WO2024098490A1 - 神经导管、制备方法及其应用 - Google Patents

神经导管、制备方法及其应用 Download PDF

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WO2024098490A1
WO2024098490A1 PCT/CN2022/137365 CN2022137365W WO2024098490A1 WO 2024098490 A1 WO2024098490 A1 WO 2024098490A1 CN 2022137365 W CN2022137365 W CN 2022137365W WO 2024098490 A1 WO2024098490 A1 WO 2024098490A1
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nerve
conductive
poly
composite
units
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French (fr)
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杜学敏
王珊珊
赵启龙
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Shenzhen Institute of Advanced Technology of CAS
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Shenzhen Institute of Advanced Technology of CAS
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/02—Inorganic materials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/02—Inorganic materials
    • A61L27/04—Metals or alloys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/14—Macromolecular materials
    • A61L27/16—Macromolecular materials obtained by reactions only involving carbon-to-carbon unsaturated bonds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/14—Macromolecular materials
    • A61L27/18—Macromolecular materials obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/14—Macromolecular materials
    • A61L27/20—Polysaccharides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/56—Porous materials, e.g. foams or sponges

Definitions

  • the present application relates to the field of biomedical technology, and in particular to a nerve conduit, a preparation method and application thereof.
  • Nerve damage caused by trauma, disease or surgery is very common.
  • both the central and peripheral nerves lack the ability to regenerate and repair themselves after injury. If they cannot be effectively intervened and treated within a limited time window, irreversible nerve function damage will occur due to neuronal apoptosis in the damaged area, leading to permanent consequences ranging from decreased motor and sensory functions to limb paralysis and even disability.
  • nerve damage is mainly treated clinically through nerve anastomosis surgery or autologous nerve transplantation, but these methods cannot be used to treat larger nerve defects (defect distance > 3 cm) and face inherent disadvantages such as a high risk of complications.
  • the existing method of constructing artificial nerve conduits with oriented structures has achieved certain results in guiding the directional elongation of neuronal axons, the effect of promoting nerve function reconstruction through guidance of a single structural factor is still limited.
  • the cellular response of neurons based on their electrical activity especially the spatial response to the electric field in the orientation direction of their neurite structure, plays an important role in forming intercellular connections.
  • the existing conductive nerve conduits have also received widespread attention in promoting nerve function reconstruction.
  • this type of conductive nerve conduit can only provide an electrically active environment that supports the electrical activity of neurons, but cannot achieve active and directional electrical stimulation of neurons. It also faces the bottleneck of limited guiding effect in promoting the elongation of neuronal axons.
  • One of the purposes of the present application is to provide a nerve catheter, comprising response units and conductive units arranged alternately in sequence, wherein the response units and the conductive units both have a through-hole array structure, the response unit can generate a thermal or electric potential gradient, and guide the directional migration of electrons or ions in the conductive unit to form an electric current along the axial direction of the nerve catheter, and the external field energy includes light or magnetic field or ultrasound.
  • the response unit and the conductive unit have the same diameter, which is 200 ⁇ m - 2 cm.
  • the thickness of the response unit is 5-300 ⁇ m, and the thickness of the conductive unit is 100 ⁇ m - 2 mm.
  • the least alternating unit combination of the response units and the conductive units that are alternately arranged in sequence is a combination of 2 response units and 1 conductive unit.
  • the minimum number of holes in the through-hole array structure is 1, and the diameter of a single hole is 50 ⁇ m - 2 mm.
  • the response unit can generate a thermal or electric potential gradient under the stimulation of external field energy, and the external field energy includes light or magnetic field or ultrasound.
  • the material of the response unit includes: one or more of photothermal material, magnetocaloric material, photovoltaic material, piezoelectric material, photothermal material composite thermoelectric material, photothermal material composite pyroelectric material, magnetocaloric material composite thermoelectric material, magnetocaloric material composite pyroelectric material, upconversion material composite photovoltaic material, and photodeformation material composite piezoelectric material.
  • the photothermal material is at least one of the following substances: carbon black, carbon nanotubes, graphene, black phosphorus, polydopamine, gold nanorods, gallium-indium alloy liquid metal, and MXene-based materials.
  • the magnetocaloric material is at least one of the following substances: ferroferric oxide, Ru-Fe-B alloy, iron, cobalt, nickel, and gadolinium.
  • the photovoltaic material is at least one of the following substances: thin-film solar cell materials including amorphous silicon, copper indium gallium selenide thin film, and cadmium telluride thin film, dye-sensitized solar cell materials based on titanium dioxide and its composites, perovskite solar cell materials based on perovskite-type organic metal halides, and organic photovoltaic materials including polyacetylene, polythiophene, polyaniline, polypyrrole and their derivatives and copolymers.
  • the piezoelectric material includes a piezoelectric crystal or a piezoelectric ceramic or a polyvinylidene fluoride ferroelectric polymer or a piezoelectric polymer
  • the piezoelectric crystal includes a quartz crystal or lithium gallate or lithium germanate or titanium germanate or lithium tantalate
  • the piezoelectric ceramic includes barium titanate or lead zirconate titanate or lead metaniobate or lead barium lithium niobate
  • the polyvinylidene fluoride ferroelectric polymer includes poly(vinylidene fluoride) or poly(vinylidene fluoride-trifluoroethylene) [P(VDF-TrFE) copolymer] or poly(vinylidene fluoride-chlorofluoroethylene) [P(VDF-CFE) copolymer] or poly(vinylidene fluoride-chlorotrifluoroethylene) [P(VDF-CTFE) copolymer] Polymer] or poly
  • the photothermal material composite thermoelectric material is a combination of the photothermal material and any one of the following thermoelectric materials; wherein the thermoelectric material includes at least one of a polymer material system and a p-type polymer thermoelectric material, the polymer material system is at least one of the following materials: polyacetylene, polyaniline, polypyrrole, polycarbazole, polythiophene, and polyvinylene derivatives, and the p-type polymer thermoelectric material is at least one of the following materials: polythiophenes, polyacetylene, polyaniline, polypyrrole, polycarbazole, and pyrrolopyrrole diketone, wherein the polythiophenes include at least one of the following materials: unsubstituted polythiophene PTh, poly(3-hexylthiophene) P3HT, poly[2,5-bis(3-tetradecylthiophene-2-yl)thiophene/[3,2
  • the photothermal composite pyroelectric material is a combination of the photothermal material and any one of the following pyroelectric materials; wherein the pyroelectric material is at least one of a polyvinylidene fluoride ferroelectric polymer and a perovskite ferroelectric ceramic, and the polyvinylidene fluoride ferroelectric polymer includes poly(vinylidene fluoride), poly(vinylidene fluoride-trifluoroethylene) [P(VDF-TrFE) copolymer], poly(vinylidene fluoride-chlorofluoroethylene) [P(VDF-CFE) copolymer], poly(vinylidene fluoride-chlorotrifluoroethylene) [P(VDF-CTFE)
  • the invention relates to a ferroelectric ceramic comprising at least one of: a poly(vinylidene fluoride-hexafluoropropylene) copolymer], a poly(vinyliden
  • the up-conversion material composite photovoltaic material is any combination of the up-conversion material and the photovoltaic material; wherein the up-conversion material is at least one of the following materials: yttrium oxide, yttrium oxysulfide, lanthanum fluoride, sodium yttrium fluoride, and sodium gadolinium fluoride.
  • the photodeformable material composite piezoelectric material is a combination of any one of the following photodeformable materials and the piezoelectric materials; wherein the photodeformable material is at least one of a photoisomerization material and a ferroelectric inorganic photodeformable material, the photoisomerization material includes at least one of azobenzene and its derivatives, spiropyran and its derivatives, and the ferroelectric inorganic photodeformable material includes at least one of lead titanate, barium titanate, potassium niobate, lithium niobate, lithium tantalate, bismuth layered perovskite structure ferroelectric, tungsten bronze type ferroelectric, bismuth ferrite, potassium dihydrogen phosphate, triammonium sulfate, Roche salt, and perovskite type organic metal halide ferroelectric.
  • the photodeformable material is at least one of a photoisomerization material and a ferroelectric inorganic photodeformable material
  • the magnetocaloric material composite thermoelectric material includes any combination of the magnetocaloric material and the thermoelectric material.
  • the magnetocaloric material composite pyroelectric material is any combination of the magnetocaloric material and the pyroelectric material.
  • the material of the conductive unit includes one or more of: polyelectrolyte hydrogel, ion gel, conductive polymer hydrogel, conductive filler-doped conductive hydrogel.
  • the polyelectrolyte hydrogel includes at least one of a polyacid electrolyte, a polyalkali electrolyte and an amphoteric electrolyte.
  • the polyacid electrolyte includes at least one of hyaluronic acid, polyethylene sulfonic acid, polyethylene phosphoric acid, polyacrylic acid, polymethyl methacrylic acid, and polystyrene sulfonic acid;
  • the polyalkali electrolyte includes at least one of polyethyleneimine, polyethyleneamine, and polyvinyl pyridine;
  • the amphoteric electrolyte includes at least one of polyphosphate, polysilicate, natural nucleic acid, and protein.
  • the ion gel is at least one of the following materials: a composite gel of polyacrylic acid and polyacrylamide, a composite gel of polyacrylic acid and chitosan, a composite gel of sodium alginate and polyacrylamide, a composite gel of polyacrylic acid and choline, a composite gel of sodium alginate and choline, a composite gel of methacrylated gelatin and choline, and a composite gel of methacrylated hyaluronic acid and choline.
  • the conductive polymer hydrogel is at least one of the following materials: polyaniline, polypyrrole, polythiophene and poly (3,4-ethylenedioxythiophene) based conductive polymer hydrogel.
  • the conductive filler-doped conductive hydrogel is any combination of a conductive filler and the conductive polymer hydrogel; wherein the conductive filler includes at least one of a metal-based conductive filler and a carbon-based conductive filler, the metal-based conductive filler includes Au or Ag, and the carbon-based conductive filler includes carbon black, graphite, carbon fiber, carbon nanotubes and graphene.
  • the second object of the present application is to provide a method for preparing the nerve conduit, comprising the following steps:
  • the response units and the conductive units are alternately constructed in the mold to form the nerve guide.
  • the step of constructing the response unit in the mold specifically includes the following steps: constructing the response unit in the mold by coating, spin coating or casting.
  • the cross-linking method is at least one of ionic cross-linking and ultraviolet light cross-linking.
  • the mold is a single closed circular tubular lumen structure, and the bottom of the mold has solid cylinders arranged along the axial direction of the lumen to form an array porous structure of the nerve conduit.
  • the third purpose of the present application is to provide an application of the nerve conduit in nerve regeneration and repair.
  • the nerve conduit provided in the present application includes response units and conductive units arranged alternately in sequence, and the response units and conductive units both have a through-hole array structure.
  • the response unit can generate a thermal or electric potential gradient and guide the directional migration of electrons or ions in the conductive unit to form an electric current along the axial direction of the nerve conduit, thereby providing axial electrical stimulation that can guide axonal elongation when used for nerve regeneration and repair; and combined with the directional structural guidance provided by the through-hole array structure, the directional elongation of neuronal axons is guided together and comprehensively.
  • the nerve conduit has a simple structure, which greatly reduces the difficulty of construction and surgical operation, and can achieve stable and controllable axial electrical stimulation through passive and wireless external field regulation, thereby promoting the regeneration and repair of central and peripheral nerve injuries, which is of great significance for promoting the regeneration and repair of central and peripheral nerve injuries, especially the reconstruction of neural function.
  • the nerve catheter preparation method provided in the present application does not require complex preparation processes and integrated packaging technology, which greatly reduces the difficulty of device construction.
  • the preparation process is simple and stable and controllable axial electrical stimulation is achieved through passive and wireless external field regulation, which greatly reduces the difficulty of construction and surgical operation. It is of great significance for promoting the regeneration and repair of central and peripheral nerve injuries, especially the reconstruction of nerve function.
  • FIG1 is a schematic diagram of the structure of a nerve conduit provided in an embodiment of the present application.
  • FIG. 2 is a flowchart showing the steps of the nerve catheter provided in this embodiment of the application.
  • first and second are used for descriptive purposes only and should not be understood as indicating or implying relative importance or implicitly indicating the number of the indicated technical features. Therefore, a feature defined as “first” or “second” may explicitly or implicitly include one or more of the features. In the description of this application, the meaning of “plurality” is two or more, unless otherwise clearly and specifically defined.
  • Figure 1 is a structural schematic diagram of a nerve catheter provided in an embodiment of the present application, including response units 10 and conductive units 20 arranged alternately in sequence, and the response units 10 and conductive units 20 both have a through-hole array structure.
  • the response unit 10 can generate a thermal or electric potential gradient and guide the directional migration of electrons or ions in the conductive unit 20 to form an electric current along the axial direction of the nerve catheter.
  • the response unit 10 and the conductive unit 20 have the same diameter, which is 200 ⁇ m - 2 cm.
  • the thickness of the response unit 10 is 5-300 ⁇ m, and the thickness of the conductive unit 20 is 100 ⁇ m - 2 mm.
  • the response units 10 and the conductive units 20 are alternately arranged in sequence, and the minimum alternating unit combination is a combination of 2 response units and 1 conductive unit.
  • the minimum number of holes in the through-hole array structure is 1, and the diameter of a single hole is 50 ⁇ m - 2 mm.
  • the response unit 10 can generate a thermal or electric potential gradient under the stimulation of external field energy, and the external field energy includes light or magnetic field or ultrasound.
  • the material of the response unit 10 includes: one or more of photothermal material, magnetocaloric material, photovoltaic material, piezoelectric material, photothermal material composite thermoelectric material, photothermal material composite pyroelectric material, magnetocaloric material composite thermoelectric material, magnetocaloric material composite pyroelectric material, upconversion material composite photovoltaic material, and photodeformation material composite piezoelectric material.
  • response unit 10 provided in this embodiment should have good energy conversion efficiency and biocompatibility.
  • the photothermal material is at least one of the following substances: carbon black, carbon nanotubes, graphene, black phosphorus, polydopamine, gold nanorods, gallium-indium alloy liquid metal, and MXene-based materials.
  • the magnetocaloric material is at least one of the following substances: ferroferric oxide, Ru-Fe-B alloy, iron, cobalt, nickel, and gadolinium.
  • the photovoltaic material is at least one of the following substances: thin-film solar cell materials including amorphous silicon, copper indium gallium selenide thin film, and cadmium telluride thin film, dye-sensitized solar cell materials based on titanium dioxide and its composites, perovskite solar cell materials based on perovskite-type organic metal halides, and organic photovoltaic materials including polyacetylene, polythiophene, polyaniline, polypyrrole and their derivatives and copolymers.
  • the piezoelectric material includes a piezoelectric crystal or a piezoelectric ceramic or a polyvinylidene fluoride ferroelectric polymer or a piezoelectric polymer
  • the piezoelectric crystal includes a quartz crystal or lithium gallate or lithium germanate or titanium germanate or lithium tantalate
  • the piezoelectric ceramic includes barium titanate or lead zirconate titanate or lead metaniobate or lead barium lithium niobate
  • the polyvinylidene fluoride ferroelectric polymer includes poly(vinylidene fluoride) or poly(vinylidene fluoride-trifluoroethylene) [P(VDF-TrFE) copolymer] or poly(vinylidene fluoride-chlorofluoroethylene) [P(VDF-CFE) copolymer] or poly(vinylidene fluoride-chlorotrifluoroethylene) [P(VDF-CTFE) copolymer] Polymer] or poly
  • the photothermal material composite thermoelectric material is a combination of the photothermal material and any one of the following thermoelectric materials; wherein the thermoelectric material includes at least one of a polymer material system and a p-type polymer thermoelectric material, the polymer material system is at least one of the following materials: polyacetylene, polyaniline, polypyrrole, polycarbazole, polythiophene, and polyvinylene derivatives, and the p-type polymer thermoelectric material is at least one of the following materials: polythiophenes, polyacetylene, polyaniline, polypyrrole, polycarbazole, and pyrrolopyrrole diketone, wherein the polythiophenes include at least one of the following materials: unsubstituted polythiophene PTh, poly(3-hexylthiophene) P3HT, poly[2,5-bis(3-tetradecylthiophene-2-yl)thiophene/[3,2
  • the photothermal composite pyroelectric material is a combination of the photothermal material and any one of the following pyroelectric materials; wherein the pyroelectric material is at least one of a polyvinylidene fluoride ferroelectric polymer and a perovskite ferroelectric ceramic, and the polyvinylidene fluoride ferroelectric polymer includes poly(vinylidene fluoride), poly(vinylidene fluoride-trifluoroethylene) [P(VDF-TrFE) copolymer], poly(vinylidene fluoride-chlorofluoroethylene) [P(VDF-CFE) copolymer], poly(vinylidene fluoride-chlorotrifluoroethylene) [P(VDF-CTFE)
  • the invention relates to a ferroelectric ceramic comprising at least one of: a poly(vinylidene fluoride-hexafluoropropylene) copolymer], a poly(vinyliden
  • the up-conversion material composite photovoltaic material is any combination of the up-conversion material and the photovoltaic material; wherein the up-conversion material is at least one of the following materials: yttrium oxide, yttrium oxysulfide, lanthanum fluoride, sodium yttrium fluoride, and sodium gadolinium fluoride.
  • the photodeformable material composite piezoelectric material is a combination of any one of the following photodeformable materials and the piezoelectric materials; wherein the photodeformable material is at least one of a photoisomerization material and a ferroelectric inorganic photodeformable material, the photoisomerization material includes at least one of azobenzene and its derivatives, spiropyran and its derivatives, and the ferroelectric inorganic photodeformable material includes at least one of lead titanate, barium titanate, potassium niobate, lithium niobate, lithium tantalate, bismuth layered perovskite structure ferroelectric, tungsten bronze type ferroelectric, bismuth ferrite, potassium dihydrogen phosphate, triammonium sulfate, Roche salt, and perovskite type organic metal halide ferroelectric.
  • the photodeformable material is at least one of a photoisomerization material and a ferroelectric inorganic photodeformable material
  • the magnetocaloric material composite thermoelectric material includes any combination of the magnetocaloric material and the thermoelectric material.
  • the magnetocaloric material composite pyroelectric material is any combination of the magnetocaloric material and the pyroelectric material.
  • the material of the conductive unit 20 includes one or more of: polyelectrolyte hydrogel, ion gel, conductive polymer hydrogel, and conductive filler-doped conductive hydrogel.
  • the conductive unit 20 should have good biocompatibility and good electron/ion transmission ability under thermal or electric field gradient.
  • the polyelectrolyte hydrogel includes at least one of a polyacid electrolyte, a polyalkali electrolyte and an amphoteric electrolyte
  • the polyacid electrolyte includes at least one of hyaluronic acid, polyethylene sulfonic acid, polyethylene phosphoric acid, polyacrylic acid, polymethyl methacrylic acid, and polystyrene sulfonic acid
  • the polyalkali electrolyte includes at least one of polyethyleneimine, polyethyleneamine, and polyvinyl pyridine
  • the amphoteric electrolyte includes at least one of polyphosphate, polysilicate, natural nucleic acid, and protein.
  • the ion gel is at least one of the following materials: a composite gel of polyacrylic acid and polyacrylamide, a composite gel of polyacrylic acid and chitosan, a composite gel of sodium alginate and polyacrylamide, a composite gel of polyacrylic acid and choline, a composite gel of sodium alginate and choline, a composite gel of methacrylated gelatin and choline, and a composite gel of methacrylated hyaluronic acid and choline.
  • the conductive polymer hydrogel is at least one of the following materials: polyaniline, polypyrrole, polythiophene and poly (3,4-ethylenedioxythiophene) based conductive polymer hydrogel.
  • the conductive filler-doped conductive hydrogel is any combination of a conductive filler and the conductive polymer hydrogel; wherein the conductive filler includes at least one of a metal-based conductive filler and a carbon-based conductive filler, the metal-based conductive filler includes Au or Ag, and the carbon-based conductive filler includes carbon black, graphite, carbon fiber, carbon nanotubes and graphene.
  • the nerve conduit provided in the above-mentioned embodiment of the present application comprises response units 10 and conductive units 20 arranged alternately in sequence, and both the response units 10 and the conductive units 20 have a through-hole array structure, and the response unit 10 can generate a thermal or electric potential gradient, and guide the directional migration of electrons or ions in the conductive unit 20, forming a current along the axial direction of the nerve conduit, thereby providing an axial electrical stimulation that can guide the elongation of axons when used for nerve regeneration and repair; and combined with the directional structural guidance provided by the through-hole array structure, the directional elongation of neuronal axons is guided in a coordinated and comprehensive manner.
  • the nerve conduit has a simple structure, which greatly reduces the difficulty of construction and surgical operation, and can achieve stable and controllable axial electrical stimulation through passive and wireless external field regulation, thereby promoting the regeneration and repair of central and peripheral nerve injuries, which is of great significance for promoting the regeneration and repair of central and peripheral nerve injuries, especially the reconstruction of nerve function.
  • FIG2 is a flowchart of a method for preparing a nerve conduit provided in the present application, comprising the following steps:
  • Step S10 construct the response unit.
  • the step of forming the response unit specifically includes the following steps: constructing the response unit in a mold by coating, spin coating or casting.
  • the mold is a single closed circular tubular lumen structure, and the bottom of the mold has solid cylinders arranged along the axial direction of the lumen to form an array porous structure of the nerve conduit.
  • Step S20 pouring a precursor material of the hydrogel constituting the conductive unit above the response unit to form a conductive unit through cross-linking.
  • the cross-linking method is at least one of ionic cross-linking and ultraviolet light cross-linking.
  • Step S30 alternately constructing the response units and the conductive units to form the nerve conduit.
  • the nerve catheter preparation method provided in the above-mentioned embodiment of the present application does not require complicated preparation process and integrated packaging technology, which greatly reduces the difficulty of device construction.
  • the preparation process is simple, and stable and controllable axial electrical stimulation is achieved through passive and wireless external field regulation, which greatly reduces the difficulty of construction and surgical operation. It is of great significance for promoting the regeneration and repair of central and peripheral nerve injuries, especially the reconstruction of nerve function.
  • An axial electrical stimulation nerve catheter system the structure of which is shown in FIG1 , comprises response units and conductive units which are alternately arranged and have a through-hole array structure; wherein the response units are made of photothermal material, and the conductive units are made of polyelectrolyte hydrogel.
  • the overall diameter of the catheter is 2 cm
  • the number of porous arrays is 4, and the pore diameter is 2 mm.
  • the number of alternating arrangements of the response unit and the conductive unit is 10 and 9 respectively.
  • the thickness of the photothermal response unit is 5 ⁇ m, and its material is a mixture of polystyrene and polydopamine; the thickness of the conductive unit is 100 ⁇ m, and its material is methacrylated hyaluronic acid hydrogel.
  • the preparation method of the neural stimulation array system comprises the following steps:
  • a polydopamine dispersion with a concentration of 1 w/v% was prepared; it was poured to the bottom of the mold and dried at 80 degrees Celsius to obtain a response unit of the catheter.
  • a precursor solution of methacrylated hyaluronic acid hydrogel containing photoinitiator 2959 was poured over the response unit in the mold, and a conductive unit was constructed by cross-linking with ultraviolet light.
  • a nerve conduit capable of external field-controlled axial electrical stimulation as claimed in claim 1 is finally formed.
  • An axial electrical stimulation nerve catheter system the structure of which is shown in FIG1 , comprises response units and conductive units which are alternately arranged and have a through-hole array structure; wherein the response units are made of magnetocaloric material, and the conductive units are made of ion gel.
  • the overall diameter of the catheter is 200 ⁇ m
  • the number of porous arrays that penetrate is 1
  • the pore diameter is 50 ⁇ m.
  • the number of alternating arrangements of the response unit and the conductive unit is 2 and 1 respectively.
  • the thickness of the response unit is 300 ⁇ m
  • its material is ferroferric oxide.
  • the thickness of the conductive unit is 2 mm, and its material is a composite gel of polymethacrylic acid, sodium alginate and choline.
  • the preparation method of the neural stimulation array system comprises the following steps:
  • a ferroferric oxide nanoparticle dispersion with a concentration of 25 w/v% was prepared; the dispersion was poured to the bottom of the mold, and dried at 60 degrees Celsius to obtain a response unit of the catheter.
  • a precursor mixed solution premixed with methacrylic acid monomer, sodium alginate, choline, and azobisisobutylamidine hydrochloride is poured above the response unit in the mold, and cross-linked for 3 hours at 60 degrees Celsius to construct a conductive unit that forms a catheter;
  • a nerve conduit capable of external field-controlled axial electrical stimulation as claimed in claim 1 is finally formed.
  • An axial electrical stimulation nerve catheter system the structure of which is shown in FIG1 , comprises response units and conductive units which are alternately arranged and have a through-hole array structure; wherein the response units are made of photovoltaic materials, and the conductive units are made of conductive polymer hydrogels.
  • the overall diameter of the catheter is 1 mm
  • the number of porous arrays is 4, and the pore diameter is 1 mm.
  • the number of alternating arrangements of the response unit and the conductive unit is 10 and 9 respectively.
  • the thickness of the response unit is 50 ⁇ m
  • its material is poly-3 hexylthiophene (P3HT).
  • the thickness of the conductive unit is 200 ⁇ m, and its material is poly (3,4-ethylenedioxythiophene): polystyrene sulfonic acid (PEDOT:PSS).
  • the preparation method of the neural stimulation array system comprises the following steps:
  • a P3HT solution with a concentration of 30 mg/mL was prepared; the solution was poured to the bottom of the mold and spin-coated at 60 degrees Celsius to obtain the response unit of the catheter.
  • a mixed solution of PEDOT:PSS and 4-dodecylbenzenesulfonic acid (DBSA) is poured above the response unit in the mold, and physically cross-linked at room temperature to construct a conductive unit;
  • a nerve conduit capable of external field-controlled axial electrical stimulation as claimed in claim 1 is finally formed.
  • An axial electrical stimulation nerve catheter system the structure of which is shown in FIG1 , comprises response units and conductive units which are alternately arranged and have a through-hole array structure; wherein the response unit is made of piezoelectric material, and the conductive unit is a conductive hydrogel doped with a conductive filler.
  • the overall diameter of the catheter is 2 cm
  • the number of porous arrays is 6, and the pore diameter is 200 ⁇ m.
  • the number of alternating arrangements of the response unit and the conductive unit is 10 and 9 respectively.
  • the thickness of the response unit is 50 ⁇ m
  • its material is polyvinylidene fluoride material.
  • the thickness of the conductive unit is 200 ⁇ m, and its material is sodium alginate choline composite gel with added liquid metal.
  • the preparation method of the neural stimulation array system comprises the following steps:
  • a polyvinylidene fluoride solution with a concentration of 10 w/v% was prepared; the solution was poured to the bottom of the mold and dried at 80 degrees Celsius to obtain a response unit of the catheter.
  • a precursor material of a sodium alginate choline composite gel of liquid metal is poured above the response unit in the mold, and CaCl2 ions are added for cross-linking to form a conductive unit;
  • a nerve conduit capable of external field-controlled axial electrical stimulation as claimed in claim 1 is finally formed.
  • An axial electrical stimulation nerve catheter system the structure of which is shown in FIG1 , comprises response units and conductive units which are alternately arranged and have a through-hole array structure; wherein the response unit is made of a photothermal material composite thermoelectric material, and the conductive unit is an ion gel.
  • the overall diameter of the catheter is 1 cm
  • the number of porous arrays is 4, and the pore diameter is 200 ⁇ m.
  • the number of alternating response units and conductive units is 10 and 9 respectively.
  • the thickness of the response unit is 50 ⁇ m
  • its material is PEDOT:PSS material with gold nanorods added.
  • the thickness of the conductive unit is 200 ⁇ m, and its material is sodium alginate and choline composite gel.
  • the preparation method of the neural stimulation array system comprises the following steps:
  • a precursor solution premixed with gold nanorods, PEDOT, PSS and DBSA is poured above the response unit in the mold, and physically cross-linked at room temperature to obtain the response unit of the catheter;
  • the precursor material of sodium alginate and choline composite gel is poured above the response unit in the mold, and CaCl2 ions are added for cross-linking to form a conductive unit;
  • a nerve conduit capable of external field-controlled axial electrical stimulation as claimed in claim 1 is finally formed.
  • An axial electrical stimulation nerve catheter system the structure of which is shown in FIG1 , comprises response units and conductive units which are alternately arranged and have a through-hole array structure; wherein the response unit is made of a photothermal material composite with a pyroelectric material, and the conductive unit is an ion gel.
  • the overall diameter of the catheter is 1 cm
  • the number of porous arrays is 4, and the pore diameter is 1 mm.
  • the number of alternating arrangements of the response unit and the conductive unit is 10 and 9 respectively.
  • the thickness of the response unit is 50 ⁇ m
  • its material is a composite of polyvinylidene fluoride and polydopamine.
  • the thickness of the conductive unit is 200 ⁇ m, and its material is a composite gel of sodium alginate and choline.
  • the preparation method of the neural stimulation array system comprises the following steps:
  • a mixed solution containing 10 w/v% polyvinylidene fluoride and 0.1 w/v% polydopamine was prepared; the solution was poured to the bottom of the mold and dried at 80 degrees Celsius to obtain a response unit of the catheter.
  • the precursor material of sodium alginate and choline composite gel is poured on the top of the response unit in the mold, and CaCl2 ions are added for cross-linking to form a conductive unit;
  • a nerve conduit capable of external field-controlled axial electrical stimulation as claimed in claim 1 is finally formed.
  • An axial electrical stimulation nerve catheter system the structure of which is shown in FIG1 , comprises response units and conductive units which are alternately arranged and have a through-hole array structure; wherein the response unit is made of a magnetocaloric material composite thermoelectric material, and the conductive unit is an ion gel.
  • the overall diameter of the catheter is 1 cm
  • the number of porous arrays is 4, and the pore diameter is 1 mm.
  • the number of alternating arrangements of the response unit and the conductive unit is 10 and 9 respectively.
  • the thickness of the response unit is 50 ⁇ m, and its material is a composite of ferroferric oxide and PEDOT:PSS.
  • the thickness of the conductive unit is 200 ⁇ m, and its material is a composite gel of sodium alginate and choline.
  • the preparation method of the neural stimulation array system comprises the following steps:
  • a precursor solution premixed with ferroferric oxide nanoparticles, PEDOT, PSS and DBSA is poured above the response unit in the mold, and physically cross-linked at room temperature to construct a catheter response unit;
  • the precursor material of sodium alginate and choline composite gel is poured above the response unit in the mold, and CaCl2 ions are added for cross-linking to form a conductive unit;
  • a nerve conduit capable of external field-controlled axial electrical stimulation as claimed in claim 1 is finally formed.
  • An axial electrical stimulation nerve catheter system the structure of which is shown in FIG1 , comprises response units and conductive units which are alternately arranged and have a through-hole array structure; wherein the response unit is made of a magnetocaloric material composite with a pyroelectric material, and the conductive unit is an ion gel.
  • the overall diameter of the catheter is 1 cm
  • the number of porous arrays is 4, and the pore diameter is 1 mm.
  • the number of alternating arrangements of the response unit and the conductive unit is 10 and 9 respectively.
  • the thickness of the response unit is 50 ⁇ m
  • its material is a mixture of polyvinylidene fluoride and ferroferric oxide.
  • the thickness of the conductive unit is 200 ⁇ m, and its material is a composite gel of sodium alginate and choline.
  • the preparation method of the neural stimulation array system comprises the following steps:
  • a mixed solution containing 10 w/v% polyvinylidene fluoride and 5 mg/mL ferrosoferric oxide nanoparticles was prepared; the solution was poured to the bottom of the mold and dried at 80 degrees Celsius to obtain the response unit of the catheter.
  • the precursor material of sodium alginate and choline composite gel is poured on the top of the response unit in the mold, and CaCl2 ions are added for cross-linking to form a conductive unit;
  • a nerve conduit capable of external field-controlled axial electrical stimulation as claimed in claim 1 is finally formed.
  • An axial electrical stimulation nerve catheter system the structure of which is shown in FIG1 , comprises response units and conductive units which are alternately arranged and have a through-hole array structure; wherein the response unit is made of an upconversion material composite photovoltaic material, and the conductive unit is an ion gel.
  • the overall diameter of the catheter is 1 cm
  • the number of porous arrays is 4, and the pore diameter is 1 mm.
  • the number of alternating arrangements of the response unit and the conductive unit is 10 and 9 respectively.
  • the thickness of the response unit is 50 ⁇ m
  • its material is poly-3 hexylthiophene (P3HT).
  • the thickness of the conductive unit is 200 ⁇ m, and its material is a composite gel of sodium alginate and choline.
  • the preparation method of the neural stimulation array system comprises the following steps:
  • a mixture solution containing 30 mg/mL P3HT and 0.1 mg/mL sodium gadolinium fluoride was prepared; the solution was poured onto the bottom of the mold and spin-coated at 60 degrees Celsius to obtain a response unit of the catheter.
  • the precursor material of sodium alginate and choline composite gel is poured above the response unit in the mold, and CaCl2 ions are added for cross-linking to form a conductive unit;
  • a nerve conduit capable of external field-controlled axial electrical stimulation as claimed in claim 1 is finally formed.
  • An axial electrical stimulation nerve catheter system the structure of which is shown in FIG1 , comprises response units and conductive units which are alternately arranged and have a through-hole array structure; wherein the response unit is made of a photodeformable material composite piezoelectric material, and the conductive unit is an ion gel.
  • the overall diameter of the catheter is 1 cm
  • the number of porous arrays is 4, and the pore diameter is 1 mm.
  • the number of alternating arrangements of the response unit and the conductive unit is 10 and 9 respectively.
  • the thickness of the response unit is 50 ⁇ m
  • its material is a mixture of polyvinylidene fluoride and azobenzene.
  • the thickness of the conductive unit is 200 ⁇ m, and its material is a composite gel of sodium alginate and choline.
  • the preparation method of the neural stimulation array system comprises the following steps:
  • a mixed solution with a polyvinylidene fluoride concentration of 5 w/v% and an azobenzene concentration of 1 w/v% was prepared; the solution was poured to the bottom of the mold and dried at 80 degrees Celsius to obtain a response unit of the catheter.
  • the precursor material of sodium alginate and choline composite gel is poured above the response unit in the mold, and CaCl2 ions are added for cross-linking to form a conductive unit;
  • a nerve conduit capable of external field-controlled axial electrical stimulation as claimed in claim 1 is finally formed.

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Abstract

一种神经导管及其制备方法。神经导管包括依次交替排列的响应单元和导电单元，响应单元和导电单元均具有贯通的多孔阵列结构，响应单元可产生热或电势梯度，并引导导电单元内电子或离子的定向迁移，形成沿神经导管的轴向方向的电流，从而在用于神经再生修复时提供可引导轴突伸长的轴向电刺激；并结合贯通多孔阵列结构提供的定向结构指引，共同作用、综合引导神经元轴突的定向伸长，该神经导管结构简单，大大降低了构造难度和手术操作难度，并且可通过无源、无线的外场调控方式实现稳定、可控的轴向电刺激，促进中枢和周围神经损伤的再生修复，对于促进中枢和周围神经损伤的再生修复特别是神经功能重建方面具有重要意义。

Description

神经导管、制备方法及其应用 技术领域
本申请涉及生物医学技术领域，特别涉及一种神经导管、制备方法及其应用。
 背景技术
因外伤、疾病或手术导致的神经损伤十分普遍。然而，无论中枢神经还是周围神经，在损伤后均缺乏自主再生修复的能力。如不能在有限的时间窗口内对其进行有效干预治疗，将会因受损部位的神经元凋亡而造成不可逆的神经功能损伤，导致轻则运动、感觉功能下降、重则肢体瘫痪乃至残疾的永久性后果。目前，临床上主要通过神经吻合手术或自体神经移植能方式治疗神经损伤，但这类方法无法用于较大程度神经缺损（缺损距离> 3 cm）的治疗,并且面临并发症发生风险高等固有弊端。
近年来，生物材料和组织工程领域的蓬勃发展为构建人工神经导管治疗神经损伤提供了新思路。人工神经导管旨在提供可支持神经再生修复的微环境，以维持神经元活性、引导神经元轴突伸长或支持施旺细胞再髓鞘化。然而，目前人工神经导管在用于较大缺损的神经损伤时仍面临神经功能重建的巨大挑战。研究表明，神经元间通过神经突结构形成的联接是实现神经功能的重要生理基础。因此，有效促进损伤部位的神经元轴突伸长并进而实现细胞间的有效联接是实现神经功能重建的关键。尽管现有通过构建具有取向结构人工神经导管的方法，在引导神经元轴突定向伸长方面取得一定的效果，但通过单一结构因素引导对神经功能重建的促进效果仍然有限。而在神经发育过程中，神经元基于其电活动实现的细胞响应，特别是对其神经突结构取向方向电场的空间响应，对于形成细胞间联接具有重要作用。基于此，现有导电神经导管在促进神经功能重建方面也得到了广泛的关注。但这类导电神经导管仅可提供支持神经元电活动的电活性环境，无法实现对神经元的主动定向电刺激，同样面临促神经元轴突伸长引导作用有限的瓶颈。
最近研究发现，通过定向电场施以主动的定向电刺激，可显著促进神经元轴突的定向伸长。伊利诺伊大学香槟分校Ralph G. Nuzzo教授领导的研究团队以及清华大学Lan Yin 教授领导的研究团队分别通过外源和内置电源构建了可提供沿神经元轴突伸长方向定向电场的神经导管，经在大鼠体内的植入实验证实，可通过此类神经导管基于定向电场施以的轴向电刺激，激活活体内受损部位神经元轴突的定向伸长，从而显著促进神经功能的重建。尽管这种基于轴向电刺激的神经导管在促神经功能重建方面取得了优异的效果，但目前此类神经导管有源、有线的构造和刺激方式显然增加了二次创伤和感染的风险；并且，在稳定、可控提供轴向电刺激方面同样面临挑战。
 技术问题
鉴于此，有必要针对现有技术中存在的缺陷提供一种安全性好且稳定可控的轴向电刺激的神经导管及其制备方法。
 技术解决方案
为解决上述问题，本申请采用下述技术方案：
本申请的目的之一，提供了一种神经导管，包括依次交替排列的响应单元和导电单元，所述响应单元和导电单元均具有贯通的多孔阵列结构，所述响应单元可产生热或电势梯度，并引导所述导电单元内电子或离子的定向迁移，形成沿所述神经导管的轴向方向的电流，所述外场能量包括光或磁场或超声。
在其中一些实施例中，所述响应单元和导电单元的直径一致，所述直径为200μm - 2cm。
在其中一些实施例中，所述响应单元的厚度为5-300 μm，所述导电单元的厚度为100μm - 2mm。
在其中一些实施例中，依次交替排列的所述响应单元和所述导电单元最少交替单元组合为2个所述响应单元和1个所述导电单元的组合。
在其中一些实施例中，所述贯通的多孔阵列结构的最小孔数量为1个，单个孔直径为 50μm - 2mm。
在其中一些实施例中，在外场能量刺激下，所述响应单元可产生热或电势梯度，所述外场能量包括光或磁场或超声。
在其中一些实施例中，所述响应单元的材质包括：光热材料、磁热材料、光伏材料、压电材料、光热材料复合热电材料、光热材料复合热释电材料、磁热材料复合热电材料、磁热材料复合热释电材料、上转换材料复合光伏材料、光致形变材料复合压电材料中的一种或多种。
在其中一些实施例中，所述光热材料为以下物质中的至少一种：炭黑、碳纳米管、石墨烯、黑磷、聚多巴胺、金纳米棒、镓铟合金液体金属、MXene基材料。
在其中一些实施例中，所述磁热材料为以下物质中的至少一种：四氧化三铁、汝铁硼合金、铁、钴、镍、钆。
在其中一些实施例中，所述光伏材料为以下物质中的至少一种：包括非晶硅、铜铟镓硒薄膜、碲化镉薄膜的薄膜太阳能电池材料，基于二氧化钛及其复合物的染料敏化太阳能电池材料，基于钙钛矿型有机金属卤化物的钙钛矿太阳能电池材料，以及包括聚乙炔、聚噻吩、聚苯胺、聚吡咯及其衍生物和共聚物的有机光伏材料。
在其中一些实施例中，所述压电材料包括压电晶体或压电陶瓷或聚偏氟乙烯类铁电聚合物或压电聚合物，所述压电晶体包括石英晶体或镓酸锂或锗酸锂或锗酸钛或钽酸锂；所述压电陶瓷包括钛酸钡或锆钛酸铅或偏铌酸铅或铌酸铅钡锂；所述聚偏氟乙烯类铁电聚合物包括聚（偏氟乙烯）或聚（偏氟乙烯-三氟乙烯） [P(VDF-TrFE)共聚物]或聚（偏氟乙烯-氯氟乙烯）[P(VDF-CFE)共聚物]或聚（偏氟乙烯-氯化三氟乙烯）[P(VDF-CTFE)共聚物]或聚（偏氟乙烯-六氟丙烯）[P(VDF-HFP)共聚物]或聚（偏氟乙烯-三氟乙烯-氯氟乙烯）[P(VDF-TrFE-CFE)三聚物]或聚（偏氟乙烯-三氟乙烯-氯化三氟乙烯）[P(VDF-TrFE-CTFE)三聚物]或聚（偏氟乙烯-三氟乙烯-六氟丙烯）[P(VDF-TrFE-HFP)三聚物]；所述压电聚合物包括奇数尼龙或聚丙烯腈或亚乙烯基二氰及其共聚物或聚脲或聚苯基氰基醚或聚氯乙烯或聚醋酸乙烯或聚丙烯或聚四氟乙烯。
在其中一些实施例中，所述光热材料复合热电材料为所述光热材料和下述热电材料中的任意一种组合；其中，所述热电材料包括高分子材料体系及p型高分子热电材料中至少一种，所述高分子材料体系为下述材料中至少一种：聚乙炔、聚苯胺、聚吡咯、聚咔唑、聚噻吩、聚对苯乙烯衍生物，所述p型高分子热电材料为下述材料中至少一种：聚噻吩类、聚乙炔类、聚苯胺类、聚吡咯类、聚咔唑类、吡咯并吡咯二酮类，其中，所述聚噻吩类包括下述材料中至少一种：无取代聚噻吩PTh、聚（3-己基噻吩）P3HT、聚[2,5-双(3-十四烷基噻吩-2-基)噻吩/[3,2-6]噻吩]PBTTT、聚(3，4-乙烯二氧噻吩)PEDOT、PEDOT：Tos、PEDOT：Tof、PEDOT：PSS。
在其中一些实施例中，所述光热材料复合热释电材料是所述光热材料和下述热释电材料中的任意一种组合；其中，所述热释电材料为聚偏氟乙烯类铁电聚合物及钙钛矿型铁电陶瓷中至少一种，所述聚偏氟乙烯类铁电聚合物包括聚（偏氟乙烯）、聚（偏氟乙烯-三氟乙烯） [P(VDF-TrFE)共聚物]、聚（偏氟乙烯-氯氟乙烯）[P(VDF-CFE)共聚物]、聚（偏氟乙烯-氯化三氟乙烯）[P(VDF-CTFE)共聚物]、聚（偏氟乙烯-六氟丙烯）[P(VDF-HFP)共聚物]、聚（偏氟乙烯-三氟乙烯-氯氟乙烯）[P(VDF-TrFE-CFE)三聚物]、聚（偏氟乙烯-三氟乙烯-氯化三氟乙烯）[P(VDF-TrFE-CTFE)三聚物]及聚（偏氟乙烯-三氟乙烯-六氟丙烯）[P(VDF-TrFE-HFP)三聚物]中至少一种，所述钙钛矿型铁电陶瓷包括钛酸钡、锆钛酸铅、偏铌酸铅、铌酸铅钡锂中至少一种。
在其中一些实施例中，所述上转换材料复合光伏材料为所述上转换材料和所述光伏材料中的任意一种组合；其中，所述上转换材料为下述材料中至少一种：氧化钇、硫氧化钇、氟化镧、氟钇化钠、氟钆化钠。
在其中一些实施例中，所述光致形变材料复合压电材料为下述光致形变材料和所述压电材料中的任意一种组合；其中，所述光致形变材料为光致异构材料及铁电类无机光致形变材料中至少一种，所述光致异构材料包括偶氮苯及其衍生物、螺吡喃及其衍生物中至少一种，所述铁电类无机光致形变材料包括钛酸铅、钛酸钡、铌酸钾、铌酸锂、钽酸锂、铋层状钙钛矿结构铁电体、钨青铜型铁电体、铁酸铋、磷酸二氢钾、硫酸三甘酸氨、罗息盐、钙钛矿型有机金属卤化物铁电体中至少一种。
在其中一些实施例中，所述磁热材料复合热电材料包括所述磁热材料和所述热电材料中的任意一种组合。
在其中一些实施例中，所述磁热材料复合热释电材料为所述磁热材料和所述热释电材料中的任意一种组合。
在其中一些实施例中，所述导电单元的材料包括：聚电解质水凝胶、离子凝胶、导电聚合物水凝胶、导电填料掺杂的导电水凝胶中的一种或多种。
在其中一些实施例中，所述聚电解质水凝胶包括聚酸类电解质、聚碱类电解质及两性电解质中至少一种，所述聚酸类电解质包括透明质酸、聚乙烯磺酸、聚乙烯磷酸、聚丙烯酸聚甲基丙烯酸、聚苯乙烯磺酸中至少一种；所述聚碱类电解质包括聚乙烯亚胺、聚乙烯胺、聚乙烯吡啶中至少一种；所述两性电解质包括聚磷酸盐、聚硅酸盐、天然的核酸、蛋白质中至少一种。
在其中一些实施例中，所述离子凝胶为下述材料中至少一种：聚丙烯酸和聚丙烯酰胺复合凝胶、聚丙烯酸和壳聚糖复合凝胶、海藻酸钠和聚丙烯酰胺复合凝胶、聚丙烯酸和胆碱复合凝胶、海藻酸钠和胆碱复合凝胶、甲基丙烯酸酰化明胶和胆碱复合凝胶、甲基丙烯酸酰化透明质酸和胆碱复合凝胶。
在其中一些实施例中，所述导电聚合物水凝胶为下述材料中至少一种：聚苯胺、聚吡咯、聚噻吩和聚（3,4-乙烯二氧噻吩）基导电聚合物水凝胶。
在其中一些实施例中，所述导电填料掺杂的导电水凝胶为导电填料和所述导电聚合物水凝胶中的任意一种组合；其中，所述导电填料包括金属系导电填料及碳系导电填料中至少一种，所述金属系导电填料包括Au或Ag，所述碳系导电填料包括炭黑、石墨、碳纤维、碳纳米管以及石墨烯。
本申请目的之二，提供了一种所述的神经导管的制备方法，包括下述步骤：
在模具内构建所述响应单元；
在所述响应单元上方灌注构成所述导电单元的水凝胶的前驱体材料，通过交联构建形成导电单元；
在所述模具内将所述响应单元和所述导电单元的交替构建，形成所述的神经导管。
在其中一些实施例中，在模具内构建所述响应单元的步骤中，具体包括下述步骤：通过涂布法、旋涂法或流延法，在模具内，构建所述响应单元。
在其中一些实施例中，所述交联的交联方式为离子交联、紫外光交联中至少一种。
在其中一些实施例中，所述模具为单封闭的圆形管腔结构，所述模具底部有沿管腔轴向排列的实心圆柱体，以形成神经导管的阵列多孔结构。
本申请目的之三，提供了一种所述的神经导管在神经再生修复中的应用。
 有益效果
本申请采用上述技术方案，其有益效果如下：
本申请提供的神经导管，包括依次交替排列的响应单元和导电单元，所述响应单元和导电单元均具有贯通的多孔阵列结构，所述响应单元可产生热或电势梯度，并引导所述导电单元内电子或离子的定向迁移，形成沿所述神经导管的轴向方向的电流，从而在用于神经再生修复时提供可引导轴突伸长的轴向电刺激；并结合贯通多孔阵列结构提供的定向结构指引，共同作用、综合引导神经元轴突的定向伸长，该神经导管结构简单，大大降低了构造难度和手术操作难度，并且可通过无源、无线的外场调控方式实现稳定、可控的轴向电刺激，促进中枢和周围神经损伤的再生修复，对于促进中枢和周围神经损伤的再生修复特别是神经功能重建方面具有重要意义。
另外，本申请提供的神经导管制备方法，无需复杂的制备工艺和集成封装技术，大大降低了器件的构建难度，制备工艺简单，通过无源、无线的外场调控方式实现稳定、可控的轴向电刺激，大大降低了构造难度和手术操作难度，对于促进中枢和周围神经损伤的再生修复特别是神经功能重建方面具有重要意义。
 附图说明
为了更清楚地说明本申请实施例的技术方案，下面将对本申请实施例或现有技术描述中所需要使用的附图作简单地介绍，显而易见地，下面所描述的附图仅仅是本申请的一些实施例，对于本领域普通技术人员来讲，在不付出创造性劳动的前提下，还可以根据这些附图获得其他的附图。
图1为本申请实施例提供的神经导管的结构示意图。
图2为申请本实施例提供的神经导管的步骤流程图。
 本发明的实施方式
下面详细描述本申请的实施例，所述实施例的示例在附图中示出，其中自始至终相同或类似的标号表示相同或类似的元件或具有相同或类似功能的元件。下面通过参考附图描述的实施例是示例性的，旨在用于解释本申请，而不能理解为对本申请的限制。
在本申请的描述中，需要理解的是，术语“上”、“下”、“水平”、“内”、“外”等指示的方位或位置关系为基于附图所示的方位或位置关系，仅是为了便于描述本申请和简化描述，而不是指示或暗示所指的装置或元件必须具有特定的方位、以特定的方位构造和操作，因此不能理解为对本申请的限制。
此外，术语“第一”、“第二”仅用于描述目的，而不能理解为指示或暗示相对重要性或者隐含指明所指示的技术特征的数量。由此，限定有“第一”、“第二”的特征可以明示或者隐含地包括一个或者更多个该特征。在本申请的描述中，“多个”的含义是两个或两个以上，除非另有明确具体的限定。
为了使本申请的目的、技术方案及优点更加清楚明白，以下结合附图及实施例，对本申请进行进一步详细说明。
请参阅图1，本申请一实施例提供的一种神经导管的结构示意图，包括依次交替排列的响应单元10和导电单元20，所述响应单元10和导电单元20均具有贯通的多孔阵列结构，所述响应单元10可产生热或电势梯度，并引导所述导电单元20内电子或离子的定向迁移，形成沿所述神经导管的轴向方向的电流。
在其中一些实施例中，所述响应单元10和导电单元20的直径一致，所述直径为200μm - 2cm。
在其中一些实施例中，所述响应单元10的厚度为5-300 μm，所述导电单元20的厚度为100μm - 2mm。
在其中一些实施例中，依次交替排列的所述响应单元10和所述导电单元20最少交替单元组合为2个所述响应单元和1个所述导电单元的组合。
在其中一些实施例中，所述贯通的多孔阵列结构的最小孔数量为1个，单个孔直径为 50μm - 2mm。
在其中一些实施例中，在外场能量刺激下，所述响应单元10可产生热或电势梯度，所述外场能量包括光或磁场或超声。
在其中一些实施例中，所述响应单元10的材质包括：光热材料、磁热材料、光伏材料、压电材料、光热材料复合热电材料、光热材料复合热释电材料、磁热材料复合热电材料、磁热材料复合热释电材料、上转换材料复合光伏材料、光致形变材料复合压电材料中的一种或多种。
可以理解，本实施例提供的所述响应单元10应具备较好的能量转化效率和生物相容性。
在其中一些实施例中，所述光热材料为以下物质中的至少一种：炭黑、碳纳米管、石墨烯、黑磷、聚多巴胺、金纳米棒、镓铟合金液体金属、MXene基材料。
在其中一些实施例中，所述磁热材料为以下物质中的至少一种：四氧化三铁、汝铁硼合金、铁、钴、镍、钆。
在其中一些实施例中，所述光伏材料为以下物质中的至少一种：包括非晶硅、铜铟镓硒薄膜、碲化镉薄膜的薄膜太阳能电池材料，基于二氧化钛及其复合物的染料敏化太阳能电池材料，基于钙钛矿型有机金属卤化物的钙钛矿太阳能电池材料，以及包括聚乙炔、聚噻吩、聚苯胺、聚吡咯及其衍生物和共聚物的有机光伏材料。
在其中一些实施例中，所述压电材料包括压电晶体或压电陶瓷或聚偏氟乙烯类铁电聚合物或压电聚合物，所述压电晶体包括石英晶体或镓酸锂或锗酸锂或锗酸钛或钽酸锂；所述压电陶瓷包括钛酸钡或锆钛酸铅或偏铌酸铅或铌酸铅钡锂；所述聚偏氟乙烯类铁电聚合物包括聚（偏氟乙烯）或聚（偏氟乙烯-三氟乙烯） [P(VDF-TrFE)共聚物]或聚（偏氟乙烯-氯氟乙烯）[P(VDF-CFE)共聚物]或聚（偏氟乙烯-氯化三氟乙烯）[P(VDF-CTFE)共聚物]或聚（偏氟乙烯-六氟丙烯）[P(VDF-HFP)共聚物]或聚（偏氟乙烯-三氟乙烯-氯氟乙烯）[P(VDF-TrFE-CFE)三聚物]或聚（偏氟乙烯-三氟乙烯-氯化三氟乙烯）[P(VDF-TrFE-CTFE)三聚物]或聚（偏氟乙烯-三氟乙烯-六氟丙烯）[P(VDF-TrFE-HFP)三聚物]；所述压电聚合物包括奇数尼龙或聚丙烯腈或亚乙烯基二氰及其共聚物或聚脲或聚苯基氰基醚或聚氯乙烯或聚醋酸乙烯或聚丙烯或聚四氟乙烯。
在其中一些实施例中，所述光热材料复合热电材料为所述光热材料和下述热电材料中的任意一种组合；其中，所述热电材料包括高分子材料体系及p型高分子热电材料中至少一种，所述高分子材料体系为下述材料中至少一种：聚乙炔、聚苯胺、聚吡咯、聚咔唑、聚噻吩、聚对苯乙烯衍生物，所述p型高分子热电材料为下述材料中至少一种：聚噻吩类、聚乙炔类、聚苯胺类、聚吡咯类、聚咔唑类、吡咯并吡咯二酮类，其中，所述聚噻吩类包括下述材料中至少一种：无取代聚噻吩PTh、聚（3-己基噻吩）P3HT、聚[2,5-双(3-十四烷基噻吩-2-基)噻吩/[3,2-6]噻吩]PBTTT、聚(3，4-乙烯二氧噻吩)PEDOT、PEDOT：Tos、PEDOT：Tof、PEDOT：PSS。
在其中一些实施例中，所述光热材料复合热释电材料是所述光热材料和下述热释电材料中的任意一种组合；其中，所述热释电材料为聚偏氟乙烯类铁电聚合物及钙钛矿型铁电陶瓷中至少一种，所述聚偏氟乙烯类铁电聚合物包括聚（偏氟乙烯）、聚（偏氟乙烯-三氟乙烯） [P(VDF-TrFE)共聚物]、聚（偏氟乙烯-氯氟乙烯）[P(VDF-CFE)共聚物]、聚（偏氟乙烯-氯化三氟乙烯）[P(VDF-CTFE)共聚物]、聚（偏氟乙烯-六氟丙烯）[P(VDF-HFP)共聚物]、聚（偏氟乙烯-三氟乙烯-氯氟乙烯）[P(VDF-TrFE-CFE)三聚物]、聚（偏氟乙烯-三氟乙烯-氯化三氟乙烯）[P(VDF-TrFE-CTFE)三聚物]及聚（偏氟乙烯-三氟乙烯-六氟丙烯）[P(VDF-TrFE-HFP)三聚物]中至少一种，所述钙钛矿型铁电陶瓷包括钛酸钡、锆钛酸铅、偏铌酸铅、铌酸铅钡锂中至少一种。
在其中一些实施例中，所述上转换材料复合光伏材料为所述上转换材料和所述光伏材料中的任意一种组合；其中，所述上转换材料为下述材料中至少一种：氧化钇、硫氧化钇、氟化镧、氟钇化钠、氟钆化钠。
在其中一些实施例中，所述光致形变材料复合压电材料为下述光致形变材料和所述压电材料中的任意一种组合；其中，所述光致形变材料为光致异构材料及铁电类无机光致形变材料中至少一种，所述光致异构材料包括偶氮苯及其衍生物、螺吡喃及其衍生物中至少一种，所述铁电类无机光致形变材料包括钛酸铅、钛酸钡、铌酸钾、铌酸锂、钽酸锂、铋层状钙钛矿结构铁电体、钨青铜型铁电体、铁酸铋、磷酸二氢钾、硫酸三甘酸氨、罗息盐、钙钛矿型有机金属卤化物铁电体中至少一种。
在其中一些实施例中，所述磁热材料复合热电材料包括所述磁热材料和所述热电材料中的任意一种组合。
在其中一些实施例中，所述磁热材料复合热释电材料为所述磁热材料和所述热释电材料中的任意一种组合。
在其中一些实施例中，所述导电单元20的材料包括：聚电解质水凝胶、离子凝胶、导电聚合物水凝胶、导电填料掺杂的导电水凝胶中的一种或多种。
可以理解，本实施例中，所述导电单元20应具备较好的生物相容性以及在热或电场梯度下良好的电子/离子传输能力。
在其中一些实施例中，所述聚电解质水凝胶包括聚酸类电解质、聚碱类电解质及两性电解质中至少一种，所述聚酸类电解质包括透明质酸、聚乙烯磺酸、聚乙烯磷酸、聚丙烯酸聚甲基丙烯酸、聚苯乙烯磺酸中至少一种；所述聚碱类电解质包括聚乙烯亚胺、聚乙烯胺、聚乙烯吡啶中至少一种；所述两性电解质包括聚磷酸盐、聚硅酸盐、天然的核酸、蛋白质中至少一种。
在其中一些实施例中，所述离子凝胶为下述材料中至少一种：聚丙烯酸和聚丙烯酰胺复合凝胶、聚丙烯酸和壳聚糖复合凝胶、海藻酸钠和聚丙烯酰胺复合凝胶、聚丙烯酸和胆碱复合凝胶、海藻酸钠和胆碱复合凝胶、甲基丙烯酸酰化明胶和胆碱复合凝胶、甲基丙烯酸酰化透明质酸和胆碱复合凝胶。
在其中一些实施例中，所述导电聚合物水凝胶为下述材料中至少一种：聚苯胺、聚吡咯、聚噻吩和聚（3,4-乙烯二氧噻吩）基导电聚合物水凝胶。
在其中一些实施例中，所述导电填料掺杂的导电水凝胶为导电填料和所述导电聚合物水凝胶中的任意一种组合；其中，所述导电填料包括金属系导电填料及碳系导电填料中至少一种，所述金属系导电填料包括Au或Ag，所述碳系导电填料包括炭黑、石墨、碳纤维、碳纳米管以及石墨烯。
本申请上述实施例提供的神经导管，包括依次交替排列的响应单元10和导电单元20，所述响应单元10和导电单元20均具有贯通的多孔阵列结构，所述响应单元10可产生热或电势梯度，并引导所述导电单元20内电子或离子的定向迁移，形成沿所述神经导管的轴向方向的电流，从而在用于神经再生修复时提供可引导轴突伸长的轴向电刺激；并结合贯通多孔阵列结构提供的定向结构指引，共同作用、综合引导神经元轴突的定向伸长，该神经导管结构简单，大大降低了构造难度和手术操作难度，并且可通过无源、无线的外场调控方式实现稳定、可控的轴向电刺激，，促进中枢和周围神经损伤的再生修复，对于促进中枢和周围神经损伤的再生修复特别是神经功能重建方面具有重要意义。
请参阅图2，为本申请提供的一种所述的神经导管的制备方法的步骤流程图，包括下述步骤：
步骤S10：构建所述响应单元。
在其中一些实施例中，在所述响应单元的步骤中，具体包括下述步骤：通过涂布法、旋涂法或流延法，在模具内，构建所述响应单元。
在其中一些实施例中，所述模具为单封闭的圆形管腔结构，所述模具底部有沿管腔轴向排列的实心圆柱体，以形成神经导管的阵列多孔结构。
步骤S20：在所述响应单元上方灌注构成所述导电单元的水凝胶的前驱体材料，通过交联构建形成导电单元。
在其中一些实施例中，所述交联的交联方式为离子交联、紫外光交联中至少一种。
步骤S30：将所述响应单元和所述导电单元的交替构建，形成所述的神经导管。
本申请上述实施例提供的神经导管制备方法，无需复杂的制备工艺和集成封装技术，大大降低了器件的构建难度，制备工艺简单，通过无源、无线的外场调控方式实现稳定、可控的轴向电刺激，大大降低了构造难度和手术操作难度，对于促进中枢和周围神经损伤的再生修复特别是神经功能重建方面具有重要意义。
以下结合具体实施例对本申请上述技术方案进行详细说明。
实施例1
一种轴向电刺激神经导管系统，结构如图1所示，该轴向电刺激神经导管系统包括交替排列、具有贯通的多孔阵列结构的响应单元和导电单元；其中，响应单元由光热材料制成，导电单元由聚电解质水凝胶制成。
本实施例中，导管的整体直径为2 cm，贯通的多孔阵列数量为4个，孔径均为2 mm。响应单元和导电单元的交替排列数量分别是10个和9个。其中，光热响应单元的厚度为5 μm，其材质为聚苯乙烯和聚多巴胺混合物材料；导电单元的厚度为100 μm，材质为甲基丙烯酸酰化透明质酸水凝胶。
该神经刺激阵列系统的制备方法，包括以下步骤：
1）响应单元制备：
使用二甲基亚砜作溶剂，配置浓度为1 w/v %聚多巴胺分散液；浇注至模具底部，80摄氏度下烘干，制得导管的响应单元。
2）导电单元制备：
在模具内的响应单元上方灌注加有光引发剂2959的甲基丙烯酸酰化透明质酸水凝胶的前驱体溶液，通过紫外光交联，构建形成导电单元。
3）神经导管组装
通过在模具内，响应单元和导电单元的交替构建，最终形成如权利要求1所述的可外场调控轴向电刺激的神经导管。
实施例2
一种轴向电刺激神经导管系统，结构如图1所示，该轴向电刺激神经导管系统包括交替排列、具有贯通的多孔阵列结构的响应单元和导电单元；其中，响应单元由磁热材料制成，导电单元由离子凝胶制成。
本实施例中，导管的整体直径为200 μm，贯通的多孔阵列数量为1个，孔径均为50 μm。响应单元和导电单元的交替排列数量分别是2个和1个。其中，响应单元的厚度为300 μm，其材质为四氧化三铁。导电单元的厚度为2 mm，其材质为聚甲基丙烯酸、海藻酸钠和胆碱的复合凝胶。
该神经刺激阵列系统的制备方法，包括以下步骤：
1）响应单元制备：
配置浓度为25 w/v% 的四氧化三铁纳米颗粒分散液；将分散液浇注至模具底部，60摄氏度下烘干，制得导管的响应单元。
2）导电单元制备：
在模具内的响应单元上方灌注预混有甲基丙烯酸单体、海藻酸钠、胆碱、偶氮二异丁基脒盐酸盐的前驱体混合溶液，60摄氏度下交联反应3小时，构建形成导管的导电单元；
3）神经导管组装
通过在模具内，响应单元和导电单元的交替构建，最终形成如权利要求1所述的可外场调控轴向电刺激的神经导管。
实施例3
一种轴向电刺激神经导管系统，结构如图1所示，该轴向电刺激神经导管系统包括交替排列、具有贯通的多孔阵列结构的响应单元和导电单元；其中，响应单元由光伏材料制成，导电单元由导电聚合物水凝胶制成。
本实施例中，导管的整体直径为1 mm，贯通的多孔阵列数量为4个，孔径均为1 mm。响应单元和导电单元的交替排列数量分别是10个和9个。其中，响应单元厚度为50 μm，其材质为聚-3己基噻吩（P3HT)。导电单元的厚度为200μm，其材质为聚（3,4-亚乙基二氧噻吩）：聚苯乙烯磺酸（PEDOT：PSS）。
该神经刺激阵列系统的制备方法，包括以下步骤：
1）响应单元制备：
使用1,2-二氯代苯作溶剂，配置浓度为30 mg/mL 的P3HT溶液；将溶液浇注至模具底部，60摄氏度下旋涂，制得导管的响应单元。
2）导电单元制备：
在模具内的响应单元上方灌注预混有PEDOT:PSS和4-十二烷基苯磺酸（DBSA）的混合溶液，室温下物理交联，构建形成导电单元；
3）神经导管组装
通过在模具内，响应单元和导电单元的交替构建，最终形成如权利要求1所述的可外场调控轴向电刺激的神经导管。
实施例4
一种轴向电刺激神经导管系统，结构如图1所示，该轴向电刺激神经导管系统包括交替排列、具有贯通的多孔阵列结构的响应单元和导电单元；其中响应单元由压电材料制成，导电单元为导电填料掺杂的导电水凝胶。
本实施例中，导管的整体直径为2 cm，贯通的多孔阵列数量为6个，孔径均为200 μm。响应单元和导电单元的交替排列数量分别是10个和9个。其中，响应单元的厚度为50 μm，其材质为聚偏氟乙烯材料。导电单元的厚度为200 μm，其材质为添加液态金属的海藻酸钠胆碱复合凝胶。
该神经刺激阵列系统的制备方法，包括以下步骤：
1）响应单元制备：
使用二甲基亚砜作溶剂，配置浓度为10 w/v% 的聚偏氟乙烯溶液；将溶液浇注至模具底部，80摄氏度下烘干，制得导管的响应单元。
2）导电单元制备：
在模具内的响应单元上方灌注液态金属的海藻酸钠胆碱复合凝胶的前驱体材料，加入CaCl2离子交联，构建形成导电单元；
3）神经导管组装
通过在模具内，响应单元和导电单元的交替构建，最终形成如权利要求1所述的可外场调控轴向电刺激的神经导管。
实施例5
一种轴向电刺激神经导管系统，结构如图1所示，该轴向电刺激神经导管系统包括交替排列、具有贯通的多孔阵列结构的响应单元和导电单元；其中响应单元由光热材料复合热电材料制成，导电单元为离子凝胶。
本实施例中，导管的整体直径为1 cm，贯通的多孔阵列数量为4个，孔径均为200 μm。响应单元和导电单元的交替排列数量分别是10个和9个。其中，，响应单元的厚度为50 μm，其材质为添加金纳米棒的PEDOT:PSS材料。导电单元的厚度为200 μm，其材质为海藻酸钠和胆碱复合凝胶。
该神经刺激阵列系统的制备方法，包括以下步骤：
1）响应单元制备：
在模具内的响应单元上方灌注预混有金纳米棒、PEDOT、PSS和DBSA的前驱体溶液，室温下物理交联，制得导管的响应单元；
2）导电单元制备：
在模具内的响应单元上方灌注海藻酸钠和胆碱复合凝胶的前驱体材料，加入CaCl2离子交联，构建形成导电单元；
3）神经导管组装
通过在模具内，响应单元和导电单元的交替构建，最终形成如权利要求1所述的可外场调控轴向电刺激的神经导管。
实施例6
一种轴向电刺激神经导管系统，结构如图1所示，该轴向电刺激神经导管系统包括交替排列、具有贯通的多孔阵列结构的响应单元和导电单元；其中响应单元由光热材料复合热释电材料制成，导电单元为离子凝胶。
本实施例中，导管的整体直径为1 cm，贯通的多孔阵列数量为4个，孔径均为1 mm。响应单元和导电单元的交替排列数量分别是10个和9个。其中，响应单元的厚度为50 μm，其材质为聚偏氟乙烯和聚多巴胺的复合物。导电单元的厚度为200 μm，其材质为海藻酸钠和胆碱复合凝胶。
该神经刺激阵列系统的制备方法，包括以下步骤：
1）响应单元制备：
使用二甲基亚砜作溶剂，配置含10 w/v%聚偏氟乙烯和0.1 w/v%聚多巴胺的混合溶液；将溶液浇注至模具底部，80摄氏度下干燥，制得导管的响应单元。
2）导电单元制备：
在模具内的响应单元上方灌注海藻酸钠和胆碱复合凝胶的前驱体材料，加入CaCl2离子交联，构建形成导电单元；
3）神经导管组装
通过在模具内，响应单元和导电单元的交替构建，最终形成如权利要求1所述的可外场调控轴向电刺激的神经导管。
实施例7
一种轴向电刺激神经导管系统，结构如图1所示，该轴向电刺激神经导管系统包括交替排列、具有贯通的多孔阵列结构的响应单元和导电单元；其中响应单元由磁热材料复合热电材料制成，导电单元为离子凝胶。
本实施例中，导管的整体直径为1 cm，贯通的多孔阵列数量为4个，孔径均为1 mm。响应单元和导电单元的交替排列数量分别是10个和9个。其中，响应单元的厚度为50 μm，其材质为四氧化三铁和PEDOT:PSS的复合物。导电单元的厚度为200 μm，其材质为海藻酸钠和胆碱复合凝胶。
该神经刺激阵列系统的制备方法，包括以下步骤：
1）响应单元制备：
在模具内的响应单元上方灌注预混有四氧化三铁纳米颗粒、PEDOT、PSS和DBSA的前驱体溶液，室温下物理交联，构建形成导管响应单元；
2）导电单元制备：
在模具内的响应单元上方灌注海藻酸钠和胆碱复合凝胶的前驱体材料，加入CaCl2离子交联，构建形成导电单元；
3）神经导管组装
通过在模具内，响应单元和导电单元的交替构建，最终形成如权利要求1所述的可外场调控轴向电刺激的神经导管。
实施例8
一种轴向电刺激神经导管系统，结构如图1所示，该轴向电刺激神经导管系统包括交替排列、具有贯通的多孔阵列结构的响应单元和导电单元；其中响应单元由磁热材料复合热释电材料制成，导电单元为离子凝胶。
本实施例中，导管的整体直径为1 cm，贯通的多孔阵列数量为4个，孔径均为1 mm。响应单元和导电单元的交替排列数量分别是10个和9个。其中，响应单元的厚度为50 μm，其材质为聚偏氟乙烯和四氧化三铁的混合物。导电单元的厚度为200 μm，其材质为海藻酸钠和胆碱复合凝胶。
该神经刺激阵列系统的制备方法，包括以下步骤：
1）响应单元制备：
使用二甲基亚砜作溶剂，配置含10 w/v%聚偏氟乙烯和5 mg/mL四氧化三铁纳米粒子的混合溶液；将溶液浇注至模具底部，80摄氏度下烘干，制得导管的响应单元。
2）导电单元制备：
在模具内的响应单元上方灌注海藻酸钠和胆碱复合凝胶的前驱体材料，加入CaCl2离子交联，构建形成导电单元；
3）神经导管组装
通过在模具内，响应单元和导电单元的交替构建，最终形成如权利要求1所述的可外场调控轴向电刺激的神经导管。
实施例9
一种轴向电刺激神经导管系统，结构如图1所示，该轴向电刺激神经导管系统包括交替排列、具有贯通的多孔阵列结构的响应单元和导电单元；其中响应单元由上转换材料复合光伏材料制成，导电单元为离子凝胶。
本实施例中，导管的整体直径为1 cm，贯通的多孔阵列数量为4个，孔径均为1 mm。响应单元和导电单元的交替排列数量分别是10个和9个。其中，响应单元的厚度为50 μm，其材质为聚-3己基噻吩（P3HT)。导电单元的厚度为200 μm，其材质为海藻酸钠和胆碱复合凝胶。
该神经刺激阵列系统的制备方法，包括以下步骤：
1）响应单元制备：
使用1,2-二氯代苯作溶剂，配置含有30 mg/mL P3HT 和0.1 mg/mL氟钆化钠的混合物溶液；将溶液浇注至模具底部，60摄氏度下旋涂，制得导管的响应单元。
2）导电单元制备：
在模具内的响应单元上方灌注海藻酸钠和胆碱复合凝胶的前驱体材料，通过加入CaCl2离子交联，构建形成导电单元；
3）神经导管组装
通过在模具内，响应单元和导电单元的交替构建，最终形成如权利要求1所述的可外场调控轴向电刺激的神经导管。
实施例10
一种轴向电刺激神经导管系统，结构如图1所示，该轴向电刺激神经导管系统包括交替排列、具有贯通的多孔阵列结构的响应单元和导电单元；其中响应单元由光致形变材料复合压电材料制成，导电单元为离子凝胶。
本实施例中，导管的整体直径为1 cm，贯通的多孔阵列数量为4个，孔径均为1 mm。响应单元和导电单元的交替排列数量分别是10个和9个。其中，响应单元的厚度为50 μm，其材质为聚偏氟乙烯和偶氮苯混合物。导电单元的厚度为200 μm，其材质为海藻酸钠和胆碱复合凝胶。
该神经刺激阵列系统的制备方法，包括以下步骤：
1）响应单元制备：
使用二甲基亚砜作溶剂，配置聚偏氟乙烯浓度为5 w/v% 、偶氮苯浓度为1 w/v%的混合溶液；将溶液浇注至模具底部，80摄氏度下烘干，制得导管的响应单元。
2）导电单元制备：
在模具内的响应单元上方灌注海藻酸钠和胆碱复合凝胶的前驱体材料，加入CaCl2离子交联，构建形成导电单元；
3）神经导管组装
通过在模具内，响应单元和导电单元的交替构建，最终形成如权利要求1所述的可外场调控轴向电刺激的神经导管。
可以理解，以上所述实施例的各技术特征可以进行任意的组合，为使描述简洁，未对上述实施例中的各个技术特征所有可能的组合都进行描述，然而，只要这些技术特征的组合不存在矛盾，都应当认为是本说明书记载的范围。
以上仅为本申请的较佳实施例而已，仅具体描述了本申请的技术原理，这些描述只是为了解释本申请的原理，不能以任何方式解释为对本申请保护范围的限制。基于此处解释，凡在本申请的精神和原则之内所作的任何修改、等同替换和改进，及本领域的技术人员不需要付出创造性的劳动即可联想到本申请的其他具体实施方式，均应包含在本申请的保护范围之内。

Claims (27)

  1. 一种神经导管，其特征在于，包括依次交替排列的响应单元和导电单元，所述响应单元和导电单元均具有贯通的多孔阵列结构，所述响应单元可产生热或电势梯度，并引导所述导电单元内电子或离子的定向迁移，形成沿所述神经导管的轴向方向的电流。
  2. 如权利要求1所述的神经导管，其特征在于，所述响应单元和导电单元的直径一致，所述直径为200μm - 2cm。
  3. 如权利要求1所述的神经导管，其特征在于，所述响应单元的厚度为5-300 μm，所述导电单元的厚度为100μm - 2mm。
  4. 如权利要求1或2或3所述基于活性界面的神经导管，其特征在于，依次交替排列的所述响应单元和所述导电单元最少交替单元组合为2个所述响应单元和1个所述导电单元的组合。
  5. 如权利要求1所述的神经导管，其特征在于，所述贯通的多孔阵列结构的最小孔数量为1个，单个孔直径为 50μm - 2mm。
  6. 如权利要求1所述的神经导管，其特征在于，在外场能量刺激下，所述响应单元可产生热或电势梯度，所述外场能量包括光或磁场或超声。
  7. 如权利要求1所述的神经导管，其特征在于，所述响应单元的材质包括：光热材料、磁热材料、光伏材料、压电材料、光热材料复合热电材料、光热材料复合热释电材料、磁热材料复合热电材料、磁热材料复合热释电材料、上转换材料复合光伏材料、光致形变材料复合压电材料中的一种或多种。
  8. 如权利要求1或7所述的神经导管，其特征在于，所述光热材料为以下物质中的至少一种：炭黑、碳纳米管、石墨烯、黑磷、聚多巴胺、金纳米棒、镓铟合金液体金属、MXene基材料。
  9. 如权利要求1或7所述的神经导管，其特征在于，所述磁热材料为以下物质中的至少一种：四氧化三铁、汝铁硼合金、铁、钴、镍、钆。
  10. 如权利要求1或7所述的神经导管，其特征在于，所述光伏材料为以下物质中的至少一种：包括非晶硅、铜铟镓硒薄膜、碲化镉薄膜的薄膜太阳能电池材料，基于二氧化钛及其复合物的染料敏化太阳能电池材料，基于钙钛矿型有机金属卤化物的钙钛矿太阳能电池材料，以及包括聚乙炔、聚噻吩、聚苯胺、聚吡咯及其衍生物和共聚物的有机光伏材料。
  11. 如权利要求1或7所述的神经导管，其特征在于，所述压电材料包括压电晶体或压电陶瓷或聚偏氟乙烯类铁电聚合物或压电聚合物，所述压电晶体包括石英晶体或镓酸锂或锗酸锂或锗酸钛或钽酸锂；所述压电陶瓷包括钛酸钡或锆钛酸铅或偏铌酸铅或铌酸铅钡锂；所述聚偏氟乙烯类铁电聚合物包括聚（偏氟乙烯）或聚（偏氟乙烯-三氟乙烯） [P(VDF-TrFE)共聚物]或聚（偏氟乙烯-氯氟乙烯）[P(VDF-CFE)共聚物]或聚（偏氟乙烯-氯化三氟乙烯）[P(VDF-CTFE)共聚物]或聚（偏氟乙烯-六氟丙烯）[P(VDF-HFP)共聚物]或聚（偏氟乙烯-三氟乙烯-氯氟乙烯）[P(VDF-TrFE-CFE)三聚物]或聚（偏氟乙烯-三氟乙烯-氯化三氟乙烯）[P(VDF-TrFE-CTFE)三聚物]或聚（偏氟乙烯-三氟乙烯-六氟丙烯）[P(VDF-TrFE-HFP)三聚物]；所述压电聚合物包括奇数尼龙或聚丙烯腈或亚乙烯基二氰及其共聚物或聚脲或聚苯基氰基醚或聚氯乙烯或聚醋酸乙烯或聚丙烯或聚四氟乙烯。
  12. 如权利要求8所述的神经导管，其特征在于，所述光热材料复合热电材料为所述光热材料和下述热电材料中的任意一种组合；其中，所述热电材料包括高分子材料体系及p型高分子热电材料中至少一种，所述高分子材料体系为下述材料中至少一种：聚乙炔、聚苯胺、聚吡咯、聚咔唑、聚噻吩、聚对苯乙烯衍生物，所述p型高分子热电材料为下述材料中至少一种：聚噻吩类、聚乙炔类、聚苯胺类、聚吡咯类、聚咔唑类、吡咯并吡咯二酮类，其中，所述聚噻吩类包括下述材料中至少一种：无取代聚噻吩PTh、聚（3-己基噻吩）P3HT、聚[2,5-双(3-十四烷基噻吩-2-基)噻吩/[3,2-6]噻吩]PBTTT、聚(3，4-乙烯二氧噻吩)PEDOT、PEDOT：Tos、PEDOT：Tof、PEDOT：PSS。
  13. 如权利要求8所述的神经导管，其特征在于，所述光热材料复合热释电材料是所述光热材料和下述热释电材料中的任意一种组合；其中，所述热释电材料为聚偏氟乙烯类铁电聚合物及钙钛矿型铁电陶瓷中至少一种，所述聚偏氟乙烯类铁电聚合物包括聚（偏氟乙烯）、聚（偏氟乙烯-三氟乙烯） [P(VDF-TrFE)共聚物]、聚（偏氟乙烯-氯氟乙烯）[P(VDF-CFE)共聚物]、聚（偏氟乙烯-氯化三氟乙烯）[P(VDF-CTFE)共聚物]、聚（偏氟乙烯-六氟丙烯）[P(VDF-HFP)共聚物]、聚（偏氟乙烯-三氟乙烯-氯氟乙烯）[P(VDF-TrFE-CFE)三聚物]、聚（偏氟乙烯-三氟乙烯-氯化三氟乙烯）[P(VDF-TrFE-CTFE)三聚物]及聚（偏氟乙烯-三氟乙烯-六氟丙烯）[P(VDF-TrFE-HFP)三聚物]中至少一种，所述钙钛矿型铁电陶瓷包括钛酸钡、锆钛酸铅、偏铌酸铅、铌酸铅钡锂中至少一种。
  14. 如权利要求10所述的神经导管，其特征在于，所述上转换材料复合光伏材料为所述上转换材料和所述光伏材料中的任意一种组合；其中，所述上转换材料为下述材料中至少一种：氧化钇、硫氧化钇、氟化镧、氟钇化钠、氟钆化钠。
  15. 如权利要求11所述的神经导管，其特征在于，所述光致形变材料复合压电材料为下述光致形变材料和所述压电材料中的任意一种组合；其中，所述光致形变材料为光致异构材料及铁电类无机光致形变材料中至少一种，所述光致异构材料包括偶氮苯及其衍生物、螺吡喃及其衍生物中至少一种，所述铁电类无机光致形变材料包括钛酸铅、钛酸钡、铌酸钾、铌酸锂、钽酸锂、铋层状钙钛矿结构铁电体、钨青铜型铁电体、铁酸铋、磷酸二氢钾、硫酸三甘酸氨、罗息盐、钙钛矿型有机金属卤化物铁电体中至少一种。
  16. 如权利要求12所述的神经导管，其特征在于，所述磁热材料复合热电材料包括所述磁热材料和所述热电材料中的任意一种组合。
  17. 如权利要求13所述的神经导管，其特征在于，所述磁热材料复合热释电材料为所述磁热材料和所述热释电材料中的任意一种组合。
  18. 如权利要求1所述的神经导管，其特征在于，所述导电单元的材料包括：聚电解质水凝胶、离子凝胶、导电聚合物水凝胶、导电填料掺杂的导电水凝胶中的一种或多种。
  19. 如权利要求18所述的神经导管，其特征在于，所述聚电解质水凝胶包括聚酸类电解质、聚碱类电解质及两性电解质中至少一种，所述聚酸类电解质包括透明质酸、聚乙烯磺酸、聚乙烯磷酸、聚丙烯酸聚甲基丙烯酸、聚苯乙烯磺酸中至少一种；所述聚碱类电解质包括聚乙烯亚胺、聚乙烯胺、聚乙烯吡啶中至少一种；所述两性电解质包括聚磷酸盐、聚硅酸盐、天然的核酸、蛋白质中至少一种。
  20. 如权利要求18所述的神经导管，其特征在于，所述离子凝胶为下述材料中至少一种：聚丙烯酸和聚丙烯酰胺复合凝胶、聚丙烯酸和壳聚糖复合凝胶、海藻酸钠和聚丙烯酰胺复合凝胶、聚丙烯酸和胆碱复合凝胶、海藻酸钠和胆碱复合凝胶、甲基丙烯酸酰化明胶和胆碱复合凝胶、甲基丙烯酸酰化透明质酸和胆碱复合凝胶。
  21. 如权利要求18所述的神经导管，其特征在于，所述导电聚合物水凝胶为下述材料中至少一种：聚苯胺、聚吡咯、聚噻吩和聚（3,4-乙烯二氧噻吩）基导电聚合物水凝胶。
  22. 如权利要求21所述的神经导管，其特征在于，所述导电填料掺杂的导电水凝胶为导电填料和所述导电聚合物水凝胶中的任意一种组合；其中，所述导电填料包括金属系导电填料及碳系导电填料中至少一种，所述金属系导电填料包括Au或Ag，所述碳系导电填料包括炭黑、石墨、碳纤维、碳纳米管以及石墨烯。
  23. 一种如权利要求1所述的神经导管的制备方法，其特征在于，包括下述步骤：
    在模具内构建所述响应单元；
    在所述响应单元上方灌注构成所述导电单元的水凝胶的前驱体材料，通过交联构建形成导电单元；
    在所述模具内将所述响应单元和所述导电单元的交替构建，形成所述的神经导管。
  24. 如权利要求23所述的神经导管的制备方法，其特征在于，在模具内构建所述响应单元的步骤中，具体包括下述步骤：通过涂布法、旋涂法或流延法，在模具内，构建所述响应单元。
  25. 如权利要求23所述的神经导管的制备方法，其特征在于，所述交联的交联方式为离子交联、紫外光交联中至少一种。
  26. 如权利要求23所述的神经导管的制备方法，其特征在于，所述模具为单封闭的圆形管腔结构，所述模具底部有沿管腔轴向排列的实心圆柱体，以形成神经导管的阵列多孔结构。
  27. 一种如权利要求1所述的神经导管在神经再生修复中的应用。
PCT/CN2022/137365 2022-11-10 2022-12-07 神经导管、制备方法及其应用 Ceased WO2024098490A1 (zh)

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