WO2024098286A1 - 神经调控器件、制备方法及其应用 - Google Patents

神经调控器件、制备方法及其应用 Download PDF

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WO2024098286A1
WO2024098286A1 PCT/CN2022/130869 CN2022130869W WO2024098286A1 WO 2024098286 A1 WO2024098286 A1 WO 2024098286A1 CN 2022130869 W CN2022130869 W CN 2022130869W WO 2024098286 A1 WO2024098286 A1 WO 2024098286A1
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substrate
poly
neuroregulatory
cells
vinylidene fluoride
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French (fr)
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杜学敏
孟庆兵
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
    • A61L27/36—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix
    • A61L27/38—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix containing added animal cells
    • 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
    • A61L27/52—Hydrogels or hydrocolloids
    • 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
    • A61L27/54—Biologically active materials, e.g. therapeutic substances
    • H—ELECTRICITY
    • H04—ELECTRIC COMMUNICATION TECHNIQUE
    • H04L—TRANSMISSION OF DIGITAL INFORMATION, e.g. TELEGRAPHIC COMMUNICATION
    • H04L27/00—Modulated-carrier systems

Definitions

  • the present application relates to the field of biomedical technology, and in particular to a neuromodulatory device, a preparation method and applications thereof.
  • Neuromodulation technology is of key significance to the development of emerging fields such as neuroscience and brain-computer interface.
  • Existing neuromodulation technology mainly applies electrical stimulation to neurons in the target area through implantable electrode devices, thereby inducing neurons to generate action potentials and become excited, thereby achieving the purpose of neuromodulation.
  • this type of neuromodulation electrode device based on electrical stimulation has shown good results in deep brain stimulation to treat neurological diseases and other fields, the existing devices are subject to the working principle and still face many disadvantages in the safety and effectiveness of neuromodulation.
  • the existing neuromodulation devices based on electrode stimulation not only have a large difference in modulus from neural tissue, but also often involve complex wiring, integration and packaging, and face high risks of tissue damage, bleeding, inflammation, exposure infection, etc. during and after implantation.
  • the information interaction mode of existing neuromodulation devices based on electrode stimulation when stimulating neuronal responses is also essentially different from the natural information interaction mode between neural clouds in neural tissue based on transmitter molecules. This difference will make it difficult for existing devices to obtain sufficient specificity during neuromodulation, and it is impossible to avoid the erroneous activation of non-target neurons around the implantation site, which will bring unpredictable side effects.
  • One of the purposes of the present application is to provide a neuroregulatory device, comprising: a substrate, living cells grown on the surface of the substrate, and a hydrogel for encapsulating the living cells on the surface of the substrate, wherein the substrate can convert external field energy into electricity and stimulate the living cells growing on its surface to respond and release neurotransmitter molecules, and the external field energy includes light or magnetic field or ultrasound.
  • the substrate has a thickness of 50-500 ⁇ m.
  • the surface morphology of the substrate is a plane or a three-dimensional structure
  • the three-dimensional structure includes at least one of a microgroove array, a microcone array, and a microcolumn array.
  • the three-dimensional structure has a width of 50 nm-20 ⁇ m, a height of 50 nm-20 ⁇ m, and a pitch of 50 nm-20 ⁇ m.
  • the substrate is at least one of piezoelectric material, photodeformation material composite piezoelectric material, photovoltaic material, upconversion material composite photovoltaic material, photothermal material composite pyroelectric material, magnetocaloric material composite pyroelectric material, and piezoelectric ion gel.
  • 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 niobate or lithium barium 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] or poly(
  • the photodeformable material composite piezoelectric material is a combination of the following photodeformable materials and any one of the piezoelectric materials; wherein the photodeformable material includes at least one of a photoisomerization material or a ferroelectric inorganic photodeformable material, and the photoisomerization material includes at least one of azobenzene and its derivatives, spiropyran and its derivatives; 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 photovoltaic material includes at least one of the following substances: organic photovoltaic materials of polyacetylene, polythiophene, polyaniline, polypyrrole, and derivatives and copolymers thereof.
  • the up-conversion material composite photovoltaic material is a combination of any one of the following up-conversion materials and the piezoelectric material; wherein the up-conversion material includes at least one of yttrium oxide, yttrium oxysulfide, lanthanum fluoride, sodium yttrium fluoride, and sodium gadolinium fluoride.
  • the photothermal material composite pyroelectric material includes any combination of photothermal material and pyroelectric material; wherein the photothermal material includes at least one of carbon black, carbon nanotubes, graphene, black phosphorus, polydopamine, gold nanorods, and gallium-indium alloy liquid metal; the pyroelectric material includes at least one of polyvinylidene fluoride ferroelectric polymers and perovskite ferroelectric ceramics, and the polyvinylidene fluoride ferroelectric polymers include poly(vinylidene fluoride), poly(vinylidene fluoride-trifluoroethylene) [P(VDF-TrFE) copolymer], poly(vinylidene fluoride-chlorofluoroethylene) [P(VDF-CFE) copolymer], poly(vinylidene fluoride At least one of poly(vinylidene fluoride-trifluoroethylene) [P(VDF-CTFE) copolymer
  • the magnetocaloric material composite pyroelectric material is a combination of any one of the following magnetocaloric materials and the pyroelectric material; wherein the magnetocaloric material includes at least one of Ru-Fe-B alloy, ferroferric oxide, iron, cobalt, nickel, and gadolinium.
  • the piezoelectric ion gel material includes at least one of a polyacrylic acid and polyacrylamide composite gel, a polyacrylic acid and chitosan composite gel, a sodium alginate and polyacrylamide composite gel, a polyacrylic acid and choline composite gel, a sodium alginate and choline composite gel, a methacrylated gelatin and choline composite gel, and a methacrylated hyaluronic acid and choline composite gel.
  • the living cells are cell types that can produce neurotransmitters; including but not limited to primary neuronal cells, neuroimmune cells, neuroendocrine cells, cell line cells that can produce neurotransmitters, and at least one of neuronal cells induced from stem cells, and the neuroimmune cells include astrocytes or microglia.
  • the hydrogel is at least one of the following materials: alginate, chitosan, gelatin and its derivatives, collagen and its derivatives, hyaluronic acid and its derivatives, extracellular matrix proteins and their derivatives, silk fibroin and its derivatives, agarose, carrageenan, dextran, basement membrane matrix, polycaprolactone, polyethylene glycol and its derivatives, propylene glycol and ethylene oxide block polymers, polyvinyl pyrrolidone.
  • the hydrogel layer has a thickness of 50-500 ⁇ m.
  • the neurotransmitter molecules include at least one of choline, monoamines, amino acids, neuropeptides, purines and nitric oxide
  • the choline includes acetylcholine
  • the monoamines include at least one of norepinephrine or epinephrine or dopamine or 5-HT or histamine
  • the amino acids include at least one of glutamate or ⁇ -aminobutyric acid or glycine.
  • the second object of the present application is to provide a method for preparing a neuromodulatory device, comprising the following steps:
  • the hydrogel is pre-crosslinked on the substrate surface so that the living cells are encapsulated on the substrate surface to obtain the neuroregulatory device.
  • the step of preparing the substrate specifically includes the following steps: preparing the substrate by a casting method or a spin coating method.
  • a planar or three-dimensional structure is formed on the surface of the substrate by photolithography, plasma dry etching or mechanical processing, and the three-dimensional structure includes at least one of a microgroove array, a microcone array and a microcolumn array.
  • the seeding density of the living cells is 10 3 -10 6 cells/cm 2 .
  • the cross-linking method is at least one of ionic cross-linking and ultraviolet light cross-linking.
  • the third purpose of this application is to provide an application of the aforementioned neuroregulatory device in the treatment of brain-computer interfaces and neurological device diseases.
  • the neuromodulatory device provided in the present application includes: a substrate, living cells grown on the surface of the substrate, and a hydrogel for encapsulating the living cells on the surface of the substrate.
  • the substrate can convert external field energy into electricity, and stimulate the living cells growing on its surface to respond and release neurotransmitter molecules.
  • the neuromodulatory device provided in the present application can induce the excitation of target neurons through the release of neurotransmitter molecules of living cells in the device under external field mediation, thereby realizing the regulation of specific neural activities and functions. It not only greatly reduces the integration complexity and construction difficulty of the device, but also can be remotely controlled through external field mediation.
  • bionic information interaction mode based on electrical stimulation and neurotransmitter molecules that is very different from the existing neuromodulatory devices, realizes the controllability and specificity of neuromodulation, and can be used for the treatment of brain-computer interfaces and neural device diseases.
  • the method for preparing the neuroregulatory device provided in the present application does not require complicated preparation processes and integrated packaging technologies, greatly reduces the difficulty of device construction, and simplifies the preparation process.
  • FIG1 is a schematic diagram of the structure of a neuromodulator provided in an embodiment of the present application.
  • FIG. 2 is a flowchart showing the steps of applying the neuromodulator provided in this embodiment.
  • 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 neuroregulatory device provided by an embodiment of the present application, including: a substrate 110, living cells 120 grown on the surface of the substrate 110, and a hydrogel 130 for encapsulating the living cells 120 on the surface of the substrate 110.
  • the substrate 110 can convert external field energy into electricity and stimulate the living cells 120 growing on its surface to respond and release neurotransmitter molecules 140.
  • the external field energy includes light or magnetic field or ultrasound.
  • the substrate has a thickness of 50-500 ⁇ m.
  • the surface morphology of the substrate is a plane or a three-dimensional structure
  • the three-dimensional structure includes at least one of a microgroove array, a microcone array, and a microcolumn array.
  • the three-dimensional structure has a width of 50 nm-20 ⁇ m, a height of 50 nm-20 ⁇ m, and a pitch of 50 nm-20 ⁇ m.
  • the substrate is at least one of a piezoelectric material, a photodeformable material composite piezoelectric material, a photovoltaic material, an upconversion material composite photovoltaic material, a photothermal material composite pyroelectric material, a magnetocaloric material composite pyroelectric material, and a piezoelectric ion gel.
  • 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 lithium barium lead 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 photodeformable material composite piezoelectric material is a combination of the following photodeformable materials and any one of the piezoelectric materials; wherein the photodeformable material includes at least one of a photoisomerization material or a ferroelectric inorganic photodeformable material, and the photoisomerization material includes at least one of azobenzene and its derivatives, spiropyran and its derivatives; 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 photovoltaic material includes at least one of the following substances: organic photovoltaic materials of polyacetylene, polythiophene, polyaniline, polypyrrole, and derivatives and copolymers thereof.
  • the up-conversion material composite photovoltaic material is a combination of any one of the following up-conversion materials and the piezoelectric material; wherein the up-conversion material includes at least one of yttrium oxide, yttrium oxysulfide, lanthanum fluoride, sodium yttrium fluoride, and sodium gadolinium fluoride.
  • the photothermal material composite pyroelectric material includes any combination of photothermal material and pyroelectric material; wherein the photothermal material includes at least one of carbon black, carbon nanotubes, graphene, black phosphorus, polydopamine, gold nanorods, and gallium-indium alloy liquid metal; the pyroelectric material includes at least one of polyvinylidene fluoride ferroelectric polymers and perovskite ferroelectric ceramics, and the polyvinylidene fluoride ferroelectric polymers include poly(vinylidene fluoride), poly(vinylidene fluoride-trifluoroethylene) [P(VDF-TrFE) copolymer], poly(vinylidene fluoride-chlorofluoroethylene) [P(VDF-CFE) copolymer], poly(vinylidene fluoride At least one of poly(vinylidene fluoride-trifluoroethylene) [P(VDF-CTFE) copolymer
  • the magnetocaloric material composite pyroelectric material is a combination of any one of the following magnetocaloric materials and the pyroelectric material; wherein the magnetocaloric material includes at least one of Ru-Fe-B alloy, ferroferric oxide, iron, cobalt, nickel, and gadolinium.
  • the piezoelectric ion gel material includes at least one of a polyacrylic acid and polyacrylamide composite gel, a polyacrylic acid and chitosan composite gel, a sodium alginate and polyacrylamide composite gel, a polyacrylic acid and choline composite gel, a sodium alginate and choline composite gel, a methacrylated gelatin and choline composite gel, and a methacrylated hyaluronic acid and choline composite gel.
  • the living cells are cell types that can produce neurotransmitters, including but not limited to primary neuronal cells, neuroimmune cells, neuroendocrine cells, cell line cells that can produce neurotransmitters, and at least one of neuronal cells induced from stem cells, and the neuroimmune cells include astrocytes or microglia.
  • the hydrogel is at least one of the following materials: alginate, chitosan, gelatin and its derivatives, collagen and its derivatives, hyaluronic acid and its derivatives, extracellular matrix proteins and their derivatives, silk fibroin and its derivatives, agarose, carrageenan, dextran, basement membrane matrix, polycaprolactone, polyethylene glycol and its derivatives, propylene glycol and ethylene oxide block polymers, polyvinyl pyrrolidone.
  • the hydrogel layer has a thickness of 50-500 ⁇ m.
  • the neurotransmitter molecules include at least one of choline, monoamines, amino acids, neuropeptides, purines and nitric oxide
  • the choline includes acetylcholine
  • the monoamines include at least one of norepinephrine or epinephrine or dopamine or 5-HT or histamine
  • the amino acids include at least one of glutamate or ⁇ -aminobutyric acid or glycine.
  • the neuromodulatory device provided in the present application induces the excitation of target neurons through the release of neurotransmitter molecules from living cells in the device under external field mediation, thereby achieving regulation of specific neural activities and functions. This not only greatly reduces the integration complexity and construction difficulty of the device, but can also be remotely controlled through external field mediation. At the same time, it also has a bionic information interaction mode based on electrical stimulation and neurotransmitter molecules that is very different from existing neuromodulatory devices, achieving controllability and specificity of neuromodulation, and can be used for brain-computer interfaces and the treatment of neural device diseases.
  • FIG. 2 is a flowchart of the steps of the method for preparing the neuromodulator provided in the present application, including the following steps S110 to S130 , and the implementation method of each step is described in detail below.
  • Step S110 preparing the substrate.
  • the step of preparing the substrate specifically includes the following steps: preparing the substrate by a casting method or a spin coating method.
  • Step S120 growing the living cells on the surface of the substrate.
  • a planar or three-dimensional structure is formed on the surface of the substrate by photolithography, plasma dry etching or mechanical processing, and the three-dimensional structure includes at least one of a microgroove array, a microcone array and a microcolumn array.
  • the seeding density of the living cells is 10 3 -10 6 cells/cm 2 .
  • Step S130 pre-crosslinking the hydrogel on the surface of the substrate so that the living cells are encapsulated on the surface of the substrate to obtain the neuromodulatory device.
  • the cross-linking method is at least one of ionic cross-linking and ultraviolet light cross-linking.
  • the method for preparing the neuroregulatory device provided in the present application does not require complicated preparation processes and integrated packaging technology, which greatly reduces the difficulty of building the device.
  • the preparation process is simple, and the prepared neuroregulatory device can be used for brain-computer interfaces and the treatment of neurological device diseases.
  • a neuromodulatory device based on an active interface comprises a responsive material substrate, living cells adhered and grown on the responsive material substrate, and a hydrogel for encapsulating the living cells; wherein the responsive material substrate is made of a piezoelectric material, the living cells are neural-like cell line cells, and the hydrogel is sodium alginate cross-linked with calcium ions.
  • the surface morphology of the responsive material substrate is a flat, structureless surface with a thickness of 50 ⁇ m.
  • the material is polyvinylidene fluoride that can generate electricity under the mediation of an ultrasonic external field; the inoculated neural-like cell line cells are highly differentiated PC12 cells; the hydrogel material is sodium alginate cross-linked with calcium ions with a thickness of 50 ⁇ m.
  • the method for preparing the active interface-based neural regulation device comprises the following steps:
  • a polyvinylidene fluoride solution with a concentration of 10 w/v% was prepared; the polyvinylidene fluoride solution was cast on a flat silicon wafer surface and dried at 80 degrees Celsius to obtain a responsive material substrate with a planar surface morphology; the prepared responsive material substrate was irradiated with a cobalt source at a dose of 15 kGy and an irradiation time of 30 minutes to complete the material sterilization.
  • the cells were inoculated on the surface of the sterilized responsive material substrate at a seeding density of 10 6 cells/cm2.
  • 3w/v% sodium alginate hydrogel prepolymer was used to cover the surface of the responsive material substrate inoculated with living cells, and then a 0.3M calcium chloride aqueous solution was added dropwise to complete the encapsulation of the hydrogel crosslinking through ionic crosslinking to obtain a neuroregulatory device based on an active interface.
  • a neuromodulatory device based on an active interface includes a responsive material substrate, living cells adhered and grown on the responsive material substrate, and a hydrogel for encapsulating the living cells; wherein the responsive material substrate is composed of a photodeformable material composited with a piezoelectric material, the living cells are neural-like cell line cells, and the hydrogel is methacrylated gelatin.
  • the surface morphology of the responsive material substrate is a microgroove array structure (microgroove width: 50 ⁇ m, height: 50 ⁇ m, spacing: 50 ⁇ m), the substrate material thickness is 500 ⁇ m, and its material is a polyvinylidene fluoride and azobenzene complex that can generate electricity under visible light irradiation; the inoculated neural-like cell line cells are highly differentiated PC12 cells; the hydrogel material is methacrylated gelatin with a thickness of 500 ⁇ m.
  • the method for preparing the active interface-based neural regulation device comprises the following steps:
  • a mixed solution of 5 w/v% polyvinylidene fluoride and 1 w/v% azobenzene was prepared; the mixed solution was cast on the surface of a microgroove array structure (microgroove width: 20 ⁇ m, height: 20 ⁇ m, spacing: 20 ⁇ m) template obtained by mechanical processing, and dried at 80 degrees Celsius to obtain a responsive material substrate with a microgroove array surface morphology; the prepared responsive material substrate was irradiated with a cobalt source at a dose of 15 kGy and an irradiation time of 30 minutes to complete the material sterilization.
  • a microgroove array structure microgroove width: 20 ⁇ m, height: 20 ⁇ m, spacing: 20 ⁇ m
  • the cells were inoculated on the surface of the sterilized responsive material substrate at a seeding density of 10 6 cells/cm2.
  • the surface of the responsive material substrate inoculated with living cells was covered with a 10 w/v% methacrylated gelatin hydrogel prepolymer solution containing 0.1 w/v% 2959 photocrosslinker, and then reacted under UV crosslinking instrument for 10 minutes.
  • the encapsulated hydrogel crosslinking was completed by UV crosslinking to obtain a neuroregulatory device based on an active interface.
  • a neuromodulatory device based on an active interface comprises a responsive material substrate, living cells adhered and grown on the responsive material substrate, and a hydrogel for encapsulating the living cells; wherein the responsive material substrate is made of photovoltaic material, the living cells are primary neurons, and the hydrogel is sodium alginate cross-linked with calcium ions.
  • the surface morphology of the responsive material substrate is a flat and structureless surface with a thickness of 50 ⁇ m.
  • the material is poly-3-hexylthiophene (P3HT) that can generate electricity under visible light irradiation; the inoculated neural-like cell line cells are highly differentiated PC12 cells; the hydrogel material is sodium alginate cross-linked by calcium ions with a thickness of 50 ⁇ m.
  • the method for preparing the active interface-based neural regulation device comprises the following steps:
  • a P3HT solution with a concentration of 30 mg/mL was prepared; the solution was poured on a flat surface of a silicon wafer and spin-coated at 60 degrees Celsius to obtain a responsive material substrate with a planar morphology; the prepared responsive material substrate was irradiated with a cobalt source at a dose of 15 kGy and an irradiation time of 30 minutes to complete the material sterilization.
  • the sterilized responsive material substrate was coated in a 0.1 mg/ml poly-lysine aqueous solution for 6 hours, and the hippocampal neuron cell suspension extracted from the fetal mouse brain was used to seed the coated responsive material substrate surface at a seeding density of 10 3 cells/cm2.
  • the surface of the responsive material substrate inoculated with living cells was covered with 3w/v% sodium alginate hydrogel prepolymer, and then 0.3M calcium chloride aqueous solution was added dropwise to complete the encapsulation of the hydrogel cross-linking through ionic cross-linking to obtain a neuroregulatory device based on an active interface.
  • a neuromodulatory device based on an active interface comprises a responsive material substrate, living cells adhered and grown on the responsive material substrate, and a hydrogel for encapsulating the living cells; wherein the responsive material substrate is made of an upconversion material composite photovoltaic material, the living cells are primary neurons, and the hydrogel is sodium alginate cross-linked with calcium ions.
  • the surface morphology of the responsive material substrate is a flat and structureless surface with a thickness of 100 ⁇ m.
  • the material is poly-3-hexylthiophene (P3HT) that can generate electricity under visible light irradiation; the inoculated neural-like cell line cells are highly differentiated PC12 cells; the hydrogel material is sodium alginate cross-linked with calcium ions with a thickness of 100 ⁇ m.
  • the method for preparing the active interface-based neural regulation device 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 on a flat surface of a silicon wafer and spin-coated at 60 degrees Celsius to obtain a responsive material substrate with a planar morphology; the prepared responsive material substrate was irradiated with a cobalt source at a dose of 15 kGy and an irradiation time of 30 minutes to complete the material sterilization.
  • the sterilized responsive material substrate was coated in a 0.1 mg/ml poly-lysine aqueous solution for 6 hours, and the hippocampal neuron cell suspension extracted from the fetal mouse brain was used to seed the coated responsive material substrate surface at a seeding density of 10 3 cells/cm2.
  • the surface of the responsive material substrate inoculated with living cells was covered with 3w/v% sodium alginate hydrogel prepolymer, and then 0.3M calcium chloride aqueous solution was added dropwise to complete the encapsulation of the hydrogel cross-linking through ionic cross-linking to obtain a neuroregulatory device based on an active interface.
  • a neuromodulatory device based on an active interface comprises a responsive material substrate, living cells adhered and grown on the responsive material substrate, and a hydrogel for encapsulating the living cells; wherein the responsive material substrate is made of a photothermal material composite with a pyroelectric material, the living cells are stem cell-induced neurons, and the hydrogel is sodium alginate cross-linked with calcium ions.
  • the surface morphology of the responsive material substrate is a micro-cone array surface, with a micro-cone width of 5 ⁇ m, a height of 5 ⁇ m, a spacing of 5 ⁇ m, and a substrate thickness of 200 ⁇ m.
  • the material is a complex of P(VDF-TrFE) copolymer and polydopamine that can generate electricity under near-infrared light irradiation; the inoculated dopaminergic neurons are obtained by differentiation of fully functional induced stem cells; the hydrogel material is sodium alginate cross-linked by calcium ions, with a thickness of 200 ⁇ m.
  • the method for preparing the active interface-based neural regulation device comprises the following steps:
  • a mixed solution containing 10 w/v% polyvinylidene fluoride and 0.1 w/v% polydopamine was prepared; the mixed solution was cast on the surface of a microcone array structure (microcone width: 5 ⁇ m, height: 5 ⁇ m, spacing: 5 ⁇ m) template obtained by plasma dry etching, and dried at 80 degrees Celsius to obtain a responsive material substrate with a microcone array surface morphology; the prepared responsive material substrate was irradiated with a cobalt source at an irradiation dose of 15 kGy and an irradiation time of 30 minutes to complete the material sterilization.
  • a microcone array structure microcone width: 5 ⁇ m, height: 5 ⁇ m, spacing: 5 ⁇ m
  • the prepared responsive material substrate was irradiated with a cobalt source at an irradiation dose of 15 kGy and an irradiation time of 30 minutes to complete the material sterilization.
  • the cell suspension of dopaminergic neurons obtained by differentiation of fully functional induced stem cells obtained by trypsin digestion was used to seed the cells on the surface of the sterilized responsive material substrate at a seeding density of 10 4 cells/cm 2 .
  • 3w/v% sodium alginate hydrogel prepolymer was used to cover the surface of the responsive material substrate inoculated with living cells, and then a 0.3M calcium chloride aqueous solution was added dropwise to complete the encapsulation of the hydrogel crosslinking through ionic crosslinking to obtain a neuroregulatory device based on an active interface.
  • a neuromodulatory device based on an active interface comprises a responsive material substrate, living cells adhered and grown on the responsive material substrate, and a hydrogel for encapsulating the living cells; wherein the responsive material substrate is made of a magnetocaloric material composite with a pyroelectric material, the living cells are neural immune cells, and the hydrogel is sodium alginate cross-linked with calcium ions.
  • the surface morphology of the responsive material substrate is a microcolumn array surface, with a microcolumn width of 5 ⁇ m, a height of 5 ⁇ m, a spacing of 5 ⁇ m, and a substrate thickness of 50 ⁇ m.
  • the material is a complex of P (VDF-TrFE) copolymer and ferroferric oxide that can generate electricity under the mediation of an alternating magnetic field;
  • the inoculated neural immune cells are mouse astrocytes;
  • the hydrogel material is sodium alginate cross-linked by calcium ions, with a thickness of 50 ⁇ m.
  • the method for preparing the active interface-based neural regulation device comprises the following steps:
  • a mixed solution containing 10 w/v% polyvinylidene fluoride and 5 mg/mL ferrosoferric oxide nanoparticles was prepared; the mixed solution was cast on the surface of a microcolumn array structure (microcolumn width: 5 ⁇ m, height: 5 ⁇ m, spacing: 5 ⁇ m) obtained by photolithography to obtain a responsive material substrate with a microcolumn array surface morphology; the prepared responsive material substrate was irradiated with a cobalt source at an irradiation dose of 15 kGy and an irradiation time of 30 minutes to complete the material sterilization.
  • the mouse astrocyte cell suspension obtained by trypsin digestion was used to seed the cells on the surface of the sterilized responsive material substrate at a seeding density of 10 4 cells/cm 2 .
  • 3w/v% sodium alginate hydrogel prepolymer was used to cover the surface of the responsive material substrate inoculated with living cells, and then a 0.3M calcium chloride aqueous solution was added dropwise to complete the encapsulation of the hydrogel crosslinking through ionic crosslinking to obtain a neuroregulatory device based on an active interface.
  • a neuromodulatory device based on an active interface comprises a responsive material substrate, living cells adhered and grown on the responsive material substrate, and a hydrogel for encapsulating the living cells; wherein the responsive material substrate is made of a piezoelectric ion gel material, the living cells are neuroendocrine cells, and the hydrogel is sodium alginate cross-linked with calcium ions.
  • the surface morphology of the responsive material substrate is a microcolumn array surface, with a microcolumn width of 50nm, a height of 50nm, a spacing of 50nm, and a substrate thickness of 50 ⁇ m.
  • the material is a complex of polymethacrylic acid and choline that can generate electricity under ultrasound mediation;
  • the inoculated neuroendocrine cells are mouse alveolar neuroendocrine cells;
  • the hydrogel material is sodium alginate cross-linked with calcium ions, with a thickness of 50 ⁇ m.
  • the method for preparing the active interface-based neural regulation device comprises the following steps:
  • An aqueous solution containing 10 w/v% methacrylic acid, 3 w/v% choline chloride and 0.1 w/v% 2959 photoinitiator is prepared; the mixed solution is cast on the surface of a microcolumn array structure (microcolumn width: 50 nm, height: 50 nm, spacing: 50 nm) template obtained by photolithography, and the mixture is reacted for 10 minutes under irradiation of an ultraviolet cross-linking instrument to obtain a responsive material substrate having a microcolumn array surface morphology; the prepared responsive material substrate is irradiated by a cobalt source at an irradiation dose of 15 kGy and an irradiation time of 30 minutes to complete the material sterilization.
  • a microcolumn array structure microcolumn width: 50 nm, height: 50 nm, spacing: 50 nm
  • the cell suspension of mouse alveolar neuroendocrine cells obtained by trypsin digestion was used to inoculate the cells on the surface of the sterilized responsive material substrate at a seeding density of 10 4 cells/cm 2 .
  • 3w/v% sodium alginate hydrogel prepolymer was used to cover the surface of the responsive material substrate inoculated with living cells, and then 0.3M calcium chloride aqueous solution was added dropwise to complete the encapsulation of the hydrogel cross-linking through ionic cross-linking to obtain a neural regulation device based on an active interface.

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Abstract

本申请提供的神经调控器件，包括：基底、生长于所述基底表面的活细胞以及用于将所述活细胞封装于所述基底表面的水凝胶，所述基底可将外场能量转化为电，并激发其表面生长的所述活细胞响应并释放神经递质分子，本申请提供的神经调控器件，通过外场介导下器件中活细胞神经递质分子的释放，诱发目标神经元兴奋，从而实现对特定神经活动和功能的调控，不但大大降低了器件的集成复杂度和构建难度，并且可通过外场介导遥控，与此同时，还具有迥异于现有神经调控器件电刺激、基于神经递质分子的仿生信息交互方式，实现了神经调控的可控性和特异性，可用于脑机接口和神经器件疾病的治疗。另外，本申请还提供了神经调控器件的制备方法。

Description

神经调控器件、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，特别涉及一种神经调控器件、制备方法及其应用。
背景技术
神经调控技术对于神经科学和脑机接口等新兴领域的发展均有着关键性意义。现有神经调控技术主要通过植入式电极器件对目标区域神经元施加电刺激，由此诱发神经元产生动作电位而兴奋，由此实现神经调控的目的。尽管这类基于电刺激的神经调控电极器件在深脑刺激治疗神经系统疾病等领域展示了不错的效果，但现有器件受制于工作原理，在神经调控的安全性和有效性上还面临诸多的弊端。具体来讲，现有基于电极刺激的神经调控器件不但在模量上与神经组织有较大差异，并且往往涉及复杂的连线、集成和封装，在植入中和植入后面临较高的组织损伤、出血、炎症、暴露感染等风险。此外，现有基于电极刺激的神经调控器件在激发神经元响应时的信息交互方式也与神经组织中神经云间基于递质分子的天然信息交互方式存在本质差异。这种差异会导致现有器件在神经调控时难以获得足够的特异性，无法规避对植入部位周围非目标神经元的错误激活，带来难以预期的副作用。
最近，通过直接植入活细胞，基于活细胞构成的活性界面与自体神经元建立联接并实现仿生的信息交互为神经调控提供了新的可能。
然而，这类技术无法程控植入活细胞的响应，这给可控的神经调控带来了 巨大的挑战。
发明内容
鉴于此，有必要针对现有技术中存在的缺陷提供一种实现对特定神经活动和功能的调控的神经调控器件及其制备方法。
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，提供了一种神经调控器件，包括：基底、生长于所述基底表面的活细胞以及用于将所述活细胞封装于所述基底表面的水凝胶，所述基底可将外场能量转化为电，并激发其表面生长的所述活细胞响应并释放神经递质分子，所述外场能量包括光或磁场或超声。
在其中一些实施例中，所述基底的厚度为50–500μm。
在其中一些实施例中，所述基底的表面形貌为平面或三维结构，所述三维结构包括微槽阵列、微锥阵列、微柱阵列中至少一种。
在其中一些实施例中，所述三维结构的尺寸宽度为50nm–20μm，高度为50nm–20μm，间距为50nm–20μm。
在其中一些实施例中，所述基底为压电材料、光致形变材料复合压电材料、光伏材料、上转换材料复合光伏材料、光热材料复合热释电材料、磁热材料复合热释电材料、压电离子凝胶中的至少一种。
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的组合；其中，所述光致形变材料包括光致异构材料或铁电类无机光致形变材料中的至少一种，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的至少一种；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的至少一种。
在其中一些实施例中，所述光伏材料包括以下物质中的至少一种：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，所述上转换材料复合光伏材料为下述上转换材料和所述压电材料中的任意一种组合；其中，所述上转换材料包括氧化钇、硫氧化 钇、氟化镧、氟钇化钠、氟钆化钠中的至少一种。
在其中一些实施例中，所述光热材料复合热释电材料包括光热材料和热释电材料中的任意一种组合；其中，所述光热材料包括炭黑、碳纳米管、石墨烯、黑磷、聚多巴胺、金纳米棒、镓铟合金液体金属中的至少一种；所述热释电材料包括聚偏氟乙烯类铁电聚合物及钙钛矿型铁电陶瓷中的至少一种，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]中的至少一种，所述钙钛矿型铁电陶瓷包括钛酸钡、锆钛酸铅、偏铌酸铅、铌酸铅钡锂中的至少一种。
在其中一些实施例中，所述磁热材料复合热释电材料为下述磁热材料和所述热释电材料中的任意一种组合；其中，所述磁热材料包括汝铁硼合金、四氧化三铁、铁、钴、镍、钆中的至少一种。
在其中一些实施例中，所述压电离子凝胶材料包括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中的至少一种。
在其中一些实施例中，所述活细胞为可产生神经递质的细胞类型；包括但 不限于原代神经元细胞、神经免疫细胞、神经内分泌细胞、可产生神经递质的细胞系细胞、以及由干细胞诱导而成的神经元细胞中的至少一种，所述神经免疫细胞包括星形胶质细胞或小胶质细胞。
在其中一些实施例中，所述水凝胶为下述材料中至少一种：海藻酸盐、壳聚糖、明胶及其衍生物、胶原蛋白及其衍生物、透明质酸及其衍生物、细胞外基质蛋白及其衍生物、丝素蛋白及其衍生物、琼脂糖、卡拉胶、葡聚糖、基底膜基质、聚己内酯、聚乙二醇及其衍生物、丙二醇与环氧乙醚嵌段聚合物、聚乙烯吡咯烷酮。
在其中一些实施例中，所述水凝胶层厚度为50–500μm。
在其中一些实施例中，所述神经递质分子包括胆碱类、单胺类、氨基酸类、神经肽类、嘌呤类及一氧化氮中的至少一种，所述胆碱类包括乙酰胆碱，所述单胺类包括去甲肾上腺素或肾上腺素或多巴胺或5-HT或组胺中的至少一种，所述氨基酸类包括谷氨酸或Y-氨基丁酸或甘氨酸中的至少一种。
本申请的目的之二，提供了一种神经调控器件的制备方法，包括下述步骤：
制备所述基底；
在所述基底表面生长所述活细胞；
将所述水凝胶预交联于所述基底表面以使所述活细胞封装于所述基底表面，得到所述的神经调控器件。
在其中一些实施例中，在制备所述基底的步骤中，具体包括下述步骤：采 用流延法或旋涂法制备所述基底。
在其中一些实施例中，通过光刻、等离子干法刻蚀或机械加工在所述基底表面形成平面或三维结构，所述三维结构包括微槽阵列、微锥阵列、微柱阵列中至少一种。
在其中一些实施例中，所述活细胞的接种密度为10 3–10 6细胞/平方厘米。
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。
本申请的目的之三，提供了一种所述的神经调控器件在脑机接口和神经器件疾病治疗中的应用。
本申请采用上述技术方案，其有益效果如下：
本申请提供的神经调控器件，包括：基底、生长于所述基底表面的活细胞以及用于将所述活细胞封装于所述基底表面的水凝胶，所述基底可将外场能量转化为电，并激发其表面生长的所述活细胞响应并释放神经递质分子，本申请提供的神经调控器件，通过外场介导下器件中活细胞神经递质分子的释放，诱发目标神经元兴奋，从而实现对特定神经活动和功能的调控，不但大大降低了器件的集成复杂度和构建难度，并且可通过外场介导遥控，与此同时，还具有迥异于现有神经调控器件电刺激、基于神经递质分子的仿生信息交互方式，实现了神经调控的可控性和特异性，可用于脑机接口和神经器件疾病的治疗。
另外，本申请提供的神经调控器件制备方法，相较现有的神经调控器件， 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。
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调控器件的结构示意图。
图2为申请本实施例提供的神经调控器件的步骤流程图。
具体实施方式
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调控器件的结构示意图，包括：基底110、生长于所述基底110表面的活细胞120以及用于将所述活细胞120封装于所述基底110表面的水凝胶130，所述基底110可将外场能量转化为电，并激发其表面生长的所述活细胞120响应并释放神经递质分子140，所述外场能量包括光或磁场或超声。
在其中一些实施例中，所述基底的厚度为50–500μm。
在其中一些实施例中，所述基底的表面形貌为平面或三维结构，所述三维结构包括微槽阵列、微锥阵列、微柱阵列中至少一种。
在其中一些实施例中，所述三维结构的尺寸宽度为50nm–20μm，高度为50nm–20μm，间距为50nm–20μm。
在其中一些实施例中，所述基底为压电材料、光致形变材料复合压电材料、光伏材料、上转换材料复合光伏材料、光热材料复合热释电材料、磁热材料复 合热释电材料、压电离子凝胶中的至少一种。
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的组合；其中，所述光致形变材料包括光致异构材料或铁电类无机光致形变材料中的至少一种，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的至少一种；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的至少一种。
在其中一些实施例中，所述光伏材料包括以下物质中的至少一种：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，所述上转换材料复合光伏材料为下述上转换材料和所述压电材料中的任意一种组合；其中，所述上转换材料包括氧化钇、硫氧化钇、氟化镧、氟钇化钠、氟钆化钠中的至少一种。
在其中一些实施例中，所述光热材料复合热释电材料包括光热材料和热释电材料中的任意一种组合；其中，所述光热材料包括炭黑、碳纳米管、石墨烯、黑磷、聚多巴胺、金纳米棒、镓铟合金液体金属中的至少一种；所述热释电材料包括聚偏氟乙烯类铁电聚合物及钙钛矿型铁电陶瓷中的至少一种，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]中的至少一种，所述钙钛矿型铁电陶瓷包括钛酸钡、锆钛酸铅、偏铌酸铅、铌酸铅钡锂中的至少一种。
在其中一些实施例中，所述磁热材料复合热释电材料为下述磁热材料和所述热释电材料中的任意一种组合；其中，所述磁热材料包括汝铁硼合金、四氧化三铁、铁，钴，镍、钆中的至少一种。
在其中一些实施例中，所述压电离子凝胶材料包括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中的至少一种。
在其中一些实施例中，所述活细胞为可产生神经递质的细胞类型；包括但不限于原代神经元细胞、神经免疫细胞、神经内分泌细胞、可产生神经递质的细胞系细胞、以及由干细胞诱导而成的神经元细胞中的至少一种，所述神经免疫细胞包括星形胶质细胞或小胶质细胞。
在其中一些实施例中，所述水凝胶为下述材料中至少一种：海藻酸盐、壳聚糖、明胶及其衍生物、胶原蛋白及其衍生物、透明质酸及其衍生物、细胞外基质蛋白及其衍生物、丝素蛋白及其衍生物、琼脂糖、卡拉胶、葡聚糖、基底膜基质、聚己内酯、聚乙二醇及其衍生物、丙二醇与环氧乙醚嵌段聚合物、聚乙烯吡咯烷酮。
在其中一些实施例中，所述水凝胶层厚度为50–500μm。
在其中一些实施例中，所述神经递质分子包括胆碱类、单胺类、氨基酸类、神经肽类、嘌呤类及一氧化氮中的至少一种，所述胆碱类包括乙酰胆碱，所述单胺类包括去甲肾上腺素或肾上腺素或多巴胺或5-HT或组胺中的至少一种，所述氨基酸类包括谷氨酸或Y-氨基丁酸或甘氨酸中的至少一种。
本申请提供的神经调控器件，通过外场介导下器件中活细胞神经递质分子的释放，诱发目标神经元兴奋，从而实现对特定神经活动和功能的调控，不但大大降低了器件的集成复杂度和构建难度，并且可通过外场介导遥控，与此同时，还具有迥异于现有神经调控器件电刺激、基于神经递质分子的仿生信息交 互方式，实现了神经调控的可控性和特异性，可用于脑机接口和神经器件疾病的治疗。
请参阅图2，为本申请提供的所述的神经调控器件的制备方法的步骤流程图，包括下述步骤S110至步骤S130，以下详细说明各个步骤的实现方式。
步骤S110：制备所述基底。
在其中一些实施例中，在制备所述基底的步骤中，具体包括下述步骤：采用流延法或旋涂法制备所述基底。
步骤S120：在所述基底表面生长所述活细胞。
在其中一些实施例中，通过光刻、等离子干法刻蚀或机械加工在所述基底表面形成平面或三维结构，所述三维结构包括微槽阵列、微锥阵列、微柱阵列中至少一种。
进一步地，所述活细胞的接种密度为10 3–10 6细胞/平方厘米。
步骤S130：将所述水凝胶预交联于所述基底表面以使所述活细胞封装于所述基底表面，得到所述的神经调控器件。
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。
本申请提供的神经调控器件制备方法，相较现有的神经调控器件，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，制备得到的神经调控器件可用于脑机接口和神经器件疾病的治疗。
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
一种基于活性界面的神经调控器件，结构如图1所示，该神经刺激器件包括响应性材料基底，在响应性材料基底粘附生长的活细胞，用于活细胞封装的水凝胶；其中，响应性材料基底由压电材料制成，活细胞为神经样细胞系细胞，水凝胶为钙离子交联的海藻酸钠。
本实施例中，响应性材料基底表面形貌为平整无结构表面，厚度为50μm，其材质为可在超声外场介导下产电的聚偏氟乙烯；所接种的神经样细胞系细胞为高分化PC12细胞；水凝胶材质为钙离子交联的海藻酸钠，厚度为50μm。
所述基于活性界面的神经调控器件的制备方法，包括以下步骤：
1)响应性材料基底制备；
使用二甲基亚砜作溶剂，配置浓度为10w/v％的聚偏氟乙烯溶液；在表面平整的硅片表面流延浇注聚偏氟乙烯溶液，80摄氏度下烘干，制得具有平面表面形貌的响应性材料基底；将制得的响应性材料基底通过钴源辐照，以15kGy的辐照剂量和30分钟的辐照时间，完成材料灭菌。
2)活细胞接种；
使用胰酶消化得到的高分化PC12细胞的细胞悬液，在灭菌处理后的响应性材料基底表面，以10 6细胞/平方厘米的接种密度接种细胞。
3)水凝胶封装；
在细胞接种至少24小时后，将3w/v％的海藻酸钠水凝胶预聚液覆盖接种活细胞的响应性材料基底表面，而后滴加0.3M的氯化钙水溶液，通过离子交联完成封装水凝胶交联，得到基于活性界面的神经调控器件。
实施例2
一种基于活性界面的神经调控器件，结构如图1所示，该神经刺激器件包括响应性材料基底，在响应性材料基底粘附生长的活细胞，用于活细胞封装的水凝胶；其中，响应性材料基底由光致形变材料复合压电材料，活细胞为神经样细胞系细胞，水凝胶为甲基丙烯酸酰化明胶。
本实施例中，响应性材料基底表面形貌为微槽阵列结构(微槽宽：50μm、高：50μm、间距：50μm)，基底材料厚度为500μm，其材质为可在可见光辐照介导下产电的聚偏氟乙烯和偶氮苯复合物；所接种的神经样细胞系细胞为高分化PC12细胞；水凝胶材质为甲基丙烯酸酰化明胶，厚度为500μm。
所述基于活性界面的神经调控器件的制备方法，包括以下步骤：
1)响应性材料基底制备；
使用二甲基亚砜作溶剂，配置聚偏氟乙烯浓度为5w/v％、偶氮苯浓度为1w/v％的混合溶液；在机械加工得到的微槽阵列结构(微槽宽：20μm、高：20μm、间距：20μm)模板表面流延浇注该混合溶液，80摄氏度下烘干，制得具有微槽阵列表面形貌的响应性材料基底；将制得的响应性材料基底通过钴源辐照，以15kGy的辐照剂量和30分钟的辐照时间，完成材料灭菌。
2)活细胞接种；
使用胰酶消化得到的高分化PC12细胞的细胞悬液，在灭菌处理后的响应性材料基底表面，以10 6细胞/平方厘米的接种密度接种细胞。
3)水凝胶封装；
在细胞接种至少24小时后，将加有0.1w/v％2959光交联剂的10w/v％的甲基丙烯酸酰化明胶水凝胶预聚液覆盖接种活细胞的响应性材料基底表面，而后在紫外交联仪辐照下反应10分钟，通过紫外光交联完成封装水凝胶交联，得到基于活性界面的神经调控器件。
实施例3
一种基于活性界面的神经调控器件，结构如图1所示，该神经刺激器件包括响应性材料基底，在响应性材料基底粘附生长的活细胞，用于活细胞封装的水凝胶；其中，响应性材料基底由光伏材料制成，活细胞为原代神经元，水凝胶为钙离子交联的海藻酸钠。
本实施例中，响应性材料基底表面形貌为平整无结构表面，厚度为50μm，其材质为可在可见光辐照介导下产电的聚-3己基噻吩(P3HT)；所接种的神经样细胞系细胞为高分化PC12细胞；水凝胶材质为钙离子交联的海藻酸钠，厚度为50μm。
所述基于活性界面的神经调控器件的制备方法，包括以下步骤：
1)响应性材料基底制备；
使用1,2-二氯代苯作溶剂，配置浓度为30mg/mL的P3HT溶液；在表面平整的硅片表面浇注该溶液，60摄氏度下旋涂，制得具有平面形貌的响应性材料基底；将制得的响应性材料基底通过钴源辐照，以15kGy的辐照剂量和30分钟的辐照时间，完成材料灭菌。
2)活细胞接种；
将灭菌处理后的响应性材料基底在浓度为0.1mg/ml的多聚赖氨酸水溶液中包被6小时，使用胎鼠大脑中消化提取的海马体神经元细胞悬液，在包被后的响应性材料基底表面，以10 3细胞/平方厘米的接种密度接种细胞。
3)水凝胶封装；
在细胞接种培养14天后，将3w/v％的海藻酸钠水凝胶预聚液覆盖接种活细胞的响应性材料基底表面，而后滴加0.3M的氯化钙水溶液，通过离子交联完成封装水凝胶交联，得到基于活性界面的神经调控器件。
实施例4
一种基于活性界面的神经调控器件，结构如图1所示，该神经刺激器件包括响应性材料基底，在响应性材料基底粘附生长的活细胞，用于活细胞封装的水凝胶；其中，响应性材料基底由上转换材料复合光伏材料制成，活细胞为原代神经元，水凝胶为钙离子交联的海藻酸钠。
本实施例中，响应性材料基底表面形貌为平整无结构表面，厚度为100μm，其材质为可在可见光辐照介导下产电的聚-3己基噻吩(P3HT)；所接种 的神经样细胞系细胞为高分化PC12细胞；水凝胶材质为钙离子交联的海藻酸钠，厚度为100μm。
所述基于活性界面的神经调控器件的制备方法，包括以下步骤：
1)响应性材料基底制备；
使用1,2-二氯代苯作溶剂，配置含有30mg/mL P3HT和0.1mg/mL氟钆化钠的混合物溶液；在表面平整的硅片表面浇注该溶液，60摄氏度下旋涂，制得具有平面形貌的响应性材料基底；将制得的响应性材料基底通过钴源辐照，以15kGy的辐照剂量和30分钟的辐照时间，完成材料灭菌。
2)活细胞接种；
将灭菌处理后的响应性材料基底在浓度为0.1mg/ml的多聚赖氨酸水溶液中包被6小时，使用胎鼠大脑中消化提取的海马体神经元细胞悬液，在包被后的响应性材料基底表面，以10 3细胞/平方厘米的接种密度接种细胞。
3)水凝胶封装；
在细胞接种培养14天后，将3w/v％的海藻酸钠水凝胶预聚液覆盖接种活细胞的响应性材料基底表面，而后滴加0.3M的氯化钙水溶液，通过离子交联完成封装水凝胶交联，得到基于活性界面的神经调控器件。
实施例5
一种基于活性界面的神经调控器件，结构如图1所示，该神经刺激器件包括响应性材料基底，在响应性材料基底粘附生长的活细胞，用于活细胞封装的 水凝胶；其中，响应性材料基底由光热材料复合热释电材料制成，活细胞为干细胞诱导神经元，水凝胶为钙离子交联的海藻酸钠。
本实施例中，响应性材料基底表面形貌为微锥阵列表面，微锥宽：5μm、高：5μm、间距：5μm，基底厚度为200μm，其材质为可在近红外光辐照介导下产电的P(VDF-TrFE)共聚物和聚多巴胺的复合物；所接种的由全功能诱导干细胞分化得到的多巴胺能神经元；水凝胶材质为钙离子交联的海藻酸钠，厚度为200μm。
所述基于活性界面的神经调控器件的制备方法，包括以下步骤：
1)响应性材料基底制备；
使用二甲基亚砜作溶剂，配置含10w/v％聚偏氟乙烯和0.1w/v％聚多巴胺的混合溶液；在等离子体干法刻蚀得到的微锥阵列结构(微锥宽：5μm、高：5μm、间距：5μm)模板表面流延浇注该混合溶液，80摄氏度下烘干，制得具有微锥阵列表面形貌的响应性材料基底；将制得的响应性材料基底通过钴源辐照，以15kGy的辐照剂量和30分钟的辐照时间，完成材料灭菌。
2)活细胞接种；
使用胰酶消化得到的全功能诱导干细胞分化得到的多巴胺能神经元的细胞悬液，在灭菌处理后的响应性材料基底表面，以10 4细胞/平方厘米的接种密度接种细胞。
3)水凝胶封装；
在细胞接种至少24小时后，将3w/v％的海藻酸钠水凝胶预聚液覆盖接种活细胞的响应性材料基底表面，而后滴加0.3M的氯化钙水溶液，通过离子交联完成封装水凝胶交联，得到基于活性界面的神经调控器件。
实施例6
一种基于活性界面的神经调控器件，结构如图1所示，该神经刺激器件包括响应性材料基底，在响应性材料基底粘附生长的活细胞，用于活细胞封装的水凝胶；其中，响应性材料基底由磁热材料复合热释电材料制成，活细胞为神经免疫细胞，水凝胶为钙离子交联的海藻酸钠。
本实施例中，响应性材料基底表面形貌为为微柱阵列表面，微柱宽：5μm、高：5μm、间距：5μm，基底厚度为50μm，其材质为可在交变磁场介导下产电的P(VDF-TrFE)共聚物和四氧化三铁的复合物；所接种的神经免疫细胞为小鼠星形胶质细胞；水凝胶材质为钙离子交联的海藻酸钠，厚度为50μm。
所述基于活性界面的神经调控器件的制备方法，包括以下步骤：
1)响应性材料基底制备；
使用二甲基亚砜作溶剂，配置含10w/v％聚偏氟乙烯和5mg/mL四氧化三铁纳米粒子的混合溶液；在光刻得到的微柱阵列结构(微柱宽：5μm、高：5μm、间距：5μm)模板表面流延浇注该混合溶液，制得具有微柱阵列表面形貌的响应性材料基底；将制得的响应性材料基底通过钴源辐照，以15kGy的辐照剂量和30分钟的辐照时间，完成材料灭菌。
2)活细胞接种；
使用胰酶消化得到的小鼠星形胶质细胞的细胞悬液，在灭菌处理后的响应性材料基底表面，以10 4细胞/平方厘米的接种密度接种细胞。
3)水凝胶封装；
在细胞接种至少24小时后，将3w/v％的海藻酸钠水凝胶预聚液覆盖接种活细胞的响应性材料基底表面，而后滴加0.3M的氯化钙水溶液，通过离子交联完成封装水凝胶交联，得到基于活性界面的神经调控器件。
实施例7
一种基于活性界面的神经调控器件，结构如图1所示，该神经刺激器件包括响应性材料基底，在响应性材料基底粘附生长的活细胞，用于活细胞封装的水凝胶；其中，响应性材料基底由压电离子凝胶材料制成，活细胞为神内分泌细胞，水凝胶为钙离子交联的海藻酸钠。
本实施例中，响应性材料基底表面形貌为为微柱阵列表面，微柱宽：50nm、高：50nm、间距：50nm，基底厚度为50μm，其材质为可在超声介导下产电的聚甲基丙烯酸和胆碱的复合物；所接种的神经内分泌细胞为小鼠肺泡神经内分泌细胞；水凝胶材质为钙离子交联的海藻酸钠，厚度为50μm。
所述基于活性界面的神经调控器件的制备方法，包括以下步骤：
1)响应性材料基底制备；
配置含10w/v％甲基丙烯酸和3w/v％氯化胆碱和0.1w/v％2959光引发剂 的水溶液；在光刻得到的微柱阵列结构(微柱宽：50nm、高：50nm、间距：50nm)模板表面流延浇注该混合溶液，紫外交联仪辐照下反应10分钟，制得具有微柱阵列表面形貌的的响应性材料基底；将制得的响应性材料基底通过钴源辐照，以15kGy的辐照剂量和30分钟的辐照时间，完成材料灭菌。
2)活细胞接种；
使用胰酶消化得到的小鼠肺泡神经内分泌细胞的细胞悬液，在灭菌处理后的响应性材料基底表面，以10 4细胞/平方厘米的接种密度接种细胞。
3)水凝胶封装；
在细胞接种至少24小时后，将3w/v％的海藻酸钠水凝胶预聚液覆盖接种活细胞的响应性材料基底表面，而后滴加0.3M的氯化钙水溶液，通过离子交联完成封装水凝胶交联，得到基于活性界面的神经调控器件
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 (22)

  1. 一种神经调控器件，其特征在于，包括：基底、生长于所述基底表面的活细胞以及用于将所述活细胞封装于所述基底表面的水凝胶，所述基底可将外场能量转化为电，并激发其表面生长的所述活细胞响应并释放神经递质分子，所述外场能量包括光或磁场或超声。
  2. 如权利要求1所述的神经调控器件，其特征在于，所述基底的厚度为50–500μm。
  3. 如权利要求1所述的神经调控器件，其特征在于，所述基底的表面形貌为平面或三维结构，所述三维结构包括微槽阵列、微锥阵列、微柱阵列中至少一种。
  4. 如权利要求1所述基于活性界面的神经调控器件，其特征在于，所述三维结构的尺寸宽度为50nm–20μm，高度为50nm–20μm，间距为50nm–20μm。
  5. 如权利要求1或2或3或4所述的神经调控器件，其特征在于，所述基底为压电材料、光致形变材料复合压电材料、光伏材料、上转换材料复合光伏材料、光热材料复合热释电材料、磁热材料复合热释电材料、压电离子凝胶中的至少一种。
  6. 如权利要求5所述的神经调控器件，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。
  7. 如权利要求5或6所述的神经调控器件，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的组合；其中，所述光致形变材料包括光致异构材料或铁电类无机光致形变材料中的至少一种，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的至少一种；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的至少一种。
  8. 如权利要求5所述的神经调控器件，其特征在于，所述光伏材料包括以下物质中的至少一种：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。
  9. 如权利要求5或6所述的神经调控器件，其特征在于，所述上转换材料复合光伏材料为下述上转换材料和所述压电材料中的任意一种组合；其中，所述上转换材料包括氧化钇、硫氧化钇、氟化镧、氟钇化钠、氟钆化钠中的至少一 种。
  10. 如权利要求5所述的神经调控器件，其特征在于，所述光热材料复合热释电材料包括光热材料和热释电材料中的任意一种组合；其中，所述光热材料包括炭黑、碳纳米管、石墨烯、黑磷、聚多巴胺、金纳米棒、镓铟合金液体金属中的至少一种；所述热释电材料包括聚偏氟乙烯类铁电聚合物及钙钛矿型铁电陶瓷中的至少一种，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]中的至少一种，所述钙钛矿型铁电陶瓷包括钛酸钡、锆钛酸铅、偏铌酸铅、铌酸铅钡锂中的至少一种。
  11. 如权利要求5或10所述的神经调控器件，其特征在于，所述磁热材料复合热释电材料为下述磁热材料和所述热释电材料中的任意一种组合；其中，所述磁热材料包括汝铁硼合金、四氧化三铁、铁，钴，镍、钆中的至少一种。
  12. 如权利要求5所述的神经调控器件，其特征在于，所述压电离子凝胶材料包括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中的至少一种。
  13. 如权利要求1所述的神经调控器件，其特征在于，所述活细胞为可产生神经递质的细胞类型；包括但不限于原代神经元细胞、神经免疫细胞、神经内分泌细胞、可产生神经递质的细胞系细胞、以及由干细胞诱导而成的神经元细胞中的至少一种，所述神经免疫细胞包括星形胶质细胞或小胶质细胞。
  14. 如权利要求1所述的神经调控器件，其特征在于，所述水凝胶为下述材料中至少一种：海藻酸盐、壳聚糖、明胶及其衍生物、胶原蛋白及其衍生物、透明质酸及其衍生物、细胞外基质蛋白及其衍生物、丝素蛋白及其衍生物、琼脂糖、卡拉胶、葡聚糖、基底膜基质、聚己内酯、聚乙二醇及其衍生物、丙二醇与环氧乙醚嵌段聚合物、聚乙烯吡咯烷酮。
  15. 如权利要求1所述的神经调控器件，其特征在于，所述水凝胶层厚度为50–500μm。
  16. 如权利要求1所述的神经调控器件，其特征在于，所述神经递质分子包括胆碱类、单胺类、氨基酸类、神经肽类、嘌呤类及一氧化氮中的至少一种，所述胆碱类包括乙酰胆碱，所述单胺类包括去甲肾上腺素或肾上腺素或多巴胺或5-HT或组胺中的至少一种，所述氨基酸类包括谷氨酸或Y-氨基丁酸或甘氨酸中的至少一种。
  17. 一种如权利要求1所述的神经调控器件的制备方法，其特征在于，包括下述步骤：
    制备所述基底；
    在所述基底表面生长所述活细胞；
    将所述水凝胶预交联于所述基底表面以使所述活细胞封装于所述基底表面，得到所述的神经调控器件。
  18. 如权利要求17所述的神经调控器件的制备方法，其特征在于，在制备所述基底的步骤中，具体包括下述步骤：采用流延法或旋涂法制备所述基底。
  19. 如权利要求17所述的神经调控器件的制备方法，其特征在于，通过光刻、等离子干法刻蚀或机械加工在所述基底表面形成平面或三维结构，所述三维结构包括微槽阵列、微锥阵列、微柱阵列中至少一种。
  20. 如权利要求17所述的神经调控器件的制备方法，其特征在于，所述活细胞的接种密度为10 3–10 6细胞/平方厘米。
  21. 如权利要求17所述的神经调控器件的制备方法，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。
  22. 一种如权利要求17所述的神经调控器件在脑机接口和神经器件疾病治疗中的应用。
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
TWI922156B (zh) 2025-01-23 2026-04-11 國立陽明交通大學 導熱導電性之蠶絲蛋白複合物及其製備方法與應用

Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20190247546A1 (en) * 2016-05-17 2019-08-15 Leibniz-Institut Für Polymerforschung Dresden E.V. Method for forming a functional network of human neuronal and glial cells
CN111013014A (zh) * 2019-12-17 2020-04-17 中国科学院深圳先进技术研究院 神经组织刺激复合材料、复合膜及神经组织假体
CN112006977A (zh) * 2020-09-08 2020-12-01 中国科学院空天信息创新研究院 光控纳米水凝胶、制备方法及在体癫痫调控与监测系统
CN112945918A (zh) * 2021-01-28 2021-06-11 中国科学院深圳先进技术研究院 一种细胞超声神经调控系统
CN112972888A (zh) * 2019-12-13 2021-06-18 中国科学院深圳先进技术研究院 一种神经刺激阵列系统及其制备方法
US20210268268A1 (en) * 2018-07-20 2021-09-02 University Of Pittsburgh - Of The Commonwealth System Of Higher Education Conformable neural interface device with hydrogel adhesion and methods of using the same
CN113621144A (zh) * 2021-06-11 2021-11-09 四川大学 磁电响应仿生水凝胶及可调细胞电学微环境磁电响应仿生水凝胶及其制备方法
US20220257662A1 (en) * 2018-10-26 2022-08-18 Tessara Therapeutics Pty Ltd Nervous system cell therapy

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20190247546A1 (en) * 2016-05-17 2019-08-15 Leibniz-Institut Für Polymerforschung Dresden E.V. Method for forming a functional network of human neuronal and glial cells
US20210268268A1 (en) * 2018-07-20 2021-09-02 University Of Pittsburgh - Of The Commonwealth System Of Higher Education Conformable neural interface device with hydrogel adhesion and methods of using the same
US20220257662A1 (en) * 2018-10-26 2022-08-18 Tessara Therapeutics Pty Ltd Nervous system cell therapy
CN112972888A (zh) * 2019-12-13 2021-06-18 中国科学院深圳先进技术研究院 一种神经刺激阵列系统及其制备方法
CN111013014A (zh) * 2019-12-17 2020-04-17 中国科学院深圳先进技术研究院 神经组织刺激复合材料、复合膜及神经组织假体
CN112006977A (zh) * 2020-09-08 2020-12-01 中国科学院空天信息创新研究院 光控纳米水凝胶、制备方法及在体癫痫调控与监测系统
CN112945918A (zh) * 2021-01-28 2021-06-11 中国科学院深圳先进技术研究院 一种细胞超声神经调控系统
CN113621144A (zh) * 2021-06-11 2021-11-09 四川大学 磁电响应仿生水凝胶及可调细胞电学微环境磁电响应仿生水凝胶及其制备方法

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
HONGXU CHEN: "Bioinspired microcone-array-based living biointerfaces: enhancing the anti-inflammatory effect and neuronal network formation", MICROSYSTEMS & NANOENGINEERING, vol. 6, no. 1, XP093169170, ISSN: 2055-7434, DOI: 10.1038/s41378-020-0172-0 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
TWI922156B (zh) 2025-01-23 2026-04-11 國立陽明交通大學 導熱導電性之蠶絲蛋白複合物及其製備方法與應用

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