Viscosity-adjustable hydrogel electrode for peripheral nerve disease diagnosis and preparation method

Abstract

The invention discloses a viscosity-adjustable hydrogel electrode for peripheral nerve disease diagnosis and a preparation method, the viscosity-adjustable hydrogel electrode comprises a flexible substrate layer, a direct-writing hydrogel interface layer and a stretchable conductive layer containing an electrode, and the stretchable conductive layer is arranged on the flexible substrate layer; the direct-writing hydrogel interface layer is arranged on the flexible substrate layer and covers the stretchable conductive layer, and the direct-writing hydrogel interface layer is used for being in direct contact with human skin tissue and being adhered to the human skin tissue; the direct-writing hydrogel interface layer comprises the following components: porous hydrogel microspheres, a quaternary ammonium-based polysaccharide viscous functional molecular chain, an ammonium sulfonate-based zwitterionic monomer, an amide monomer, an initiator and a cross-linking agent. Viscosity can be regulated and controlled by controlling the temperature, stable attachment and stripping with skin tissue are achieved, manufacturing efficiency is high, high-fidelity neural signal collection is provided, meanwhile, cost reduction is guaranteed, the requirement for constant and continuous high-quality signal collection is met, and high stretchability and viscosity adjustability are achieved.

Description

Technical Field

[0001] The present invention specifically relates to a viscosity - adjustable hydrogel electrode for diagnosing peripheral nerve diseases and a preparation method thereof. Background Art

[0002] In recent years, bioelectrodes with high stretchability and flexibility can achieve conformal contact with the skin, adapt to the deformation of the skin, and flexible epidermal electrodes are widely used in the acquisition of electrophysiological signals in the field of nerve electrostimulation. Among them, nerve electrostimulation is of great significance for the diagnosis of nerve diseases and also has a deep application in the rehabilitation of nerve diseases. The upper limb nerves, as the front - end of limb drive and behavior perception, are closely related to daily life. The upper limb nerves being diseased often leads to restricted limb behavior of the patient, causing great obstacles to their life.

[0003] Electromyography, as one of the commonly used nerve electrophysiological monitoring methods, can capture and record the nerve electrical activities of patients. By analyzing the conduction velocity, latency, and amplitude of nerve signals, the abnormal conditions of the diseased nerves of the patients can be understood. Currently, hospitals and medical institutions mostly use commercial electromyography instruments for the analysis and recording of electromyography. Medical staff diagnose upper limb nerve diseases and adjust treatment or surgical plans based on the feedback of electromyography, which provides assistance for suppressing and curing the patient's condition. However, commercial electromyography instruments still have certain limitations. For example, their high price leads to a high procurement threshold and a small number of purchases. The front - end acquisition devices are mostly rigid, non - stretchable, have a large modulus of elasticity, and are difficult to achieve conformal attachment to the lesions of patients. Due to the different damaged positions of the upper limb nerves of patients (different skin states and deformation states) and different ages (infants, adults, the elderly), it is extremely difficult to collect accurate low - noise signals. The rigid commercial electrodes increase the burden on the diagnosis and treatment process.

[0004] To achieve the accurate diagnosis of upper limb nerve diseases and the acquisition of signals with high fidelity and high anti - motion artifact, researchers have developed the front - end acquisition device into a flexible electrode. For example, hydrogel materials are developed to optimize the conformal attachment ability of the electrode and achieve high - quality signal acquisition. However, most current hydrogel interfaces use a casting process, which has low manufacturing efficiency, low manufacturing precision, uneven cross - link density, inconsistent signal acquisition quality, uncontrollable viscosity, and is easy to cause damage to the patient's skin tissue. It is impossible to manufacture a high - quality hydrogel electrode interface layer with a controllable density, and its commercialization and industrialization levels are low, making it impossible to be widely applied to the outpatient clinics and treatments of patients on a large scale. Therefore, it is necessary to develop a flexible hydrogel electrode with high stretchability, high manufacturing precision, high manufacturing efficiency, uniform cross - link density, and adjustable viscosity to meet the requirements of constant and continuous high - quality signal acquisition for nerve disease diagnosis. Summary of the Invention

[0005] The object of the present invention is to provide a viscosity-adjustable hydrogel electrode for diagnosing peripheral nerve diseases and a preparation method thereof. The viscosity can be regulated by controlling the temperature to achieve stable adhesion and peeling from skin tissues. In particular, the components of the direct-write hydrogel interface layer are conducive to making 3D direct-write ink, which is manufactured by 3D printing. It has excellent flexibility and conductivity, high manufacturing efficiency, provides high-fidelity nerve signal acquisition while ensuring cost reduction, avoids cross-infection of patients, and meets the requirements of constant and continuous high-quality signal acquisition, high stretchability and adjustable viscosity.

[0006] The technical solution adopted by the present invention is as follows: A viscosity-adjustable hydrogel electrode for diagnosing peripheral nerve diseases, comprising a flexible base layer, a direct-write hydrogel interface layer and a stretchable conductive layer including an electrode. The flexible base layer serves as the flexible frame base of the electrode, the stretchable conductive layer is disposed on the flexible base layer, and the direct-write hydrogel interface layer is disposed on the flexible base layer and covers the stretchable conductive layer. The direct-write hydrogel interface layer is used to directly contact and adhere to human skin tissues; the viscosity of the direct-write hydrogel interface layer changes correspondingly when the temperature changes, and the viscosity can be regulated by controlling the temperature to achieve stable adhesion and peeling from skin tissues. Among them, the components of the direct-write hydrogel interface layer include porous hydrogel microspheres, quaternary ammonium group polysaccharide adhesive functional molecular chains, ammonium sulfonate zwitterionic monomers, amide monomers, initiators and crosslinking agents.

[0007] Preferably, the components forming the direct-write hydrogel interface layer are combined with deionized water to form 3D direct-write ink, which is patterned into a fixed shape by a 3D direct-write nozzle and forms the direct-write hydrogel interface layer through ultraviolet-induced polymerization.

[0008] Preferably, the porous hydrogel microspheres are poly(N-isopropylacrylamide-based / carboxyl-based) microspheres.

[0009] Preferably, the ammonium group polysaccharide adhesive functional molecular chain is formed by grafting 3,4,5-trihydroxybenzoic acid and / or 3,4,5-trihydroxybenzoic acid derivatives onto quaternary ammonium salt chitosan and / or quaternary ammonium salt chitosan derivatives.

[0010] Preferably, in the direct-write hydrogel interface layer, the mass fractions of the porous hydrogel microspheres, quaternary ammonium group polysaccharide adhesive functional molecular chains, ammonium sulfonate zwitterionic monomers, amide monomers, initiators and crosslinking agents are 10 wt%-33 wt%, 10 wt%-15 wt%, 10 wt%-15 wt%, 10 wt%-20 wt%, 5 wt%-10 wt%, 0.01 wt%-0.05 wt%, 0.02 wt%-0.1 wt% respectively, and the balance is water.

[0011] Preferably, the poly(N-isopropylacrylamide) / carboxyl microspheres are obtained by polymerizing carboxyl macromolecular chains with N-isopropylacrylamide monomers.

[0012] Preferably, the mass fractions of N-isopropylacrylamide monomers and carboxyl macromolecular chains in the porous hydrogel microspheres are 15 wt%-20 wt% and 2.5 wt%-5 wt%, respectively.

[0013] Preferably, the mass fractions of quaternary ammonium salt chitosan and / or its derivatives and 3,4,5-trihydroxybenzoic acid and / or its derivatives in the ammonium polysaccharide sticky functional molecular chain are 40 wt%-50 wt% and 5 wt%-10 wt%, respectively.

[0014] Preferably, the preparation method of the porous hydrogel microspheres is as follows: S311. Dissolve 10 mmol-20 mmol of N-isopropylacrylamide monomers and 2 mmol-4 mmol of carboxyl macromolecular chains in 5-10 ml of deionized water. After stirring until the solution is evenly mixed, add it to 50-100 ml of cyclohexane, and perform degassing treatment for a time T1 (T1 is 0.5-1 h); S312. Add 3-5 ml of potassium persulfate APS solution with a concentration mass fraction of 0.02-0.04 wt% to the above solution. After stirring evenly, continuously stir the solution and heat it in a water bath for 1 h to finally polymerize poly(N-isopropylacrylamide) / carboxyl microspheres; S313. Add the above poly(N-isopropylacrylamide) / carboxyl microspheres to 50-100 ml of absolute ethanol and shake for a time T2 (T2 is 5-10 min), pour it into a centrifuge and centrifuge for a time T3 (T3 is 5-10 min), and take the precipitate at the bottom layer of the solution; S314. Add the above bottom layer precipitate to 50-100 ml of deionized water and shake at 800 r / min for a time T4 (T4 is 5-10 min), pour it into a centrifuge and centrifuge for a time T5 (T5 is 5-10 min) to obtain a poly(N-isopropylacrylamide) / carboxyl microsphere solution, add it to a freeze dryer for freeze drying to obtain poly(N-isopropylacrylamide) / carboxyl microspheres; The preparation method of the ammonium polysaccharide sticky functional molecular chain (3-2) is as follows: S321. Dissolve 5 mmol-10 mmol of quaternary ammonium salt chitosan and / or its derivatives in 100-150 ml of 2-morpholinoethanesulfonic acid solution. Add sodium hydroxide to the above solution to adjust the pH value to 5.0-6.0, and stir magnetically until the solution is evenly mixed. After degassing treatment for a time T6 (T6 is 0.5-1 h), obtain a quaternary ammonium salt chitosan solution; S322. 1-3mmol 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride, 1-3mmol N-hydroxysuccinimide, and 1-3mmol ascorbic acid are added to 10-15ml 2-morpholineethanesulfonic acid solution, 2-5ml anhydrous ethanol is added to the above solution, sodium hydroxide is added to adjust the pH value of the above solution to 5.0-6.0, and magnetic stirring is performed until the solution is mixed uniformly; S323. The mixed solution obtained in step S322 is added dropwise to the quaternary ammonium chitosan solution, and the degassing treatment time is T7 (T7 is 0.5-1h), and the magnetic stirring time is T8 (T8 is 10-15h); S324. Place the solution obtained in the above step S323 in a dialysis bag, completely immerse it in deionized water and turn on magnetic stirring. After dialysis time T9 (T9 is 48-72h), take out the solution in the dialysis bag and add it to a freeze dryer for freeze drying to obtain quaternary ammonium polysaccharide adhesive functional molecular chains.

[0015] A method for preparing the above-mentioned viscosity-adjustable hydrogel electrode for peripheral nerve disease diagnosis comprises the following steps: Step S1, preparing porous hydrogel microspheres, quaternary ammonium polysaccharide adhesive functional molecular chains, ammonium sulfonate zwitterionic monomers, amide monomers, initiators, crosslinking agents and deionized water in proportion, and stirring until the solution is evenly mixed to obtain 3D direct writing ink; Step S2, spin coating polydimethylsiloxane prepolymer on the glass, stirring and spreading it thoroughly, and placing it in an oven at 70-90° C. for curing to complete the preparation of the flexible substrate layer; Step S3, peeling the flexible substrate layer from the glass, attaching the PVC mask layer and obtaining a stretchable conductive layer by laser engraving to form a flexible device; Step S4, add benzophenone solution to the flexible device, treat for 5-10 minutes, inject 3D direct writing ink into the 3D direct writing nozzle, place the flexible device under the 3D direct writing nozzle for direct writing, adjust the pressure to 50-400 kPa and the printing speed to 20-40 mm s −1 After the patterning direct writing is completed, UV curing is performed for 1-2 hours to finally obtain a viscosity-adjustable hydrogel electrode for the diagnosis of peripheral nerve diseases.

[0016] The beneficial effects of the present invention are: 1. In the present invention, the direct-written hydrogel interface layer is used to directly contact and adhere to human skin tissue. The direct-written hydrogel interface layer, which is composed of porous hydrogel microspheres, quaternary ammonium polysaccharide adhesion functional molecular chains, ammonium sulfonate zwitterionic monomers, amide monomers, initiators, and crosslinkers, will change its viscosity correspondingly when the temperature changes. The viscosity can be regulated by controlling the temperature to achieve stable attachment and detachment from skin tissue. In particular, the components of the direct-written hydrogel interface layer are conducive to making 3D direct-writing ink, which is manufactured by 3D printing. This viscosity-tunable hydrogel electrode has excellent flexibility and conductivity, high manufacturing efficiency, provides high-fidelity nerve signal acquisition while ensuring cost reduction, avoids cross-infection of patients, and has the requirements of constant and continuous high-quality signal acquisition, high stretchability, and adjustable viscosity. In particular, it is suitable for use in the diagnosis of upper limb nerve diseases.

[0017] 2. In the present invention, the synthesized porous hydrogel microspheres have a shorter heating time for synthesis and smaller synthesized microspheres, and can be directly used for printing. Description of the Drawings Figure 1 It is a schematic diagram of the viscosity-tunable hydrogel electrode for diagnosing peripheral nerve diseases in the embodiment of the present invention.

[0018] Figure 2 It is a process flow chart of the preparation method of the viscosity-tunable hydrogel electrode for diagnosing peripheral nerve diseases in the embodiment of the present invention; Figure 3 It is a preparation flow chart of the porous hydrogel microspheres in the embodiment of the present invention.

[0019] Figure 4 It is a rheological property diagram of the porous hydrogel microspheres in the embodiment of the present invention.

[0020] Figure 5 It is a schematic diagram of the direct-written hydrogel interface layer in the embodiment of the present invention.

[0021] Figure 6 It is a schematic diagram of the viscosity regulation principle of the viscosity-tunable hydrogel electrode for diagnosing peripheral nerve diseases in the embodiment of the present invention; Figure 7 It is a working schematic diagram of the viscosity-tunable hydrogel electrode for diagnosing peripheral nerve diseases in the embodiment of the present invention.

[0022] Figure 8 It is a monitoring schematic diagram of the viscosity-tunable hydrogel electrode for diagnosing peripheral nerve diseases in the embodiment of the present invention.

[0023] In the figure: 1 - flexible base layer; 2 - stretchable conductive layer; 3 - direct-written hydrogel interface layer; 4 - 3D direct-written ink; 5 - 3D direct-writing nozzle; 7 - PVC mask layer; 8 - N-isopropylacrylamide-polyaspartic acid prepolymer solution; 9 - beaker; 10 - glass rod; 11 - magnetic stirring table; 12 - three-necked flask; 13 - magnetic stir bar; 14 - dropper; 16 - test tube; 17 - poly(N-isopropylacrylamide)-polyaspartic acid (PNIPAM-PASP) microspheres; 18 - shaker; 19 - centrifuge; 20 - glass petri dish; 21 - freeze dryer; 22 - cooling viscosity change curve of porous hydrogel microspheres; 23 - heating viscosity change curve of porous hydrogel microspheres; 24 - hydrogen bond, 25 - electrostatic coupling; 26 - physical crosslinking; 27 - covalent crosslinking; 28 - hydration layer; 29 - proximal end of the radial nerve groove; 30 - distal end of the elbow; 31 - radial nerve; 32 - reference electrode; 33 - recording electrode; 34 - nerve signal collected by the hydrogel epidermal electrode; 35 - nerve signal collected by the commercial electrode; 3-1 - poly(N-isopropylacrylamide) (PNIPAM) microspheres; 3-2 - molecular chain of methacryloylethyl sulfobetaine (SBMA); 3-3 - molecular chain of polyquaternary ammonium chitosan-3,4,5-trihydroxybenzoic acid (QCS-GA); 3-4 - water molecules; 6-1 is glass; 6-2 is a polymethyl methacrylate (PMMA) mold; 15-1 - nitrogen direction; 15-2 - nitrogen. Specific embodiments

[0024] In order to make the objectives, technical solutions and advantages of the present invention clearer, the present invention will be further described in detail below with reference to the accompanying drawings and embodiments. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not used to limit the present invention.

[0025] In the description of the present invention, it should be understood that if there are terms such as "center", "longitudinal", "transverse", "length", "width", "thickness", "upper", "lower", "front", "rear", "left", "right", "vertical", "horizontal", "top", "bottom", "inner", "outer", "clockwise", "counterclockwise", etc., the orientation or positional relationship indicated is based on the orientation or positional relationship shown in the drawings. It is only for the convenience of describing the present invention and simplifying the description, rather than indicating or implying that the device or element referred to must have a specific orientation, be constructed and operated in a specific orientation. Therefore, it should not be construed as a limitation to the present invention. In addition, the terms "first" and "second" are only used for descriptive purposes and cannot be understood as indicating or implying relative importance or implicitly specifying the quantity of the indicated technical features. Thus, the features defined with "first" and "second" may explicitly or implicitly include one or more of the said features. In the description of the present invention, "a plurality" means two or more unless otherwise specifically defined.

[0026] In the description of the present invention, it should be noted that unless otherwise clearly defined and limited, the terms "mounted", "connected" and "coupled" should be understood in a broad sense. For example, it may be a fixed connection, a detachable connection or an integral connection. It may be a mechanical connection or an electrical connection. It may be directly connected or indirectly connected through an intermediate medium, and it may be the communication inside two elements or the interaction relationship between two elements. For those of ordinary skill in the art, the specific meanings of the above terms in the present invention can be understood according to specific circumstances.

[0027] Example 1 A viscosity-adjustable hydrogel electrode for diagnosing peripheral nerve diseases, comprising a flexible base layer 1, a direct-written hydrogel interface layer 3, and a stretchable conductive layer 2 containing electrodes. The flexible base layer 1 serves as the flexible framework base of the electrode. The stretchable conductive layer 2 is disposed on the flexible base layer 1. The direct-written hydrogel interface layer 3 is disposed on the flexible base layer and covers the stretchable conductive layer 2. The direct-written hydrogel interface layer 3 is used to directly contact and adhere to human skin tissue. The viscosity of the direct-written hydrogel interface layer 3 changes correspondingly when the temperature changes, and the viscosity can be regulated by controlling the temperature to achieve stable attachment and peeling from the skin tissue. The stretchable conductive layer 2 contains electrodes and is located below the direct-written hydrogel interface layer 3. It has excellent stretchability and conductivity, can achieve conformal attachment to the skin to be measured, and improve the anti-motion artifact ability of the electrode. Among them, the components of the direct-written hydrogel interface layer 3 include porous hydrogel microspheres 3-1, quaternary ammonium-based polysaccharide adhesive functional molecular chains 3-2, ammonium sulfonate-based zwitterionic monomers, amide monomers, initiators, and crosslinkers.

[0028] Furthermore, the 3D direct writing ink 4 composed of the components forming the direct writing hydrogel interface layer 3 (i.e., porous hydrogel microspheres 3-1, quaternary ammonium polysaccharide sticky functional molecular chains 3-2, ammonium sulfonate zwitterionic monomers, amide monomers, initiators, and crosslinkers) is patterned into a fixed shape by a 3D direct writing nozzle 5 and polymerized by ultraviolet initiation to form the direct writing hydrogel interface layer 3; the direct writing hydrogel interface layer has high precision and high signal fidelity, and can achieve conformal attachment to the skin to be measured and stable high-quality nerve signal acquisition.

[0029] Among them, as Figure 4 shown, the porous hydrogel microspheres 3-1 in the components combine with deionized water at room temperature, increasing the viscosity of the 3D direct writing ink 4 to achieve 3D direct writing; the dynamic combination and recombination of the porous hydrogel microspheres 3-1 and water molecules 3-4 under temperature changes will directly affect the viscosity of the 3D direct writing ink 4. At high temperatures, the hydrogen bonds between the porous hydrogel microspheres 3-1 and water molecules 3-4 in the 3D direct writing ink 4 break, the porous hydrogel microspheres 3-1 shrink, and the viscosity of the 3D direct writing ink 4 decreases while the fluidity increases. At low temperatures, hydrogen bonds are formed between the porous hydrogel microspheres 3-1 and water molecules 3-4 in the 3D direct writing ink 4, the porous hydrogel microspheres 3-1 absorb water and swell, and the viscosity of the 3D direct writing ink 4 increases while the fluidity decreases. Furthermore, at room temperature, the 3D direct writing ink 4 containing porous hydrogel microspheres 3-1 has strong viscosity and weak fluidity, which is easy to complete high-precision hydrogel manufacturing by 3D direct writing. After the hydrogel is formed, the temperature is raised, the porous hydrogel microspheres 3-1 shrink, and a hydration layer 28 appears at the interface to achieve viscosity regulation.

[0030] Furthermore, the diameter of the 3D direct writing nozzle 5 is 160 μm - 210 μm, the applied pressure is set to 50 - 400 kPa, and the printing speed is 20 - 40 mm s −1 , the 3D direct writing ink 4 has a viscosity of 4×10 -1 -7×10 3 -7×10 4 Pa·s at a shear rate of 0.01 s

[0031] Furthermore, the porous hydrogel microspheres 3-1 are poly N-isopropylacrylamide-based / carboxyl-based microspheres.

[0032] Furthermore, the quaternary ammonium polysaccharide sticky functional molecular chain 3-2 is formed by grafting 3,4,5-trihydroxybenzoic acid and / or 3,4,5-trihydroxybenzoic acid derivatives onto quaternary ammonium chitosan and / or quaternary ammonium chitosan derivatives.

[0033] The derivatives of quaternary ammonium chitosan in the ammonium-based polysaccharide adhesive functional molecular chain 3-2 can be one or more, and the derivatives of 3,4,5-trihydroxybenzoic acid in the ammonium-based polysaccharide adhesive functional molecular chain 3-2 can be one or more.

[0034] Further, the stretchable conductive layer is an EEC conductive composite material composed of cured conductive silver paste. The conductive silver paste is formed by mixing micron-scale silver flakes and polydimethylsiloxane (PDMS) in a ratio of 2:1.

[0035] The material of the flexible base layer 1 is polydimethylsiloxane.

[0036] Further, in the direct-write hydrogel interface layer 3, the mass fractions of the porous hydrogel microspheres 3-1, quaternary ammonium polysaccharide adhesive functional molecular chains 3-2, ammonium sulfonate zwitterionic monomers, amide monomers, initiators, and crosslinkers are 10 wt%-33 wt%, 10 wt%-15 wt%, 10 wt%-15 wt%, 10 wt%-20 wt%, 5 wt%-10 wt%, 0.01 wt%-0.05 wt%, and 0.02 wt%-0.1 wt% respectively, and the balance is water. Among them, the ammonium sulfonate zwitterionic monomer is methacryloylethyl sulfobetaine, the amide monomer is any one or more of acrylamide, N,N-dimethylacrylamide monomers and their derivatives, the crosslinker is one or more of N,N'-methylenebisacrylamide and poly(ethylene glycol) acrylate, and the initiator is one or more of α-ketoglutaric acid, Irgacure1173, and Irgacure3279.

[0037] Further, the poly N-isopropylacrylamide-based / carboxyl microspheres are obtained by inverse emulsion polymerization.

[0038] Further, the poly N-isopropylacrylamide-based / carboxyl microspheres are obtained by polymerizing carboxyl-based macromolecular chains with N-isopropylacrylamide monomers.

[0039] The N-isopropylacrylamide monomers are one or more of N-isopropylacrylamide monomers and their derivatives, and the carboxyl-based macromolecular chains are any one or more of polyaspartic acid, alginic acid, and their derivatives.

[0040] Further, the mass fractions of the N-isopropylacrylamide monomers and carboxyl-based macromolecular chains in the porous hydrogel microspheres 3-1 are 15 wt%-20 wt% and 2.5 wt%-5 wt% respectively.

[0041] Further, the mass fractions of quaternary ammonium chitosan and / or its derivatives and 3,4,5-trihydroxybenzoic acid and / or its derivatives in the ammonium polysaccharide adhesive functional molecular chain 3-2 are 40 wt%-50 wt% and 5 wt%-10 wt% respectively.

[0042] As Figure 3 shown, the preparation method of the porous hydrogel microspheres 3-1 is as follows: S311, Dissolve 10 mmol-20 mmol of N-isopropylacrylamide monomers and 2 mmol-4 mmol of carboxyl macromolecular chains in a beaker 9 containing 5-10 ml of deionized water, and use a glass rod 10 to stir well until the solution is evenly mixed, then add it to 50-100 ml of cyclohexane, and degas for 0.5-1 h to obtain an N-isopropylacrylamide-polyaspartic acid prepolymer solution 8.

[0043] S312, Add 50-100 ml of cyclohexane and 3-5 ml of a potassium persulfate APS solution with a concentration mass fraction of 0.02-0.04 wt% to the above solution in a three-necked flask 12, stir magnetically until evenly mixed, then continuously stir the solution and heat it in a water bath for 1 h, where the rotation speed of the magnetic stirrer 13 is 500-1500 r / min. Dropwise add the N-isopropylacrylamide-polyaspartic acid prepolymer solution 8 through a dropper 14, then degas the three-necked flask 12 with nitrogen 15-2 for 10 min, carry out a water bath at 60-80 °C and continuously stir magnetically for 3-5 h, and finally polymerize to obtain poly-N-isopropylacrylamide-polyaspartic acid (PNIPAM-PASP) microspheres 17; S313, Pour off the supernatant of the three-necked flask 12, then add 50-100 ml of absolute ethanol to the poly-N-isopropylacrylamide-polyaspartic acid (PNIPAM-PASP) microspheres 17, pour them into a test tube 16 in batches and place them on a shaker 18 set at 800 r / min for shaking for 5-10 min, pour them into a centrifuge 19 set at 5000-10000 r / min for centrifugation for 5-10 min, and then take the precipitate for standby; S314, Pour the above bottom precipitate into a beaker 9 and add 50-100 ml of deionized water, pour it into a test tube 16 in batches and shake it at 800 r / min for 5-10 min, pour it into a test tube 16 in batches and place it on a shaker 18 set at 800 r / min for shaking for 5-10 min, pour it into a centrifuge 19 set at 5000-10000 r / min for centrifugation for 5-10 min, then take the precipitate and add it to a glass petri dish 20 and place it in a freeze dryer 21 for freeze-drying at -35—45 °C for 12-26 h, and finally obtain poly-N-isopropylacrylamide-polyaspartic acid (PNIPAM-PASP) microspheres 17.

[0044] The preparation method of the ammonium-based polysaccharide sticky functional molecular chain 3-2 is as follows: S321. Dissolve 5 mmol - 10 mmol of quaternary ammonium salt chitosan and / or derivatives in beaker 9 containing 100 - 150 ml of 2-morpholinoethanesulfonic acid solution. Add sodium hydroxide to beaker 9 to adjust the pH value to 5.0 - 6.0. Place it on the magnetic stirring table 11 for magnetic stirring, where the rotation speed of the magnetic stirrer 13 is 500 - 1000 r / min until the solution is evenly mixed, and degas for 0.5 - 1 h; S322. Add 1 - 3 mmol of 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride, 1 - 3 mmol of N-hydroxysuccinimide, and 1 - 3 mmol of ascorbic acid to beaker 9. Add 2 - 5 ml of absolute ethanol to beaker 9. Add sodium hydroxide to adjust the pH value of the above solution to 5.0 - 6.0 and keep the magnetic stirring always on until the solution is evenly mixed; S323. Dropwise add the quaternary ammonium salt chitosan solution to beaker 9 obtained in the above step S322, degas for 0.5 - 1 h, and place it on the magnetic stirring table 11 for magnetic stirring for 10 - 15 h; S324. Pour the solution in beaker 9 obtained in the above step S323 into a dialysis bag, completely immerse it in deionized water, and place it on the magnetic stirring table 11 with the magnetic stirring continuously on, where the rotation speed of the magnetic stirrer 13 is 332 - 500 r / min. After dialysis for 48 - 72 h, take out the solution in the dialysis bag and add it to the freeze dryer 21 for freeze-drying at -35 - 45 °C for 12 - 26 h to obtain the polyquaternary ammonium salt chitosan-3,4,5-trihydroxybenzoic acid (QCS-GA) molecular chain 3-3.

[0045] Example 2 A preparation method for a viscosity-adjustable hydrogel electrode used for diagnosing peripheral nerve diseases in Example 1 includes the following steps: S1. Add the poly(N-isopropylacrylamide)-polyaspartic acid (PNIPAM-PASP) microspheres 17 to beaker 9, and add deionized water (the mass ratio of poly(N-isopropylacrylamide)-polyaspartic acid (PNIPAM-PASP) microspheres 17 to deionized water is 1:6), the polyquaternary ammonium salt chitosan-3,4,5-trihydroxybenzoic acid (QCS-GA) molecular chain 3-3, methacryloylethyl sulfobetaine, acrylamide, N,N'-methylenebisacrylamide, and Irgacure3279. After magnetic stirring until uniform, make it into 3D direct writing ink 4; S2. Use an ultrasonic cleaner to thoroughly clean the glass 6-1 substrate for 10 min. After drying it with nitrogen for 5 min, use a spin coater to spin coat a polydimethylsiloxane (PDMS) prepolymer solution (the mass ratio of prepolymer to curing agent is 10:1) at 332 - 500 r / min. Let it stand for 5 min to allow it to spread evenly, and then place it in an oven at 70 °C for 60 min to complete the flexible base layer 1. S3. After peeling the flexible base layer 1 from the glass 6-1 substrate, attach a 0.3-mm-thick PVC mask layer 7 and perform patterning treatment on it using a laser engraver (power 40 w, speed 33 - 50 mm / s). Use the screen printing process to pattern-print the ECC conductive composite material on the flexible base layer 1, and then place it in an oven at 160 °C for 1 h. After peeling off the PVC mask layer 7, obtain the stretchable conductive layer 2 to form the flexible device. S4. Immerse the above flexible device in a 95% benzophenone solution (the mass ratio of ethanol to benzophenone is 95:5) for 5 - 10 min. Attach a square polymethyl methacrylate (PMMA) 6-2 mold around the flexible device and place it under the 3D direct writing nozzle 5 (select an 180-μm nozzle, set the air pressure to 150 kPa and the printing speed to 33 mm s −1 ), and use the 3D direct writing ink 4 for 3D direct writing. After ultraviolet curing at 365 nm for one hour, remove the polymethyl methacrylate (PMMA) 6-2 mold to form the direct-written hydrogel interface layer 3, and thus obtain the sticky-adjustable hydrogel electrode.

[0046] The structure of the formed direct-written hydrogel interface layer 3 is as Figure 5 shown, where 3-1 is poly(N-isopropylacrylamide) (PNIPAM) microspheres, 3-2 is the molecular chain of methacryloylethyl sulfobetaine (SBMA), 3-3 is the molecular chain of polyquaternary ammonium salt chitosan-3,4,5-trihydroxybenzoic acid (QCS-GA), and 3-4 is water molecules.

[0047] Working principle of the present invention: The direct-write hydrogel interface layer patterns 3D direct-write ink through a 3D direct-write nozzle under appropriate applied pressure and printing speed conditions and then undergoes ultraviolet curing crosslinking to obtain a hydrogel electrode. Among them, the components of the direct-write hydrogel interface layer include porous hydrogel microspheres, quaternary ammonium group polysaccharide adhesive functional molecular chains, ammonium sulfonate zwitterionic monomers, amide monomers, initiators, and crosslinking agents. After the above components are mechanically stirred evenly, 3D direct-write ink with appropriate shear rate and viscosity is obtained. The porous hydrogel microspheres combine with deionized water at room temperature to increase the viscosity of the 3D direct-write ink, thereby realizing 3D direct writing. The direct-write hydrogel interface layer is used to adhere to the skin to be measured of the diseased nerve of the patient. At this time, the temperature of the direct-write hydrogel interface layer is relatively low, and N-isopropylacrylamide in the porous hydrogel microspheres 3-1 shows a hydrophilic state and forms hydrogen bonds 24 with water molecules 3-4. The quaternary ammonium group polysaccharide adhesive functional molecular chains 3-3 and ammonium sulfonate zwitterionic monomers 3-2 in the direct-write hydrogel interface layer 3 establish electrostatic bonds 25, Schiff bases, Michael addition reactions, and hydrogen bonds 24 with the skin to be measured, realizing the stable attachment of the direct-write hydrogel interface layer 3 to the skin to be measured; when the electromyogram of the diseased nerve of the patient is collected, the direct-write hydrogel interface layer 3 is heated, and N-isopropylacrylamide in the porous hydrogel microspheres shows a hydrophobic state and generates a hydration layer 28. The electrostatic bonds 25, Schiff bases, Michael addition reactions, and hydrogen bonds 24 between the direct-write hydrogel interface layer 3 and the skin to be measured are destroyed, and the viscosity is reduced, realizing the benign peeling of the viscosity-adjustable hydrogel electrode.

[0048] As Figure 8 shown, the nerve signal 34 collected by the viscosity-adjustable hydrogel electrode has lower noise and stronger signal stability, while the fidelity of the nerve signal 35 collected by the commercial electrode is relatively low. Therefore, the viscosity-adjustable hydrogel electrode has excellent collection performance and stability in the diagnosis of upper limb nerve diseases.

[0049] The viscosity-adjustable hydrogel electrode of the present invention can adjust the hydrophilic and hydrophobic states of the porous hydrogel microspheres by adjusting the temperature, realize the establishment and destruction of the interfacial hydration layer, thereby realizing the adjustability of chemical adhesion and physical adhesion between the interfaces, and further ensuring the rapid regulation of viscosity and seamless attachment to the diseased nerve when collecting nerve signals, improving the signal quality. After the nerve signal is collected, the viscosity-adjustable hydrogel electrode is cooled to realize benign peeling from the skin tissue, avoiding skin damage to the patient; The viscosity - adjustable hydrogel electrode of the present invention realizes the increase in the viscosity of the 3D direct - writing ink by adjusting the ratio of porous hydrogel microspheres to deionized water at room temperature, thereby achieving high - efficiency 3D direct - writing. The manufacturing process is efficient and has high efficiency. Compared with the traditional casting process, it has high manufacturing accuracy, stable signal acquisition performance, and uniform cross - link density, and is easy to be applied in large - scale industrial reproduction. At the same time, by modifying the ammonium - based polysaccharide sticky functional molecular chain, the viscosity of the viscosity - adjustable hydrogel electrode is significantly improved. Furthermore, when collecting nerve signals, it can be seamlessly attached to the skin to be measured, improving signal fidelity, reducing the diagnosis and treatment cost of patients, and avoiding cross - infection. The direct - writing hydrogel interface layer provided by the present invention significantly improves its viscosity by modifying zwitterionic groups and catechol groups, and establishing electrostatic bonds, Schiff bases, Michael addition reactions, and hydrogen bonds with the skin to be measured respectively. In the 3D direct - writing ink provided by the present invention, porous hydrogel microspheres form hydrogen bonds with water molecules, thereby absorbing water and increasing the volume of the porous hydrogel microspheres, changing the rheology, and then achieving the rheological properties required for 3D direct - writing ink and realizing 3D direct - writing.

[0050] The direct - writing hydrogel interface layer provided by the present invention has excellent biocompatibility and can realize long - term monitoring of nerve electrical signals without causing adverse reactions in skin tissues.

[0051] The usage method of the viscosity - adjustable hydrogel electrode in this embodiment is as Figure 7 shown: The radial nerve, as a representative nerve of the upper - limb nerves, its nerve diseases are common in clinical scenarios. This embodiment takes the radial nerve as an example to show the usage method of the viscosity - adjustable hydrogel electrode. During the process of measuring the diseased nerve of a patient, the viscosity - adjustable hydrogel electrode is divided into positive and negative electrodes and attached together to the proximal 29 of the radial nerve groove and the distal 30 of the elbow. Among them, the positive electrode is close to the proximal end, and the negative electrode is close to the distal end. The interface layer absorbs environmental water and establishes chemical adhesion and physical adhesion with the skin tissue. Then, two viscosity - adjustable hydrogel electrodes are taken and attached to the recording electrode 32 and the reference electrode 33, and a viscosity - adjustable hydrogel electrode is directly attached between the recording electrode 32 and the reference electrode 33 as the ground electrode. First, a voltage is applied to the positive and negative electrodes at the proximal 29 of the radial nerve groove, and the nerve signals of the recording electrode 32 are recorded. Then, a voltage is applied to the positive and negative electrodes at the distal 30 of the elbow and the nerve signals are recorded. Based on the two nerve signals, the latency, conduction velocity, and amplitude of the motor nerve of the radial nerve can be measured. After the recording is completed, the temperature of the direct - writing hydrogel interface layer of all the used hydrogel electrodes is increased to generate a hydrated layer 28, and the chemical adhesion and physical adhesion of the interface layer are reduced, and finally, a benign peeling is achieved.

[0052] After the direct - writing hydrogel interface layer 3 is heated to 38 - 42 °C, the porous hydrogel microspheres 3 - 1 enter the hydrophobic state, thereby realizing benign peeling from the skin tissue. The heating of the direct - writing hydrogel interface layer 3 can be achieved by an external heat source.

[0053] It should be noted that in this text, relational terms such as first and second are only used to distinguish one entity or operation from another entity or operation, and do not necessarily require or imply any actual relationship or order between these entities or operations. Moreover, the terms "comprising", "including" or any other variant thereof are intended to cover non-exclusive inclusion, so that a process, method, article or device comprising a series of elements not only includes those elements, but also includes other elements not expressly listed, or further includes elements inherent to such process, method, article or device.

[0054] It should be understood that those of ordinary skill in the art can make improvements or modifications based on the above description, and all such improvements and modifications shall fall within the protection scope of the appended claims of the present invention.

Claims

1. A viscosity-adjustable hydrogel electrode for peripheral nerve disease diagnosis, characterized in that: The invention comprises a flexible substrate layer (1), a direct-writing hydrogel interface layer (3) and a stretchable conductive layer (2) comprising an electrode, wherein the stretchable conductive layer (2) is arranged on the flexible substrate layer (1), the direct-writing hydrogel interface layer is arranged on the flexible substrate layer and covers the stretchable conductive layer (2), and the direct-writing hydrogel interface layer is used for directly contacting and adhering to human skin tissue; The components of the direct writing hydrogel interface layer include porous hydrogel microspheres (3-1), quaternary ammonium polysaccharide adhesive functional molecular chains (3-2), ammonium sulfonate zwitterionic monomers, amide monomers, initiators and crosslinking agents.

2. The viscosity-adjustable hydrogel electrode for peripheral nerve disease diagnosis according to claim 1, characterized in that: The components forming the direct writing hydrogel interface layer are combined with deionized water to form a 3D direct writing ink (4), which is patterned into a fixed shape by a 3D direct writing nozzle (5), and is polymerized by ultraviolet initiation to form the direct writing hydrogel interface layer (3).

3. The viscosity-adjustable hydrogel electrode for peripheral nerve disease diagnosis according to claim 1, characterized in that: The porous hydrogel microspheres (3-1) are poly (N-isopropylacrylamide) / carboxyl-based microspheres.

4. The viscosity-adjustable hydrogel electrode for peripheral nerve disease diagnosis according to claim 1, characterized in that: The ammonium polysaccharide adhesive functional molecular chain (3-2) is formed by grafting 3,4,5-trihydroxybenzoic acid and / or 3,4,5-trihydroxybenzoic acid derivatives onto quaternary ammonium salt chitosan and / or quaternary ammonium salt chitosan derivatives.

5. The viscosity-adjustable hydrogel electrode for peripheral nerve disease diagnosis according to claim 1, characterized in that: In the direct-writing hydrogel interface layer, the mass fractions of the porous hydrogel microspheres (3-1), the quaternary ammonium polysaccharide adhesive functional molecular chains (3-2), the ammonium sulfonate zwitterionic monomers, the amide monomers, the initiator and the cross-linking agent are 10 wt%-33 wt%, 10 wt%-15 wt%, 10 wt%-15 wt%, 10 wt%-20 wt%, 5 wt%-10 wt%, 0.01 wt%-0.05 wt%, and 0.02wt%-0.1 wt%, respectively.

6. The viscosity-adjustable hydrogel electrode for peripheral nerve disease diagnosis according to claim 3, characterized in that: The poly N-isopropylacrylamide / carboxyl microspheres are obtained by polymerizing carboxyl macromolecular chains and N-isopropylacrylamide monomers.

7. The viscosity-adjustable hydrogel electrode for peripheral nerve disease diagnosis according to claim 6, characterized in that: The mass fractions of N-isopropylacrylamide monomers and carboxyl macromolecular chains in the porous hydrogel microspheres (3-1) are 15 wt%-20 wt% and 2.5 wt%-5 wt%, respectively.

8. The viscosity-adjustable hydrogel electrode for peripheral nerve disease diagnosis according to claim 4, characterized in that: The mass fractions of quaternary ammonium salt chitosan and / or its derivatives and 3,4,5-trihydroxybenzoic acid and / or its derivatives in the ammonium polysaccharide adhesive functional molecular chain (3-2) are 40 wt%-50 wt% and 5 wt%-10 wt%, respectively.

9. The viscosity-adjustable hydrogel electrode for peripheral nerve disease diagnosis according to claim 1, characterized in that: The preparation method of the porous hydrogel microspheres (3-1) is as follows: S311. The N-isopropyl acrylamide monomer and the carboxyl macromolecular chain are dissolved in deionized water, stirred until the solution is uniformly mixed, and then added to cyclohexane and degassed; S312. A potassium persulfate solution is added to the above solution, and the solution is stirred evenly and then heated in a water bath for a certain period of time, and finally polymerized to obtain poly-N-isopropylacrylamide / carboxyl microspheres; S313. The poly (N-isopropylacrylamide) / carboxyl microspheres are added to anhydrous ethanol and shaken, poured into a centrifuge for centrifugation, and then the bottom precipitate of the solution is taken; S314. The bottom precipitate is added to deionized water and shaken, poured into a centrifuge for centrifugation to obtain a poly N-isopropylacrylamide / carboxyl microsphere solution, added to a freeze dryer for freeze drying to obtain a poly N-isopropylacrylamide / carboxyl microsphere; The preparation method of the ammonium polysaccharide adhesive functional molecular chain (3-2) is: S321. The quaternary ammonium chitosan and / or its derivatives are dissolved in a 2-morpholineethanesulfonic acid solution, sodium hydroxide is added to the solution to adjust the pH value to 5.0-6.0, magnetic stirring is performed until the solution is uniformly mixed, and degassed to obtain a quaternary ammonium chitosan solution; S322. 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride, N-hydroxysuccinimide and ascorbic acid are added to the 2-morpholineethanesulfonic acid solution, anhydrous ethanol is added to the solution, sodium hydroxide is added to adjust the pH value of the solution to 5.0-6.0, and magnetic stirring is performed until the solution is uniformly mixed; S323. The mixed solution obtained in step S322 is added dropwise to the quaternary ammonium chitosan solution, and after degassing, stirred for a certain period of time; S324. Place the solution obtained in the above step S323 in a dialysis bag, completely immerse it in deionized water and turn on magnetic stirring. After dialysis for a certain period of time, take out the solution in the dialysis bag and add it to a freeze dryer for freeze drying to obtain quaternary ammonium polysaccharide sticky functional molecular chains.

10. A method for preparing a viscosity-adjustable hydrogel electrode for peripheral nerve disease diagnosis as claimed in any one of claims 1 to 9, characterized in that: The steps include: The porous hydrogel microspheres (3-1), the quaternary ammonium polysaccharide adhesive functional molecular chains (3-2), the ammonium sulfonate zwitterionic monomers, the amide monomers, the initiator, the crosslinking agent and the deionized water are mixed in proportion and stirred until the solution is uniformly mixed to obtain the 3D direct writing ink (4); The flexible substrate layer (1) is attached to the mask layer and a stretchable conductive layer (2) is obtained by laser engraving to form a flexible device; After dropping benzophenone solution into the flexible device, 3D direct writing ink (4) is injected into the 3D direct writing nozzle (5), and the flexible device is placed under the 3D direct writing nozzle (5) for direct writing. After the patterned direct writing is completed, ultraviolet curing is performed to finally obtain a hydrogel electrode with adjustable viscosity for peripheral nerve disease diagnosis.

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