CN115591025B - Nerve regulation device, preparation method and application thereof - Google Patents
Nerve regulation device, preparation method and application thereof Download PDFInfo
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- CN115591025B CN115591025B CN202211397878.4A CN202211397878A CN115591025B CN 115591025 B CN115591025 B CN 115591025B CN 202211397878 A CN202211397878 A CN 202211397878A CN 115591025 B CN115591025 B CN 115591025B
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Abstract
The application provides a neuromodulation device, including: the nerve regulation device provided by the application can induce target neuron excitation through the release of the living cell neurotransmitter molecules in the device under the mediation of the external field, thereby realizing the regulation of specific nerve activity and function, greatly reducing the integration complexity and construction difficulty of the device, realizing the remote control through the mediation of the external field, simultaneously realizing the controllability and the specificity of nerve regulation by adopting a bionic information interaction mode based on neurotransmitter molecules and different from the electrical stimulation of the traditional nerve regulation device. In addition, the application also provides a preparation method of the nerve control device.
Description
Technical Field
The application relates to the technical field of biomedicine, in particular to a nerve control device, a preparation method and application thereof.
Background
The nerve regulation technology has critical significance for the development of the emerging fields such as neuroscience, brain-computer interfaces and the like. The existing nerve regulation technology mainly applies electric stimulation to neurons in a target area through an implanted electrode device, so that the neurons are induced to generate action potentials to excite, and the aim of nerve regulation is fulfilled. Although such nerve control electrode devices based on electrical stimulation show good effects in the fields of deep brain stimulation for treating nervous system diseases and the like, the existing devices are subject to working principles and face a plurality of defects in the safety and effectiveness of nerve control. In particular, existing electrode stimulation-based neuromodulation devices not only have a large difference in modulus from neural tissue, but often involve complex wiring, integration, and packaging, with high risks of tissue damage, bleeding, inflammation, exposure to infection, and the like during and after implantation. In addition, the information interaction mode of the conventional nerve regulation and control device based on electrode stimulation when exciting neuron response is also basically different from the natural information interaction mode based on transmitter molecules among nerve clouds in nerve tissues. Such differences can lead to the difficulty in achieving sufficient specificity of existing devices in neuromodulation, inability to circumvent false activation of non-target neurons surrounding the implantation site, and resulting in unexpected side effects.
Recently, by directly implanting living cells, an active interface formed by the living cells is connected with an autologous neuron, and bionic information interaction is realized, so that new possibility is provided for nerve regulation.
However, such techniques fail to program the response of implanted living cells, which presents a significant challenge for controllable neuromodulation.
Disclosure of Invention
In view of the foregoing, it is desirable to provide a neuromodulation device and method of making the same that achieves modulation of specific neural activity and function, in response to the deficiencies of the prior art.
In order to solve the problems, the following technical scheme is adopted in the application:
one of the objects of the present application is to provide a neuromodulation 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, the substrate being capable of converting external field energy, including light or a magnetic field or ultrasound, into electricity and stimulating the living cells grown on its surface to respond and release neurotransmitter molecules.
In some of these embodiments, the substrate has a thickness of 50-500 μm.
In some embodiments, the surface topography of the substrate is a planar or three-dimensional structure comprising at least one of an array of micro-grooves, an array of micro-cones, and an array of micro-pillars.
In some of these embodiments, the three-dimensional structures have dimensions ranging from 50nm to 20 μm in width, from 50nm to 20 μm in height, and from 50nm to 20 μm in pitch.
In some embodiments, the substrate is at least one of a piezoelectric material, a photo-deformable material composite piezoelectric material, a photovoltaic material, an up-conversion material composite photovoltaic material, a photo-thermal material composite pyroelectric material, a magneto-thermal material composite pyroelectric material, and a piezoelectric ion gel.
In some of these embodiments, the piezoelectric material comprises a piezoelectric crystal or a piezoelectric ceramic or a polyvinylidene fluoride-based ferroelectric polymer or a piezoelectric polymer, the piezoelectric crystal comprising a quartz crystal or lithium gallate or lithium germanate or titanium germanate or lithium tantalate; the piezoelectric ceramic comprises barium titanate or lead zirconate titanate or lead metaniobate or lead barium lithium niobate; the polyvinylidene fluoride ferroelectric polymer comprises poly (vinylidene fluoride) or poly (vinylidene fluoride-trifluoroethylene) [ P (VDF-TrFE) copolymer ] or poly (vinylidene fluoride-chlorotrifluoroethylene) [ P (VDF-CFE) copolymer ] or poly (vinylidene fluoride-chlorotrifluoroethylene) [ P (VDF-CTFE) copolymer ] or poly (vinylidene fluoride-hexafluoropropylene) [ P (VDF-HFP) copolymer ] or poly (vinylidene fluoride-trifluoroethylene-chlorotrifluoroethylene) [ P (VDF-TrFE-CFE) terpolymer ] or poly (vinylidene fluoride-trifluoroethylene-chlorotrifluoroethylene) [ P (VDF-TrFE-CTFE) terpolymer ] or poly (vinylidene fluoride-trifluoroethylene-hexafluoropropylene) [ P (VDF-TrFE-HFP) terpolymer ]; the piezoelectric polymer comprises odd nylon or polyacrylonitrile or vinylidene dicyano and copolymer thereof, polyurea or polyphenyl cyanoether or polyvinyl chloride or polyvinyl acetate or polypropylene or polytetrafluoroethylene.
In some of these embodiments, the photoformable material composite piezoelectric material is a combination of any one of the following photoformable materials and the piezoelectric material; wherein the photoinduced deformation material comprises at least one of photoinduced isomerism material or ferroelectric inorganic photoinduced deformation material, and the photoinduced isomerism material comprises at least one of azobenzene and derivatives thereof, spiropyran and derivatives thereof; the ferroelectric inorganic photoinduced deformation material comprises at least one of lead titanate, barium titanate, potassium niobate, lithium tantalate, bismuth layered perovskite structure ferroelectric, tungsten bronze ferroelectric, bismuth ferrite, monopotassium phosphate, ammonium triglycinate sulfate, rochlote and perovskite type organic metal halide ferroelectric.
In some of these embodiments, the photovoltaic material comprises at least one of the following: organic photovoltaic materials of polyacetylene, polythiophene, polyaniline, polypyrrole, derivatives and copolymers thereof.
In some of these embodiments, the upconverting material composite photovoltaic material is any one of the following upconverting materials and the piezoelectric material in combination; wherein the up-conversion material comprises at least one of yttrium oxide, yttrium oxysulfide, lanthanum fluoride, sodium yttrium fluoride and sodium gadolinium fluoride.
In some embodiments, the photothermal material composite pyroelectric material comprises any combination of a photothermal material and a pyroelectric material; the photo-thermal material comprises at least one of carbon black, carbon nano tubes, graphene, black phosphorus, polydopamine, gold nanorods and gallium indium alloy liquid metal; the pyroelectric material comprises at least one of a polyvinylidene fluoride ferroelectric polymer and a perovskite ferroelectric ceramic, wherein the polyvinylidene fluoride ferroelectric polymer comprises at least one of poly (vinylidene fluoride), poly (vinylidene fluoride-trifluoroethylene) [ P (VDF-TrFE) copolymer ], poly (vinylidene fluoride-chlorotrifluoroethylene) [ P (VDF-CFE) copolymer ], poly (vinylidene fluoride-chlorotrifluoroethylene) [ P (VDF-CTFE) copolymer ], poly (vinylidene fluoride-hexafluoropropylene) [ P (VDF-HFP) copolymer ], poly (vinylidene fluoride-trifluoroethylene-chlorotrifluoroethylene) [ P (VDF-TrFE-CFE) terpolymer ], poly (vinylidene fluoride-trifluoroethylene-chlorotrifluoroethylene) [ P (VDF-TrFE-CTFE) terpolymer ] and poly (vinylidene fluoride-trifluoroethylene-hexafluoropropylene) [ P (VDF-TrFE-HFP) terpolymer), and the perovskite ferroelectric ceramic comprises at least one of lead titanate, lead titanate and barium niobate.
In some embodiments, the magnetocaloric material composite pyroelectric material is any one of the following magnetocaloric materials and pyroelectric materials; the magnetocaloric material comprises at least one of Ru-Fe-B alloy, ferroferric oxide, iron, cobalt, nickel and gadolinium.
In some embodiments, the piezoelectric ion gel material comprises 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 methacrylic acid acylated gelatin and choline composite gel, a methacrylic acid acylated hyaluronic acid and choline composite gel.
In some of these embodiments, the living cell is a neurotransmitter-producing cell type; including but not limited to at least one of primary neuronal cells, neuroimmune cells including astrocytes or microglia, neuroendocrine cells, neurotransmitter-producing cell line cells, and neuronal cells induced by stem cells.
In some of these embodiments, 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 its derivatives, silk fibroin and its derivatives, agarose, carrageenan, dextran, basement membrane matrix, polycaprolactone, polyethylene glycol and its derivatives, propylene glycol and epoxy ether block polymer, polyvinylpyrrolidone.
In some of these embodiments, the hydrogel layer has a thickness of 50-500 μm.
In some of these embodiments, the neurotransmitter molecule comprises at least one of cholines, monoamines, amino acids, neuropeptides, purines, and nitric oxide, the cholines comprise acetylcholine, the monoamines comprise at least one of norepinephrine or epinephrine or dopamine or 5-HT or histamine, and the amino acids comprise at least one of glutamate or Y-aminobutyric acid or glycine.
The second object of the present application is to provide a method for preparing a neuromodulation device, comprising the steps of:
preparing the substrate;
growing the living cells on the surface of the substrate;
and pre-crosslinking the hydrogel on the surface of the substrate to enable the living cells to be packaged on the surface of the substrate, so as to obtain the nerve control device.
In some of these embodiments, in the step of preparing the substrate, the following steps are specifically included: the substrate is prepared by a casting method or a spin coating method.
In some of these embodiments, a planar or three-dimensional structure is formed on the substrate surface by photolithography, plasma dry etching, or machining, the three-dimensional structure including at least one of an array of micro-grooves, an array of micro-cones, and an array of micro-pillars.
In some of these embodiments, the viable cells have an seeding density of 10 3 –10 6 Cells per square centimeter.
In some embodiments, the crosslinking mode of the crosslinking is at least one of ionic crosslinking and ultraviolet crosslinking.
The application provides an application of the nerve regulating device in treating brain-computer interface and nerve device diseases.
By adopting the technical scheme, the application has the following beneficial effects:
the application provides a neuromodulation device, including: the nerve regulation device provided by the application can induce target neuron excitation through the release of the living cell neurotransmitter molecules in the device under the mediation of the external field, thereby realizing the regulation of specific nerve activity and function, greatly reducing the integration complexity and construction difficulty of the device, realizing the remote control through the mediation of the external field, simultaneously realizing the controllability and the specificity of nerve regulation by adopting a bionic information interaction mode based on neurotransmitter molecules and different from the electrical stimulation of the traditional nerve regulation device.
In addition, compared with the existing nerve regulation device, the nerve regulation device manufacturing method does not need complex manufacturing technology and integrated packaging technology, greatly reduces the construction difficulty of the device, and is simple in manufacturing technology.
Drawings
In order to more clearly illustrate the technical solutions of the embodiments of the present application, the drawings used in the embodiments of the present application or the description of the prior art will be briefly described below, and it is obvious that the drawings described below are only some embodiments of the present application, and that other drawings may be obtained according to these drawings without inventive effort for a person skilled in the art.
Fig. 1 is a schematic structural diagram of a neuromodulation device according to an embodiment of the present application.
Fig. 2 is a flowchart of steps for applying for the neuromodulation device provided in the present embodiment.
Detailed Description
Embodiments of the present application are described in detail below, examples of which are illustrated in the accompanying drawings, wherein the same or similar reference numerals refer to the same or similar elements or elements having the same or similar functions throughout. The embodiments described below by referring to the drawings are exemplary and intended for the purpose of explaining the present application and are not to be construed as limiting the present application.
In the description of the present application, it should be understood that the terms "upper," "lower," "horizontal," "inner," "outer," and the like indicate an orientation or a positional relationship based on that shown in the drawings, and are merely for convenience of description and simplification of the description, and do not indicate or imply that the apparatus or element in question must have a specific orientation, be configured and operated in a specific orientation, and therefore should not be construed as limiting the present application.
Furthermore, the terms "first," "second," and the like, are used for descriptive purposes only and are not to be construed as indicating or implying a relative importance or implicitly indicating the number of technical features indicated. Thus, a feature defining "a first" or "a second" may explicitly or implicitly include one or more such feature. In the description of the present application, the meaning of "a plurality" is two or more, unless explicitly defined otherwise.
In order to make the objects, technical solutions and advantages of the present application more apparent, the present application will be further described in detail with reference to the accompanying drawings and examples.
Referring to fig. 1, a schematic structural diagram of a neuromodulation device according to an embodiment of the present application includes: 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, including light or a magnetic field or ultrasound, into electricity and excite the living cells 120 grown on the surface thereof to respond to and release neurotransmitter molecules 140.
In some of these embodiments, the substrate has a thickness of 50-500 μm.
In some embodiments, the surface topography of the substrate is a planar or three-dimensional structure comprising at least one of an array of micro-grooves, an array of micro-cones, and an array of micro-pillars.
In some of these embodiments, the three-dimensional structures have dimensions ranging from 50nm to 20 μm in width, from 50nm to 20 μm in height, and from 50nm to 20 μm in pitch.
In some embodiments, the substrate is at least one of a piezoelectric material, a photo-deformable material composite piezoelectric material, a photovoltaic material, an up-conversion material composite photovoltaic material, a photo-thermal material composite pyroelectric material, a magneto-thermal material composite pyroelectric material, and a piezoelectric ion gel.
In some of these embodiments, the piezoelectric material comprises a piezoelectric crystal or a piezoelectric ceramic or a polyvinylidene fluoride-based ferroelectric polymer or a piezoelectric polymer, the piezoelectric crystal comprising a quartz crystal or lithium gallate or lithium germanate or titanium germanate or lithium tantalate; the piezoelectric ceramic comprises barium titanate or lead zirconate titanate or lead metaniobate or lead barium lithium niobate; the polyvinylidene fluoride ferroelectric polymer comprises poly (vinylidene fluoride) or poly (vinylidene fluoride-trifluoroethylene) [ P (VDF-TrFE) copolymer ] or poly (vinylidene fluoride-chlorotrifluoroethylene) [ P (VDF-CFE) copolymer ] or poly (vinylidene fluoride-chlorotrifluoroethylene) [ P (VDF-CTFE) copolymer ] or poly (vinylidene fluoride-hexafluoropropylene) [ P (VDF-HFP) copolymer ] or poly (vinylidene fluoride-trifluoroethylene-chlorotrifluoroethylene) [ P (VDF-TrFE-CFE) terpolymer ] or poly (vinylidene fluoride-trifluoroethylene-chlorotrifluoroethylene) [ P (VDF-TrFE-CTFE) terpolymer ] or poly (vinylidene fluoride-trifluoroethylene-hexafluoropropylene) [ P (VDF-TrFE-HFP) terpolymer ]; the piezoelectric polymer comprises odd nylon or polyacrylonitrile or vinylidene dicyano and copolymer thereof, polyurea or polyphenyl cyanoether or polyvinyl chloride or polyvinyl acetate or polypropylene or polytetrafluoroethylene.
In some of these embodiments, the photoformable material composite piezoelectric material is a combination of any one of the following photoformable materials and the piezoelectric material; wherein the photoinduced deformation material comprises at least one of photoinduced isomerism material or ferroelectric inorganic photoinduced deformation material, and the photoinduced isomerism material comprises at least one of azobenzene and derivatives thereof, spiropyran and derivatives thereof; the ferroelectric inorganic photoinduced deformation material comprises at least one of lead titanate, barium titanate, potassium niobate, lithium tantalate, bismuth layered perovskite structure ferroelectric, tungsten bronze ferroelectric, bismuth ferrite, monopotassium phosphate, ammonium triglycinate sulfate, rochlote and perovskite type organic metal halide ferroelectric.
In some of these embodiments, the photovoltaic material comprises at least one of the following: organic photovoltaic materials of polyacetylene, polythiophene, polyaniline, polypyrrole, derivatives and copolymers thereof.
In some of these embodiments, the upconverting material composite photovoltaic material is any one of the following upconverting materials and the piezoelectric material in combination; wherein the up-conversion material comprises at least one of yttrium oxide, yttrium oxysulfide, lanthanum fluoride, sodium yttrium fluoride and sodium gadolinium fluoride.
In some embodiments, the photothermal material composite pyroelectric material comprises any combination of a photothermal material and a pyroelectric material; the photo-thermal material comprises at least one of carbon black, carbon nano tubes, graphene, black phosphorus, polydopamine, gold nanorods and gallium indium alloy liquid metal; the pyroelectric material comprises at least one of a polyvinylidene fluoride ferroelectric polymer and a perovskite ferroelectric ceramic, wherein the polyvinylidene fluoride ferroelectric polymer comprises at least one of poly (vinylidene fluoride), poly (vinylidene fluoride-trifluoroethylene) [ P (VDF-TrFE) copolymer ], poly (vinylidene fluoride-chlorotrifluoroethylene) [ P (VDF-CFE) copolymer ], poly (vinylidene fluoride-chlorotrifluoroethylene) [ P (VDF-CTFE) copolymer ], poly (vinylidene fluoride-hexafluoropropylene) [ P (VDF-HFP) copolymer ], poly (vinylidene fluoride-trifluoroethylene-chlorotrifluoroethylene) [ P (VDF-TrFE-CFE) terpolymer ], poly (vinylidene fluoride-trifluoroethylene-chlorotrifluoroethylene) [ P (VDF-TrFE-CTFE) terpolymer ] and poly (vinylidene fluoride-trifluoroethylene-hexafluoropropylene) [ P (VDF-TrFE-HFP) terpolymer), and the perovskite ferroelectric ceramic comprises at least one of lead titanate, lead titanate and barium niobate.
In some embodiments, the magnetocaloric material composite pyroelectric material is any one of the following magnetocaloric materials and pyroelectric materials; the magnetocaloric material comprises at least one of Ru-Fe-B alloy, ferroferric oxide, iron, cobalt, nickel and gadolinium.
In some embodiments, the piezoelectric ion gel material comprises 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 methacrylic acid acylated gelatin and choline composite gel, a methacrylic acid acylated hyaluronic acid and choline composite gel.
In some of these embodiments, the living cell is a neurotransmitter-producing cell type; including but not limited to at least one of primary neuronal cells, neuroimmune cells including astrocytes or microglia, neuroendocrine cells, neurotransmitter-producing cell line cells, and neuronal cells induced by stem cells.
In some of these embodiments, 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 its derivatives, silk fibroin and its derivatives, agarose, carrageenan, dextran, basement membrane matrix, polycaprolactone, polyethylene glycol and its derivatives, propylene glycol and epoxy ether block polymer, polyvinylpyrrolidone.
In some of these embodiments, the hydrogel layer has a thickness of 50-500 μm.
In some of these embodiments, the neurotransmitter molecule comprises at least one of cholines, monoamines, amino acids, neuropeptides, purines, and nitric oxide, the cholines comprise acetylcholine, the monoamines comprise at least one of norepinephrine or epinephrine or dopamine or 5-HT or histamine, and the amino acids comprise at least one of glutamate or Y-aminobutyric acid or glycine.
The nerve regulation and control device provided by the application can induce target neuron excitation through the release of living cell neurotransmitter molecules in the device under the mediation of the external field, so that the regulation and control of specific nerve activities and functions are realized, the integration complexity and the construction difficulty of the device are greatly reduced, and the nerve regulation and control device can be remotely controlled through the mediation of the external field, meanwhile, the nerve regulation and control device has a bionic information interaction mode which is different from the electric stimulation of the traditional nerve regulation and control device and is based on neurotransmitter molecules, the controllability and the specificity of nerve regulation and control are realized, and the nerve regulation and control device can be used for treating brain-computer interface and nerve device diseases.
Referring to fig. 2, a step flow chart of a method for manufacturing a neuromodulation device provided in the present application includes the following steps S110 to S130, and the implementation manner of each step is described in detail below.
Step S110: the substrate is prepared.
In some of these embodiments, in the step of preparing the substrate, the following steps are specifically included: the substrate is prepared by a casting method or a spin coating method.
Step S120: growing the living cells on the surface of the substrate.
In some of these embodiments, a planar or three-dimensional structure is formed on the substrate surface by photolithography, plasma dry etching, or machining, the three-dimensional structure including at least one of an array of micro-grooves, an array of micro-cones, and an array of micro-pillars.
Further, the inoculation density of the living cells is 10 3 –10 6 Cells per square centimeter.
Step S130: and pre-crosslinking the hydrogel on the surface of the substrate to enable the living cells to be packaged on the surface of the substrate, so as to obtain the nerve control device.
In some embodiments, the crosslinking mode of the crosslinking is at least one of ionic crosslinking and ultraviolet crosslinking.
Compared with the existing nerve regulation device, the nerve regulation device manufacturing method does not need complex manufacturing technology and integrated packaging technology, greatly reduces the construction difficulty of the device, is simple in manufacturing technology, and can be used for treating brain-computer interface and nerve device diseases.
The above technical solutions of the present application are described in detail below with reference to specific embodiments.
Example 1
A nerve regulation device based on an active interface, the structure of which is shown in figure 1, the nerve stimulation device comprises a responsive material substrate, living cells which are adhered and grown on the responsive material substrate, and hydrogel for packaging the living cells; the responsive material substrate is made of piezoelectric materials, living cells are nerve-like cell line cells, and the hydrogel is calcium ion crosslinked sodium alginate.
In the embodiment, the surface appearance of the substrate of the responsive material is a flat unstructured surface, the thickness is 50 mu m, and the material is polyvinylidene fluoride which can generate electricity under the mediation of an ultrasonic external field; the inoculated nerve-like cell line cells are highly differentiated PC12 cells; the hydrogel material is calcium ion crosslinked sodium alginate, and the thickness is 50 μm.
The preparation method of the nerve control device based on the active interface comprises the following steps:
1) Preparing a responsive material substrate;
preparing a polyvinylidene fluoride solution with the concentration of 10w/v% by using dimethyl sulfoxide as a solvent; casting polyvinylidene fluoride solution on the surface of a silicon wafer with a flat surface, and drying at 80 ℃ to obtain a responsive material substrate with a planar surface morphology; and irradiating the prepared responsive material substrate through a cobalt source, and completing material sterilization at an irradiation dose of 15kGy and an irradiation time of 30 minutes.
2) Inoculating living cells;
cell suspension of highly differentiated PC12 cells obtained by pancreatin digestion was used as a substrate surface of a sterilized responsive material at a ratio of 10 6 Cell seeding density cells/cm.
3) Packaging hydrogel;
after at least 24 hours of cell inoculation, 3w/v% sodium alginate hydrogel prepolymer liquid is covered on the surface of a substrate of a responsive material inoculated with living cells, then 0.3M calcium chloride aqueous solution is dripped, and the encapsulated hydrogel is crosslinked through ionic crosslinking, so that the nerve control device based on an active interface is obtained.
Example 2
A nerve regulation device based on an active interface, the structure of which is shown in figure 1, the nerve stimulation device comprises a responsive material substrate, living cells which are adhered and grown on the responsive material substrate, and hydrogel for packaging the living cells; the responsive material substrate is made of a photoinduced deformation material and a piezoelectric material, living cells are nerve-like cell line cells, and the hydrogel is methacrylic acid acylated gelatin.
In the embodiment, the substrate surface morphology of the responsive material is a micro-groove array structure (micro-groove width: 50 μm, height: 50 μm, interval: 50 μm), the thickness of the substrate material is 500 μm, and the substrate material is polyvinylidene fluoride and azobenzene compound capable of generating electricity under the mediation of visible light irradiation; the inoculated nerve-like cell line cells are highly differentiated PC12 cells; the hydrogel material is methacrylic acid acylated gelatin, and the thickness is 500 mu m.
The preparation method of the nerve control device based on the active interface comprises the following steps:
1) Preparing a responsive material substrate;
preparing a mixed solution with the concentration of polyvinylidene fluoride of 5w/v% and the concentration of azobenzene of 1w/v% by using dimethyl sulfoxide as a solvent; casting the mixed solution on the surface of a micro-groove array structure (micro-groove width: 20 mu m, height: 20 mu m, interval: 20 mu m) template obtained by mechanical processing, and drying at 80 ℃ to obtain a responsive material substrate with the micro-groove array surface morphology; and irradiating the prepared responsive material substrate through a cobalt source, and completing material sterilization at an irradiation dose of 15kGy and an irradiation time of 30 minutes.
2) Inoculating living cells;
cell suspension of highly differentiated PC12 cells obtained by pancreatin digestion was used as a substrate surface of a sterilized responsive material at a ratio of 10 6 Cell seeding density cells/cm.
3) Packaging hydrogel;
after at least 24 hours of cell inoculation, 10w/v% methacrylic acid acylated gelatin hydrogel prepolymerization solution added with 0.1w/v%2959 photo-crosslinking agent is covered on the surface of a substrate of a responsive material inoculated with living cells, then the reaction is carried out for 10 minutes under the irradiation of an ultraviolet crosslinking instrument, and the crosslinking of the encapsulated hydrogel is completed through ultraviolet crosslinking, so that the nerve control device based on an active interface is obtained.
Example 3
A nerve regulation device based on an active interface, the structure of which is shown in figure 1, the nerve stimulation device comprises a responsive material substrate, living cells which are adhered and grown on the responsive material substrate, and hydrogel for packaging the living cells; the responsive material substrate is made of a photovoltaic material, living cells are primary neurons, and the hydrogel is calcium ion crosslinked sodium alginate.
In the embodiment, the surface appearance of the substrate of the responsive material is a flat unstructured surface, the thickness is 50 mu m, and the material is poly-3 hexyl thiophene (P3 HT) capable of generating electricity under the mediation of visible light irradiation; the inoculated nerve-like cell line cells are highly differentiated PC12 cells; the hydrogel material is calcium ion crosslinked sodium alginate, and the thickness is 50 μm.
The preparation method of the nerve control device based on the active interface comprises the following steps:
1) Preparing a responsive material substrate;
preparing a P3HT solution with the concentration of 30mg/mL by using 1, 2-dichlorobenzene as a solvent; pouring the solution on the surface of a silicon wafer with a flat surface, and spin-coating at 60 ℃ to prepare a responsive material substrate with a planar morphology; and irradiating the prepared responsive material substrate through a cobalt source, and completing material sterilization at an irradiation dose of 15kGy and an irradiation time of 30 minutes.
2) Inoculating living cells;
coating sterilized substrate of responsive material in polylysine water solution at concentration of 0.1mg/ml for 6 hr, digesting the extracted hippocampal neuron cell suspension in fetal mouse brain, and coating the coated surface of responsive material substrate with 10% of 3 Cell seeding density cells/cm.
3) Packaging hydrogel;
after the cells are inoculated and cultured for 14 days, 3w/v% sodium alginate hydrogel prepolymer liquid is covered on the surface of a substrate of a responsive material inoculated with living cells, then 0.3M calcium chloride aqueous solution is dripped, and the encapsulated hydrogel is crosslinked through ionic crosslinking, so that the nerve control device based on an active interface is obtained.
Example 4
A nerve regulation device based on an active interface, the structure of which is shown in figure 1, the nerve stimulation device comprises a responsive material substrate, living cells which are adhered and grown on the responsive material substrate, and hydrogel for packaging the living cells; the responsive material substrate is made of an up-conversion material composite photovoltaic material, living cells are primary neurons, and the hydrogel is calcium ion crosslinked sodium alginate.
In the embodiment, the surface appearance of the substrate of the responsive material is a flat unstructured surface, the thickness is 100 mu m, and the material is poly-3 hexyl thiophene (P3 HT) capable of generating electricity under the mediation of visible light irradiation; the inoculated nerve-like cell line cells are highly differentiated PC12 cells; the hydrogel material is calcium ion crosslinked sodium alginate, and the thickness is 100 μm.
The preparation method of the nerve control device based on the active interface comprises the following steps:
1) Preparing a responsive material substrate;
preparing a mixture solution containing 30mg/mL of P3HT and 0.1mg/mL of sodium gadolinium fluoride by using 1, 2-dichlorobenzene as a solvent; pouring the solution on the surface of a silicon wafer with a flat surface, and spin-coating at 60 ℃ to prepare a responsive material substrate with a planar morphology; and irradiating the prepared responsive material substrate through a cobalt source, and completing material sterilization at an irradiation dose of 15kGy and an irradiation time of 30 minutes.
2) Inoculating living cells;
coating sterilized substrate of responsive material in polylysine water solution at concentration of 0.1mg/ml for 6 hr, digesting the extracted hippocampal neuron cell suspension in fetal mouse brain, and coating the coated surface of responsive material substrate with 10% of 3 Cell seeding density cells/cm.
3) Packaging hydrogel;
after the cells are inoculated and cultured for 14 days, 3w/v% sodium alginate hydrogel prepolymer liquid is covered on the surface of a substrate of a responsive material inoculated with living cells, then 0.3M calcium chloride aqueous solution is dripped, and the encapsulated hydrogel is crosslinked through ionic crosslinking, so that the nerve control device based on an active interface is obtained.
Example 5
A nerve regulation device based on an active interface, the structure of which is shown in figure 1, the nerve stimulation device comprises a responsive material substrate, living cells which are adhered and grown on the responsive material substrate, and hydrogel for packaging the living cells; the responsive material substrate is made of a photo-thermal material and a pyroelectric material, living cells are stem cells for inducing neurons, and the hydrogel is calcium ion crosslinked sodium alginate.
In this embodiment, the surface morphology of the substrate of the responsive material is a surface of a micro-cone array, and the micro-cone width: 5 μm, high: 5 μm, pitch: 5 μm, the thickness of the substrate is 200 μm, and the material is a compound of P (VDF-TrFE) copolymer and polydopamine which can generate electricity under the mediation of near infrared light irradiation; the inoculated dopaminergic neurons obtained by full-function induction stem cell differentiation; the hydrogel material is calcium ion crosslinked sodium alginate, and the thickness is 200 μm.
The preparation method of the nerve control device based on the active interface comprises the following steps:
1) Preparing a responsive material substrate;
preparing a mixed solution containing 10w/v% polyvinylidene fluoride and 0.1w/v% polydopamine by using dimethyl sulfoxide as a solvent; casting the mixed solution on the surface of a micro-cone array structure (micro-cone width: 5 mu m, height: 5 mu m, interval: 5 mu m) template obtained by plasma dry etching, and drying at 80 ℃ to obtain a responsive material substrate with micro-cone array surface morphology; and irradiating the prepared responsive material substrate through a cobalt source, and completing material sterilization at an irradiation dose of 15kGy and an irradiation time of 30 minutes.
2) Inoculating living cells;
cell suspension of dopaminergic neurons obtained by inducing stem cell differentiation using total function obtained by pancreatin digestion is prepared by sterilizing 10% of the surface of the substrate of the responsive material 4 Cell seeding density cells/cm.
3) Packaging hydrogel;
after at least 24 hours of cell inoculation, 3w/v% sodium alginate hydrogel prepolymer liquid is covered on the surface of a substrate of a responsive material inoculated with living cells, then 0.3M calcium chloride aqueous solution is dripped, and the encapsulated hydrogel is crosslinked through ionic crosslinking, so that the nerve control device based on an active interface is obtained.
Example 6
A nerve regulation device based on an active interface, the structure of which is shown in figure 1, the nerve stimulation device comprises a responsive material substrate, living cells which are adhered and grown on the responsive material substrate, and hydrogel for packaging the living cells; the responsive material substrate is made of a magnetocaloric material and a pyroelectric material, living cells are nerve immune cells, and hydrogel is calcium ion crosslinked sodium alginate.
In this embodiment, the surface morphology of the substrate of the responsive material is a micro-pillar array surface, and the micro-pillar width: 5 μm, high: 5 μm, pitch: 5 μm, the thickness of the substrate is 50 μm, and the material is a compound of P (VDF-TrFE) copolymer and ferroferric oxide which can generate electricity under the mediation of an alternating magnetic field; the vaccinated neuroimmune cells were mouse astrocytes; the hydrogel material is calcium ion crosslinked sodium alginate, and the thickness is 50 μm.
The preparation method of the nerve control device based on the active interface comprises the following steps:
1) Preparing a responsive material substrate;
preparing a mixed solution containing 10w/v% polyvinylidene fluoride and 5mg/mL ferroferric oxide nano particles by using dimethyl sulfoxide as a solvent; casting the mixed solution on the surface of a template of a micro-column array structure (the micro-column width is 5 mu m, the height is 5 mu m, and the distance is 5 mu m) obtained by photoetching to prepare a responsive material substrate with the micro-column array surface morphology; and irradiating the prepared responsive material substrate through a cobalt source, and completing material sterilization at an irradiation dose of 15kGy and an irradiation time of 30 minutes.
2) Inoculating living cells;
cell suspension of mouse astrocytes obtained by pancreatin digestion was used as a substrate surface of a sterilized responsive material at a ratio of 10 4 Cell seeding density cells/cm.
3) Packaging hydrogel;
after at least 24 hours of cell inoculation, 3w/v% sodium alginate hydrogel prepolymer liquid is covered on the surface of a substrate of a responsive material inoculated with living cells, then 0.3M calcium chloride aqueous solution is dripped, and the encapsulated hydrogel is crosslinked through ionic crosslinking, so that the nerve control device based on an active interface is obtained.
Example 7
A nerve regulation device based on an active interface, the structure of which is shown in figure 1, the nerve stimulation device comprises a responsive material substrate, living cells which are adhered and grown on the responsive material substrate, and hydrogel for packaging the living cells; the responsive material substrate is made of a piezoelectric ion gel material, living cells are endocrine cells, and the hydrogel is calcium ion crosslinked sodium alginate.
In this embodiment, the surface morphology of the substrate of the responsive material is a micro-pillar array surface, and the micro-pillar width: 50nm, high: 50nm, spacing: 50nm, wherein the thickness of the substrate is 50 mu m, and the substrate is made of a compound of polymethacrylic acid and choline which can generate electricity under the mediation of ultrasound; the inoculated neuroendocrine cells are mouse alveolar neuroendocrine cells; the hydrogel material is calcium ion crosslinked sodium alginate, and the thickness is 50 μm.
The preparation method of the nerve control device based on the active interface comprises the following steps:
1) Preparing a responsive material substrate;
preparing an aqueous solution containing 10w/v% methacrylic acid, 3w/v% choline chloride and 0.1w/v%2959 photoinitiator; casting the mixed solution on the surface of a template of a micro-column array structure (the micro-column width is 50nm, the micro-column height is 50nm, and the distance is 50 nm) obtained by photoetching, and reacting for 10 minutes under the irradiation of an ultraviolet crosslinking instrument to obtain a responsive material substrate with the micro-column array surface morphology; and irradiating the prepared responsive material substrate through a cobalt source, and completing material sterilization at an irradiation dose of 15kGy and an irradiation time of 30 minutes.
2) Inoculating living cells;
cell suspension of mouse alveolar neuroendocrine cells obtained by pancreatin digestion was used as a substrate surface of a sterilized responsive material at a ratio of 10 4 Cell seeding density cells/cm.
3) Packaging hydrogel;
after at least 24 hours of cell inoculation, covering the surface of a substrate of a responsive material inoculated with living cells with 3w/v% sodium alginate hydrogel prepolymerization solution, then dripping 0.3M calcium chloride aqueous solution, and completing encapsulation hydrogel crosslinking through ionic crosslinking to obtain the nerve control device based on an active interface
It will be understood that the technical features of the above-described embodiments may be combined in any manner, and that all possible combinations of the technical features in the above-described embodiments are not described for brevity, however, they should be considered as being within the scope of the description provided in the present specification, as long as there is no contradiction between the combinations of the technical features.
The foregoing description of the preferred embodiments of the present application has been provided for the purpose of illustrating the general principles of the present application and is not meant to limit the scope of the present application in any way. Any modifications, equivalent substitutions and improvements made within the spirit and principles of the present application, and other embodiments of the present application, which may occur to those skilled in the art without the exercise of inventive faculty, are intended to be included within the scope of the present application, based on the teachings herein.
Claims (19)
1. A neuromodulation 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, the substrate being capable of converting external field energy, including light or a magnetic field or ultrasound, into electricity and stimulating the living cells grown on the surface thereof to respond and release neurotransmitter molecules;
the living cells are neurotransmitter-producing cell types; including but not limited to at least one of primary neuronal cells, neuroimmune cells including astrocytes or microglia, neuroendocrine cells, neurotransmitter-producing cell line cells, and neuronal cells induced by stem cells.
2. The neuromodulation device as in claim 1, wherein the substrate has a thickness of 50-500 μm.
3. The neuromodulation device of claim 1, wherein the surface topography of the substrate is a planar or three-dimensional structure comprising at least one of a micro-groove array, a micro-cone array, a micro-pillar array.
4. The neuromodulation device as in claim 3, wherein the three-dimensional structure has dimensions of 50nm to 20 μm in width, 50nm to 20 μm in height, and 50nm to 20 μm in pitch.
5. The neuromodulation device as in claim 1,2, 3, or 4, wherein the substrate is at least one of a piezoelectric material, a photo-deformable material composite piezoelectric material, a photovoltaic material, an up-conversion material composite photovoltaic material, a photo-thermal material composite pyroelectric material, a magneto-thermal material composite pyroelectric material.
6. The neuromodulation device as in claim 5, wherein the piezoelectric material comprises a piezoelectric crystal or a piezoelectric ceramic or a piezoelectric polymer, the piezoelectric crystal comprising a quartz crystal or lithium gallate or lithium germanate or titanium germanate or lithium tantalate; the piezoelectric ceramic comprises barium titanate or lead zirconate titanate or lead metaniobate or lead barium lithium niobate; the piezoelectric polymer comprises odd nylon or polyacrylonitrile or vinylidene dicyano and copolymer thereof, polyurea or polyphenyl cyanoether or polyvinyl chloride or polyvinyl acetate or polypropylene or polytetrafluoroethylene.
7. The neuromodulation device of claim 5, wherein the photo-deformable material composite piezoelectric material is a combination of any one of the following photo-deformable materials and the piezoelectric material; wherein the photoinduced deformation material comprises at least one of photoinduced isomerism material or ferroelectric inorganic photoinduced deformation material, and the photoinduced isomerism material comprises at least one of azobenzene and derivatives thereof, spiropyran and derivatives thereof; the ferroelectric inorganic photoinduced deformation material comprises at least one of lead titanate, barium titanate, potassium niobate, lithium tantalate, bismuth layered perovskite structure ferroelectric, tungsten bronze ferroelectric, bismuth ferrite, monopotassium phosphate, ammonium triglycinate sulfate, rochlote and perovskite type organic metal halide ferroelectric.
8. The neuromodulation device of claim 5, wherein the photovoltaic material comprises at least one of: organic photovoltaic materials of polyacetylene, polythiophene, polyaniline, polypyrrole, derivatives and copolymers thereof.
9. The neuromodulation device of claim 5, wherein the upconverting material composite photovoltaic material is any combination of an upconverting material and the piezoelectric material; wherein the up-conversion material comprises at least one of yttrium oxide, yttrium oxysulfide, lanthanum fluoride, sodium yttrium fluoride and sodium gadolinium fluoride.
10. The neuromodulation device of claim 5, wherein the photothermal material composite pyroelectric material comprises any combination of a photothermal material and a pyroelectric material; the photo-thermal material comprises at least one of carbon black, carbon nano tubes, graphene, black phosphorus, polydopamine, gold nanorods and gallium indium alloy liquid metal; the pyroelectric material comprises at least one of a polyvinylidene fluoride ferroelectric polymer and a perovskite ferroelectric ceramic, wherein the polyvinylidene fluoride ferroelectric polymer comprises at least one of poly (vinylidene fluoride), poly (vinylidene fluoride-trifluoroethylene) [ P (VDF-TrFE) copolymer ], poly (vinylidene fluoride-chlorotrifluoroethylene) [ P (VDF-CFE) copolymer ], poly (vinylidene fluoride-chlorotrifluoroethylene) [ P (VDF-CTFE) copolymer ], poly (vinylidene fluoride-hexafluoropropylene) [ P (VDF-HFP) copolymer ], poly (vinylidene fluoride-trifluoroethylene-chlorotrifluoroethylene) [ P (VDF-TrFE-CFE) terpolymer ], poly (vinylidene fluoride-trifluoroethylene-chlorotrifluoroethylene) [ P (VDF-TrFE-CTFE) terpolymer ] and poly (vinylidene fluoride-trifluoroethylene-hexafluoropropylene) [ P (VDF-TrFE-HFP) terpolymer), and the perovskite ferroelectric ceramic comprises at least one of lead titanate, lead titanate and barium niobate.
11. The neuromodulation device of claim 5, wherein the magnetocaloric material composite pyroelectric material is any combination of the magnetocaloric material and the pyroelectric material; the magnetocaloric material comprises at least one of Ru-Fe-B alloy, ferroferric oxide, iron, cobalt, nickel and gadolinium.
12. The neuromodulation device as in claim 1, wherein 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 its derivatives, silk fibroin and its derivatives, agarose, carrageenan, dextran, basement membrane matrix, polycaprolactone, polyethylene glycol and its derivatives, propylene glycol and epoxy ether block polymer, polyvinylpyrrolidone.
13. The neuromodulation device as in claim 1, wherein the hydrogel layer has a thickness of 50-500 μm.
14. The neuromodulation device as in claim 1, wherein the neurotransmitter molecule comprises at least one of cholines, monoamines, amino acids, neuropeptides, purines, and nitric oxide, the cholines comprising acetylcholine, the monoamines comprising at least one of norepinephrine or epinephrine or dopamine or 5-HT or histamine, and the amino acids comprising at least one of glutamate or Y-aminobutyric acid or glycine.
15. A method of making a neuromodulation device as in claim 1, comprising the steps of:
preparing the substrate;
growing the living cells on the surface of the substrate;
and pre-crosslinking the hydrogel on the surface of the substrate to enable the living cells to be packaged on the surface of the substrate, so as to obtain the nerve control device.
16. The method of manufacturing a neuromodulation device as in claim 15, wherein in the step of manufacturing the substrate, specifically comprising the steps of: the substrate is prepared by a casting method or a spin coating method.
17. The method of claim 15, wherein the substrate surface is formed by lithography, plasma dry etching, or mechanical processing into a planar or three-dimensional structure comprising at least one of a micro-groove array, a micro-cone array, and a micro-pillar array.
18. The method of preparing a neuromodulation device as in claim 15, wherein the viable cells have an seeding density of 10 3 –10 6 Cells per square centimeter.
19. The method of claim 15, wherein the cross-linking is at least one of ionic cross-linking and ultraviolet cross-linking.
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