WO2020107345A1 - 一种功能化植入式柔性电极及其应用 - Google Patents

一种功能化植入式柔性电极及其应用 Download PDF

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WO2020107345A1
WO2020107345A1 PCT/CN2018/118271 CN2018118271W WO2020107345A1 WO 2020107345 A1 WO2020107345 A1 WO 2020107345A1 CN 2018118271 W CN2018118271 W CN 2018118271W WO 2020107345 A1 WO2020107345 A1 WO 2020107345A1
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poly
acid
layer
methacrylate
functional
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French (fr)
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杜学敏
崔欢庆
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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
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N1/00—Electrotherapy; Circuits therefor
    • A61N1/02—Details
    • A61N1/04—Electrodes
    • A61N1/05—Electrodes for implantation or insertion into the body, e.g. heart electrode

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  • the invention relates to a functional implantable flexible electrode and its application, in particular to a functional implantable flexible electrode having a functional layer capable of forming current or voltage by triggering and its application, and belongs to the technical field of biological materials.
  • Nerve electrical stimulation therapy is a treatment method that regulates nerves without damaging nerve tissue. It can play a role in treating or partially restoring nerve function. Because this method is safe, minimally invasive, etc., and for certain special neurological diseases, such as cardiac pacemakers, cochlear implants, and artificial retinas, it is indeed an irreplaceable method, which has been successfully applied clinical.
  • neural electrical stimulation prostheses With the continuous innovation and development of new technologies, more neural electrical stimulation prostheses have gradually been applied, and are bringing new hope to people suffering from Parkinson's disease, epilepsy, motor disorders, stroke, depression and other diseases . Neural prosthesis will help patients with nerve injury to repair and rebuild damaged nerve function and improve their quality of life. With the social needs for the treatment of neurological diseases, the research and development of functional electronic devices have become the objective requirements of the medical industry and the whole society.
  • macrophages will gather around the implanted electrodes and wrap the implant.
  • Microglia cells are subsequently activated, and then secrete reactive oxygen species and inflammatory cytokines, some of which are toxic, so their neighboring neurons may be damaged, seriously affecting the performance of nerve electrodes, and unable to meet the purpose of long-term implantation.
  • the main purpose of the present invention is to provide a new functional implantable flexible electrode, with a view to solving one or more of the current long-term neural prosthesis implantation effectiveness, stability, reliability problems Pcs.
  • Another object of the present invention is to provide a microelectrode array containing the above functional implantable flexible electrode and a corresponding neural prosthesis.
  • the present invention provides a functional implantable flexible electrode, which at least includes a functional layer capable of generating current or voltage.
  • the invention provides a brand-new electrode, which includes at least the above functional layer, and on this basis, it may further include a base layer and a further conductive layer.
  • This electrode can be obtained by combining the base layer with the functional layer, the base layer provides support, and the functional layer provides current or voltage; the electrode can also be obtained by coupling the functional layer to a traditional electrode with a base layer and a conductive layer In this way, the electrode does not need the external power supply function, and the current or voltage can be provided through the functional layer to achieve the stimulation effect.
  • the functional layer can generate current by triggering in one or more of light, electricity, magnetism, sound, heat and force. Voltage.
  • the present invention provides a functional layer that can trigger the formation of current or voltage through light, electricity, magnetism, sound, heat, force, etc., so that the flexible electrode of the present invention can achieve the function of a nerve stimulation device without complicated circuit connection and device packaging. It not only greatly reduces the risk of surgery, but also the safety risk of long-term implantation, but also expands the application field of nerve stimulation devices.
  • the material of the functional layer includes one or a combination of two or more of field effect transistors, light emitting diodes, photodiodes, optoelectronic materials, piezoelectric materials, magnetoelectric materials, and the like.
  • the material of the functional layer includes one or a combination of two or more of optoelectronic materials, conductive materials, magnetoelectric materials, and ultrasonic and photodeformable materials.
  • optoelectronic materials include gallium arsenide, copper indium gallium selenide, cadmium telluride, perovskite, dye-sensitized materials, CIGS materials, optoelectronic organic materials, optoelectronic polymer materials, polyvinylidene fluoride, polytrifluorochloroethylene, One or a combination of two or more of polytrifluoroethylene, piezoelectric ceramics, Cr 2 O 3 , Ti 2 O 3 ; conductive materials include platinum, gold, platinum-iridium alloy, silver, magnesium, titanium nitride, iridium oxide , Indium tin oxide, gallium indium alloy, gallium indium tin alloy, graphene, carbon nanotubes, conductive polymer materials and combinations of one or more of two or more of them, preferably, the above conductive polymer Materials include polypyrrole, polyphenylene sulfide, polyparaphenylene, polyaniline, polythiophene, and
  • the functional implantable flexible electrode of the present invention may be composed of a stimulation end, a lead portion, and a functional end; wherein, the stimulation end includes a base layer (or stimulation end base layer), a conductive layer, and a conductive layer At the stimulation site on the surface of the layer, the conductive layer is located on the surface of the basal layer; the functional end includes a basal layer (or functional end basal layer, a basal layer different from the stimulation end) and a functional layer.
  • the stimulation end and the functional end are connected together through the lead part, and the functional layer generates current or voltage under the trigger of light, electricity, magnetism, sound, heat, and force, etc., and transmits it to the stimulation end through the lead part.
  • the stimulation site at the stimulation end realizes the corresponding stimulation function.
  • the functional implantable flexible electrode is composed of a stimulation end coupled with a functional layer, that is, the functional layer and the various layers of the stimulation end are compounded together, and may specifically have the following two structures (but not limited thereto):
  • the first structure the stimulation end includes a base layer, a conductive layer, and stimulation sites provided on the surface of the conductive layer.
  • the functional layer is located on the surface of the base layer or embedded in the base layer (for example, the functional material is combined with the base layer material Into a base layer with both the function of the base and the corresponding function of the functional material), the conductive layer is located on the surface of the functional layer or the surface of the base layer embedded with the functional layer: in this structure, the functional layer can actually play the role of lead at the same time , It will generate electric current or voltage under the trigger of light, electricity, magnetism, sound, heat and force, etc., and transmit it to various stimulation sites.
  • the second structure the stimulation end includes two base layers, a conductive layer and a functional layer, the conductive layer is located between the two base layers, and the functional layer is on the surface of the base layer at the top: under this structure, the functional layer is in the light , Electricity, magnetism, sound, heat and force are triggered to produce electric current or voltage, which is transmitted to various stimulation sites through the middle conductive layer.
  • the present invention can also modify the aforementioned functional implantable flexible electrode to further provide a flexible electrode with corresponding functions.
  • the modification methods include electrochemical modification on the electrode surface, modification of biological materials, and modification of polymer materials on the back of the electrode. Electrochemical modification of the electrode surface can reduce the electrode surface impedance and improve the stimulation efficiency.
  • a plating layer is provided on the stimulation site of the stimulation end of the electrode, and the material of the plating layer includes one or a combination of two or more of inorganic materials, conductive polymer materials, or composite materials thereof.
  • the inorganic material of the plating layer includes one or a combination of two or more of carbon nanotubes, graphene, titanium, platinum, rhodium, palladium, iridium, gold, and niobium.
  • the organic polymer material of the plating layer includes one of polyionic liquid, polypyrrole, polyphenylene sulfide, polyparaphenylene, polyaniline, polythiophene, hydrogel, and derivatives thereof One or a combination of two or more.
  • the morphology of the electroplated layer is a microstructure
  • the microstructure includes microparticles, micropillars, microneedles, microchips, micropores, microtubes, microwires, microcones, or more than two types The microstructure composite structure or its multi-level composite structure.
  • the thickness of the microstructure is, for example, 20 nm-200 ⁇ m.
  • the microparticles (particle size), micropillars (length), microneedles (length), microchips (length), micropores (pore diameter), microtubes (tube diameter), microwires (length ), the size of the micro-cone (axial length) structure can be controlled to 1nm-20 ⁇ m.
  • a biomaterial layer may be modified on the electrode stimulation site, and the biomaterial may be modified by physical or chemical methods through molecular-level design such as molecular hydrogen bonding, van der Waals force, hydrophile-hydrophobic interaction, electrostatic interaction.
  • the material of the biomaterial layer includes one or a combination of two or more of polypeptides, proteins, hydrogels, and composites thereof, and the thickness of the biomaterial layer may preferably be 1 nm-50 ⁇ m.
  • the hydrogel may include a hydrogel formed of the following materials: poly(N-isopropylacrylamide), poly(N-n-propylacrylamide), poly(N-ring Propylacrylamide), poly(N-isopropylmethacrylamide), protein, poly(N-ethylacrylamide), poly(N-acryloyloxy-N-propylpiperazine), poly( N-(L)-(1-hydroxymethyl)propyl methacrylamide), poly[N-(2-methacryloyloxyethyl)pyrrolidone], poly[N-(3-acryloyloxypropyl) Group) pyrrolidone], poly[N-(3-methacryloyloxypropyl)pyrrolidone], poly[N-(2-acryloyloxypropyl)pyrrolidone], poly[N-(1-methyl-2 -Acryloyloxyethyl)pyrrolidone], poly(2-alkyl-2-
  • the biomaterial layer may contain an anti-inflammatory drug, and the anti-inflammatory drug includes, for example, one or more of dexamethasone, prednisone, bolexone, and anti-inflammatory polypeptide. combination.
  • the anti-inflammatory drug contained in the biomaterial layer can make the flexible electrode of the present invention have an anti-inflammatory function, so that the flexible electrode can be implanted for a long time.
  • a polymer material layer may be modified on the back of the functionalized implantable flexible electrode. Modification of the polymer material layer on the back of the electrode of the present invention can make the flexible electrode have a shape adaptability and functionalization, which can not only realize implantation in a minimally invasive manner, but also ensure that the electrode can effectively match biological tissue after implantation and improve stimulation Effectiveness; In addition, this can also realize the wide electrode design, increase the stimulation area, expand the nerve stimulation function, and solve the technical problem of artificial retinal tubular vision.
  • the material of the polymer material layer may include poly(N-isopropylacrylamide), poly(N-n-propylacrylamide), poly(N-cyclopropylacrylamide), poly(N-isopropylacrylamide) Methacrylamide), poly(N-ethylacrylamide), poly(N-acryloyloxy-N-propylpiperazine), poly(N-(L)-(1-hydroxymethyl)propyl Methacrylamide), poly[N-(2-methacryloyloxyethyl)pyrrolidone], poly[N-(3-acryloyloxypropyl)pyrrolidone], poly[N-(3-methacryl Acyloxypropyl)pyrrolidone], poly[N-(2-acryloyloxypropyl)pyrrolidone], poly[N-(1-methyl-2-acryloyloxyethyl)pyrrolidone], poly(2-alkane Yl-2-oxoline), poly(2-ethy
  • the polymer material layer modified on the back of the electrode may contain an anti-inflammatory drug, and the anti-inflammatory drug includes, for example, one or more of dexamethasone, prednisone, boraxon, or anti-inflammatory polypeptide. Species.
  • an anti-inflammatory drug in the polymer material layer can make the flexible electrode of the present invention have an anti-inflammatory function, so that the flexible electrode can be implanted for a long time.
  • the material of the base layer may include polyimide, parylene, polydimethylsiloxane, medical silicone, poly(N-isopropyl) (Acrylamide), poly(N-n-propylacrylamide), poly(N-cyclopropylacrylamide), poly(N-isopropylmethacrylamide), poly(N-ethylacrylamide), Poly(N-acryloyloxy-N-propylpiperazine), poly(N-(L)-(1-hydroxymethyl)propylmethacrylamide), poly[N-(2-methacrylic Acyloxyethyl)pyrrolidone], poly[N-(3-acryloyloxypropyl)pyrrolidone], poly[N-(3-methacryloyloxypropyl)pyrrolidone], poly[N-(2-propene Acyloxypropyl)pyrrolidone], poly[N-(1-methyl-2-acrylamide
  • the material of the conductive layer may include one or a combination of two or more of a conductive metal material, a conductive inorganic material, and a conductive polymer material; preferably, the conductive metal material includes platinum, gold, platinum-iridium alloy, for example , Silver, magnesium, titanium nitride, iridium oxide, indium tin oxide, gallium indium alloy and gallium indium tin alloy one or a combination of two or more; conductive inorganic materials such as graphene and carbon nanotubes One or a combination of two; conductive polymer materials include, for example, one or a combination of two or more of polypyrrole, polyphenylene sulfide, polyparaphenylene, polyaniline, polythiophene, and their derivatives.
  • the conductive metal material includes platinum, gold, platinum-iridium alloy, for example , Silver, magnesium, titanium nitride, iridium oxide, indium tin oxide, gallium indium alloy and gallium indium
  • the total thickness of the functionalized implantable flexible electrode is 1 ⁇ m-5.5 mm, preferably 1 ⁇ m-300 ⁇ m, wherein the thickness of the base layer is 1 ⁇ m-5 mm (preferably 3 ⁇ m-10 ⁇ m), and the thickness of the conductive layer 20nm-200 ⁇ m (preferably 20nm-10 ⁇ m, the thickness of the functional layer is 1 ⁇ m-200 ⁇ m.
  • the base layer thickness, conductive layer thickness, functional layer thickness given here are all functional implantable flexible electrodes including these layers. The thickness does not mean that all functional implantable flexible electrodes include these layers at the same time.
  • the size of the stimulation end is 0.1 mm-2 cm (preferably 0.05 mm-1.5 cm), and the diameter of a single stimulation site (generally circular) is 20 nm-5 mm (Preferably 20 nm-500 ⁇ m), the pitch of stimulation sites is 1 ⁇ m-1 mm (preferably 1 ⁇ m-600 ⁇ m), and the number of stimulation sites is 10-1000000 (preferably 60-1000000, more preferably 60-100000).
  • the total thickness of the functionalized wide implantable microelectrode array may be 1 ⁇ m-200 ⁇ m, wherein the thickness of the base layer is 1 ⁇ m-20 ⁇ m, the thickness of the conductive layer is 20 nm-100 ⁇ m, and the size of the stimulation end is 0.1 mm-2cm, the diameter of a single stimulation site is 20nm-5mm, the spacing of stimulation sites is 1 ⁇ m-1mm, and the number of stimulation sites is 60-2000.
  • the functional implantable flexible electrode of the present invention can be prepared by micro-nano processing, 3D printing, printing, spin coating or spraying, and a suitable preparation method can be selected according to different structures of the flexible electrode.
  • the present invention provides the above-mentioned functionalized wide-width implantable microelectrode array in the preparation of implantable artificial retina, implantable cochlear implant, implantable cardiac implantable dirty pacemaker, implantable deep brain stimulation Application.
  • the present invention provides a neural prosthesis including the above-mentioned functionalized wide-width implantable microelectrode array; for example, the neural prosthesis includes an implantable artificial retina, an implantable cochlear implant, and an implantable heart Pacemaker or implanted deep brain stimulator.
  • the invention forms a functional layer of current or voltage by triggering (such as light, electricity, magnetism, sound, heat, force, etc.) so that the flexible electrode of the invention can realize the function of a nerve stimulation device without complicated wiring connection and device packaging, not only It greatly reduces the risk of surgery and the safety risk of long-term implantation, and it also expands the application field of nerve stimulation devices.
  • the present invention can also perform electrochemical modification and biomaterial modification on the electrode surface, which can not only reduce the electrode surface impedance and improve the stimulation efficiency, but also ensure the biocompatibility of the implanted device after implantation and prevent long-term implantation immunity reaction.
  • the invention can also be modified by the polymer material on the back of the electrode, so that the flexible electrode has the shape adaptability change function, which can not only realize the implantation in the minimally invasive manner, but also ensure that the electrode can effectively match the biological tissue after implantation and improve Stimulation effectiveness;
  • it can also realize the wide electrode design, increase the area of the stimulation area, and expand the nerve stimulation function, such as solving the technical problem of artificial retinal tubular vision.
  • the technical solutions provided by the present invention can solve the problems of long-term implantation effectiveness, stability and reliability of existing neural prostheses, and at the same time achieve minimally invasive implantation of neural prosthesis, adaptive matching tissue, large-area stimulation, etc.
  • kinds of functions can solve the problems of long-term implantation effectiveness, stability and reliability of existing neural prostheses, and at the same time achieve minimally invasive implantation of neural prosthesis, adaptive matching tissue, large-area stimulation, etc.
  • FIG. 1 is a schematic diagram of the stimulation site array of the electrode of Example 1.
  • FIG. 1 is a schematic diagram of the stimulation site array of the electrode of Example 1.
  • FIG. 2 is a surface modification effect diagram of the functionalized wide-width electrode of Example 1.
  • Example 3 is a curled state (left) of the functionalized wide-width electrode of Example 1 and a self-expanding effect diagram after implantation of the eyeball (right).
  • FIG. 4 is a view of the effect of widening the field of vision after implantation of the narrow electrode (left) and the functionalized wide-width electrode (right) of Example 1.
  • FIG. 4 is a view of the effect of widening the field of vision after implantation of the narrow electrode (left) and the functionalized wide-width electrode (right) of Example 1.
  • FIG. 5 is an array view of surface stimulation sites of the functionalized electrode of Example 2.
  • FIG. 6 is a photo-controllable deformation diagram of the functionalized electrode of Example 3.
  • FIG. 7 is an effect diagram of the functionalized electrode of Embodiment 3 adaptively illuminating the lighting LED.
  • This embodiment provides a functional implantable flexible electrode, which is a functional wide-width electrode.
  • the electrode includes a stimulation end, a lead part and a functional end, and the total length is 6 cm.
  • the stimulation end and the functional end pass through the lead Partly connected.
  • the stimulation end is rectangular, the length is 1.2cm, the width is 0.6cm, the stimulation area is 1.2cm ⁇ 0.6cm, the diameter of the single stimulation site in the stimulation end is 300 ⁇ m, the height is 80 ⁇ m, and the distance between the stimulation sites is 412.5 ⁇ m, the number of stimulation channels is 126;
  • the lead part is rectangular, 4 cm long, 0.4 cm wide, and the lead spacing is 10 ⁇ m;
  • the functional end is rectangular, 1.2 cm long, and 0.6 cm wide.
  • the stimulation site array of the stimulation end of the electrode is shown in FIG. 1.
  • the stimulation end of the implantable flexible electrode includes a base layer and a conductive layer, and the stimulation site of the stimulation end is decorated with an electroplating layer and a biological material modification layer, and a polystyrene sulfonate is grafted on the back of the electrode Acid hydrogel layer.
  • the material of the base layer is polyimide with a thickness of 5 ⁇ m; the material of the conductive layer is Au with a thickness of 50 nm; the material of the electroplated layer is platinum with a morphology of platinum micro-pillar nanolayers with a thickness of 0.8 ⁇ m;
  • the material of the modified layer of the biological material is polythiophene with a thickness of 0.5 ⁇ m; the modified layer on the back of the electrode is a polyp-styrenesulfonic acid hydrogel layer with a thickness of 100 ⁇ m.
  • the functional end of the implantable flexible electrode has a functional layer that can be triggered by light to form a current.
  • the material of the functional layer is polytrifluoroethylene, and its thickness is 200 ⁇ m.
  • the polytrifluoroethylene doped with azobenzene polymer is chemically grafted to form a functional layer on the polyimide (base layer) as a functional end, and the functional layer can generate a current through light irradiation.
  • Electrochemical modification At room temperature, add 500 mL of water, 2.0 mmol of potassium chloroplatinate and 0.08 mmol of citric acid to the container, and perform ultrasonic dispersion. Place the above electrode in the front solution and let stand at room temperature for 48h. Subsequently, the electrode was immersed in ultrapure water for 2 hours to remove unreacted chemicals and poorly adhered platinum nanomaterials, and platinum nanoparticulate nanolayers, ie electroplated layers, were obtained on the surface of the electrode stimulation site.
  • the electrode impedance after electrochemical modification is a low impedance of 4.65 k ⁇ cm 2 , and its cathode charge storage capacity is as high as 25.4 mC ⁇ cm -2 .
  • the surface modification effect is shown in FIG. 2.
  • Biomaterial modification place the above modified electrode in a mixture containing 0.3M 3,4-ethylenedioxythiophene and 0.5M mercapto-functionalized vinyl monomer at 0.5mA ⁇ cm -1 Electroplating at a current density of 30 min, followed by placing the electrode in ultrapure water for 24 h to remove unreacted chemicals, and a biomaterial modification layer was obtained on the surface of the electrode stimulation site.
  • the biocompatibility test results show that the biotoxicity is 0, indicating that the biocompatibility effect is very good.
  • (c) Modification of the back of the electrode the back of the electrode is treated with vinyl silane on the back of the polyimide, through sodium styrene sulfonate, N-isopropyl acrylamide and vinyl silane, using benzoyl peroxide as the initiator, Chemical grafting was carried out under thermally initiated polymerization at 90°C, and a layer of polyp-styrenesulfonic acid hydrogel was grafted and copolymerized on the back of the electrode.
  • the functionalized wide-width electrode can be curled and fixed, and is self-expanded to fit the retinal layer after being implanted in the eyeball, as shown in FIG.
  • the functional electrode is in a curled state before implantation and has a small size, and can be easily implanted into the eyeball. After the eyeball is implanted, the functional electrode is on the polystyrene sulfonic acid hydrogel layer Driven by the automatic expansion.
  • the electrode can generate a voltage by illuminating to stimulate the optic nerve to produce a light-sensing signal. Because the electrode is a wide-amplitude electric field and the polar stimulation area is relatively large, it can achieve a wider field of view. Compared with the tubular field of view obtained by a narrow electrode, the visual recovery effect of blind patients can be greatly optimized, as shown in FIG. 4.
  • This embodiment provides a functional implantable flexible electrode, the electrode has a stimulation end and a lead portion of the stimulation end, and the electrode length is 6 cm.
  • the stimulation end (stimulation area) is rectangular, the area is 1.2cm ⁇ 0.9cm, the diameter of a single stimulation site in the stimulation end is 150 ⁇ m, the distance between the stimulation sites is 260 ⁇ m, the number of stimulation channels is 1000, the local structure of the stimulation end As shown in Figure 5.
  • the area of the lead part is 1.2 cm ⁇ 0.2 cm, the lead pitch is 10 ⁇ m, and the width of a single lead is 5 ⁇ m.
  • the stimulation end of the electrode is composed of a base layer (composite with a functional material capable of forming current through light), a conductive layer, and the stimulation site of the stimulation end is decorated with an electroplating layer, a biological material modification layer, and the back of the electrode A layer of polycaprolactone copolymer is grafted.
  • the material of the base layer is polyimide with a thickness of 6 ⁇ m; the material of the conductive layer is Au with a thickness of 50 nm; the functional material that can form a current through light is a perovskite photoelectric material with a thickness of 200 ⁇ m, calcium
  • the titanium ore material is compounded in the polyimide as the base layer, the covering position is the lead part of the stimulation end, the functional layer is connected to the stimulation site and also has a lead function; the material of the plating layer is platinum, and its morphology is columnar nano
  • the thickness of the layer is 350 nm; the material of the modified layer of the biomaterial is elastin polypeptide with a thickness of 500 nm; the material of the modified layer on the back of the electrode is a polycaprolactone copolymer with a thickness of 100 ⁇ m.
  • the current generated by the photoelectric material (functional layer) of the functional electrode is directly transmitted to the corresponding stimulation site to stimulate the optic nerve.
  • Electrochemical modification Under a room temperature environment, 500 mL of water, 2.0 mmol of chloroplatinic acid and 8 mmol of citric acid were added to the container, and subjected to ultrasonic dispersion to obtain a modified solution. Place the above-mentioned electrode in the modification solution, and use Ag/AgCl as the reference electrode to deposit by constant potential method. Subsequently, the electrode was immersed in ultrapure water for 2 hours to remove unreacted chemical substances and platinum nanomaterials with poor adhesion to obtain a columnar nanolayer, that is, an electroplated layer.
  • the electrode impedance after electrochemical modification is a low impedance of 4.35k ⁇ cm 2 , and its cathode charge storage capacity is as high as 26.4mC ⁇ cm -2 .
  • Biomaterial modification deposit the above-mentioned modified electrode through the layer-by-layer deposition (LBL) method of the biomaterial layer, as follows: immerse the electrode programmatically in a 20 wt% elastin polypeptide solution through the LBL deposition equipment Then, lift it up and repeat the work 100 times to organize 100 layers of elastin polypeptide to modify the upper elastin polypeptide layer to obtain a modified layer of biological material.
  • LBL layer-by-layer deposition
  • (c) Modification of the back surface of the electrode the back surface of the polyimide base layer is treated with vinyl silane, and the electrode is coated with a caprolactone monomer prepolymerization solution under a gamma ray source for 30 minutes to achieve chemistry Grafting, grafting and copolymerizing a layer of polycaprolactone copolymer on the back of the electrode.
  • the electrode includes a stimulation end, a lead part and a functional end, and has a total length of 6 cm and a width of 0.8 cm.
  • the stimulation area of the stimulation end is 0.8cm ⁇ 1.5cm
  • the diameter of a single stimulation site in the stimulation end is 500 ⁇ m
  • the distance between the stimulation sites is 750 ⁇ m
  • the number of stimulation channels is 10.
  • the lead part is rectangular, with a length of 3.0 cm, a width of 0.8 cm, and a lead pitch of 0.5 mm.
  • the area of the functional end is 0.8cm ⁇ 1.5cm.
  • the stimulation end of the electrode includes a base layer and a conductive layer.
  • the base layer is made of polydimethylsiloxane with a thickness of 10 ⁇ m;
  • the conductive layer is made of gallium indium alloy with a thickness of 1 ⁇ m;
  • the stimulation end is modified with a biological material modification layer, the material of which is polypyrrole, and its thickness is 0.6 ⁇ m.
  • the functional end includes a base layer and a functional layer.
  • the base layer is made of polydimethylsiloxane with a thickness of 10 ⁇ m;
  • the functional layer is made of piezoelectric material GaFeO 3 with a thickness of 200 ⁇ m;
  • the stimulation end and the function end are connected together through the lead part;
  • the back surface of the electrode is provided with a modified layer of the back surface of the electrode, which is made of polyacrylic acid hydrogel and has a thickness of 100 ⁇ m.
  • FIG. 6 The figure on the left of FIG. 6 is a schematic diagram of a functionalized electrode, showing the structure of the electrode.
  • the controllable deformation effect of this electrode can be seen through the two left and right figures in FIG. 6.
  • the functional effect of the functional implantable flexible electrode is shown in FIG. 7, the electrode is connected with an LED lamp, and the functional effect of the electrode is tested using light.
  • the LED does not light up before the light is illuminated, and the LED light is lit after the light is illuminated, indicating that the electrode is deformed under the driving of the polyacrylic acid hydrogel on the back modification layer to generate pressure after being illuminated, and then the piezoelectric material of the functional layer generates current and Turn on the LED light.
  • Electrodes by 3D printing using polydimethylsiloxane as the substrate, the gallium indium liquid metal is printed on the substrate by a 3D printer and solidified to form a conductive layer, and then a layer of Parylene encapsulates the metal circuit to expose the stimulation site To obtain the stimulation end of the flexible electrode.
  • the piezoelectric material GaFeO 3 is formed on the surface of the substrate layer as a functional layer by printing, and the functional end is prepared.
  • the stimulation end and the functional end are connected together through the lead part to obtain a flexible electrode.
  • Biomaterial modification place the above electrode in a pyrrole mixture containing 0.6M, electroplating at current density of 0.8mA ⁇ cm -1 for 30min, and then place the electrode in ultrapure water for 24h to remove unreacted chemical substances To obtain a modified layer of biological materials.
  • the biocompatibility test results show that the biotoxicity is 0, indicating that the biocompatibility effect is very good.
  • (b) Modification of the back of the electrode the back of the electrode is treated with vinyl silane to treat the back of the polyimide.
  • the ammonium persulfate is used as the initiator and an accelerator is added to polymerize the acrylic monomer functionalized with spiropyran at room temperature to achieve chemistry Grafting, grafting and copolymerizing a layer of spiropyran functionalized polyacrylic acid hydrogel on the back of the electrode.
  • the electrode includes two base layers, one conductive layer, and one LED functional layer, wherein one conductive layer is located between the two base layers; the base layer
  • the material is Parylene, its thickness is 10 microns, the material of the conductive layer is titanium and gold, its thickness is 80nm; the functional layer is a round LED layer, its diameter is 80 microns, each LED lamp serves as a stimulation site, its Stimulated by external power supply.
  • a sodium alginate/chitosan composite hydrogel layer is grafted on the back of the electrode.
  • the top layer of the top layer of the photostimulation electrode is made with a thickness of 9 microns.
  • Three groups of circular holes are opened directly above the circular pad of the metal layer in the middle of the electrode, and each group includes two circles, each of which has a diameter of 160 microns and a pitch of 730 microns.
  • Electrochemical corrosion or dilute hydrochloric acid corrodes the aluminum sacrificial layer to complete the release of the photostimulation electrode.
  • Electrode backside modification The electrode backside (front side refers to the substrate on which the LED chip is soldered, and the backside is the side without the chip) is treated with plasma on the backside of polyethylene terephthalate, on the backside of the electrode by the LBL method Graft a layer of sodium alginate/chitosan composite hydrogel layer.
  • the electrode is modified with functional materials, which can not only effectively solve the problem of the fit between the electrode and the nerve tissue, but also realize the light stimulation of the nerve tissue and expand the application of multifunctional nerve electrodes.

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Abstract

一种功能化植入式柔性电极及其应用。该功能化植入式柔性电极至少包括能产生电流或电压的功能层。通过触发能够形成电流或电压的功能层使得柔性电极无需复杂的线路连接和器件封装，即可实现神经刺激器件的功能，不仅极大降低了手术风险以及长期植入的安全性风险，更是拓展了神经刺激器件的应用领域。这种功能化宽幅植入式电极可在制备植入式人造视网膜、植入式人工耳蜗、植入式心脏起搏器、植入式深脑刺激器中应用。

Description

一种功能化植入式柔性电极及其应用 技术领域
本发明涉及一种功能化植入式柔性电极及其应用，特别涉及具有可通过触发形成电流或电压的功能层的功能化植入式柔性电极及其应用，属于生物材料技术领域。
背景技术
随着生活节奏的不断加快，由于人们身心经常处于高度紧张的状态，使得视网膜色素炎、黄斑病变、抑郁症、癫痫等神经系统疾病日益增多。与此同时，全球老龄化更是加剧了神经性疾病概率，并成为一大社会负担。
通过穿戴或植入式的神经电刺激疗法的迅速发展以及神经假体的出现为广大的患者带来了新的希望。神经电刺激疗法是一种在不破坏神经组织的前提下通过调节神经进行治疗方法，它可以起到治疗或部分恢复神经功能的作用。由于该方法具有安全、微创等特点，并且，对于某些特殊的神经系统疾病来说，如心脏起搏器、人工耳蜗和人造视网膜等，确是无可替代的方法，目前已经成功应用于临床。
随着新技术的不断创新和发展，如今更多的神经电刺激假体已经逐渐走向应用，正在为患有帕金森症、癫痫、运动神经障碍、中风、抑郁症等疾病的人带来新的希望。神经假体将帮助神经损伤患者实现受损神经功能的修复和重建，改善其生活质量。伴随着治疗神经性疾病的社会需求，功能化电子器件的研究和发展已经成为医疗产业和全社会的客观要求。
虽然目前神经假体的研究正在快速进展，但至今尚只有植入式心脏起博器、人工耳蜗、人造视网膜等为数不多的植入式神经假体进入临床应用。目前这个领域的工作正面临很多科学技术难题带来的挑战，其中最大的困难之一就是长期植入可靠性、有效性及稳定性。拿人造视网膜假体来说，由于现有电极还是通过传统方法设计，不具备特殊功能，无法解决手术高风险、管状视野、生物相容性，以及植入后有效性、稳定性与可靠性差等重大问题。例如神经电极的生物相容性问题，生物相容性差的神经电极植入人体可能会损害多个组织部分，包括毛细血管、细胞外基质和细胞。另外，巨噬细胞会聚集到植入的电极周围，将植入体包裹。小胶质细胞随后被激活，然后分泌活性氧物质以及炎性细胞因子，其中一些因子具有毒性，因此其邻近神经元可能被损害，严重影响神经电极的性能，无法满足长期植入的目的。
发明内容
为解决上述技术问题，本发明的主要目的在于提供一种新的功能化植入式柔性电极，以期能解决目前神经假体长期植入的有效性、稳定性、可靠性问题中的一个或多个。
本发明的另一目的在于提供含上述功能化植入式柔性电极的微电极阵列及相应的神经假体。
为实现上述目的，一方面，本发明提供一种功能化植入式柔性电极，其至少包括能产生电流或电压的功能层。
本发明提供的是一种全新的电极，其至少包括上述功能层，在此基础上，还可以包括基底层以及进一步的导电层。这个电极可以通过将基底层与功能层复合得到，基底层提供支撑，功能层提供电流或电压；该电极也可以是将功能层耦合设计到带有基底层和导电层的传统电极上而得到的，这样电极就不需要外界电源功能，通过功能层即可提供电流或电压以实现刺激效果。
在本发明提供的功能化植入式柔性电极中，优选地，所述功能层能够通过光、电、磁、声、热和力中的一种或两种以上的方式的触发而产生电流或电压。本发明设置可通过光、电、磁、声、热、力等触发形成电流或电压的功能层，使得本发明的柔性电极无需复杂的线路连接和器件封装，即可实现神经刺激器件的功能，不仅极大降低了手术风险，长期植入安全性风险，更是拓展了神经刺激器件的应用领域。
在一些实施方式中，功能层的材料包括场效应晶体管、发光二极管、光电二极管、光电材料、压电材料和磁电材料等中的一种或两种以上的组合。优选地，功能层的材料包括光电材料、导电材料、磁电材料和超声波与光致形变材料中的一种或两种以上的组合。其中，光电材料包括砷化镓、铜铟镓硒、碲化镉、钙钛矿、染料敏化材料、CIGS材料、光电有机材料、光电高分子材料、聚偏氟乙烯、聚三氟氯乙烯、聚三氟乙烯、压电陶瓷、Cr 2O 3、Ti 2O 3中的一种或两种以上的组合；导电材料包括铂、金、铂铱合金、银、镁、氮化钛、氧化铱、铟锡氧化物、镓铟合金、镓铟锡合金、石墨烯、碳纳米管、导电高分子材料及其它们的复合物中的一种或两种以上的组合，优选地，上述导电高分子材料包括聚吡咯、聚苯硫醚、聚对苯撑、聚苯胺、聚噻吩及它们的衍生物中的一种或两种以上的组合；磁电材料包括GaFeO 3、LiCoPO 4、TbPO 4、REMnO 3、REMn 2O 5、TbMn 2O 5、BiFeO 3、BaTiO 3、Pb(Zr,Ti)O 3、(1-x)[Pb(Mg 1/3Nb 2/3)O 3]-x[PbTiO 3](PMN-PT，其中X为0.1-0.9)中的一种或两种以上的组合；超声波与光致形变材料包括螺吡喃、二芳烯、萘并吡喃、偶氮苯及它们的聚合物和衍生物中的一种或两种以上的组合。
在一些实施方式中，本发明的功能化植入式柔性电极可以由刺激端、引线部分、功能端组成；其中，刺激端包括基底层(或称刺激端基底层)、导电层以及设置于导电层表面的刺激位点，导电层位于基底层的表面；功能端包括基底层(或称功能端基底层，不同于刺激端的基底层)和功能层。在该结构中，刺激端和功能端通过引线部分连接在一起，功能层在光、电、磁、声、热和力等的触发下产生电流或电压，并通过引线部分传递到刺激端，通过刺激端的刺激位点来实现相应的刺激功能。
在一些实施方式中，该功能化植入式柔性电极由耦合有功能层的刺激端组成，即功能层与刺激端的各个层复合在一起，具体可以有以下两种结构(但不限于此)：
第一种结构：刺激端包括基底层、导电层以及设置于导电层表面的刺激位点，功能层位于基底层的表面或者嵌入基底层之中(例如将功能材料与基底层材料复合在一起制成兼具基底功能和功能材料相应功能的基底层)，导电层位于功能层的表面或者嵌有功能层的基底层的表面：在这种结构下，功能层实际上可以同时起到引线的作用，将其在光、电、磁、声、热和力等的触发下产生电流或电压传递到各个刺激位点。
第二种结构：刺激端包括两层基底层、导电层和功能层，导电层位于两层基底层之间，功能层位于顶部的基底层的表面：在这种结构下，功能层在在光、电、磁、声、热和力等的触发下产生电流或电压，并通过中间的导电层传递到各个刺激位点。
本发明还可以对前述功能化植入式柔性电极进行修饰进一步提供具有相应功能的柔性电极，修饰的方法包括在电极表面的电化学修饰、生物材料修饰，以及电极背面的高分子材料修饰等。通过在电极表面进行电化学修饰，能够降低电极表面阻抗、提升刺激效率。
在一些实施方式中，在电极的刺激端的刺激位点上设有电镀层，该电镀层的材料包括无机材料、导电高分子材料或它们的复合材料中的一种或两种以上的组合。
在一些实施方式中，所述电镀层的无机材料包括碳纳米管、石墨烯、钛、铂、铑、钯、铱、金和铌等中的一种或两种以上的组合。
在一些实施方式中，所述电镀层的有机高分子材料包括聚离子液体、聚吡咯、聚苯硫醚、聚对苯撑、聚苯胺、聚噻吩、水凝胶和它们的衍生物中的一种或两种以上的组合。
在一些实施方式中，所述电镀层的形貌为微结构，所述微结构包括微颗粒、微柱、微针、微片、微孔、微管、微线、微锥结构或两种以上的微结构的复合结构或其多级复合结构。在一些实施方式中，所述微结构的厚度例如为20nm-200μm。在一些实施方式中，所述微颗粒(粒径)、微柱(长度)、微针(长度)、微片(长度)、微孔(孔径)、 微管(管径)、微线(长度)、微锥(轴向长度)结构的尺寸可以控制为1nm-20μm。
在一些实施方式中，所述电极刺激位点上可以修饰有生物材料层，生物材料通过分子层面设计如分子氢键、范德华力、亲疏水作用、静电作用，通过物理或化学方法将其修饰到柔性电极上，所述生物材料层的材料包括多肽、蛋白、水凝胶和它们的复合物中的一种或者两种以上的组合，所述生物材料层的厚度优选可以为1nm-50μm。通过在电极表面进行生物材料修饰，能够确保植入式柔性电极植入后的生物相容性，防止长期植入的免疫反应。
在一些生物材料层中，所述水凝胶可以包括由如下材料形成的水凝胶：聚(N-异丙基丙烯酰胺)、聚(N-正丙基丙烯酰胺)、聚(N-环丙基丙烯酰胺)、聚(N-异丙基甲基丙烯酰胺)、蛋白、聚(N-乙基丙烯酰胺)、聚(N-丙烯酰氧基-N-丙基哌嗪)、聚(N-(L)-(1-羟甲基)丙基甲基丙烯酰胺)、聚[N-(2-甲基丙烯酰氧乙基)吡咯烷酮]、聚[N-(3-丙烯酰氧丙基)吡咯烷酮]、聚[N-(3-甲基丙烯酰氧丙基)吡咯烷酮]、聚[N-(2-丙烯酰氧丙基)吡咯烷酮]、聚[N-(1-甲基-2-丙烯酰氧乙基)吡咯烷酮]、聚(2-烷基-2-唑啉)、聚(2-乙基-2-唑啉)、聚(2-异丙基-2-唑啉)、聚(2-正丙基-2-唑啉)、聚甲基丙烯酸二甲氨乙酯、聚(N-乙烯基环己内酰胺)、聚丙烯酰吡咯烷、聚甲基乙烯基醚、聚甲氧基乙基乙烯基醚、聚乙氧基乙基乙烯基醚、聚乙氧基乙氧基乙烯基醚、聚环氧丙烷、聚(低聚(乙二醇)单甲醚甲基丙烯酸酯)、聚有机膦腈、弹性蛋白样多肽、琼脂糖、聚乙烯醇、壳聚糖、淀粉、聚丙烯酰胺、聚乙烯吡咯烷酮、透明质酸、透明质酸钠、聚苯乙烯磺酸钠、聚对苯乙烯磺酸、聚甲基丙烯酸羟乙酯、聚乙二醇、聚丁二醇、聚乙二醇甲基丙烯酸酯、聚乙二醇丙烯酸酯、基质胶、明胶、海藻酸、胶原、聚L-赖氨酸、聚L-谷胺酸、羟丙基甲基纤维素、羟乙基纤维素、羧甲基纤维素、羧乙烯聚合物、卡拉胶、玻尿酸、聚乙烯醇、聚甲基丙烯酸甲酯、聚甲基丙烯酸乙酯、聚甲基丙烯酸叔丁基酯、聚丙烯酸甲酯、聚丙烯酸乙酯、聚乙烯基吡啶、聚丙烯酸、聚L-谷氨酸、聚组氨酸、聚天冬氨酸、聚[(2-二甲基氨基)甲基丙烯酸乙酯]、聚甲基丙烯酸、聚乙基丙烯酸、聚丙基丙烯酸、聚乙烯基苯甲酸、聚衣康酸、聚乙二醇丙烯酸酯磷酸、聚乙二醇甲基丙烯酸酯磷酸、聚乙烯磷酸、聚(4-乙烯基-苯基磷酸)、聚乙烯磺酸、聚(4-苯乙烯磺酸)、聚乙烯苯硼酸、聚甲基丙烯酸二甲氨基乙酯、聚甲基丙烯酸二乙氨基乙酯、聚(N-乙基吡咯烷甲基丙烯酸酯)聚合物和它们的共聚物中的一种或两种以上的组合。
在一些实施方式中，所述生物材料层中可以含有抗炎药，所述抗炎药例如包括地塞米松、强的松、保泰松和抗炎性多肽中的一种或两种以上的组合。生物材料层中含有抗 炎药可使本发明柔性电极具有抗炎功能，从而使得所述柔性电极能长期植入。
在一些实施方式中，在所述功能化植入式柔性电极的背面可以修饰有高分子材料层。在本发明电极背面修饰上高分子材料层，可使柔性电极具备形状适应性改变功能化，这既可以实现微创方式植入，还可以确保电极植入后能有效匹配生物体组织，提高刺激有效性；再者这还可以实现电极宽幅设计，增加刺激区域面积，拓展神经刺激功能，解决人造视网膜管状视野技术难题。所述高分子材料层的材料可以包括聚(N-异丙基丙烯酰胺)、聚(N-正丙基丙烯酰胺)、聚(N-环丙基丙烯酰胺)、聚(N-异丙基甲基丙烯酰胺)、聚(N-乙基丙烯酰胺)、聚(N-丙烯酰氧基-N-丙基哌嗪)、聚(N-(L)-(1-羟甲基)丙基甲基丙烯酰胺)、聚[N-(2-甲基丙烯酰氧乙基)吡咯烷酮]、聚[N-(3-丙烯酰氧丙基)吡咯烷酮]、聚[N-(3-甲基丙烯酰氧丙基)吡咯烷酮]、聚[N-(2-丙烯酰氧丙基)吡咯烷酮]、聚[N-(1-甲基-2-丙烯酰氧乙基)吡咯烷酮]、聚(2-烷基-2-唑啉)、聚(2-乙基-2-唑啉)、聚(2-异丙基-2-唑啉)、聚(2-正丙基-2-唑啉)、聚甲基丙烯酸二甲氨乙酯、聚(N-乙烯基环己内酰胺)、聚丙烯酰吡咯烷、聚甲基乙烯基醚、聚甲氧基乙基乙烯基醚、聚乙氧基乙基乙烯基醚、聚乙氧基乙氧基乙烯基醚、聚环氧丙烷、聚(低聚(乙二醇)单甲醚甲基丙烯酸酯)、聚有机膦腈、蛋白、弹性蛋白样多肽、琼脂糖、聚乙烯醇、壳聚糖、淀粉、聚丙烯酰胺、聚乙烯吡咯烷酮、透明质酸、透明质酸钠、聚苯乙烯磺酸钠、聚对苯乙烯磺酸、聚甲基丙烯酸羟乙酯、聚乙二醇、聚丁二醇、聚乙二醇甲基丙烯酸酯、聚乙二醇丙烯酸酯、基质胶、明胶、海藻酸、胶原、聚L-赖氨酸、聚L-谷胺酸、羟丙基甲基纤维素、羟乙基纤维素、羧甲基纤维素、羧乙烯聚合物、卡拉胶、玻尿酸、聚乙烯醇、聚甲基丙烯酸甲酯、聚甲基丙烯酸乙酯、聚甲基丙烯酸叔丁基酯、聚丙烯酸甲酯、聚丙烯酸乙酯、聚乙烯基吡啶、聚碳酸酯、聚酰亚胺、醋酸纤维素、尼龙、聚(乙烯基对苯二甲酸酯)、聚磷腈、全氟磺酸、聚乙烯、聚苯乙烯、酚醛树脂、聚丙烯酸、聚L-谷氨酸、聚组氨酸、聚天冬氨酸、聚[(2-二甲基氨基)甲基丙烯酸乙酯]、聚甲基丙烯酸、聚乙基丙烯酸、聚丙基丙烯酸、聚乙烯基苯甲酸、聚衣康酸、聚乙二醇丙烯酸酯磷酸、聚乙二醇甲基丙烯酸酯磷酸、聚乙烯磷酸、聚(4-乙烯基-苯基磷酸)、聚乙烯磺酸、聚(4-苯乙烯磺酸)、聚乙烯苯硼酸、聚甲基丙烯酸二甲氨基乙酯、聚甲基丙烯酸二乙氨基乙酯、聚(N-乙基吡咯烷甲基丙烯酸酯)、聚(2-乙烯基吡啶)、聚(N-丙烯酰基-N-烯基哌嗪)、聚丙烯酰吗啉、聚(4-乙烯基吡啶)、聚乙烯亚胺树状大分子、聚乙烯醇、预氧化丙烯腈、聚氨酯、环氧树脂、乙烯-醋酸乙烯酯共聚物、聚酰亚胺、聚己内酯、聚吡咯烷酮、聚多巴胺、弹性蛋白多肽@黑鳞纳米颗粒复合水凝胶、聚乳酸、聚乙醇酸、聚乳酸-羟基乙酸共聚物材料和它们的衍生物中的 一种或两种以上的组合。
在一些实施方式中，电极背面修饰的高分子材料层中可以含有抗炎药，所述抗炎药例如包括地塞米松、强的松、保泰松或抗炎性多肽中的一种或多种。高分子材料层中含有抗炎药可使本发明的柔性电极具有抗炎功能，从而使得柔性电极能长期植入。
在一些实施方式中，基底层(包括各种具体结构下的基底层)的材料可以包括聚酰亚胺、聚对二甲苯、聚二甲基硅氧烷、医用硅胶、聚(N-异丙基丙烯酰胺)、聚(N-正丙基丙烯酰胺)、聚(N-环丙基丙烯酰胺)、聚(N-异丙基甲基丙烯酰胺)、聚(N-乙基丙烯酰胺)、聚(N-丙烯酰氧基-N-丙基哌嗪)、聚(N-(L)-(1-羟甲基)丙基甲基丙烯酰胺)、聚[N-(2-甲基丙烯酰氧乙基)吡咯烷酮]、聚[N-(3-丙烯酰氧丙基)吡咯烷酮]、聚[N-(3-甲基丙烯酰氧丙基)吡咯烷酮]、聚[N-(2-丙烯酰氧丙基)吡咯烷酮]、聚[N-(1-甲基-2-丙烯酰氧乙基)吡咯烷酮]、聚(2-烷基-2-唑啉)、聚(2-乙基-2-唑啉)、聚(2-异丙基-2-唑啉)、聚(2-正丙基-2-唑啉)、聚甲基丙烯酸二甲氨乙酯、聚(N-乙烯基环己内酰胺)、聚丙烯酰吡咯烷、聚甲基乙烯基醚、聚甲氧基乙基乙烯基醚、聚乙氧基乙基乙烯基醚、聚乙氧基乙氧基乙烯基醚、聚环氧丙烷、聚(低聚(乙二醇)单甲醚甲基丙烯酸酯)、聚有机膦腈、蛋白、弹性蛋白样多肽、琼脂糖、聚乙烯醇、壳聚糖、淀粉、聚丙烯酰胺、聚乙烯吡咯烷酮、透明质酸、透明质酸钠、聚苯乙烯磺酸钠、聚对苯乙烯磺酸、聚甲基丙烯酸羟乙酯、聚乙二醇、聚丁二醇、聚乙二醇甲基丙烯酸酯、聚乙二醇丙烯酸酯、基质胶、明胶、海藻酸、胶原、聚L-赖氨酸、聚L-谷胺酸、羟丙基甲基纤维素、羟乙基纤维素、羧甲基纤维素、羧乙烯聚合物、卡拉胶、玻尿酸、聚乙烯醇、聚甲基丙烯酸甲酯、聚甲基丙烯酸乙酯、聚甲基丙烯酸叔丁基酯、聚丙烯酸甲酯、聚丙烯酸乙酯、聚乙烯基吡啶、聚碳酸酯、聚酰亚胺、醋酸纤维素、尼龙、聚(乙烯基对苯二甲酸酯)、聚磷腈、全氟磺酸、聚乙烯、聚苯乙烯、酚醛树脂、聚丙烯酸、聚L-谷氨酸、聚组氨酸、聚天冬氨酸、聚[(2-二甲基氨基)甲基丙烯酸乙酯]、聚甲基丙烯酸、聚乙基丙烯酸、聚丙基丙烯酸、聚乙烯基苯甲酸、聚衣康酸、聚乙二醇丙烯酸酯磷酸、聚乙二醇甲基丙烯酸酯磷酸、聚乙烯磷酸、聚(4-乙烯基-苯基磷酸)、聚乙烯磺酸、聚(4-苯乙烯磺酸)、聚乙烯苯硼酸、聚甲基丙烯酸二甲氨基乙酯、聚甲基丙烯酸二乙氨基乙酯、聚(N-乙基吡咯烷甲基丙烯酸酯)、聚(2-乙烯基吡啶)、聚(N-丙烯酰基-N-烯基哌嗪)、聚丙烯酰吗啉、聚(4-乙烯基吡啶)、聚乙烯亚胺树状大分子、聚乙烯醇、预氧化丙烯腈、聚氨酯、环氧树脂、乙烯-醋酸乙烯酯共聚物、聚酰亚胺、聚己内酯、聚吡咯烷酮、聚多巴胺、弹性蛋白多肽@黑鳞纳米颗粒复合水凝胶、聚乳酸、聚乙醇酸、聚乳酸-羟基乙酸共聚物材料和它们的衍生物中的一种或多种的复合物、聚 氨酯、聚对苯二甲酸乙二醇酯、聚乳酸、聚己内酯、螺吡喃、聚乙二醇、聚乙烯醇、二芳烯、萘并吡喃、偶氮苯、肉桂酰、香豆素、蒽材料和它们的衍生物中的一种或两种以上的组合。
在一些实施方式中，导电层的材料可以包括导电金属材料、导电无机材料和导电高分子材料中的一种或两种以上的组合；优选地，导电金属材料例如包括铂、金、铂铱合金、银、镁、氮化钛、氧化铱、铟锡氧化物、镓铟合金和镓铟锡合金中的一种或两种以上的组合；导电无机材料例如包括石墨烯和碳纳米管中的一种或两种的组合；导电高分子材料例如包括聚吡咯、聚苯硫醚、聚对苯撑、聚苯胺、聚噻吩及它们的衍生物中的一种或两种以上的组合。
在一些实施方式中，功能化植入式柔性电极的总厚度为1μm-5.5mm，优选为1μm-300μm，其中，基底层的厚度为1μm-5mm(优选为3μm-10μm)，导电层的厚度为20nm-200μm(优选为20nm-10μm，功能层的厚度为1μm-200μm。此处给出的基底层厚度、导电层厚度、功能层厚度均为功能化植入式柔性电极包括这些层时的厚度，并不代表所有的功能化植入式柔性电极均同时包括这些层。
在一些实施方式中，在功能化植入式柔性电极中，刺激端的尺寸为0.1mm-2cm(优选为0.05mm-1.5cm)，单个刺激位点(一般为圆形)的直径为20nm-5mm(优选为20nm-500μm)，刺激位点的间距为1μm-1mm(优选为1μm-600μm)，刺激位点的数目为10-1000000(优选为60-1000000，更优选为60-100000)。
在一些实施方式中，功能化宽幅植入式微电极阵列的总厚度可以为1μm-200μm，其中，基底层的厚度为1μm-20μm，导电层的厚度为20nm-100μm，且刺激端的尺寸为0.1mm-2cm，单个刺激位点的直径为20nm-5mm，刺激位点的间距为1μm-1mm，刺激位点的数目为60-2000。
本发明的功能植入式柔性电极可以是通过微纳加工、3D打印、印刷、旋涂或喷涂方式制备得到的，可以根据柔性电极的不同结构选择合适的制备方法。
再一方面，本发明提供上述的功能化宽幅植入式微电极阵列在制备植入式人造视网膜、植入式人工耳蜗、植入式心植入式脏起搏器、植入式深脑刺激器中的应用。
再一方面，本发明提供一种神经假体，其包括上述的功能化宽幅植入式微电极阵列；所述神经假体例如包括植入式人造视网膜、植入式人工耳蜗、植入式心脏起博器或植入式深脑刺激器。
相对于现有技术，本发明的有益效果为：
本发明通过触发(例如光、电、磁、声、热、力等)形成电流或电压的功能层使得本发明柔性电极无需复杂的线路连接和器件封装，即可实现神经刺激器件的功能，不仅极大降低了手术风险以及长期植入的安全性风险，更是拓展了神经刺激器件的应用领域。此外，本发明还可通过在电极表面进行电化学修饰和生物材料修饰，不仅能够降低电极表面阻抗提升刺激效率，同时能够确保植入器件植入后的生物相容性，防止长期植入的免疫反应。另外，本发明还可通过电极背面的高分子材料修饰，使柔性电极具备形状适应性改变功能，这既可以实现微创方式植入，还可以确保电极植入后能有效匹配生物体组织，提高刺激有效性；再者还可以实现电极宽幅设计，增加刺激区域面积，拓展神经刺激功能，例如解决人造视网膜管状视野技术难题。
总之，本发明提供的技术方案，既可以解决现有神经假体长期植入有效性、稳定性与可靠性问题，同时实现神经假体微创植入、适应性匹配组织、大面积刺激等多种功能。
附图说明
图1为实施例1的电极的刺激位点阵列示意图。
图2为实施例1的功能化宽幅电极的表面修饰效果图。
图3为实施例1的功能化宽幅电极卷曲状态(左)以及植入眼球后自展开效果图(右)。
图4为窄电极(左)与实施例1的功能化宽幅电极(右)植入后视野拓展效果图。
图5为实施例2的功能化电极的表面刺激位点阵列图。
图6为实施例3的功能化电极的光致可控形变图。
图7为实施例3的功能化电极自适应贴合光照点亮LED效果图。
具体实施方式
为了对本发明的技术特征、目的和有益效果有更加清楚的理解，现结合具体实施例对本发明的技术方案进行以下详细说明，应理解这些实例仅用于说明本发明而不用于限制本发明的范围。实施例中，各原始试剂材料均可商购获得，未注明具体条件的实验方法为所属领域熟知的常规方法和常规条件，或按照仪器制造商所建议的条件。
实施例1
本实施例提供了一种功能化植入式柔性电极，其是一种功能化宽幅电极，该电极包括刺激端、引线部分及功能端，其总长度为6cm，刺激端与功能端通过引线部分连接。其中，刺激端为长方形，长为1.2cm、宽为0.6cm，刺激区域面积为1.2cm×0.6cm，在刺激端内的单个刺激位点直径为300μm，高度为80μm，刺激位点间 距为412.5μm，刺激通道数为126；引线部分为长方形，长为4cm，宽为0.4cm，引线间距为10μm；功能端为长方形，长为1.2cm，宽为0.6cm。该电极的刺激端的刺激位点阵列如图1所示。
该植入式柔性电极的刺激端包括一层基底层、一层导电层，并且，刺激端的刺激位点上修饰有电镀层、生物材料修饰层，电极的背面接枝有一层聚对苯乙烯磺酸水凝胶层。基底层的材料为聚酰亚胺，其厚度为5μm；导电层的材料为Au，其厚度为50nm；电镀层的材料为铂，其形貌为铂微柱状纳米层，其厚度为0.8μm；生物材料修饰层的材料为聚噻吩，其厚度为0.5μm；电极背面修饰层为聚对苯乙烯磺酸水凝胶层，其厚度为100μm。
该植入式柔性电极的功能端具有一层可通过光触发形成电流的功能层。该功能层的材料为聚三氟乙烯，其厚度为200μm。
本实施例的功能化植入式柔性电极是通过以下步骤制备的：
1、宽幅电极的微纳加工制备
以硅为基底，在其上面旋涂聚酰亚胺并固化，随后在其表面采用负胶剥离的方法设计出Au图案化导电层，并进行光刻，随后在导电层上旋涂上一层聚酰亚胺作为绝缘层，并掩模刻蚀暴露出电极和焊盘窗口，并释放出电极。
将偶氮苯聚合物掺杂的聚三氟乙烯通过化学接枝键合的方式于聚酰亚胺(基底层)上形成功能层，以作为功能端，该功能层通过光照就可以产生电流。
2、电极表面修饰
(a)电化学修饰：在室温环境下，在容器中加入500mL水、2.0mmol的氯铂酸钾和0.08mmol的柠檬酸，并进行超声分散。将上述电极置于前面溶液中，室温下静置48h。随后，将电极浸入超纯水中2h除去未反应的化学物质和粘附性差的铂纳米材料，在电极刺激位点表面得到铂纳米颗粒状纳米层，即电镀层。电化学修饰后的电极阻抗为4.65kΩ·cm 2的低阻抗，其阴极电荷存储能力高达25.4mC·cm -2，表面修饰效果如图2所示。
(b)生物材料修饰：将上述修饰好的电极置于含有0.3M的3,4-乙烯二氧噻吩、0.5M巯基功能化的乙烯基单体的混合液中，在0.5mA·cm -1的电流密度下电镀30min，随后将电极置于超纯水中24h除去未反应化学物质，在电极刺激位点表面得到生物材料修饰层。生物相容性测试结果表明，生物毒性为0级，表明生物相容性效果非常好。
(c)电极背面修饰：将电极背面通过乙烯基硅烷处理聚酰亚胺背面，通过苯乙烯磺酸钠、N-异丙基丙烯酰胺与乙烯基硅烷，以过氧化苯甲酰为引发剂，在90℃热引发 聚合下进行化学接枝，在电极背面上接枝共聚一层聚对苯乙烯磺酸水凝胶层。该功能化宽幅电极可以卷曲固定，待植入眼球内后自展开贴合视网膜层，如图3所示，其中，左图为卷曲状态，右图为植入眼球之后自展开的状态。由图3可以看出，该功能电极在植入之前为卷曲状态，尺寸较小，可以很方便地植入眼球之中，植入眼球之后，功能电极在聚对苯乙烯磺酸水凝胶层的带动下自动展开。
3、将电极的刺激端通过引线连接到电极的功能端。由于功能层的存在，使得该电极通过光照即可产生电压进而刺激视神经产生光感信号。由于该电极为宽幅电，极刺激区域比较大，因而可以实现更广阔的视野，较之窄电极获得的管状视野而言，可以极大优化失明患者的视觉恢复效果，如图4所示。
实施例2
本实施例提供了一种功能化植入式柔性电极，该电极具有刺激端及刺激端的引线部分，电极长度为6cm。其中，刺激端(刺激区域)为长方形，面积为1.2cm×0.9cm，在刺激端内的单个刺激位点直径为150μm，刺激位点间距为260μm，刺激通道数为1000，该刺激端的局部结构如图5所示。引线部分面积为1.2cm×0.2cm，引线间距为10μm，单条引线宽为5μm。
该电极的刺激端由一层基底层(复合有可通过光照形成电流的功能材料)、一层导电层组成，并且，刺激端的刺激位点上修饰有电镀层、生物材料修饰层，电极的背面接枝有一层聚己内酯共聚物层。其中，基底层的材料为聚酰亚胺，其厚度为6μm；导电层的材料为Au，其厚度为50nm；可通过光照形成电流的功能材料为钙钛矿光电材料，其厚度为200μm，钙钛矿材料复合在作为基底层的聚酰亚胺之中，其覆盖位置为刺激端的引线部分，功能层连接到刺激位点兼具引线作用；电镀层的材料为铂，其形貌为柱状纳米层，其厚度为350nm；生物材料修饰层的材料为弹性蛋白多肽，其厚度为500nm；电极背面修饰层的材料为聚己内酯共聚物，其厚度为100μm。
该功能电极的光电材料(功能层)产生的电流直接传递到相应刺激位点进而刺激视神经。
本实施例的功能化植入式柔性电极是通过以下步骤制备的：
1、微纳加工制备电极
以硅为基底，在其上面旋涂钙钛矿光电材料与聚酰亚胺的复合物作为基底层并固化，随后在其表面采用负胶剥离的方法设计出Au图案化导电层，并进行光刻，随后在导电层上旋涂上一层聚酰亚胺，并掩模刻蚀暴露出电极和焊盘窗口，并释放出电极。
2、电极表面修饰
(a)电化学修饰：在室温环境下，在容器中加入500mL水、2.0mmol的氯铂酸和8mmol的柠檬酸，并进行超声分散，得到修饰溶液。将上述电极置于修饰溶液中，以Ag/AgCl为参比电极，通过恒电位方式进行沉积。随后，将电极浸入超纯水中2h除去未反应的化学物质和粘附性差的铂纳米材料，得到柱状纳米层，即电镀层。电化学修饰后的电极阻抗为4.35kΩ·cm 2的低阻抗，其阴极电荷存储能力高达26.4mC·cm -2。
(b)生物材料修饰：将上述修饰好的电极通过层层沉积(LBL)的方式沉积生物材料层，具体如下：将电极通过LBL沉积设备程序化地浸入浓度为20wt％的弹性蛋白多肽溶液中，然后提拉起来，并重复该工作100次以组织100层弹性蛋白多肽，即可修饰上弹性蛋白多肽层，得到生物材料修饰层。生物相容性测试结果表明，生物毒性为0级，表明生物相容性效果非常好。
(c)电极背面修饰：通过乙烯基硅烷处理聚酰亚胺基底层的背面，通过将背面涂覆有己内酯单体预聚液的电极置于伽马射线源下辐照30min即可实现化学接枝，在电极背面上接枝共聚一层聚己内酯共聚物层。
实施例3
本实施例提供了功能化植入式柔性电极，该电极如图6所示。该电极包括刺激端、引线部分及功能端，其总长度为6cm，宽度为0.8cm。其中，刺激端的刺激区域面积为0.8cm×1.5cm，在刺激端内的单个刺激位点直径为500μm，刺激位点间距为750μm，刺激通道数为10。引线部分为长方形，其长度为3.0cm，宽度为0.8cm，引线间距为0.5mm。功能端的面积为0.8cm×1.5cm。
该电极的刺激端包括一层基底层、一层导电层，基底层的材料为聚二甲基硅氧烷，其厚度为10μm；导电层的材料为镓铟合金，其厚度为1μm；刺激端的刺激位点上修饰有生物材料修饰层，其材料为聚吡咯，其厚度为0.6μm。
功能端包括一层基底层和一层功能层，基底层的材料为聚二甲基硅氧烷，其厚度为10μm；功能层的材料为压电材料GaFeO 3，其厚度为200μm；
刺激端和功能端通过引线部分连接在一起；
该电极的背面设有电极背面修饰层，其材料为聚丙烯酸水凝胶，其厚度为100μm。
图6左边的图为功能化电极的示意图，显示了电极的结构。通过图6中的左右两个图可以看出该电极的可控形变效果。该功能化植入式柔性电极的功能效果如图7所示，该电极连接有LED灯，采用光照测试该电极的功能效果。在进行光照之前LED不亮， 待光照后即点亮LED灯，表明光照后电极在背面修饰层的聚丙烯酸水凝胶的带动下发生形变产生压力，进而由功能层的压电材料产生电流而点亮LED灯。
本实施例的功能化植入式柔性电极是通过以下步骤制备的：
1、3D打印制备电极：以聚二甲基硅氧烷为基底，通过3D打印机将镓铟液态金属打印到基底上固化形成导电层，再用一层Parylene C封装金属线路，暴露出刺激位点，进而获得柔性电极的刺激端。
以聚二甲基硅氧烷为基底，通过印刷的方式将压电材料GaFeO 3形成于基底层表面作为功能层，制备得到功能端。
通过引线部分将刺激端和功能端连接在一起，得到柔性电极。
2、电极表面修饰
(a)生物材料修饰：将上述电极置于含有0.6M的吡咯混合液中，在电流密度为0.8mA·cm -1下电镀30min，随后将电极置于超纯水中24h除去未反应化学物质，得到生物材料修饰层。生物相容性测试结果表明，生物毒性为0级，表明生物相容性效果非常好。
(b)电极背面修饰：将电极背面通过乙烯基硅烷处理聚酰亚胺背面，通过以过硫酸铵为引发剂，并加入促进剂在室温下使螺吡喃功能化的丙烯酸单体聚合实现化学接枝，在电极背面上接枝共聚一层螺吡喃功能化的聚丙烯酸水凝胶层。
实施例4
本实施例提供了一种功能化植入式柔性电极，该电极包括两层基底层、一层导电层、一层LED功能层，其中，一层导电层位于两层基底层中间；基底层的材料为Parylene C，其厚度为10微米，导电层的材料为钛和金，其厚度为80nm；功能层为圆形LED层，其直径为80微米，每个LED灯作为一个刺激位点，其通过外界电源供电进行刺激。该电极的背面接枝有海藻酸钠/壳聚糖复合水凝胶层。
本实施例提供的电极是通过以下步骤制备的：
1、电极的制备
(1.1)在硅片上溅射或热蒸发沉积一层450微米厚的铝作为牺牲层。
(1.2)旋涂一层Parylene C，经过前烘、曝光、显影和固化，制作得到图形化的底层基底层，其厚度为12微米；在光刺激电极底层基底层上面开有三个长方形孔，三个长方形孔的尺寸均为210微米×260微米、中心距为500微米；在光刺激电极底层基底层上面开有两个圆形孔，两个圆形孔的直径均为300微米、中心距为1.5毫米；在光刺 激电极底层基底层上面开有四个方形孔，四个方形孔的尺寸为300微米×300微米、中心距为1.5毫米；以上的孔为分别开设。
(1.3)溅射一层钛和一层金，厚度分别为28纳米和290纳米，旋涂4微米厚正性光刻胶AZ4620，经过前烘、光刻、显影和后烘，采用湿法刻蚀得到图形化的光刺激电极中间金属层；光刺激电极中间金属层(即钛和金形成的导电层)的一端有三组圆形焊盘，每组包括两个圆，两个圆的直径均为180微米；光刺激电极中间金属层的另一端有四路长方形焊盘，其中一路作为公共电路用于连接所有微型LED裸芯片的阴极金焊盘。
(1.4)制作得到图形化的光刺激电极顶层基底层，厚度为9微米，在与光刺激电极底层基底层相同位置处开有一样大小的长方形孔、圆形孔和方孔，同时在光刺激电极中间金属层的圆形焊盘正上方开有三组圆形孔，每组包括两个圆，两个圆的直径均为160微米、间距为730微米。
(1.5)旋涂30微米厚的SU-8胶，经过前烘、曝光、显影和后烘，在光刺激电极顶层基底层上设计放置微型LED裸芯片的长方形凹槽，该长方形凹槽内部尺寸均为240微米×290微米、中心距为500微米。
(1.6)用细针头沾无色透明的耐高温瞬干胶涂抹在长方形凹槽内，如有条件可使用点胶机代替。
(1.7)用镊子将单个微型LED裸芯片夹起，其阴、阳极金焊盘朝上放置在长方形凹槽内，轻轻按压微型LED裸芯片顶部以确保微型LED裸芯片位置水平，耐高温瞬干胶完全与微型LED裸芯片四周接触且不溢出覆盖顶部，等耐高温瞬干胶固化完成固定；其中：微型LED裸芯片的型号为Cree公司的TR2227、尺寸为220×270×50微米；微型LED裸芯片的阴、阳极金焊盘直径为80微米、间距为135微米。
(1.8)在金丝球焊机上使用直径25微米的金丝连接微型LED裸芯片的阴、阳极金焊盘和对应的光刺激电极中间金属层一端的圆形焊盘，由于底层聚合物绝缘层为柔性衬底，金丝无法和圆形焊盘牢靠连接，这里仅将金丝的第二键合点轻轻压在圆形焊盘上。
(1.9)在圆形焊盘上用毛细玻璃管涂抹少量导电银浆，确保金丝和圆形焊盘牢靠连接，尽量保证导电银浆在直径160微米的圆形焊盘范围内。
(1.10)在微型LED裸芯片、圆形焊盘和金丝上方用细针头涂抹透明环氧树脂胶以实现封装，保证光刺激电极释放后微型LED裸芯片不会脱落、金线牢固可靠，同时导电银浆不会发生反应。
(1.11)通过电化学腐蚀或者稀盐酸腐蚀铝牺牲层，完成光刺激电极释放，使用电 化学腐蚀法，可以在高浓度NaCl溶液中将光刺激电极放到电解池阳极，电压0.7-1.0V，腐蚀铝牺牲层到光刺激电极自动脱落；使用稀盐酸腐蚀法，可以按照浓盐酸：去离子水＝1：4腐蚀铝牺牲层到光刺激电极自动脱落。
2、电极表面修饰
电极背面修饰：将电极背面(正面是指焊接有LED芯片一侧的基底，背面是没有芯片的那一面)通过plasma处理聚对苯二甲酸乙二醇酯背面，通过LBL方法，在电极背面上接枝一层海藻酸钠/壳聚糖复合水凝胶层。
该电极通过功能材料修饰，不仅可以有效解决电极与神经组织间的贴合问题，而且还可以实现光刺激神经组织，拓展多功能神经电极的应用。
最后说明的是：以上实施例仅用于说明本发明的实施过程和特点，而非限制本发明的技术方案，尽管参照上述实施例对本发明进行了详细说明，本领域的普通技术人员应当理解：依然可以对本发明进行修改或者等同替换，而不脱离本发明的精神和范围的任何修改或局部替换，均应涵盖在本发明的保护范围当中。

Claims (20)

  1. 一种功能化植入式柔性电极，其至少包括能产生电流或电压的功能层。
  2. 根据权利要求1所述的功能化植入式柔性电极，其中，所述功能层能够通过光、电、磁、声、热和力中的一种或两种以上的方式的触发而产生电流或电压。
  3. 根据权利要求1或2所述的功能化植入式柔性电极，其中，该功能化植入式柔性电极由刺激端、引线部分、功能端组成；
    其中，所述刺激端包括基底层、导电层以及设置于导电层表面的刺激位点；
    所述功能端包括基底层和所述功能层。
  4. 根据权利要求1或2所述的功能化植入式柔性电极，其中，该功能化植入式柔性电极由耦合有功能层的刺激端组成；
    其中，所述刺激端包括基底层、导电层以及设置于导电层表面的刺激位点，所述功能层位于所述基底层的表面或者嵌入所述基底层之中，所述导电层位于所述功能层的表面或者嵌有所述功能层的基底层的表面；或者，所述刺激端包括两层基底层、导电层和功能层，所述导电层位于两层基底层之间，所述功能层位于顶部的基底层的表面。
  5. 根据权利要求1-4任一项所述的功能化植入式柔性电极，其中，所述功能层的材料包括场效应晶体管、发光二极管、光电二极管、光电材料、压电材料和磁电材料中的一种或两种以上的组合。
  6. 根据权利要求5所述的功能化植入式柔性电极，其中，所述功能层的材料包括光电材料、导电材料、磁电材料和超声波与光致形变材料中的一种或两种以上的组合；
    优选地，所述光电材料包括砷化镓、铜铟镓硒、碲化镉、钙钛矿、染料敏化材料、CIGS材料、光电有机材料、光电高分子材料、聚偏氟乙烯、聚三氟氯乙烯、聚三氟乙烯、压电陶瓷、Cr 2O 3、Ti 2O 3中的一种或两种以上的组合；
    所述导电材料包括铂、金、铂铱合金、银、镁、氮化钛、氧化铱、铟锡氧化物、镓铟合金、镓铟锡合金、石墨烯、碳纳米管、导电高分子材料及其它们的复合物中的一种或两种以上的组合；更优选地，所述导电高分子材料包括聚吡咯、聚苯硫醚、聚对苯撑、聚苯胺、聚噻吩及它们的衍生物中的一种或两种以上的组合；
    所述磁电材料包括GaFeO 3、LiCoPO 4、TbPO 4、REMnO 3、REMn 2O 5、TbMn 2O 5、BiFeO 3、BaTiO 3、Pb(Zr,Ti)O 3、(1-x)[Pb(Mg 1/3Nb 2/3)O 3]-x[PbTiO 3]中的一种或两种以上的组合；
    所述超声波与光致形变材料包括螺吡喃、二芳烯、萘并吡喃、偶氮苯及它们的聚合物和衍生物中的一种或两种以上的组合。
  7. 根据权利要求3或4所述的功能化植入式柔性电极，其中，所述基底层的材料包括聚酰亚胺、聚对二甲苯、聚二甲基硅氧烷、医用硅胶、聚(N-异丙基丙烯酰胺)、聚(N-正丙基丙烯酰胺)、聚(N-环丙基丙烯酰胺)、聚(N-异丙基甲基丙烯酰胺)、聚(N-乙基丙烯酰胺)、聚(N-丙烯酰氧基-N-丙基哌嗪)、聚(N-(L)-(1-羟甲基)丙基甲基丙烯酰胺)、聚[N-(2-甲基丙烯酰氧乙基)吡咯烷酮]、聚[N-(3-丙烯酰氧丙基)吡咯烷酮]、聚[N-(3-甲基丙烯酰氧丙基)吡咯烷酮]、聚[N-(2-丙烯酰氧丙基)吡咯烷酮]、聚[N-(1-甲基-2-丙烯酰氧乙基)吡咯烷酮]、聚(2-烷基-2-唑啉)、聚(2-乙基-2-唑啉)、聚(2-异丙基-2-唑啉)、聚(2-正丙基-2-唑啉)、聚甲基丙烯酸二甲氨乙酯、聚(N-乙烯基环己内酰胺)、聚丙烯酰吡咯烷、聚甲基乙烯基醚、聚甲氧基乙基乙烯基醚、聚乙氧基乙基乙烯基醚、聚乙氧基乙氧基乙烯基醚、聚环氧丙烷、聚(低聚(乙二醇)单甲醚甲基丙烯酸酯)、聚有机膦腈、蛋白、弹性蛋白样多肽、琼脂糖、聚乙烯醇、壳聚糖、淀粉、聚丙烯酰胺、聚乙烯吡咯烷酮、透明质酸、透明质酸钠、聚苯乙烯磺酸钠、聚对苯乙烯磺酸、聚甲基丙烯酸羟乙酯、聚乙二醇、聚丁二醇、聚乙二醇甲基丙烯酸酯、聚乙二醇丙烯酸酯、基质胶、明胶、海藻酸、胶原、聚L-赖氨酸、聚L-谷胺酸、羟丙基甲基纤维素、羟乙基纤维素、羧甲基纤维素、羧乙烯聚合物、卡拉胶、玻尿酸、聚乙烯醇、聚甲基丙烯酸甲酯、聚甲基丙烯酸乙酯、聚甲基丙烯酸叔丁基酯、聚丙烯酸甲酯、聚丙烯酸乙酯、聚乙烯基吡啶、聚碳酸酯、聚酰亚胺、醋酸纤维素、尼龙、聚(乙烯基对苯二甲酸酯)、聚磷腈、全氟磺酸、聚乙烯、聚苯乙烯、酚醛树脂、聚丙烯酸、聚L-谷氨酸、聚组氨酸、聚天冬氨酸、聚[(2-二甲基氨基)甲基丙烯酸乙酯]、聚甲基丙烯酸、聚乙基丙烯酸、聚丙基丙烯酸、聚乙烯基苯甲酸、聚衣康酸、聚乙二醇丙烯酸酯磷酸、聚乙二醇甲基丙烯酸酯磷酸、聚乙烯磷酸、聚(4-乙烯基-苯基磷酸)、聚乙烯磺酸、聚(4-苯乙烯磺酸)、聚乙烯苯硼酸、聚甲基丙烯酸二甲氨基乙酯、聚甲基丙烯酸二乙氨基乙酯、聚(N-乙基吡咯烷甲基丙烯酸酯)、聚(2-乙烯基吡啶)、聚(N-丙烯酰基-N-烯基哌嗪)、聚丙烯酰吗啉、聚(4-乙烯基吡啶)、聚乙烯亚胺树状大分子、聚乙烯醇、预氧化丙烯腈、聚氨酯、环氧树脂、乙烯-醋酸乙烯酯共聚物、聚酰亚胺、聚己内酯、聚吡咯烷酮、聚多巴胺、弹性蛋白多肽@黑鳞纳米颗粒复合水凝胶、聚乳酸、聚乙醇酸、聚乳酸-羟基乙酸共聚物材料和它们的衍生物中的一种或多种的复合物、聚氨酯、聚对苯二甲酸乙二醇酯、聚乳酸、聚己内酯、螺吡喃、聚乙二醇、聚乙烯醇、二芳烯、萘并吡喃、偶氮苯、肉桂酰、香豆素、蒽材料和它们的衍生物中的一种或两种以上的组合。
  8. 根据权利要求3或4所述的功能化植入式柔性电极，其中，所述导电层的材料包括导电金属材料、导电无机材料和导电高分子材料中的一种或两种以上的组合；
    优选地，所述导电金属材料包括铂、金、铂铱合金、银、镁、氮化钛、氧化铱、铟锡氧化物、镓铟合金和镓铟锡合金中的一种或两种以上的组合；
    优选地，所述导电无机材料包括石墨烯和碳纳米管中的一种或两种的组合；
    优选地，所述导电高分子材料包括聚吡咯、聚苯硫醚、聚对苯撑、聚苯胺、聚噻吩及它们的衍生物中的一种或两种以上的组合。
  9. 根据权利要求3或4所述的功能化植入式柔性电极，其中，在电极的刺激位点上进一步设有电镀层，该电镀层的材料包括无机材料、导电高分子材料或它们的复合材料中的一种或两种以上的组合；
    优选地，所述电镀层的无机材料包括碳纳米管、石墨烯、钛、铂、铑、钯、铱、金和铌中的一种或两种以上的组合；
    优选地，所述电镀层的有机高分子材料包括聚离子液体、聚吡咯、聚苯硫醚、聚对苯撑、聚苯胺、聚噻吩、水凝胶和它们的衍生物中的一种或两种以上的组合。
  10. 根据权利要求9所述的功能化植入式柔性电极，其中，所述电镀层的形貌为微结构，所述微结构包括微颗粒、微柱、微针、微片、微孔、微管、微线、微锥结构或两种以上的微结构的复合结构；
    优选地，所述微结构的厚度为20nm-200μm，所述微颗粒、微柱、微针、微片、微孔、微管、微线、微锥结构的尺寸为1nm-20μm。
  11. 根据权利要求3或4所述的功能化植入式柔性电极，其中，在电极的刺激位点上修饰有生物材料层，所述生物材料层的材料包括多肽、蛋白、水凝胶和它们的复合物中的一种或者两种以上的组合；
    所述生物材料层的厚度优选为1nm-50μm。
  12. 根据权利要求9或11所述的功能化植入式柔性电极，其中，所述水凝胶包括由如下材料形成的水凝胶：聚(N-异丙基丙烯酰胺)、聚(N-正丙基丙烯酰胺)、聚(N-环丙基丙烯酰胺)、聚(N-异丙基甲基丙烯酰胺)、蛋白、聚(N-乙基丙烯酰胺)、聚(N-丙烯酰氧基-N-丙基哌嗪)、聚(N-(L)-(1-羟甲基)丙基甲基丙烯酰胺)、聚[N-(2-甲基丙烯酰氧乙基)吡咯烷酮]、聚[N-(3-丙烯酰氧丙基)吡咯烷酮]、聚[N-(3-甲基丙烯酰氧丙基)吡咯烷酮]、聚[N-(2-丙烯酰氧丙基)吡咯烷酮]、聚[N-(1-甲基-2-丙烯酰氧乙基)吡咯烷酮]、聚(2-烷基-2-唑啉)、聚(2-乙基-2-唑啉)、聚(2-异丙基-2-唑啉)、聚(2-正丙基-2-唑啉)、聚甲基丙烯酸二甲氨乙酯、聚(N-乙烯基环己内酰胺)、聚丙烯酰吡咯烷、聚甲基乙烯基醚、聚甲氧基乙基乙烯基醚、聚乙氧基乙基乙烯基醚、聚乙氧基乙氧基乙烯基醚、聚环氧丙烷、聚(低聚(乙二醇)单甲醚甲基丙烯酸酯)、聚有机膦腈、弹性蛋白样多肽、琼脂糖、聚乙烯醇、 壳聚糖、淀粉、聚丙烯酰胺、聚乙烯吡咯烷酮、透明质酸、透明质酸钠、聚苯乙烯磺酸钠、聚对苯乙烯磺酸、聚甲基丙烯酸羟乙酯、聚乙二醇、聚丁二醇、聚乙二醇甲基丙烯酸酯、聚乙二醇丙烯酸酯、基质胶、明胶、海藻酸、胶原、聚L-赖氨酸、聚L-谷胺酸、羟丙基甲基纤维素、羟乙基纤维素、羧甲基纤维素、羧乙烯聚合物、卡拉胶、玻尿酸、聚乙烯醇、聚甲基丙烯酸甲酯、聚甲基丙烯酸乙酯、聚甲基丙烯酸叔丁基酯、聚丙烯酸甲酯、聚丙烯酸乙酯、聚乙烯基吡啶、聚丙烯酸、聚L-谷氨酸、聚组氨酸、聚天冬氨酸、聚[(2-二甲基氨基)甲基丙烯酸乙酯]、聚甲基丙烯酸、聚乙基丙烯酸、聚丙基丙烯酸、聚乙烯基苯甲酸、聚衣康酸、聚乙二醇丙烯酸酯磷酸、聚乙二醇甲基丙烯酸酯磷酸、聚乙烯磷酸、聚(4-乙烯基-苯基磷酸)、聚乙烯磺酸、聚(4-苯乙烯磺酸)、聚乙烯苯硼酸、聚甲基丙烯酸二甲氨基乙酯、聚甲基丙烯酸二乙氨基乙酯、聚(N-乙基吡咯烷甲基丙烯酸酯)聚合物和它们的共聚物中的一种或两种以上的组合。
  13. 根据权利要求11所述的功能化植入式柔性电极，其中，所述生物材料层中含有抗炎药，优选地，所述抗炎药包括地塞米松、强的松、保泰松和抗炎性多肽中的一种或两种以上的组合。
  14. 根据权利要求1-13任一项所述的功能化植入式柔性电极，其中，该功能化植入式柔性电极的背面修饰有高分子材料层。
  15. 根据权利要求14所述的功能化植入式柔性电极，其中，所述高分子材料层的材料包括聚(N-异丙基丙烯酰胺)、聚(N-正丙基丙烯酰胺)、聚(N-环丙基丙烯酰胺)、聚(N-异丙基甲基丙烯酰胺)、聚(N-乙基丙烯酰胺)、聚(N-丙烯酰氧基-N-丙基哌嗪)、聚(N-(L)-(1-羟甲基)丙基甲基丙烯酰胺)、聚[N-(2-甲基丙烯酰氧乙基)吡咯烷酮]、聚[N-(3-丙烯酰氧丙基)吡咯烷酮]、聚[N-(3-甲基丙烯酰氧丙基)吡咯烷酮]、聚[N-(2-丙烯酰氧丙基)吡咯烷酮]、聚[N-(1-甲基-2-丙烯酰氧乙基)吡咯烷酮]、聚(2-烷基-2-唑啉)、聚(2-乙基-2-唑啉)、聚(2-异丙基-2-唑啉)、聚(2-正丙基-2-唑啉)、聚甲基丙烯酸二甲氨乙酯、聚(N-乙烯基环己内酰胺)、聚丙烯酰吡咯烷、聚甲基乙烯基醚、聚甲氧基乙基乙烯基醚、聚乙氧基乙基乙烯基醚、聚乙氧基乙氧基乙烯基醚、聚环氧丙烷、聚(低聚(乙二醇)单甲醚甲基丙烯酸酯)、聚有机膦腈、蛋白、弹性蛋白样多肽、琼脂糖、聚乙烯醇、壳聚糖、淀粉、聚丙烯酰胺、聚乙烯吡咯烷酮、透明质酸、透明质酸钠、聚苯乙烯磺酸钠、聚对苯乙烯磺酸、聚甲基丙烯酸羟乙酯、聚乙二醇、聚丁二醇、聚乙二醇甲基丙烯酸酯、聚乙二醇丙烯酸酯、基质胶、明胶、海藻酸、胶原、聚L-赖氨酸、聚L-谷胺酸、羟丙基甲基纤维素、羟乙基纤维素、羧甲基纤维素、羧乙烯聚合物、卡拉胶、玻尿酸、聚乙烯醇、聚甲基丙烯酸甲酯、聚甲基丙烯酸乙酯、聚甲基丙烯酸叔丁基酯、聚丙烯酸甲酯、 聚丙烯酸乙酯、聚乙烯基吡啶、聚碳酸酯、聚酰亚胺、醋酸纤维素、尼龙、聚(乙烯基对苯二甲酸酯)、聚磷腈、全氟磺酸、聚乙烯、聚苯乙烯、酚醛树脂、聚丙烯酸、聚L-谷氨酸、聚组氨酸、聚天冬氨酸、聚[(2-二甲基氨基)甲基丙烯酸乙酯]、聚甲基丙烯酸、聚乙基丙烯酸、聚丙基丙烯酸、聚乙烯基苯甲酸、聚衣康酸、聚乙二醇丙烯酸酯磷酸、聚乙二醇甲基丙烯酸酯磷酸、聚乙烯磷酸、聚(4-乙烯基-苯基磷酸)、聚乙烯磺酸、聚(4-苯乙烯磺酸)、聚乙烯苯硼酸、聚甲基丙烯酸二甲氨基乙酯、聚甲基丙烯酸二乙氨基乙酯、聚(N-乙基吡咯烷甲基丙烯酸酯)、聚(2-乙烯基吡啶)、聚(N-丙烯酰基-N-烯基哌嗪)、聚丙烯酰吗啉、聚(4-乙烯基吡啶)、聚乙烯亚胺树状大分子、聚乙烯醇、预氧化丙烯腈、聚氨酯、环氧树脂、乙烯-醋酸乙烯酯共聚物、聚酰亚胺、聚己内酯、聚吡咯烷酮、聚多巴胺、弹性蛋白多肽@黑鳞纳米颗粒复合水凝胶、聚乳酸、聚乙醇酸、聚乳酸-羟基乙酸共聚物材料和它们的衍生物中的一种或两种以上的组合。
  16. 根据权利要求14或15所述的功能化植入式柔性电极，其中，所述高分子材料层中含有抗炎药，优选地，所述抗炎药包括地塞米松、强的松、保泰松和抗炎性多肽中的一种或两种以上的组合。
  17. 根据权利要求1-16中任一项所述的功能化植入式柔性电极，其中，该功能化植入式柔性电极的总厚度为1μm-5.5mm，优选为1μm-300μm；
    其中，功能层的厚度为1μm-200μm；
    当该功能化植入式柔性电极具有基底层时，所述基底层的厚度为1μm-5mm，优选为3μm-10μm；
    当该功能化植入式柔性电极具有导电层时，所述导电层的厚度为20nm-200μm，优选为20nm-10μm。
  18. 根据权利要求3或4所述的功能化植入式柔性电极，其中，所述刺激端的尺寸为0.1mm-2cm，优选为0.05mm-1.5cm；
    单个刺激位点的直径为20nm-5mm，优选为20nm-500μm；
    刺激位点的间距为1μm-1mm，优选为1μm-600μm；
    刺激位点的数目为10-1000000，优选为60-1000000，更优选为60-100000。
  19. 权利要求1-18任一项所述的功能化植入式柔性电极在制备植入式人造视网膜、植入式人工耳蜗、植入式心植入式脏起搏器、植入式深脑刺激器中的应用。
  20. 一种神经假体，其包括权利要求1-18任一项所述的功能化植入式柔性电极；所述神经假体例如包括植入式人造视网膜、植入式人工耳蜗、植入式心脏起博器或植入式深脑刺激器。
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