WO2023045126A1 - 一种喷射原位生成的微创神经接口及其制备方法和应用 - Google Patents

一种喷射原位生成的微创神经接口及其制备方法和应用 Download PDF

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WO2023045126A1
WO2023045126A1 PCT/CN2021/138563 CN2021138563W WO2023045126A1 WO 2023045126 A1 WO2023045126 A1 WO 2023045126A1 CN 2021138563 W CN2021138563 W CN 2021138563W WO 2023045126 A1 WO2023045126 A1 WO 2023045126A1
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layer
conductive
self
conductive particles
dispersion
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French (fr)
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都展宏
沙葆凝
赵生卓
程宇航
赵冠楠
毕国强
王立平
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中国科学院深圳先进技术研究院
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/24—Detecting, measuring or recording bioelectric or biomagnetic signals of the body or parts thereof
    • A61B5/316—Modalities, i.e. specific diagnostic methods
    • A61B5/388—Nerve conduction study, e.g. detecting action potential of peripheral nerves
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/24—Detecting, measuring or recording bioelectric or biomagnetic signals of the body or parts thereof
    • A61B5/25—Bioelectric electrodes therefor
    • A61B5/263—Bioelectric electrodes therefor characterised by the electrode materials
    • A61B5/268—Bioelectric electrodes therefor characterised by the electrode materials containing conductive polymers, e.g. PEDOT:PSS polymers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/24—Detecting, measuring or recording bioelectric or biomagnetic signals of the body or parts thereof
    • A61B5/25—Bioelectric electrodes therefor
    • A61B5/279—Bioelectric electrodes therefor specially adapted for particular uses
    • A61B5/294—Bioelectric electrodes therefor specially adapted for particular uses for nerve conduction study [NCS]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/40—Detecting, measuring or recording for evaluating the nervous system
    • A61B5/4076—Diagnosing or monitoring particular conditions of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N1/00—Electrotherapy; Circuits therefor
    • A61N1/02—Details
    • A61N1/04—Electrodes
    • A61N1/0404—Electrodes for external use
    • A61N1/0408—Use-related aspects
    • A61N1/0456—Specially adapted for transcutaneous electrical nerve stimulation [TENS]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N1/00—Electrotherapy; Circuits therefor
    • A61N1/02—Details
    • A61N1/04—Electrodes
    • A61N1/0404—Electrodes for external use
    • A61N1/0472—Structure-related aspects
    • A61N1/0492—Patch electrodes
    • A61N1/0496—Patch electrodes characterised by using specific chemical compositions, e.g. hydrogel compositions, adhesives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N1/00—Electrotherapy; Circuits therefor
    • A61N1/18—Applying electric currents by contact electrodes
    • A61N1/32—Applying electric currents by contact electrodes alternating or intermittent currents
    • A61N1/36—Applying electric currents by contact electrodes alternating or intermittent currents for stimulation
    • A61N1/3605—Implantable neurostimulators for stimulating central or peripheral nerve system
    • A61N1/3606—Implantable neurostimulators for stimulating central or peripheral nerve system adapted for a particular treatment
    • A61N1/36103—Neuro-rehabilitation; Repair or reorganisation of neural tissue, e.g. after stroke
    • H—ELECTRICITY
    • H01—ELECTRIC ELEMENTS
    • H01B—CABLES; CONDUCTORS; INSULATORS; SELECTION OF MATERIALS FOR THEIR CONDUCTIVE, INSULATING OR DIELECTRIC PROPERTIES
    • H01B1/00—Conductors or conductive bodies characterised by the conductive materials; Selection of materials as conductors
    • H01B1/14—Conductive material dispersed in non-conductive inorganic material
    • H—ELECTRICITY
    • H01—ELECTRIC ELEMENTS
    • H01B—CABLES; CONDUCTORS; INSULATORS; SELECTION OF MATERIALS FOR THEIR CONDUCTIVE, INSULATING OR DIELECTRIC PROPERTIES
    • H01B1/00—Conductors or conductive bodies characterised by the conductive materials; Selection of materials as conductors
    • H01B1/20—Conductive material dispersed in non-conductive organic material
    • H—ELECTRICITY
    • H01—ELECTRIC ELEMENTS
    • H01B—CABLES; CONDUCTORS; INSULATORS; SELECTION OF MATERIALS FOR THEIR CONDUCTIVE, INSULATING OR DIELECTRIC PROPERTIES
    • H01B13/00—Apparatus or processes specially adapted for manufacturing conductors or cables

Definitions

  • the invention belongs to the field of medical detection elements, and in particular relates to a minimally invasive nerve interface generated in situ by spraying, a preparation method and application thereof.
  • Neural interface is an interface for the interaction between external artificial equipment and the nervous system information of organisms. It can be used to measure nerve signals and detect diseases. In particular, it has good prevention and treatment effects on inflammation and degenerative diseases of the nervous system. Ability to diagnose early. At the same time, the neural interface can also be used to stimulate the nervous system. According to the different purposes of the incoming stimulation, common ones include controlling muscles, stimulating the visual cortex, stimulating the auditory cortex, stimulating the tactile cortex, and stimulating temperature receptors. In addition, there is a class of neural interfaces that are mainly used for therapy and repair. After common injuries such as crush and pull injuries, nerves will show a more active tendency to repair through stimulation with a certain frequency and current.
  • Neural interfaces in the current state of the art include traditional invasive electrodes and traditional non-invasive interfaces.
  • the traditional invasive electrodes include a nerve cuff, which consists of one or more electrodes located on an insulating substrate. The substrate is prevented and treated by surgical operations, and the electrode exit point surrounds the nerve outer surface of the nerve trunk. While this approach allows for very direct integration with the target nerve, multiple points of failure and the complexity of the implantation procedure increase surgical risk and cost and can lead to substantial variability in the effectiveness of peripheral nerve interfaces.
  • the traditional non-invasive interface is not invasive, its nerve stimulation and recording cannot be used for fine nervous system function regulation due to the high signal noise and poor traceability.
  • a neural interface generated in situ by injection and a system for preparing the neural interface generated in situ by injection are provided.
  • the neural interface provided by the present invention can realize the in situ generation of neural interface in vivo by colloid injection , to solve the problem of excessive damage and slow recovery during the traditional nerve interface implantation process; at the same time, it can also solve the problem that small nerves cannot be implanted through surgery or the surgery is too complicated.
  • One aspect of the present invention provides a neural interface generated in situ by a jet, the neural interface includes a skin-coated electrode, a conductive self-connecting internal electrode; the conductive self-connecting internal electrode is generated in situ in the skin by a conductive self-connecting electrode dispersion, and One end is connected to the nerve, and the other end is detachably connected to the skin-applied electrode on the surface of the skin; the conductive self-connecting electrode dispersion contains an isotonic dispersion and conductive particles with a viscous layer on the outside;
  • the set polydopamine layer and the oxidatively polymerized bond layer are selected from polyethylenedioxythiophene layer and polypyrrole layer.
  • the concentration of conductive particles with an external viscous layer in the conductive self-connecting electrode dispersion is 0.1 mg/mL-100 mg/mL, preferably 1 mg/mL-50 mg/mL, for example 2 mg/mL, 3 mg/mL, 4 mg/mL, 5 mg/mL, 6 mg/mL, 7 mg/mL, 8 mg/mL, 9 mg/mL, 10 mg/mL, 15 mg/mL, 20 mg/mL, 25 mg/mL, 30 mg/mL, 35 mg/mL, 40 mg/mL, 50 mg/mL.
  • the isotonic dispersion is selected from solutions with a concentration of 280-320 mmol/L, such as physiological saline, phosphate buffered saline, 5% glucose aqueous solution, and boric acid buffer.
  • the conductive particles are selected from metal nanomaterials, carbon nanomaterials, MXene or any of the above-mentioned modified conductive particles.
  • the metal nanomaterials are selected from silver nanomaterials, iron nanomaterials, magnesium nanomaterials, and aluminum nanomaterials; carbon nanomaterials are selected from graphene and carbon nanotubes; and the MXene is selected from Ti 3 C 2 , Ti 2 C , Nb 2 C, V 2 C, Mo 2 C.
  • the preparation method of the conductive particles comprising an adhesive layer on the outside is:
  • step 2) Further in-situ polymerization to obtain oxidative polymerization into a bond layer: disperse ethylenedioxythiophene raw material or pyrrole raw material in a water-soluble organic solvent, and add step 2) to the aqueous solution of conductive particles with a polymerized dopamine layer, without oxidizing agent Under the conditions of , the conductive particles having a polymerized dopamine layer and an oxidatively polymerized bonding layer with an external adhesive layer were obtained.
  • the skin-covered electrode is detachably connected to the conductive self-connecting inner electrode.
  • the method for in-situ generation of the conductive self-connecting internal electrode in the skin is to inject the dispersion of the conductive self-connecting internal electrode into the skin, and the liquid path formed by the injection of the conductive self-connecting internal electrode dispersion, the conductive self-connecting After the isotonic dispersion in the internal electrode dispersion is removed, the conductive particles containing the viscous layer on the outside are self-connected to form a conductive self-connected internal electrode.
  • the method of injecting the conductive self-connecting internal electrode dispersion into the skin is to use a pressure device that generates a high-pressure jet micro-water column to allow the conductive self-connecting internal electrode dispersion to penetrate the human epidermis and reach the subcutaneous.
  • the pressure device for generating a high-pressure jet micro-water column is selected from a jet injector.
  • the skin electrode is selected from a patch electrode; preferably, the patch electrode has an adhesion site made of conductive hydrogel or elastomer, and a conductive wire.
  • Another aspect of the present invention provides a system for preparing a jet in situ generated neural interface, the system comprising a conductive self-connecting internal electrode dispersion, an injection device, and a skin-coated electrode,
  • the conductive self-connecting electrode dispersion comprises an isotonic dispersion and conductive particles with a viscous layer on the outside; wherein the viscous layer is a polydopamine layer and an oxidatively polymerized bond layer arranged sequentially outside the conductive particles; the oxidatively polymerized bond layer It is selected from a polyethylene dioxythiophene layer and a polypyrrole layer; the injection device is a pressure device that generates a high-pressure jet micro-water column; preferably a jet injector.
  • the concentration of conductive particles with an external viscous layer in the conductive self-connecting electrode dispersion is 0.1 mg/mL-100 mg/mL, preferably 1 mg/mL-50 mg/mL, for example 2 mg/mL, 3 mg/mL, 4 mg/mL, 5 mg/mL, 6 mg/mL, 7 mg/mL, 8 mg/mL, 9 mg/mL, 10 mg/mL, 15 mg/mL, 20 mg/mL, 25 mg/mL, 30 mg/mL, 35 mg/mL, 40 mg/mL, 50 mg/mL.
  • the isotonic dispersion is selected from solutions with a concentration of 280-320 mmol/L, such as physiological saline, phosphate buffered saline, 5% glucose aqueous solution, and boric acid buffer.
  • the conductive particles are selected from metal nanomaterials, carbon nanomaterials, MXene or any of the above-mentioned modified conductive particles.
  • the metal nanomaterials are selected from silver nanomaterials, iron nanomaterials, magnesium nanomaterials, and aluminum nanomaterials; carbon nanomaterials are selected from graphene and carbon nanotubes; and the MXene is selected from Ti 3 C 2 , Ti 2 C , Nb 2 C, V 2 C, Mo 2 C.
  • the system further includes an external device for recording electrical signals.
  • Another aspect of the present invention provides a preparation method of a neural interface generated in situ by jets.
  • the dispersion liquid of the internal electrode of the electrical self-connection is injected subcutaneously through the injection device, and the liquid path formed by the injection of the dispersion liquid of the internal electrode of the conductive self-connection generates a conductive self-interface.
  • the inner electrode is connected, and the skin electrode is attached to the implantation site; the injection device is a pressure device that generates a high-pressure jet micro-water column; preferably a jet injector.
  • Another aspect of the present invention provides the application of the above-mentioned nerve interface generated in situ by the jet, and the application is for nerve electrical signal collection, nerve repair, nerve disease treatment interface, nerve disease diagnosis sensor, or electrical stimulation of nerves.
  • a conductive self-connecting electrode dispersion comprises an isotonic dispersion and conductive particles with a viscous layer on the outside; A dopamine layer and an oxidatively polymerized bond layer; the oxidatively polymerized bond layer is selected from polyethylenedioxythiophene layer and polypyrrole layer.
  • the concentration of conductive particles with an external viscous layer in the conductive self-connecting electrode dispersion is 0.1 mg/mL-100 mg/mL, preferably 1 mg/mL-50 mg/mL, for example 2 mg/mL, 3 mg/mL, 4 mg/mL, 5 mg/mL, 6 mg/mL, 7 mg/mL, 8 mg/mL, 9 mg/mL, 10 mg/mL, 15 mg/mL, 20 mg/mL, 25 mg/mL, 30 mg/mL, 35 mg/mL, 40 mg/mL, 50 mg/mL.
  • the isotonic dispersion is selected from solutions with a concentration of 280-320 mmol/L, such as physiological saline, phosphate buffered saline, 5% glucose aqueous solution, and boric acid buffer.
  • the conductive particles are selected from metal nanomaterials, carbon nanomaterials, MXene or any of the above-mentioned modified conductive particles.
  • the metal nanomaterials are selected from silver nanomaterials, iron nanomaterials, magnesium nanomaterials, and aluminum nanomaterials; carbon nanomaterials are selected from graphene and carbon nanotubes; and the MXene is selected from Ti 3 C 2 , Ti 2 C , Nb 2 C, V 2 C, Mo 2 C.
  • Another aspect of the present invention provides the application of the above conductive self-connecting electrode dispersion liquid in the preparation of neural interfaces.
  • Some specific embodiments of the present invention provide a neural interface generated in situ by jets, the neural interface includes a skin-coated electrode, a conductive self-connecting internal electrode, the conductive self-connecting internal electrode is generated in situ in the skin, and one end is connected to the nerve , and the other end is detachably connected to the skin surface electrode.
  • the conductive self-connecting electrode dispersion comprises an isotonic dispersion and conductive particles with a viscous layer on the outside; wherein the viscous layer is a polydopamine layer and an oxidatively polymerized polydopamine layer sequentially arranged outside the conductive particles. key layer.
  • the concentration of the conductive particles with an external viscous layer in the conductive self-connecting electrode dispersion is 0.1 mg/mL-100 mg/mL, preferably 1 mg/mL-50 mg/mL, For example, 2 mg/mL, 3 mg/mL, 4 mg/mL, 5 mg/mL, 6 mg/mL, 7 mg/mL, 8 mg/mL, 9 mg/mL, 10 mg/mL, 15 mg/mL mL, 20 mg/mL, 25 mg/mL, 30 mg/mL, 35 mg/mL, 40 mg/mL, 50 mg/mL.
  • the isotonic dispersion is selected from solutions with a concentration of 280-320 mmol/L, such as physiological saline, phosphate-buffered saline, 5% glucose aqueous solution, and boric acid buffer.
  • the conductive particles are selected from metal nanomaterials, carbon nanomaterials, MXene or any of the above-mentioned modified conductive particles.
  • the metal nanomaterial is selected from silver nanomaterials, iron nanomaterials, magnesium nanomaterials, and aluminum nanomaterials;
  • the carbon nanomaterials are selected from graphene and carbon nanotubes.
  • the MXene is selected from Ti 3 C 2 , Ti 2 C, Nb 2 C, V 2 C and Mo 2 C.
  • the oxidatively polymerized bonding layer is selected from polyethylenedioxythiophene layer and polypyrrole layer.
  • the above-mentioned conductive particles comprising an adhesive layer on the outside are obtained by the following methods:
  • step 2) Further in-situ polymerization to obtain oxidative polymerization into a bond layer: disperse ethylenedioxythiophene raw material or pyrrole raw material in a water-soluble organic solvent, and add step 2) to the aqueous solution of conductive particles with a polymerized dopamine layer. Under the condition of an oxidizing agent, conductive particles having a polymerized dopamine layer and an oxidatively polymerized bonding layer are obtained.
  • the skin-covered electrode is detachably connected to the conductive self-connecting inner electrode.
  • the method for in-situ generation of the conductive self-connecting internal electrodes in the skin is to inject the dispersion liquid of the conductive self-connecting internal electrodes subcutaneously, and the liquid path formed by the injection of the conductive self-connecting internal electrode dispersion liquid, the conductive self-connecting internal electrodes After the isotonic dispersion in the self-connected internal electrode dispersion is removed, the conductive particles comprising an adhesive layer on the outside are self-connected to form a conductive self-connected internal electrode.
  • the method of injecting the conductive self-connecting internal electrode dispersion into the subcutaneous is to use a pressure device that generates a high-pressure jet micro-water column to allow the conductive self-connecting internal electrode dispersion to penetrate the human epidermis and reach the subcutaneous.
  • the pressure device for generating a high-pressure jet micro-water column is selected from a jet injector.
  • the jet injector has a launch end for storing liquid, and a part is a pressure device for pushing the liquid to spray.
  • the pressure device When the trigger is pulled, the pressure device will be triggered to push the launch end for storing liquid to spray forward, producing a jet injection effect, and the self-connected internal Electrode dispersion jet implantation in vivo.
  • the skin-coated electrodes are selected from patch electrodes; preferably, the patch electrodes have adhesion sites made of conductive hydrogel or elastomer, and conductive wires.
  • the conductive particles comprising the sticky layer are surface-modified MXene nanosheets, which have Na ions and sulfonic acid intercalation, while the surface also has polydopamine layer and polyethylenedioxythiophene layer.
  • the polydopamine layer and the polyethylenedioxythiophene layer are arranged in sequence.
  • the polyethylenedioxythiophene layer accounts for 0.05%-0.8% of the total mass of the surface-modified MXene nanosheets, preferably 0.3%-0.7%, more preferably 0.5%.
  • the above-mentioned surface-modified MXene nanosheets are obtained by the following method:
  • dopamine is prepolymerized in alkaline buffer solution, and then the prepolymerization solution is mixed with Na ion and sulfonic acid intercalation modified MXene nanosheets to obtain a polymerized dopamine layer And Na ion and sulfonic acid intercalation modified MXene nanosheets;
  • step 2 Further in-situ polymerization to obtain a non-oxidative polyethylenedioxythiophene layer: disperse the ethylenedioxythiophene raw material in a water-soluble organic solvent, and add it to the aqueous solution of MXene nanosheets obtained in step 2), under conditions that do not contain an oxidizing agent MXene nanosheets with a polymerized dopamine layer and a non-oxidative polyethylenedioxythiophene layer, and intercalation modification of Na ions and sulfonic acid were obtained.
  • the two-dimensional MXene nano-substrate in step a) is selected from Ti 3 C 2 , Ti 2 C, Nb 2 C, V 2 C or Mo 2 C A combination of one or more; the two-dimensional MXene nano-substrate is obtained by selectively etching the MAX phase ceramics through HF acid; the MAX phase ceramics are selected from Ti 3 AlC 2 , Ti 2 AlC, Nb 2 AlC A combination of one or more of , V 2 AlC, Mo 2 AlC; the alkaline solution containing sodium ions is selected from NaOH solution, Na 2 CO 3 solution, NaHCO 3 solution, KOH solution, K 2 CO 3 solution, KHCO 3 solution; use water to wash to neutral after sodium ion intercalation, for example, wash to pH 7-8; sulfanilic acid diazonium salt is obtained by reacting sulfanilic acid, hydrochloric acid and sodium nitrite, preferably, the above-mentioned
  • the pH value of the alkaline buffer solution in step b) is selected from 8.5-9; the mass ratio of the MXene nanosheets modified by the intercalation of dopamine and Na ions and sulfonic acid is 1:6-20, preferably 1:8-12.
  • the ethylenedioxythiophene raw material in step c) is selected from 3,4-ethylenedioxythiophene;
  • the mass ratio of the intercalated modified MXene nanosheets is 0.001-0.01:1, preferably 0.003-0.008:1, more preferably 0.005:1.
  • no oxidizing agent is added in the reaction of step c).
  • the system includes a conductive self-connecting internal electrode dispersion, an injection device, and a skin-covered electrode.
  • the conductive self-connecting electrode dispersion contains Isotonic dispersion liquid and conductive particles with a viscous layer on the outside; wherein the viscous layer is a polydopamine layer and an oxidatively polymerized bonding layer arranged in sequence on the outside of the conductive particles.
  • the concentration of the conductive particles with an external viscous layer in the conductive self-connecting electrode dispersion is 0.1 mg/mL-100 mg/mL, preferably 1 mg/mL-50 mg/mL, For example, 2 mg/mL, 3 mg/mL, 4 mg/mL, 5 mg/mL, 6 mg/mL, 7 mg/mL, 8 mg/mL, 9 mg/mL, 10 mg/mL, 15 mg/mL mL, 20 mg/mL, 25 mg/mL, 30 mg/mL, 35 mg/mL, 40 mg/mL, 50 mg/mL.
  • the isotonic dispersion is selected from solutions with a concentration of 280-320 mmol/L, such as physiological saline, phosphate-buffered saline, 5% aqueous glucose solution, and boric acid buffer.
  • the system further includes an external device for recording electrical signals.
  • Some specific embodiments of the present invention provide a method for preparing a neural interface generated in situ by spraying, injecting the electrical self-connecting internal electrode dispersion into the subcutaneous area through an injection device, and generating a conductive interface through the liquid path formed by the injection of the conductive self-connecting internal electrode dispersion.
  • a liquid pathway is formed, connecting the outer skin and nerves, and as the isotonic dispersion is continuously transferred by the tissue, the remaining conductive self-connecting particles Will be further oxidized to form a stable junction pathway.
  • Some specific embodiments of the present invention provide the application of the above-mentioned neural interface generated in situ by spraying, and the neural interface is used for recording and transmitting nerve electrical signals, collecting nerve electrical signals, nerve repair, neurological disease treatment interface, neurological disease diagnostic sensor, Or electrical stimulation of the nerve.
  • the neural interface can be applied to human body or animal body.
  • MXene-N Na + intercalated MXene material
  • sulfanilic acid Suspend 3g of sulfanilic acid in 30 mL of water and cool to 0-5°C. A solution of 9 mL HCl and 30 mL water was precooled to 0-5 °C and slowly added to the suspension with stirring in an ice bath. After 15 min, a cold solution of 2.4 g of sodium nitrite (18 mL) was added dropwise to the suspension and stirred for 30 min to obtain a diazonium salt solution.
  • the diazonium salt solution synthesized above was added dropwise to the aqueous dispersion of MXene-N while stirring in an ice bath, and the mixture was kept at 0-5°C for about 4 hours. After the reaction, the mixture was centrifuged and washed several times, and then centrifuged at 4000 rpm for 1 h to separate large aggregates and unreacted particles. Then, the supernatant was lyophilized into MXene-NS powders (MXene nanosheets modified by intercalation of Na ions and sulfonic acid).
  • MXene-NS powder was dispersed with 60 mL of deionized water at a concentration of 2.5 mg/mL, and 15 mL of Tris-HCl solution (pH 8.5) was added dropwise to the solution. At the same time, 15 mg of dopamine (DA) was added to 15 mL of Tris-HCl solution (pH 8.5) and stirred for 15 minutes for prepolymerization. Then the DA prepolymerization solution was added dropwise into the MXene-NS solution and stirred for 4 h to obtain MXene-NSD nanosheets (MXene nanosheets with polymerized dopamine layer and intercalation modification of Na ions and sulfonic acid). MXene-NSD nanosheets were centrifuged and washed several times.
  • MXene-NSD-PEDOT nanosheets Redisperse 32 g MXene-NSD nanosheets with 60 mL deionized water, and dissolve 160 mg 3,4-ethylenedioxythiophene (EDOT) in 10 mL ethanol; then add the EDOT solution dropwise to MXene-NSD solution and stirred at room temperature for 24 hours. Afterwards, the solution was centrifuged, washed several times and then freeze-dried to obtain MXene-NSD-PEDOT nanosheets (with a layer of polymerized dopamine and a layer of non-oxidative polyethylenedioxythiophene, and the intercalation of Na ions and sulfonic acid modified MXene nanosheets), that is, conductive self-connecting dispersions.
  • EDOT 3,4-ethylenedioxythiophene
  • Example 1 Disperse the conductive self-connecting particles of Example 1 in the isotonic liquid dispersion system physiological saline at a concentration of 5 mg/mL and disperse evenly.
  • Embodiment 3 configuration of jet injection channel and skin-coated electrodes
  • the dispersion prepared in Example 2 was loaded into a jet injector.
  • the target implantation area is determined, and then the jet injector loaded with the dispersion of conductive self-connecting particles is directed at the corresponding area.
  • the conductive self-connecting particle dispersion will be implanted into the corresponding area, and as the isotonic dispersion is continuously transferred by the tissue, the remaining conductive self-connecting particles will be further oxidized to form a stable connection pathway.
  • the mouse model equipped with jet injection channel and skin-coated electrodes is shown in Figure 2. It can be observed that a pair of skin-coated electrodes are installed on the outside of the mouse's legs.
  • the mouse is placed on a small animal treadmill and collects nerve signals in a state of exercise. and the corresponding state of motion.
  • the collection of neural signals is shown in Figure 3. It can be seen from Figure 3 that the difference of nerve signals in different stages of the mice in the exercise state.
  • Example 1 The method of Example 1 was used to prepare conductive self-connecting particles, the only difference being that the MXene-NS powder was replaced by nano-iron powder to prepare nFe-NSD-PEDOT conductive self-connecting nanoparticles.
  • Example 1 The method of Example 1 was used to prepare conductive self-connecting particles, the only difference being that the MXene-NS powder was replaced by carbon nanotubes to prepare nC-NSD-PEDOT conductive self-connecting nanoparticles.
  • Example 1 The method of Example 1 was used to prepare conductive self-connecting particles, the only difference being that MXene-NS powder was replaced by graphene, and 3,4-ethylenedioxythiophene was replaced by pyrrole, and Gr-NSD-PPy conductive self-connecting nanoparticles were prepared. .
  • the conductive self-connecting particles of Examples 4-6 were dispersed in water and then dried. Under a scanning electron microscope, observe the surface morphology when dried in a natural state at room temperature. Scanning electron micrographs show that the above-mentioned conductive self-connecting particles have self-connecting properties.

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Abstract

一种喷射原位生成的微创神经接口及其制备方法和应用。具体公开了一种射流原位生成的神经接口，神经接口包含贴皮电极、导电自连接内电极；导电自连接内电极在皮肤内由导电自连接电极分散液原位生成，且一端与神经连接，另一端在皮肤表面与贴皮电极可拆卸的连接；导电自连接电极分散液包含等渗分散液以及外部包含粘性层的导电颗粒；粘性层为在导电颗粒外部依次设置的聚多巴胺层和氧化聚合成键层，氧化聚合成键层选自聚乙烯二氧噻吩层、聚吡咯层。以及射流原位生成的神经接口在神经电信号收集、或对神经进行电刺激中的用途。神经接口植入程序的复杂度低，植入过程损伤小、对运动限制小且生物相容性高。

Description

一种喷射原位生成的微创神经接口及其制备方法和应用 技术领域
本发明属于医用检测元件领域，具体涉及一种喷射原位生成的微创神经接口及其制备方法和应用。
 背景技术
神经接口是外界人工设备与生物体的神经系统信息交互的界面，其可以用于测量神经信号，并用于检测疾病，特别地，其针对神经系统的炎症、退行性病变等具有很好的预防和提前诊断的能力。同时神经接口还可以用于对神经系统传入刺激，依照传入刺激的目的不同，常见的有控制肌肉、刺激视觉皮层、刺激听觉皮层、刺激触觉皮层、刺激温度感受器等。此外，还有一类神经接口主要用于治疗和修复。在常见的损伤如压伤和拉拔伤后通过一定频率和电流的刺激，神经将表现出更活跃的修复倾向。
目前现有技术中的神经接口包括传统侵入性电极和传统非侵入接口。其中，传统侵入性的电极有神经袖带，其由一个或多个位于绝缘衬底上的电极组成，衬底通过外科手术防治，电极出点围绕神经干的神经外表面。虽然这种方法可以非常直接地与目标神经结合，但多点故障和植入程序的复杂性增加了手术风险和成本，并可能导致外周神经接口效果大量的可变性。传统非侵入接口虽然没有侵入性，但是其的神经刺激与记录则因为信号噪音多，溯源性差等导致无法用于精细的神经系统功能调控。
采用目前现有技术中的传统侵入性电极和传统非侵入接口无法实现细小的，无法通过手术植入或手术操作过于复杂的神经接口植入，同时如果采用非侵入方式无法保证信号的稳定性和准确性。
 技术问题
为解决现有技术中的问题，提供了一种喷射原位生成的神经接口以及制备喷射原位生成的神经接口的系统，本发明提供的神经接口能够通过胶体喷射实现在体内原位生成神经接口，解决了解决传统神经界面植入过程中的损伤过大，恢复缓慢的问题；同时还能解决细小神经无法通过手术植入或者手术过于复杂的问题。
 技术解决方案
本发明一个方面提供一种射流原位生成的神经接口，所述神经接口包含贴皮电极、导电自连接内电极；导电自连接内电极在皮肤内由导电自连接电极分散液原位生成，且一端与神经连接，另一端在皮肤表面与贴皮电极可拆卸的连接；所述导电自连接电极分散液包含等渗分散液以及外部包含粘性层的导电颗粒；其中粘性层为在导电颗粒外部依次设置的聚多巴胺层和氧化聚合成键层，所述氧化聚合成键层选自聚乙烯二氧噻吩层、聚吡咯层。
在本发明的技术方案中，所述导电自连接电极分散液中外部包含粘性层的导电颗粒的浓度为0.1mg/mL-100mg/mL，优选为1 mg/mL -50 mg/mL，例如为2 mg/mL、3 mg/mL、4 mg/mL、5 mg/mL、6 mg/mL、7 mg/mL、8 mg/mL、9 mg/mL、10 mg/mL、15 mg/mL、20 mg/mL、25 mg/mL、30 mg/mL、35 mg/mL、40 mg/mL、50 mg/mL。
在本发明的技术方案中，所述的等渗分散液选自浓度为280~320mmol/L的溶液，例如生理盐水、磷酸盐缓冲盐溶液、5%葡萄糖水溶液、硼酸缓冲液。
在本发明的技术方案中，所述的导电颗粒选自金属纳米材料、碳纳米材料、MXene或上述任一种经过修饰的上述导电颗粒。例如所述金属纳米材料选自银纳米材料、铁纳米材料、镁纳米材料、铝纳米材料；碳纳米材料选自石墨烯、碳纳米管；所述的MXene选自Ti 3C 2、Ti 2C、Nb 2C、V 2C、Mo 2C。
在本发明的技术方案中，所述外部包含粘性层的导电颗粒的制备方法为：
1）利用迈克尔加成反应聚合多巴胺：将多巴胺在碱性缓冲溶液中进行预聚合，然后将预聚溶液与导电颗粒混合反应，得到具有聚合多巴胺层的导电颗粒；
2）进一步原位聚合获得氧化聚合成键层：将乙烯二氧噻吩原料或吡咯原料分散在水溶性有机溶剂中，并加入步骤2）具有聚合多巴胺层的导电颗粒的水溶液中，在不包含氧化剂的条件下进行，获得具有聚合多巴胺层和氧化聚合成键层的外部包含粘性层的导电颗粒。
在本发明的技术方案中，所述贴皮电极与导电自连接内电极可拆卸的连接。
在本发明的技术方案中，导电自连接内电极在皮肤内原位生成的方法为将导电自连接内电极分散液注射至皮下，导电自连接内电极分散液注射形成的液体通路，导电自连接内电极分散液中的等渗分散液被移除后外部包含粘性层的导电颗粒自连接生成导电自连接内电极。
在本发明的技术方案中，将导电自连接内电极分散液注射至皮下的方法为采用产生高压射流微水柱的压力装置使其中的导电自连接内电极分散液穿透人体表皮到达皮下。
在本发明的技术方案中，所述产生高压射流微水柱的压力装置选自射流注射器。
在本发明的技术方案中，所述贴皮电极选自贴片电极；优选地，所述贴片电极具有导电水凝胶或弹性体构成的粘附位点，以及导电导线。
本发明另一个方面提供了一种用于制备射流原位生成的神经接口的系统，所述系统包括导电自连接内电极分散液、注射装置以及贴皮电极，
所述导电自连接电极分散液包含等渗分散液以及外部包含粘性层的导电颗粒；其中粘性层为在导电颗粒外部依次设置的聚多巴胺层和氧化聚合成键层；所述氧化聚合成键层选自聚乙烯二氧噻吩层、聚吡咯层；所述注射装置为产生高压射流微水柱的压力装置；优选为射流注射器。
在本发明的技术方案中，所述导电自连接电极分散液中外部包含粘性层的导电颗粒的浓度为0.1mg/mL-100mg/mL，优选为1 mg/mL -50 mg/mL，例如为2 mg/mL、3 mg/mL、4 mg/mL、5 mg/mL、6 mg/mL、7 mg/mL、8 mg/mL、9 mg/mL、10 mg/mL、15 mg/mL、20 mg/mL、25 mg/mL、30 mg/mL、35 mg/mL、40 mg/mL、50 mg/mL。
在本发明的技术方案中，所述的等渗分散液选自浓度为280~320mmol/L的溶液，例如生理盐水、磷酸盐缓冲盐溶液、5%葡萄糖水溶液、硼酸缓冲液。
在本发明的技术方案中，导电颗粒选自金属纳米材料、碳纳米材料、MXene或上述任一种经过修饰的上述导电颗粒。例如所述金属纳米材料选自银纳米材料、铁纳米材料、镁纳米材料、铝纳米材料；碳纳米材料选自石墨烯、碳纳米管；所述的MXene选自Ti 3C 2、Ti 2C、Nb 2C、V 2C、Mo 2C。
在本发明的技术方案中，所述系统中还包括外部记录电信号的装置。
本发明再一个方面提供了一种射流原位生成的神经接口的制备方法，通过注射装置将电自连接内电极分散液注射至皮下，导电自连接内电极分散液注射形成的液体通路生成导电自连接内电极，贴附贴皮电极于植入位点；所述注射装置为产生高压射流微水柱的压力装置；优选为射流注射器。
本发明再一个方面提供了上述射流原位生成的神经接口的应用，所述应用为神经电信号收集、神经修复、神经疾病治疗界面、神经疾病诊断传感器、或对神经进行电刺激中的用途。
本发明再一个方面提供了一种导电自连接电极分散液，所述导电自连接电极分散液包含等渗分散液以及外部包含粘性层的导电颗粒；其中粘性层为在导电颗粒外部依次设置的聚多巴胺层和氧化聚合成键层；所述氧化聚合成键层选自聚乙烯二氧噻吩层、聚吡咯层。
在本发明的技术方案中，所述导电自连接电极分散液中外部包含粘性层的导电颗粒的浓度为0.1mg/mL-100mg/mL，优选为1 mg/mL -50 mg/mL，例如为2 mg/mL、3 mg/mL、4 mg/mL、5 mg/mL、6 mg/mL、7 mg/mL、8 mg/mL、9 mg/mL、10 mg/mL、15 mg/mL、20 mg/mL、25 mg/mL、30 mg/mL、35 mg/mL、40 mg/mL、50 mg/mL。
在本发明的技术方案中，所述的等渗分散液选自浓度为280~320mmol/L的溶液，例如生理盐水、磷酸盐缓冲盐溶液、5%葡萄糖水溶液、硼酸缓冲液。
在本发明的技术方案中，导电颗粒选自金属纳米材料、碳纳米材料、MXene或上述任一种经过修饰的上述导电颗粒。例如所述金属纳米材料选自银纳米材料、铁纳米材料、镁纳米材料、铝纳米材料；碳纳米材料选自石墨烯、碳纳米管；所述的MXene选自Ti 3C 2、Ti 2C、Nb 2C、V 2C、Mo 2C。
本发明再一个方面提供了上述导电自连接电极分散液在制备神经接口中的应用。
 有益效果 附图说明
为了使本发明的上述目的、特征和优点能够更加明显易懂，下面对本发明的具体实施方式做详细的说明，但不能理解为对本发明的可实施范围的限定。
本发明一些具体实施方案提供了一种射流原位生成的神经接口，所述神经接口包含贴皮电极、导电自连接内电极，导电自连接内电极在皮肤内原位生成，且一端与神经连接，另一端在皮肤表面与贴皮电极可拆卸的连接。
在本发明的一些具体实施方案中，所述导电自连接电极分散液包含等渗分散液以及外部包含粘性层的导电颗粒；其中粘性层为在导电颗粒外部依次设置的聚多巴胺层和氧化聚合成键层。
在本发明的一些具体实施方案中，所述导电自连接电极分散液中外部包含粘性层的导电颗粒的浓度为0.1mg/mL-100mg/mL，优选为1 mg/mL -50 mg/mL，例如为2 mg/mL、3 mg/mL、4 mg/mL、5 mg/mL、6 mg/mL、7 mg/mL、8 mg/mL、9 mg/mL、10 mg/mL、15 mg/mL、20 mg/mL、25 mg/mL、30 mg/mL、35 mg/mL、40 mg/mL、50 mg/mL。
在本发明的一些具体实施方案中，所述的等渗分散液选自浓度为280~320mmol/L的溶液，例如生理盐水、磷酸盐缓冲盐溶液、5%葡萄糖水溶液、硼酸缓冲液。
在本发明的一些具体实施方案中，导电颗粒选自金属纳米材料、碳纳米材料、MXene或上述任一种经过修饰的上述导电颗粒。例如所述金属纳米材料选自银纳米材料、铁纳米材料、镁纳米材料、铝纳米材料；碳纳米材料选自石墨烯、碳纳米管。所述的MXene选自Ti 3C 2、Ti 2C、Nb 2C、V 2C、Mo 2C。
在本发明的一些具体实施方案中，氧化聚合成键层选自聚乙烯二氧噻吩层、聚吡咯层。
在本发明的一些具体实施方案中，上述外部包含粘性层的导电颗粒通过以下方法获得：
1）利用迈克尔加成反应聚合多巴胺：将多巴胺在碱性缓冲溶液中进行预聚合，然后将预聚溶液与导电颗粒混合反应，得到具有聚合多巴胺层的导电颗粒；
2）进一步原位聚合获得氧化聚合成键层层：将乙烯二氧噻吩原料或吡咯原料分散在水溶性有机溶剂中，并加入步骤2）具有聚合多巴胺层的导电颗粒的水溶液中，在不包含氧化剂的条件下进行获得具有聚合多巴胺层和氧化聚合成键层的导电颗粒。
在本发明的一些具体实施方案中，所述贴皮电极与导电自连接内电极可拆卸的连接。
在本发明的一些具体实施方案中，导电自连接内电极在皮肤内原位生成的方法为将导电自连接内电极分散液注射至皮下，导电自连接内电极分散液注射形成的液体通路，导电自连接内电极分散液中的等渗分散液被移除后外部包含粘性层的导电颗粒自连接生成导电自连接内电极。
在本发明的一些具体实施方案中，将导电自连接内电极分散液注射至皮下的方法为采用产生高压射流微水柱的压力装置使其中的导电自连接内电极分散液穿透人体表皮到达皮下。
在本发明的一些具体实施方案中，所述产生高压射流微水柱的压力装置选自射流注射器。所述射流注射器具有储存液体的发射端，一部分为推动液体喷射的压力装置，当扣动扳机，压力装置会被触发，推动储存液体的发射端向前喷射，产生射流注入效果，将自连接内电极分散液射流植入体内。
在本发明的一些具体实施方案中，所述贴皮电极选自贴片电极；优选地，所述贴片电极具有导电水凝胶或弹性体构成的粘附位点，以及导电导线。
在本发明的一个优选的具体实施方案中，所述包含粘性层的导电颗粒为表面改性的MXene纳米片，所述MXene纳米片中具有Na离子和磺酸插层，同时表面还具有聚多巴胺层和聚乙烯二氧噻吩层。聚多巴胺层和聚乙烯二氧噻吩层依次设置。聚乙烯二氧噻吩层占表面改性的MXene纳米片总质量的0.05%-0.8%，优选为0.3%-0.7%，更优选为0.5%。
在本发明的一个优选的具体实施方案中，上述表面改性的MXene纳米片通过以下方法获得：
a）Na离子和磺酸的插层改性：将二维MXene纳米片分散在含有钠离子的碱性溶液中，混合获得Na离子插层的二维MXene纳米片；将Na离子插层的二维MXene纳米片与磺胺酸重氮盐反应，得到Na离子和磺酸的插层改性的MXene纳米片；
b）利用迈克尔加成反应聚合多巴胺：将多巴胺在碱性缓冲溶液中进行预聚合，然后将预聚溶液与Na离子和磺酸的插层改性的MXene纳米片混合反应，得到具有聚合多巴胺层且Na离子和磺酸的插层改性的MXene纳米片；
c）进一步原位聚合获得非氧化性聚乙烯二氧噻吩层：将乙烯二氧噻吩原料分散在水溶性有机溶剂中，并加入步骤2）所得MXene纳米片的水溶液中，在不包含氧化剂的条件下进行获得具有聚合多巴胺层和非氧化性聚乙烯二氧噻吩层，且Na离子和磺酸的插层改性的MXene纳米片。
在本发明的一个优选的具体实施方案中，其中步骤a）中所述二维MXene纳米基片选自Ti 3C 2、Ti 2C、Nb 2C、V 2C或Mo 2C中的其中一种或多种的组合；所述二维MXene纳米基片通过将MAX相陶瓷通过HF酸进行选择性刻蚀获得；所述MAX相陶瓷选自Ti 3AlC 2、Ti 2AlC、Nb 2AlC、V 2AlC、Mo 2AlC中的其中一种或多种的组合；含有钠离子的碱性溶液选自NaOH溶液、Na 2CO 3溶液、NaHCO 3溶液、KOH溶液、K 2CO 3溶液、KHCO 3溶液；钠离子插层后采用水冲洗至中性，例如冲洗至pH值为7-8；磺胺酸重氮盐通过将磺胺酸、盐酸与亚硝酸钠反应获得，优选地，上述反应在-5~10℃条件下反应；磺胺酸重氮盐与钠离子插层MXene纳米片在0-5℃下反应2-10小时，离心去除分离大的聚集体和未反应的颗粒。
在本发明的一个优选的具体实施方案中，其中步骤b）中碱性缓冲溶液的pH值选自8.5-9；多巴胺与Na离子和磺酸的插层改性的MXene纳米片的质量比为1:6-20，优选为1:8-12。
在本发明的一个优选的具体实施方案中，其中步骤c）中乙烯二氧噻吩原料选自3,4-乙烯二氧噻吩；乙烯二氧噻吩原料与具有聚合多巴胺层且Na离子和磺酸的插层改性的MXene纳米片的质量比为0.001-0.01:1，优选为0.003-0.008:1，更优选为0.005:1。优选地，步骤c）反应中不添加氧化剂。
本发明另一个方面提供了一种用于制备射流原位生成的神经接口的系统，所述系统包括导电自连接内电极分散液、注射装置以及贴皮电极，所述导电自连接电极分散液包含等渗分散液以及外部包含粘性层的导电颗粒；其中粘性层为在导电颗粒外部依次设置的聚多巴胺层和氧化聚合成键层。
在本发明的一些具体实施方案中，所述导电自连接电极分散液中外部包含粘性层的导电颗粒的浓度为0.1mg/mL-100mg/mL，优选为1 mg/mL -50 mg/mL，例如为2 mg/mL、3 mg/mL、4 mg/mL、5 mg/mL、6 mg/mL、7 mg/mL、8 mg/mL、9 mg/mL、10 mg/mL、15 mg/mL、20 mg/mL、25 mg/mL、30 mg/mL、35 mg/mL、40 mg/mL、50 mg/mL。
在本发明的一些具体实施方案中，所述的等渗分散液选自浓度为280~320mmol/L的溶液，例如生理盐水、磷酸盐缓冲盐溶液、5%葡萄糖水溶液、硼酸缓冲液。
在本发明的一些具体实施方案中，所述系统中还包括外部记录电信号的装置。
本发明一些具体实施方案提供了一种喷射原位生成的神经接口的制备方法，通过注射装置将电自连接内电极分散液注射至皮下，导电自连接内电极分散液注射形成的液体通路生成导电自连接内电极，贴附贴皮电极于植入位点。其中，当导电自连接内电极分散液被注射到受试者皮下后，形成了液体通路，连通皮肤外侧和神经，随着其中的等渗分散液不断被组织转移，留下的导电自连接颗粒将进一步氧化形成稳定的连接通路。
本发明一些具体实施方案提供了上述喷射原位生成的神经接口的应用，所述神经接口用于记录和传输神经电信号、神经电信号收集、神经修复、神经疾病治疗界面、神经疾病诊断传感器、或对神经进行电刺激。
在本发明中，所述神经接口可以应用于人体或动物体。
实施例1 制备导电自连接颗粒
1）将3 g Ti 3AlC 2粉末缓慢浸入装有40 mL HF水溶液的聚四氟乙烯烧杯中，并在室温下蚀刻48小时。然后将所得悬浮液转移到离心管中并离心。湿沉淀物用去离子水洗涤并离心数次。得到二维MXene材料Ti 3C 2。倾析上一步液体后，向离心管中滴加少量稀NaOH溶液，将溶液转移至烧杯中，搅拌2小时。将产物离心并用大量去离子水洗涤数次，直至顶部液体的pH值为7-8，得到MXene-N（Na +插层的MXene材料）。将 3g 磺胺酸悬浮在30 mL水中，冷却至0-5℃。将9 mL HCl 和30 mL水的溶液预冷至0-5℃，并在冰浴条件下搅拌下缓慢加入悬浮液中。15分钟后，将2.4 g亚硝酸钠（18 mL）的冷溶液滴加到悬浮液中，搅拌30分钟，得到重氮盐溶液。将上述合成的重氮盐溶液在冰浴中边搅拌边滴加到MXene-N的水分散液中，混合物在0-5℃保持约4小时。反应结束后，将混合物离心并洗涤数次，然后以4000 rpm离心1小时以分离大的聚集体和未反应的颗粒。然后，将上清液冻干成MXene-NS 粉末（Na离子和磺酸的插层改性的MXene纳米片）。
2）将获得的MXene-NS粉末以2.5 mg/mL的浓度用60 mL去离子水分散，并向溶液中滴加15 mL Tris-HCl溶液（pH 8.5）。同时，将 15 mg多巴胺（DA）加入15 mL Tris-HCl 溶液（pH 8.5）搅拌15分钟进行预聚合。然后将DA预聚合溶液滴加到MXene-NS溶液中并搅拌4小时，得到MXene-NSD纳米片（具有聚合多巴胺层且Na离子和磺酸的插层改性的MXene纳米片）。MXene-NSD 纳米片经过离心和洗涤数次。
3）用60 mL去离子水将32 g MXene-NSD 纳米片重新分散，将160 mg 3,4-乙烯二氧噻吩（EDOT）溶于10 mL 乙醇中；然后将EDOT溶液滴加到MXene-NSD溶液中并在室温下搅拌24小时。之后，将溶液离心，洗涤数次后冻干，获得MXene-NSD-PEDOT纳米片（具有聚合多巴胺层和非氧化性聚乙烯二氧噻吩层，且Na离子和磺酸的插层改性的MXene纳米片），即导电自连接分散液。
实施例2 配制导电自连接分散液
将实施例1导电自连接颗粒以5 mg/mL的浓度分散在等渗液体分散体系生理盐水中分散均匀。
实施例3配置喷射注射通路和贴皮电极
将实施例2制备得到的分散液装入射流注射器上。确定目标植入区域，然后将装载有导电自连接颗粒的分散液的射流注射器对准相应区域。扣动扳机后，导电自连接颗粒分散液将被植入对应区域，随着等渗分散液不断被组织转移，留下的导电自连接颗粒将进一步氧化形成稳定的连接通路。
将贴皮电极贴附于植入位点，使导电通路连通，将连接通路接收到的神经电信号传输出去。
配置喷射注射通路和贴皮电极的小鼠模型见图2，可以观察到小鼠腿部外侧安装一对贴皮电极，小鼠在被放置在小动物跑步机，并运动状态下的收集神经信号和对应的运动状态。神经信号的采集如图3。通过图3可以看出，小鼠在运动状态下不同阶段的神经信号的区别。
实施例4制备导电自连接颗粒nFe-NSD-PEDOT
采用实施例1的方法制备导电自连接颗粒，区别仅在于将MXene-NS 粉末替换为纳米铁粉制备得到nFe-NSD-PEDOT导电自连接纳米颗粒。
实施例5制备导电自连接颗粒nC-NSD-PEDOT
采用实施例1的方法制备导电自连接颗粒，区别仅在于将MXene-NS 粉末替换为碳纳米管制备得到nC-NSD-PEDOT导电自连接纳米颗粒。
实施例6制备导电自连接颗粒Gr-NSD-PPy
采用实施例1的方法制备导电自连接颗粒，区别仅在于将MXene-NS粉末替换为石墨烯，将3,4-乙烯二氧噻吩替换为吡咯，制备得到Gr-NSD-PPy导电自连接纳米颗粒。
实施例7导电自连接颗粒的自连接测试
将实施例4-6导电自连接颗粒分散在水中，然后干燥。通过扫描电镜下，观察在室温自然状态下干燥时的表面形貌。扫描电镜图显示上述导电自连接颗粒具有自连接性能。

Claims (10)

  1. 一种射流原位生成的神经接口，其特征在于，所述神经接口包含贴皮电极和导电自连接内电极；所述导电自连接内电极在皮肤内由导电自连接电极分散液原位生成，且一端与神经连接，另一端在皮肤表面与贴皮电极可拆卸的连接；所述导电自连接电极分散液包含等渗分散液以及外部包含粘性层的导电颗粒；其中粘性层为在导电颗粒外部依次设置的聚多巴胺层和氧化聚合成键层，所述氧化聚合成键层选自聚乙烯二氧噻吩层、聚吡咯层；
    优选地，所述导电自连接电极分散液中外部包含粘性层的导电颗粒的浓度为0.1mg/mL-100mg/mL，更优选为1 mg/mL -50 mg/mL；
    优选地，所述的等渗分散液选自浓度为280~320mmol/L的溶液，例如生理盐水、磷酸盐缓冲盐溶液、5%葡萄糖水溶液、硼酸缓冲液；
    优选地，所述的导电颗粒选自金属纳米材料、碳纳米材料、MXene或上述任一种经过修饰的上述导电颗粒；更优选地，所述金属纳米材料选自银纳米材料、铁纳米材料、镁纳米材料、铝纳米材料，所述碳纳米材料选自石墨烯、碳纳米管，所述的MXene选自Ti 3C 2、Ti 2C、Nb 2C、V 2C、Mo 2C；
    优选地，所述贴皮电极与导电自连接内电极可拆卸的连接；更优选地，所述贴皮电极选自贴片电极。
  2. 根据权利要求1所述的射流原位生成的神经接口，其特征在于，所述外部包含粘性层的导电颗粒的制备方法为：
    1）利用迈克尔加成反应聚合多巴胺：将多巴胺在碱性缓冲溶液中进行预聚合，然后将预聚溶液与导电颗粒混合反应，得到具有聚合多巴胺层的导电颗粒；
    2）进一步原位聚合获得氧化聚合成键层：将乙烯二氧噻吩原料或吡咯原料分散在水溶性有机溶剂中，并加入步骤2）具有聚合多巴胺层的导电颗粒的水溶液中，在不包含氧化剂的条件下进行，获得具有聚合多巴胺层和氧化聚合成键层的外部包含粘性层的导电颗粒。
  3. 根据权利要求1所述的射流原位生成的神经接口，其特征在于，导电自连接内电极在皮肤内原位生成的方法为将导电自连接内电极分散液注射至皮下，导电自连接内电极分散液注射形成的液体通路，导电自连接内电极分散液中的等渗分散液被移除后外部包含粘性层的导电颗粒自连接生成导电自连接内电极；
    优选地，将导电自连接内电极分散液注射至皮下的方法为采用产生高压射流微水柱的压力装置使其中的导电自连接内电极分散液穿透人体表皮到达皮下；
    更优选地，所述产生高压射流微水柱的压力装置选自射流注射器。
  4. 一种用于制备射流原位生成的神经接口的系统，其特征在于，所述系统包括导电自连接内电极分散液、注射装置以及贴皮电极，
    所述导电自连接电极分散液包含等渗分散液以及外部包含粘性层的导电颗粒；其中粘性层为在导电颗粒外部依次设置的聚多巴胺层和氧化聚合成键层；
    所述氧化聚合成键层选自聚乙烯二氧噻吩层、聚吡咯层；
    所述注射装置为产生高压射流微水柱的压力装置；优选为射流注射器；
    优选地，所述导电自连接电极分散液中外部包含粘性层的导电颗粒的浓度为0.1mg/mL-100mg/mL，更优选为1 mg/mL -50 mg/mL；
    优选地，所述等渗分散液选自浓度为280~320mmol/L的溶液；
    优选地，所述导电颗粒选自金属纳米材料、碳纳米材料、MXene或上述任一种经过修饰的上述导电颗粒。
  5. 根据权利要求4所述的用于制备射流原位生成的神经接口的系统，其特征在于，所述系统中还包括外部记录电信号的装置。
  6. 根据权利要求4所述的用于制备射流原位生成的神经接口的系统，其特征在于，所述外部包含粘性层的导电颗粒的制备方法为：
    1）利用迈克尔加成反应聚合多巴胺：将多巴胺在碱性缓冲溶液中进行预聚合，然后将预聚溶液与导电颗粒混合反应，得到具有聚合多巴胺层的导电颗粒；
    2）进一步原位聚合获得氧化聚合成键层：将乙烯二氧噻吩原料或吡咯原料分散在水溶性有机溶剂中，并加入步骤2）具有聚合多巴胺层的导电颗粒的水溶液中，在不包含氧化剂的条件下进行，获得具有聚合多巴胺层和氧化聚合成键层的外部包含粘性层的导电颗粒。
  7. 权利要求1-3任一项所述的射流原位生成的神经接口的制备方法，其特征在于，通过注射装置将电自连接内电极分散液注射至皮下，导电自连接内电极分散液注射形成的液体通路生成导电自连接内电极，贴附贴皮电极于植入位点；所述注射装置为产生高压射流微水柱的压力装置；优选为射流注射器。
  8. 权利要求1-3任一项所述的射流原位生成的神经接口的应用，其特征在于，所述应用为在神经电信号收集、神经修复、神经疾病治疗界面、神经疾病诊断传感器、或对神经进行电刺激中的用途。
  9. 一种导电自连接电极分散液，其特征在于，所述导电自连接电极分散液包含等渗分散液以及外部包含粘性层的导电颗粒；其中粘性层为在导电颗粒外部依次设置的聚多巴胺层和氧化聚合成键层；所述氧化聚合成键层选自聚乙烯二氧噻吩层、聚吡咯层；
    优选地，所述导电自连接电极分散液中外部包含粘性层的导电颗粒的浓度为0.1mg/mL-100mg/mL，优选为1 mg/mL -50 mg/mL；
    优选地，所述的等渗分散液选自浓度为280~320mmol/L的溶液；
    优选地，导电颗粒选自金属纳米材料、碳纳米材料、MXene或上述任一种经过修饰的上述导电颗粒；更优选地，金属纳米材料选自银纳米材料、铁纳米材料、镁纳米材料、铝纳米材料，碳纳米材料选自石墨烯、碳纳米管，所述MXene选自Ti 3C 2、Ti 2C、Nb 2C、V 2C、Mo 2C。
  10. 根据权利要求9所述的导电自连接电极分散液的用途，其特征在于，所述用途为导电自连接电极分散液在制备神经接口中的应用。
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