 104 and the second nanostructure 107 are arranged vertically opposite each other), and a gap is formed between the first nanostructure 104 and the second nanostructure 107 by a flexible insulator 108; a hydrogel adhesion film 109 is attached to the upper surface of the triboelectric encapsulation body, and the first electrode layer 103 and the second electrode layer 106 are electrically connected to the electrodes arranged on the upper surface of the encapsulation body 101.

[0034] Based on the above technical solutions, the triboelectric encapsulation body enables the conversion of human walking bio-energy into electrical energy; the hydrogel adhesion membrane provides space for cell migration and growth, as well as tissue adhesion. In use, such as... Figure 2As shown, the device adheres to the surface of the cartilage 200 within the joint via a hydrogel adhesive membrane. When the flexible triboelectric device is subjected to compression or lateral shearing, the process of contact separation of the triboelectric layers generates charge. This charge is transferred from the triboelectric layers to the electrode layers, thereby applying electrical stimulation to the chondrocytes, promoting their proliferation and anabolism, and achieving cartilage repair and regeneration. The power generation principle of the triboelectric encapsulation is as follows: A tiny gap exists between the first triboelectric layer 102 and the second triboelectric layer 105, allowing for charge transfer during friction. The triboelectric generation process consists of two stages. The first stage is the contact stage: when the two triboelectric layers are subjected to force (such as force generated by external mechanical devices or human movement), they approach and come into contact. Due to the different materials of the two electrode plates, triboelectric charging occurs between them, i.e., electrons transfer from one electrode plate to the other, creating a potential difference between the two electrode plates. The second stage is the separation stage: when the external force disappears or decreases, causing the two electrode plates to begin separating, the previously formed potential difference drives electron flow, thereby generating current. During this process, electrons flow back to the original electrode plate or through an external circuit, forming electrical energy output.

[0035] According to one embodiment of the present invention, the inventors investigated the output voltage signals of devices with and without nanostructured friction layers during practical testing. The results showed that the relatively smooth surface of the nanostructured film significantly increased the contact area upon contact, resulting in a substantial increase in the output voltage signal. The present invention allows for adjustment of the output electrical signal magnitude by modifying different surface structures, such as achieving an electrical stimulation parameter of 200 mV / cm for osteoarthritis treatment. Specifically, the nanostructure refers to nanoscale pits and / or protrusions.

[0036] According to one embodiment of the present invention, the first friction layer 102 is made of poly(lactic-co-glycolic acid) copolymer, and the second friction layer 105 is made of polycaprolactone. Using biodegradable materials poly(lactic-co-glycolic acid) (PLGA) and polycaprolactone (PCL) as the triboelectric layer structure allows for slow degradation in vivo and also facilitates triboelectric charging. The thicknesses of the first and second friction layers are 50–100 μm, respectively. The length and width of the first friction layer 102 and the second friction layer 105 can be adjusted according to the size of the joint soft tissue, for example, a length of 10 mm and a width of 10 mm.

[0037] According to one embodiment of the present invention, the first electrode layer 103 and the second electrode layer 106 are both made of PEDOT:PSS, a highly biocompatible flexible electrode material to meet the needs of implantable electrical stimulators for in vivo treatment. The length and width of the first electrode layer and the second electrode layer can be set according to the length and width of the first friction layer and the second friction layer, with the aim of covering the friction layer. Preferably, the thickness of the first electrode layer and the second electrode layer are 5μm to 10μm respectively. Similarly, preferably, the electrodes disposed on the upper surface of the package body include electrode A 111 and electrode B 112, which are electrically connected to the first electrode layer 103 and the second electrode layer 106 respectively. The material of electrode A 111 and electrode B 112 are both PEDOT:PSS, and the thickness of electrode A and electrode B are 5μm to 10μm respectively. The material of the connection circuit 110 between the first electrode layer 103 and the second electrode layer 106 and the electrodes A 111 and B 112 is PEDOT:PSS.

[0038] According to one embodiment of the present invention, the flexible insulator 108 is arranged around the periphery (outer edge) between the first nanostructure 107 and the second nanostructure 108 to form the gap in the middle; the width of the flexible insulator is 1 / 20 to 1 / 10 of the width of the first or second friction electrode layer in the horizontal x or y direction; the thickness of the flexible insulator 108 is 50 to 100 μm; the flexible insulator 108 is made of an insulating biodegradable flexible polymer, such as polyvinyl alcohol, which is different from the two friction layers. Polyvinyl alcohol (PVA), as the spacer between the two friction layers, can slowly degrade in vivo. The length of the flexible insulator 108 can be determined according to the length of the first and second friction layers.

[0039] According to one embodiment of the present invention, the encapsulation body 101 is made of an insulating flexible polymer material, such as polylactic-co-glycolic acid copolymer (PLGA). Specifically, an insulating flexible polymer material with a suitable degradation rate can be selected based on the application scenario. Using PLGA as the encapsulation material serves two purposes: firstly, the entire triboelectric nanogenerator is thermo-encapsulated with a PLGA film to prevent the intrusion of bodily fluids; secondly, this material can slowly degrade within the body.

[0040] According to one embodiment of the present invention, the hydrogel adhesion membrane 109 is made of methacrylamide gelatin (GelMA), which has good adhesion properties and can be slowly degraded in vivo; specifically, the hydrogel uses 10% methacrylamide gelatin (GelMA), and its Young's modulus is close to that of cartilage tissue. The thickness of the hydrogel adhesion membrane 110 is 0.5-1 mm. The length and width of the hydrogel adhesion membrane 109 are positively correlated with the dimensions of the upper surface of the encapsulation body, and the coverage area must at least exceed the electrode portion of the encapsulation body.

[0041] Part Two, such as Figure 3 As shown, the present invention provides a method for preparing an implantable electrical stimulator for the treatment of osteoarthritis as described in any of the above claims, comprising the following steps: S1, preparing a first friction film and forming a nanostructure on the surface of the first friction film, and depositing a first electrode on the side of the first friction film away from the nanostructure to obtain a first friction electrode layer; S2, preparing a second friction film and forming a nanostructure on the surface of the second friction film, and depositing a second electrode on the side of the second friction film away from the nanostructure to obtain a second friction electrode layer; S3, preparing the flexible insulator and separating the first friction electrode layer and the second friction electrode layer with the flexible insulator, and then encapsulating the entire structure with an encapsulation layer having a connecting circuit deposited thereon, and electrically connecting the first electrode and the second electrode to the electrode disposed on the upper surface of the encapsulation layer to obtain a triboelectric encapsulation body; S4, attaching a hydrogel adhesive film to the upper surface of the triboelectric encapsulation body to obtain the implantable electrical stimulator for the treatment of osteoarthritis.

[0042] According to one embodiment of the present invention, the step of forming the nanostructure includes: placing one side of the first friction film or the second friction film in a NaOH solution for reaction; preferably, the concentration of the NaOH solution is 2 mol / L and the reaction time is 30 minutes.

[0043] According to one embodiment of the present invention, the method for preparing the encapsulation layer with deposited connection circuits includes: surface modification treatment of the encapsulation layer using oxygen PLASMA to introduce oxygen-containing hydrophilic groups, followed by deposition of a PEDOT:PSS thin film by spraying and patterning with a 532nm laser to obtain electrode patterns and connection circuits. The step of bonding the hydrogel film includes: surface modification treatment of the upper surface of the encapsulation layer using oxygen PLASMA to introduce oxygen-containing hydrophilic groups, followed by casting the hydrogel onto the upper surface of the encapsulation layer and achieving in-situ crosslinking through ultraviolet exposure. The amino and methacrylate groups in GelMA can react with carboxyl groups on the surface to form amide bonds, and the hydroxyl and amino groups in GelMA can form hydrogen bonds with hydroxyl and carboxyl groups on the surface, thereby achieving strong adhesion of GelMA to the surface of the triboelectric nanogenerator. Laser treatment can induce a selective photothermal reaction between the electrode PEDOT:PSS and the polymer substrate. The laser is absorbed at the PEDOT:PSS interface, resulting in partial phase separation in PEDOT:PSS and the formation of micron- and nano-scale interlocks at the interface. This achieves high conductivity optimization of PEDOT:PSS and strong adhesion between it and the substrate.

[0044] Part Three, the present invention provides the use of the implantable electrical stimulator described in any of the preceding claims or the implantable electrical stimulator prepared by the method described in any of the preceding claims in the preparation of products for treating osteoarthritis.

[0045] According to one embodiment of the present invention, in use, the device adheres to cartilage tissue via a bridging polymer chitosan (CS) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) / N-hydroxysuccinimide (NHS). This is because the main functional groups present on the surface of cartilage tissue include amino, hydroxyl, and carboxyl groups. The adhesion between the hydrogel and the tissue involves the formation of topological entanglement and interpenetrating networks, as well as the generation of amide bonds, electrostatic interactions, and hydrogen bonds. Under humid conditions, chitosan chains can penetrate into the tissue and form topological entanglement with tissue molecules. This entanglement structure allows for a tight connection between the bridging polymer and the tissue, thereby improving the adhesion strength. EDC first activates the carboxylic acid groups to form an activated intermediate. Then, NHS reacts with the intermediate to generate NHS ester. The NHS ester reacts with the amino compound to form stable amide bonds, thereby enhancing adhesion and stability.

[0046] According to one embodiment of the present invention, in practical applications, this device can simultaneously guide the migration and anabolic metabolism of chondrocytes by outputting a specific electrical stimulation parameter of 200mV / cm at a physiological frequency, thereby accelerating the regeneration of articular cartilage. The present invention can adjust the magnitude of the output electrical signal by changing the size of the thin film material and different surface structures.

[0047] The present invention will now be described in further detail with reference to specific embodiments. The given embodiments are merely illustrative of the invention and not intended to limit its scope. The embodiments provided below can serve as a guide for further improvements by those skilled in the art and do not constitute a limitation on the invention in any way.

[0048] Unless otherwise specified, the methods used in the following embodiments are conventional methods, performed according to the techniques or conditions described in the literature in this field or according to the product instructions. Unless otherwise specified, the materials and reagents used in the following embodiments are commercially available.

[0049] Example 1 As shown in Figure 1, the implantable electrical stimulator for the treatment of osteoarthritis in this embodiment includes: A triboelectric power generation package includes a package body 101 made of PLGA and a first triboelectric electrode layer and a second triboelectric power generation layer encapsulated within the package body. The first triboelectric power generation layer includes a first triboelectric layer 102 made of PLGA and a first electrode layer 103 made of PEDOT:PSS disposed on the surface of the first triboelectric layer. The surface of the first triboelectric layer 102 away from the first electrode layer 103 has a first nanostructure 104. The second triboelectric power generation layer includes a second triboelectric layer 105 made of PCL and a second electrode layer 106 made of PEDOT:PSS disposed on the surface of the second triboelectric layer. The surface of the second triboelectric layer 105 away from the second electrode layer 106 has a second nanostructure 107. The first and second triboelectric layers have a length of 10 mm, a width of 10 mm, and a thickness of 100 μm. The first electrode layer 103 and the second electrode layer 106 have a length of 10 mm, a width of 10 mm, and a thickness of 5 μm (fully covering the non-nanostructure side). The first friction layer 102 and the second friction layer 105, having nanostructures on their sides, are disposed opposite each other. A gap is formed between the first nanostructure 104 and the second nanostructure 107 by a flexible insulator 108 made of PVA. Specifically, the flexible insulator 108 is arranged around the periphery between the first and second nanostructures to form a gap in the middle. The length of the flexible insulator 108 is consistent with the width of the first friction layer 102 and the second friction layer 105 in the horizontal x or y direction. The width of the flexible insulator is 1 / 15 of the width of the first or second friction layer in the horizontal x or y direction. The thickness of the flexible insulator 108 is 75 μm. A hydrogel adhesive film 109 made of GelMA is attached to the upper surface of the triboelectric power generation package. The hydrogel adhesive film 109 has a length of 10mm, a width of 10mm, and a thickness of 1mm. The first electrode layer 103 and the second electrode layer 106 are electrically connected to electrodes A111 and B112, both made of PEDOT:PSS, which are set on the upper surface of the package body by a connection circuit 110 made of PEDOT:PSS. The thickness of electrodes A and B is 5μm.

[0050] according to Figure 3 The specific steps for preparing the above-mentioned implantable electrical stimulator for the treatment of osteoarthritis are as follows: (1) PLGA was dissolved in chloroform at a concentration of 5% (w / v), cast onto a glass mold, air-dried for 12 hours, and then placed in a vacuum oven for 12 hours to remove residual solvent. It was then reacted in 2M NaOH solution for about 10 minutes to form nanostructures on the film surface. The film was washed three times with deionized water and dried at 40°C. A PEDOT:PSS electrode was deposited on the back side of the film surface by spraying. Patterned PCL films with nanostructures on the surface and the back electrode were fabricated using the same method. PVA was dissolved in deionized water at a concentration of 5% (w / v) and cast into a plastic petri dish to dry.

[0051] Comparing the different surface results of forming nanostructures and not forming nanostructures, such as Figure 4 The different surface structures of the films shown are untreated PCL (A) and PLGA (C) surfaces, and PCL (B) and PLGA (D) surfaces with nanostructures.

[0052] As shown in the figure below, Figure 5 The curves in the figures all represent the output signals of thin films measuring 1*2cm. Curve A represents the output signal of PCLs and PLGAs with flat surfaces and no surface nanostructures, while curve B represents the corresponding output curve of PCLs and PLGAs with surface nanostructures. The nanostructured thin films significantly increase the contact area during contact due to their relatively smooth surfaces, thus resulting in a substantial increase in the output voltage signal.

[0053] (2) The PLGA encapsulation layer was manufactured using the same casting method. It was then cut to a suitable size and treated with oxygen PLASMA (60W, oxygen, 5min). After surface treatment, PEDOT:PSS electrodes were deposited by spraying and patterned using laser processing (532nm). The electrodes were then removed by ultrasonic cleaning. Finally, the device was encapsulated using a heat sealer.

[0054] Figure 6The change in water contact between the film and the plasma before and after treatment shows that the smaller contact area after treatment indicates a significant improvement in hydrophilicity, which increases the adhesion to the gel.

[0055] (3) Specific preparation of GelMA hydrogel: First, the water-soluble, cell-compatible photoinitiator LAP (lithium phenyl-2,4,6-trimethylbenzoylphosphinate) was dissolved in PBS solution at a concentration of 0.1% (w / v). Then, GelMA was dissolved in LAP solution at a concentration of 10% (w / v). The solution was heated in a 50°C water bath for 30 minutes to promote dissolution. After sterilization by filtration through a 0.22-micron filter, it was stored in the dark. The GelMA hydrogel was cast onto the surface of the PLGA encapsulation layer after plasma treatment (60W power, oxygen, 5 min), and in-situ crosslinking was achieved by UV exposure for 30 s.

[0056] The implantable electrical stimulator is obtained through the above steps. A photograph of the actual device is shown below. Figure 7 As shown.

[0057] During testing, a small amount of 2% CS and 12 mg / ml EDC / NHS were evenly applied to the hydrogel surface. The device was then pressed onto the cartilage surface for 3 minutes to achieve bonding between the device and the cartilage (purchased porcine cartilage). The bonding strength (tested using a tensile testing machine with 180° peel and shear tests) was as follows: Figure 8-9 As shown, the control group used only GelMA gel.

[0058] Preliminary experimental results: Changes in RNA expression levels of type II collagen under bidirectional pulsed electrical stimulation at 200 mV / cm, 1 Hz, and 5% duty cycle were detected at 1 and 2 weeks. Type II collagen is a major component of the extracellular matrix of chondrocytes and a crucial marker for stem cell differentiation into chondrocytes. Figure 10 The results showed that the expression level of COL2 increased significantly under electrical stimulation, indicating that electrical stimulation can effectively promote the chondrogenic differentiation of stem cells and accelerate the regeneration of articular cartilage.

[0059] The results above demonstrate that the device of this invention can adjust the output voltage signal as needed. By outputting a specific electrical stimulation parameter of 200mV / cm at a physiological frequency, it can simultaneously guide the migration and anabolic metabolism of chondrocytes, accelerating the regeneration of articular cartilage. For in vivo treatment, no additional power supply is required; bioenergy can be converted into electrical energy. The implantable electrical stimulator of this invention possesses certain peel strength and shear strength, meeting the requirements for in vivo treatment.

[0060] The present invention has been described in detail above. Those skilled in the art will recognize that the invention can be practiced in a wide range of ways with equivalent parameters, concentrations, and conditions without departing from its spirit and scope. While specific embodiments have been provided, it should be understood that further modifications can be made to the invention. In summary, according to the principles of the invention, this application is intended to include any changes, uses, or improvements to the invention, including modifications made using conventional techniques known in the art that depart from the scope disclosed herein.

Claims

1. An implantable electrical stimulator, comprising: include: A triboelectric encapsulation includes an encapsulation body and a first triboelectric electrode layer and a second triboelectric layer encapsulated within the encapsulation body. The first triboelectric power generation layer includes a first friction layer and a first electrode layer disposed on the surface of the first friction layer, wherein the surface of the first friction layer away from the first electrode layer has a first nanostructure; the second triboelectric power generation layer includes a second friction layer and a second electrode layer disposed on the surface of the second friction layer, wherein the surface of the second friction layer away from the second electrode layer has a second nanostructure; the first friction layer and the second friction layer are made of different materials and are both biodegradable materials; the sides of the first friction layer and the second friction layer with nanostructures are disposed opposite each other, and a gap is formed between the first nanostructure and the second nanostructure by a flexible insulator; A hydrogel adhesive film is attached to the upper surface of the triboelectric encapsulation body, and the first electrode layer and the second electrode layer are electrically connected to electrodes disposed on the upper surface of the encapsulation body.

2. The implantable electrical stimulator according to claim 1, characterized in that: The first friction layer is made of polylactic acid-glycolic acid copolymer, and the second friction layer is made of polycaprolactone; The thicknesses of the first friction layer and the second friction layer are 50–100 μm, respectively.

3. The implantable electrical stimulator according to any one of claims 1-2, characterized in that: Both the first electrode layer and the second electrode layer are made of PEDOT:PSS. The thicknesses of the first electrode layer and the second electrode layer are 5 μm to 10 μm, respectively.

4. The implantable electrical stimulator according to any one of claims 1-3, characterized in that: The flexible insulator is arranged in a ring around the periphery between the first nanostructure and the second nanostructure to form the gap in the middle; The width of the flexible insulator is 1 / 20 to 1 / 10 of the width of the first friction layer or the second friction layer in the horizontal x or y direction; The thickness of the flexible insulator is 50–100 μm; The flexible insulator is made of a biodegradable flexible polymer that is different from the two friction layers.

5. The implantable electrical stimulator according to any one of claims 1-4, characterized in that: The encapsulation body is made of an insulating flexible polymer material.

6. The implantable electrical stimulator according to any one of claims 1-5, characterized in that: The hydrogel adhesion film is made of methacrylamide gelatin; The thickness of the hydrogel adhesion film is 0.5 to 1 mm.

7. A method for preparing an implantable electrical stimulator according to any one of claims 1-6, characterized in that, Includes the following steps: S1. Prepare a first friction film and form a nanostructure on the surface of the first friction film. Deposit a first electrode on the side of the first friction film away from the nanostructure to obtain the first friction electrode layer. S2. Prepare a second friction film and form a nanostructure on the surface of the second friction film. Deposit a second electrode on the side of the second friction film away from the nanostructure to obtain the second friction electrode layer. S3. Prepare the flexible insulator and use the flexible insulator to separate the first triboelectric electrode layer and the second triboelectric electrode layer. Then, encapsulate the entire structure with an encapsulation layer on which a connection circuit is deposited and electrically connect the first electrode and the second electrode to the electrode provided on the upper surface of the encapsulation layer, thereby obtaining a triboelectric power generation encapsulation body. S4. The hydrogel is attached to the upper surface of the triboelectric encapsulation to obtain the implantable electrical stimulator for the treatment of osteoarthritis.

8. The method for preparing an implantable electrical stimulator according to claim 7, characterized in that: The step of forming the nanostructure includes: placing one side of the first friction film or the second friction film in a NaOH solution for reaction.

9. The method for preparing an implantable electrical stimulator according to any one of claims 7-8, characterized in that: The method for preparing the encapsulation layer with the deposited connection circuit includes: using oxygen PLASMA to perform surface modification treatment on the upper surface of the encapsulation layer to introduce oxygen-containing hydrophilic groups, and then depositing a PEDOT:PSS thin film by spraying and patterning it with a 532nm laser to obtain the electrode pattern and connection circuit. The steps of bonding the hydrogel film include: using oxygen PLASMA to perform surface modification treatment on the upper surface of the encapsulation layer to introduce oxygen-containing hydrophilic groups, then casting the hydrogel onto the upper surface of the encapsulation layer, and achieving in-situ crosslinking through ultraviolet exposure.

10. The use of the implantable electrical stimulator according to any one of claims 1-6 or the implantable electrical stimulator prepared by the method according to any one of claims 7-9 in the preparation of products for treating osteoarthritis.

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