WO2020107341A1 - 一种功能化宽幅植入式微电极阵列及其制备方法与应用 - Google Patents

一种功能化宽幅植入式微电极阵列及其制备方法与应用 Download PDF

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WO2020107341A1
WO2020107341A1 PCT/CN2018/118245 CN2018118245W WO2020107341A1 WO 2020107341 A1 WO2020107341 A1 WO 2020107341A1 CN 2018118245 W CN2018118245 W CN 2018118245W WO 2020107341 A1 WO2020107341 A1 WO 2020107341A1
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layer
poly
width
microelectrode array
functionalized
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French (fr)
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杜学敏
王娟
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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
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G63/00—Macromolecular compounds obtained by reactions forming a carboxylic ester link in the main chain of the macromolecule
    • C08G63/02—Polyesters derived from hydroxycarboxylic acids or from polycarboxylic acids and polyhydroxy compounds
    • C08G63/06—Polyesters derived from hydroxycarboxylic acids or from polycarboxylic acids and polyhydroxy compounds derived from hydroxycarboxylic acids
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G63/00—Macromolecular compounds obtained by reactions forming a carboxylic ester link in the main chain of the macromolecule
    • C08G63/78—Preparation processes
    • C—CHEMISTRY; METALLURGY
    • C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
    • C09D—COATING COMPOSITIONS, e.g. PAINTS, VARNISHES OR LACQUERS; FILLING PASTES; CHEMICAL PAINT OR INK REMOVERS; INKS; CORRECTING FLUIDS; WOODSTAINS; PASTES OR SOLIDS FOR COLOURING OR PRINTING; USE OF MATERIALS THEREFOR
    • C09D105/00—Coating compositions based on polysaccharides or on their derivatives, not provided for in groups C09D101/00 or C09D103/00
    • C09D105/04—Alginic acid; Derivatives thereof
    • C—CHEMISTRY; METALLURGY
    • C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
    • C09D—COATING COMPOSITIONS, e.g. PAINTS, VARNISHES OR LACQUERS; FILLING PASTES; CHEMICAL PAINT OR INK REMOVERS; INKS; CORRECTING FLUIDS; WOODSTAINS; PASTES OR SOLIDS FOR COLOURING OR PRINTING; USE OF MATERIALS THEREFOR
    • C09D105/00—Coating compositions based on polysaccharides or on their derivatives, not provided for in groups C09D101/00 or C09D103/00
    • C09D105/08—Chitin; Chondroitin sulfate; Hyaluronic acid; Derivatives thereof
    • C—CHEMISTRY; METALLURGY
    • C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
    • C09D—COATING COMPOSITIONS, e.g. PAINTS, VARNISHES OR LACQUERS; FILLING PASTES; CHEMICAL PAINT OR INK REMOVERS; INKS; CORRECTING FLUIDS; WOODSTAINS; PASTES OR SOLIDS FOR COLOURING OR PRINTING; USE OF MATERIALS THEREFOR
    • C09D167/00—Coating compositions based on polyesters obtained by reactions forming a carboxylic ester link in the main chain; Coating compositions based on derivatives of such polymers
    • C09D167/04—Polyesters derived from hydroxycarboxylic acids, e.g. lactones
    • C—CHEMISTRY; METALLURGY
    • C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
    • C09D—COATING COMPOSITIONS, e.g. PAINTS, VARNISHES OR LACQUERS; FILLING PASTES; CHEMICAL PAINT OR INK REMOVERS; INKS; CORRECTING FLUIDS; WOODSTAINS; PASTES OR SOLIDS FOR COLOURING OR PRINTING; USE OF MATERIALS THEREFOR
    • C09D4/00—Coating compositions, e.g. paints, varnishes or lacquers, based on organic non-macromolecular compounds having at least one polymerisable carbon-to-carbon unsaturated bond ; Coating compositions, based on monomers of macromolecular compounds of groups C09D183/00 - C09D183/16

Definitions

  • the invention relates to a functionalized wide-width implantable microelectrode array and a preparation method thereof.
  • Nerve electrical stimulation therapy is a method of treating nerves by regulating nerves without damaging nerve tissue. It can play a role in treating or partially restoring nerve function. Because this method is safe and effective, for some special neurological diseases, the pacemaker, cochlear implant and artificial retina involved in this method are irreplaceable, and it has been successfully applied in clinical practice.
  • 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 narrow width electrode will also cause difficulties in the design and production of microelectrode sites, lines, and spacing on the electrode. This greatly increases the complexity of the microelectrode micromachining process, and the yield is very low.
  • the materials currently used in microelectrode arrays are poor in biocompatibility, the body is prone to rejection or immune reactions, and does not have anti-inflammatory functions, making it difficult to meet the effectiveness and safety of long-term implantation.
  • one of the objects of the present invention is to provide an implantable microelectrode array, in order to solve one or more of the above technical problems.
  • Another object of the present invention is to provide the application of the implantable microelectrode array.
  • Still another object of the present invention is to provide a method for manufacturing the above-mentioned implantable microelectrode array.
  • the present invention provides a functionalized wide-width microelectrode array, which includes a functional layer, a base layer, a conductive layer, and an insulating layer arranged in sequence; wherein, the functional layer is The thickness of the monomolecular layer, polymer material layer and/or polymer composite layer is 1 nm-1000 ⁇ m.
  • the functional layer and the conductive layer are located on both sides of the base layer, and the insulating layer is on the conductive layer.
  • the material is the same as the base layer. This insulating layer exposes the stimulation site (conductive) of the electrode for stimulation.
  • the biocompatibility of the microelectrode array can be improved.
  • the electrode deformation can be driven by the trigger of the polymer, and the addition of additional materials such as black phosphorus can be used to realize the controlled deformation by external field trigger similar to NIR light.
  • the functional layer is a monomolecular layer, and the monomolecular layer includes a monomolecular micro-nano structure layer formed by alkane, silane, or fluoroalkane treatment on the surface of the base layer.
  • the functional layer on the surface of the base layer is a monomolecular layer, and the monomolecular layer includes a monomolecular micro-nano structure layer formed by alkane, silane, or fluoroalkane treatment on the surface of the base layer , That is, design some microchannels, microarrays and other structures behind the electrode substrate.
  • the surface energy of the material on the back of the electrode can be reduced by the design of the monomolecular layer micro-nano structure, and the electrode can be deformed after encountering the liquid, so that the obtained implanted micro-electrode array has a shape adaptability change function.
  • tools help to fold or bend it before unfolding to achieve minimally invasive implantation, which can greatly reduce the risk of surgery.
  • the number of stimulation channels in the functionalized wide-width microelectrode array is 60-2400, the specific number can be selected according to need , For example 2000, 1024.
  • the functionalized wide-width microelectrode array is composed of a stimulation end, a lead portion, and a pad end.
  • the shape of the stimulation end may be any suitable shape, preferably rectangular, square, circular or irregular geometric shape.
  • the size of the stimulation end is preferably 0.1 cm-1.5 cm, wherein when the stimulation end is rectangular, its length is 0.1-1.5 cm, and its width is 0.1-1.5 cm.
  • the stimulation end includes multiple stimulation sites, and each stimulation site corresponds to a stimulation channel.
  • the size of a single stimulation site is 50 nm-5 mm (preferably 100 ⁇ m), and the distance between adjacent stimulation sites is 20 ⁇ m-1 mm (preferably 300 ⁇ m).
  • the shape of the stimulation site can be arbitrary, such as rectangle, circle, square and other irregular geometric shapes.
  • the above size range refers to its length and width of 50nm-5mm; when When the stimulation site is round or square, the above size range refers to the diameter or side length of 50nm-5mm; when the stimulation site is irregular shape, the above size range refers to the size of 50nm in any direction -5mm.
  • the lead portion may be rectangular; preferably, the rectangle has a length of 1 cm-15 cm and a width of 0.2 cm-2 cm.
  • the lead portion may include a plurality of leads, and the distance between adjacent leads is 1 ⁇ m to 1 mm.
  • the shape of the lead portion is the aggregate shape of the guide line. For example, the above-mentioned rectangle is a top view shape.
  • the size of the pad end can be 0.5mm-20cm.
  • the pad end may include a plurality of pads, the size of a single pad is 0.2mm-5mm, and the distance between adjacent pads is 20 ⁇ m-1mm.
  • the shape of the pad end may be any suitable shape, preferably rectangular, square, circular or irregular geometric shape. When the shape of the pad end is rectangular, its length is 0.5mm-20cm, and the width is 0.3mm-5cm; when the shape of the pad end is square, its side length is 0.5mm-20cm; when the shape of the pad end is round At this time, its diameter is 0.5mm-20cm.
  • the shape of a single pad can be arbitrary, such as rectangle, circle, square and other irregular geometric shapes.
  • the above size range refers to its length and width of 50nm-5mm; when soldering When the disk is circular or square, the above-mentioned size range refers to its diameter or side length of 50nm-5mm; when the pad is irregularly shaped, the above-mentioned size range refers to the size of 50nm-5mm in either direction.
  • the present invention breaks through the prejudice of the prior art that the width of the microelectrode array cannot be higher than 4.5mm, and provides a wide-width microelectrode array, which can greatly improve the resolution and reduce the processing of microelectrodes due to its increased width
  • the technological complexity of the process improves the yield.
  • the design of the functional layer the minimally invasive implantation of the traditional electrode and the controlled deformation after implantation to fit the three-dimensional curved tissue surface can be achieved, which reduces the operation.
  • the risk of implantation improves the information transmission efficiency of electrodes and biological tissues, thereby improving the reliability and effectiveness of long-term implantation of the device.
  • the thickness of the base layer is 3 ⁇ m-80 ⁇ m.
  • the material of the base layer is polyimide, parylene, polydimethylsiloxane, medical silica gel, polyurethane, polyethylene terephthalate One or a combination of several materials such as glycol esters, polylactic acid, polycaprolactone and their derivatives.
  • the thickness of the conductive layer is 20 nm-10 ⁇ m.
  • the material of the conductive layer is one or a combination of magnesium, gold, platinum, platinum-iridium alloy, gallium indium alloy, gallium indium tin alloy, and the like.
  • the polymer materials in the polymer material layer and the polymer composite layer as the functional layer are poly(N-isopropylacrylamide), poly(N -N-propyl acrylamide), poly(N-cyclopropyl acrylamide), poly(N-isopropyl methacrylamide), poly(N-ethyl acrylamide), poly(N-acryloxy -N-propylpiperazine), poly(N-(L)-(1-hydroxymethyl)propylmethacrylamide), poly[N-(2-methacryloyloxyethyl)pyrrolidone], Poly[N-(3-acryloyloxypropyl)pyrrolidone], poly[N-(3-methacryloyloxypropyl)pyrrolidone], poly[N-(2-acryloyloxypropyl)pyrrolidone], Poly[N-(1-methyl-2-acryloyloxyethacrylamide, poly(N-(2-methacryloyloxypropyl)pyr
  • the above polymer material is poly(N-isopropylacrylamide), polyvinyl alcohol, chitosan, polylactic acid, polyethylene glycol methacrylate, polyethylene glycol One or a combination of alcohol acrylate, matrigel, gelatin, alginic acid, collagen, etc. These materials have good biocompatibility characteristics, and can easily design related structures and functions.
  • the additional material other than the polymer material in the polymer composite layer as the functional layer is nano-gold, nano-silver, nano-copper, nano-platinum, nano-palladium , Nano germanium, carbon nanotubes, carbon black, black phosphorus, copper sulfide, molybdenum disulfide, graphene, bismuth selenide, polypyrrole, polyaniline, polyethylene dioxythiophene, polystyrene sulfonate, indocyanine Green, porphyrin liposomes, Fe 2 O 3 , Fe 3 O 4 , FeCo, NiFe, CoFeO, NiFeO, MnFeO, LaFeCoSi, GdSiGe, LaFe 11.6 Si 1.4 C 0.2 H 0.7 , La(Fe,Si) 13 , NiMnGa , MnCoGe 0.99 In 0.01
  • the polymer material layer and the polymer composite layer as the functional layer further contain anti-inflammatory drugs, and the anti-inflammatory drugs may include dexamethasone and prednisone , Baotaisong or anti-inflammatory peptides, etc.
  • the anti-inflammatory drugs are contained in the polymer material layer and the polymer composite layer, which can make the micro-electrode array have anti-inflammatory functions, reduce the immune inflammation problem after electrode implantation, and thereby improve the effectiveness and safety of long-term device implantation Sex.
  • the thickness of the insulating layer and the like and the size of other structures not limited can be controlled as needed.
  • the functionalized wide-width microelectrode array provided by the present invention has a large stimulation area and has a shape adaptability changing function: by increasing the size of the microelectrode, the number of arrays can be increased, and the resolution of the patient can be greatly improved; Folding or curling can realize the minimally invasive implantation of the electrode array, greatly reducing the risk of surgery; designing a layer of polymer material or polymer composite behind the microelectrode array can improve the biocompatibility of the electrode and can also achieve The functionalization of electrodes, such as loading anti-inflammatory drugs, improves the effectiveness and safety of long-term device implantation.
  • the invention also provides a method for preparing the functionalized wide-width microelectrode array, which includes the following steps:
  • the back surface of the microelectrode array (the surface on the side where the base layer is in contact with the functional layer) is processed by laser, and then a polymer material layer or a polymer composite layer is formed on the back surface of the microelectrode array to obtain the functionalized wide width Microelectrode array.
  • the step of forming the microelectrode array on the surface of the substrate is performed in the following manner:
  • the base material is coated and cured on the surface of the base to form a base layer
  • the second layer of base material is coated on the surface of the conductive layer and cured to form an insulating layer;
  • steps (1)-(5) are to prepare the micro-electrode array by means of micro-machining.
  • the micro-electrode array can also be formed by spraying, brushing or printing on the substrate.
  • the base layer can be formed by spin coating in step (1), and the conductive layer can be formed by magnetron sputtering/electron beam evaporation/printing/brush coating in step (3), step (4)
  • the insulating layer can be formed by spin coating.
  • etching can be performed by RIE to expose the stimulation sites and pads.
  • the Lift-Off method can be used.
  • the monomolecular micro-nano structure layer (ie, the monomolecular layer) is formed by performing alkane, silane, or fluoroalkane treatment on the surface of the base layer.
  • the polymer material layer and the polymer composite layer are formed by a chemical grafting method or a coating method; wherein, the chemical grafting method may be a condensation reaction or a copolymerization reaction
  • the polymer layer is grafted on the surface of the electrode to form a polymer layer;
  • the coating method may be a solution of a concentration of 0.1wt-50wt% prepared by a polymer material or a composite of a polymer material and an additional material, and then coated on The electrode surface is dried to obtain a polymer material layer or a polymer composite layer.
  • the invention also provides the application of the functionalized wide-width microelectrode array in the preparation of implantable artificial retina, implantable cochlear implant, implantable cardiac implantable dirty pacemaker and implantable deep brain stimulator.
  • the invention also provides a neural prosthesis, which includes the above-mentioned functionalized wide-width microelectrode array; the neural prosthesis is preferably an implantable artificial retina, an implantable cochlear implant, an implantable cardiac pacemaker or an implant Into the deep brain stimulator.
  • the functionalized wide-width microelectrode provided by the invention can not only realize the ultra-high density design of the electrode, but also can realize the minimally invasive implantation of the electrode (less than 5mm incision), and the electrode greatly increases the stimulation area after implantation, which can be widely It is used in the field of brain-computer interfaces such as artificial retinas, cochlear implants, cardiac pacemakers, and deep brain stimulators.
  • the scleral incision cannot be greater than 5mm, so there are specific restrictions on the size of the electrode during micromachining, for example, the width cannot be greater than 4.5mm.
  • the existing lithography technology can only be designed in the size of 4.5mm, lower resolution (small number of stimulation sites) is easier to achieve, and when the resolution is increased, for example, 1500 channels (more stimulation sites), Designing so many stimulation sites on such a small area requires that the size of each stimulation site and connection is particularly small, and when the size is less than the processing accuracy of the equipment (many times, due to equipment performance limitations and operator experience , The size of nearly 10 times the processing accuracy can not be designed), it is impossible to achieve high-density design. Therefore, due to the limitation of the processing method and the lack of the functional layer design in the present invention, the conventional electrode can only obtain a lower density electrode.
  • the present invention designs a functionalized wide-width microelectrode array, and the main beneficial effects are as follows:
  • microelectrode By increasing the size of the microelectrode, it can effectively adjust the microelectrode site, line, spacing and other related parameters, thereby reducing the complexity of the microelectrode micromachining process and greatly improving the yield of high-cost microelectrode arrays. Solve the design problems of high-density microelectrode arrays.
  • the biocompatibility of the electrode can be improved, and the electrode can also be functionalized, such as loading anti-inflammatory drugs to improve the long-term device The effectiveness and safety of the implant.
  • FIG. 1 is a schematic diagram of the structure of functionalized wide-width microelectrode arrays of Examples 1 and 2.
  • FIG. 1 is a schematic diagram of the structure of functionalized wide-width microelectrode arrays of Examples 1 and 2.
  • FIG. 2 is a schematic diagram of a 126-channel flexible functional electrode array in Example 2.
  • FIG. 2 is a schematic diagram of a 126-channel flexible functional electrode array in Example 2.
  • FIG. 3 is a schematic diagram of a 1024-channel flexible electrode array in Example 6.
  • FIG. 4 is a self-expanding deformation diagram and a microscope diagram of electrode circuits of the functional electrode array in Example 2.
  • FIG. 4 is a self-expanding deformation diagram and a microscope diagram of electrode circuits of the functional electrode array in Example 2.
  • Example 5 is a developed view of the curled state of the functional electrode of Example 2 and the use of 808 nm near-infrared illumination after implantation in the eyeball.
  • This embodiment provides an implantable microelectrode array, and its preparation method includes the following steps:
  • a layer of polyimide with a thickness of 10 ⁇ m was spin-coated on the surface of the 4-inch cleaned and dried silicon wafer (substrate), and then a layer of AZ5214 photoresist was spin-coated on the surface, and exposed and developed.
  • a gold layer with a thickness of 150 nm is formed by magnetron sputtering, and then a second layer of polyimide is spin-coated and cured, and the electrode stimulation sites and pad points are exposed by RIE etching, and the electrodes are removed from the substrate Release the upper part to obtain a 126-channel flexible electrode array.
  • the back surface of the obtained electrode was first treated with plasma for 3 minutes, and then exposed to a steam atmosphere of fluorosilane for 5 minutes to obtain a functionalized wide-width electrode treated with fluorinated monolayers.
  • the implantable microelectrode array includes a stimulation end, a lead portion, and a pad end.
  • the stimulation end is rectangular, the size is 1.2 cm wide x 0.5 cm long, the diameter of a single stimulation site in the stimulation end is 150 ⁇ m, the distance between the stimulation sites is 600 ⁇ m, and the number of stimulation channels is 126.
  • the lead part has a rectangular shape with a length of 4 cm, a width of 0.4 cm, and a lead pitch of 8 ⁇ m.
  • the maximum side length of the electrode pad end is 1.1 cm, the minimum side length is 0.6 cm, the diameter of a single pad is 100 ⁇ m, the pad site spacing is 400 ⁇ m, and the number of pads is 126.
  • This embodiment provides an implantable microelectrode array, and its preparation method includes the following steps:
  • a layer of polyimide (substrate layer) is spin-coated on the surface of the 4-inch cleaned and dried silicon wafer (substrate), and then a layer of AZ5214 photoresist is spin-coated on the surface, and exposed and developed.
  • a layer of gold with a thickness of 120 nm was formed by magnetron sputtering, and then a second layer of polyimide was spin-coated and cured.
  • the electrode stimulation sites and pad points were exposed by RIE etching, and the electrodes were removed from the substrate Release the upper part to obtain a 126-channel flexible electrode array.
  • microelectrode array obtained above was treated with vinyl silane to treat the back surface of polyimide (base layer), and the caprolactone monomer mixed with black phosphorus was induced to copolymerize with vinyl silane by gamma rays for 30 minutes, thereby achieving chemical grafting Finally, a polycaprolactone copolymer layer was grafted and copolymerized on the back of the electrode, and the obtained functional electrode array is shown in FIG. 2.
  • the implantable microelectrode array includes a stimulation end, a lead portion, and a pad end.
  • the stimulation end is rectangular, the size is 1.2 cm wide x 0.5 cm long, the diameter of a single stimulation site in the stimulation end is 150 ⁇ m, the distance between the stimulation sites is 600 ⁇ m, and the number of stimulation channels is 126.
  • the lead part has a rectangular shape with a length of 4 cm, a width of 0.4 cm, and a lead pitch of 8 ⁇ m.
  • the maximum side length of the pad end is 1.1 cm, the minimum side length is 0.6 cm, the diameter of a single pad is 100 ⁇ m, the pad site spacing is 400 ⁇ m, and the number of pads is 126.
  • FIG. 4 is a self-expanding deformation diagram and an electrode circuit microscope diagram of the functional electrode array of this embodiment, wherein the following two pictures are the metal circuit microscope diagrams corresponding to the curling of the stimulation end and the unfolding, from which the curling process can be seen No loss of electrode wiring.
  • FIG. 5 is a diagram showing the effect of the electrode curling state and the expansion caused by light after implantation in the eyeball. It can be seen from Fig. 5 that the functional electrode is in a curled state before implantation and has a small size, and can be easily implanted in the eyeball. After implanting the eyeball, the functional electrode can be automatically deployed by irradiating with 808nm near infrared light.
  • a polycaprolactone copolymer layer is copolymerized on the back of the microelectrode array, which can improve the biocompatibility of the electrode.
  • This embodiment provides an implantable microelectrode array, and its preparation method includes the following steps:
  • a layer of polyimide with a thickness of 10 ⁇ m was spin-coated on the surface of the 4-inch cleaned and dried silicon wafer, and then a layer of AZ5214 photoresist was spin-coated on the surface, and exposed and developed.
  • a platinum layer with a thickness of 120 nm was formed by magnetron sputtering, and then a second layer of polyimide with a thickness of 8 ⁇ m was spin-coated and cured. After the electrode site was exposed by RIE etching, the electrode was removed from The substrate was released and a 256-channel flexible electrode array was obtained.
  • a functional layer of polyethylene glycol with a thickness of 100 ⁇ m is coated on the back of the electrode.
  • the structure of the implantable microelectrode array obtained in this embodiment includes a stimulation end, a lead part and a pad end.
  • the stimulation end is circular with a diameter of 0.8 cm.
  • the diameter of a single stimulation site in the stimulation end is 145 ⁇ m, the distance between the stimulation sites is 600 ⁇ m, and the number of stimulation channels is 256.
  • the lead part has a rectangular shape with a length of 4 cm, a width of 0.4 cm, and a lead pitch of 8 ⁇ m.
  • the maximum side length of the electrode pad end is 1.2 cm, the minimum side length is 0.6 cm, the diameter of a single pad is 100 ⁇ m, the pad site spacing is 400 ⁇ m, and the number of pads is 256.
  • This embodiment provides an implantable microelectrode array, and its preparation method includes the following steps:
  • a layer of polyimide with a thickness of 10 ⁇ m was spin-coated on the surface of the 4-inch cleaned and dried silicon wafer, and then a layer of AZ5214 photoresist was spin-coated on the surface, and exposed and developed.
  • a platinum layer with a thickness of 120 nm was formed by magnetron sputtering, and then a second layer of polyimide with a thickness of 8 ⁇ m was spin-coated and cured. After the electrode site was exposed by RIE etching, the electrode was removed from The substrate was released and a 256-channel flexible electrode array was obtained.
  • the back of the electrode was treated with plasma, and the electrode was fixed on the LBL device by the LBL method.
  • the process of repeated immersion in sodium alginate solution-extraction-immersion in chitosan solution was controlled by programming, and then a layer with a thickness of 100 ⁇ m was grafted on the back of the electrode Sodium alginate/chitosan composite hydrogel layer.
  • the structure of the implantable microelectrode array obtained in this embodiment includes a stimulation end, a lead part and a pad end.
  • the stimulation end is circular with a diameter of 0.8 cm.
  • the diameter of a single stimulation site in the stimulation end is 145 ⁇ m, the distance between the stimulation sites is 600 ⁇ m, and the number of stimulation channels is 256.
  • the lead portion is rectangular, for example, the rectangle has a length of 4 cm, a width of 0.4 cm, and a lead pitch of 8 ⁇ m.
  • the maximum side length of the pad end is 1.2cm, the minimum side length is 0.6cm, the diameter of a single pad is 100 ⁇ m, the pad site spacing is 400 ⁇ m, and the number of pads is 256.
  • This embodiment provides an implantable microelectrode array, and its preparation method includes the following steps:
  • a layer of polydimethylsiloxane with a thickness of 20 ⁇ m was spin-coated on the surface of the 4-inch cleaned and dried silicon wafer, and then a layer of AZ5214 photoresist was spin-coated on the surface, and exposed and developed.
  • a platinum layer with a thickness of 120 nm was formed by magnetron sputtering, and then a second layer of polydimethylsiloxane with a thickness of 10 ⁇ m was spin-coated and cured. After the electrode sites were exposed by RIE etching, The electrodes were released from the substrate to obtain a 256-channel flexible electrode array.
  • a functional layer of polyvinyl alcohol with a thickness of 150 ⁇ m is coated on the back of the electrode.
  • the structure of the implantable microelectrode array obtained in this embodiment includes a stimulation end, a lead part and a pad end.
  • the stimulation end is circular with a diameter of 0.8 cm.
  • the diameter of a single stimulation site in the stimulation end is 145 ⁇ m, the distance between the stimulation sites is 600 ⁇ m, and the number of stimulation channels is 256.
  • the lead part has a rectangular shape with a length of 4 cm, a width of 0.4 cm, and a lead pitch of 8 ⁇ m.
  • the maximum side length of the pad end is 1.2cm, the minimum side length is 0.6cm, the diameter of a single pad is 100 ⁇ m, the pad site spacing is 400 ⁇ m, and the number of pads is 256.
  • This embodiment provides an implantable microelectrode array, and its preparation method includes the following steps:
  • N-isopropylacrylamide functional layer After plasma treatment on the back of the electrode for 5 minutes, and then reacting with vinyl silane for 30 minutes, polymerizing it with N-isopropylacrylamide prepolymerization solution under ultraviolet light for 60 minutes, a layer with a thickness of 150 ⁇ m can be obtained N-isopropylacrylamide functional layer.
  • the structure of the implantable microelectrode array obtained in this embodiment is shown in FIG. 3, and the structure of the embedded microelectrode array includes a stimulation end, a lead portion and a pad end.
  • the stimulation end is rectangular, with a length of 1.2 cm and a width of 0.5 cm.
  • the diameter of a single stimulation site in the stimulation end is 120 ⁇ m, the distance between the stimulation sites is 220 ⁇ m, and the number of stimulation channels is 1024.
  • the lead part has a rectangular shape with a length of 4 cm, a width of 0.4 cm, and a lead pitch of 6 ⁇ m.
  • the maximum side length of the pad end is 1.2 cm, the minimum side length is 0.6 cm, the diameter of a single pad is 100 ⁇ m, the pad site spacing is 400 ⁇ m, and the number of pads is 1024.
  • This embodiment provides an implantable microelectrode array, and its preparation method includes the following steps:
  • a layer of Parylene with a thickness of 10 ⁇ m is deposited on the surface of the 4-inch cleaned and dried silicon wafer, and then a layer of AZ5214 photoresist is spin-coated on the surface, and exposed and developed.
  • a layer of magnesium was formed by 3D printing, and then a second layer of Parylene with a thickness of 10 ⁇ m was deposited. After the electrode sites were exposed by RIE etching, the electrodes were released from the substrate to obtain a 60-channel flexible electrode array.
  • the structure of the implantable microelectrode array obtained in this embodiment includes a stimulation end, a lead part and a pad end.
  • the stimulation end is rectangular, with a length of 0.7 cm and a width of 0.5 cm.
  • the diameter of a single stimulation site in the stimulation end is 300 ⁇ m, the distance between the stimulation sites is 450 ⁇ m, and the number of stimulation channels is 60.
  • the lead portion has a rectangular shape with a length of 4 cm, a width of 0.4 cm, and a lead pitch of 50 ⁇ m.
  • the maximum side length of the pad end is 1 cm, the minimum side length is 0.6 cm, the diameter of a single pad is 200 ⁇ m, the pad site spacing is 360 ⁇ m, and the number of pads is 60.
  • This embodiment provides an implantable microelectrode array, and its preparation method includes the following steps:
  • a layer of polylactic acid with a thickness of 30 ⁇ m was spin-coated on the surface of the 4-inch cleaned and dried silicon wafer, and then a layer of AZ5214 photoresist was spin-coated on the surface, and exposed and developed.
  • a layer of gallium indium was formed by brush coating, and then a second layer of polylactic acid with a thickness of 10 ⁇ m was spin-coated.
  • the electrode site was exposed by RIE etching, the electrode was released from the substrate to obtain a 60-channel flexible electrode In the array, the electrode stimulation end is rectangular, with a length of 0.7cm and a width of 0.5cm.
  • the structure of the implantable microelectrode array obtained in this embodiment includes a stimulation end, a lead part and a pad end.
  • the stimulation end is rectangular, with a length of 0.7 cm and a width of 0.5 cm.
  • the diameter of a single stimulation site in the stimulation end is 300 ⁇ m, the distance between the stimulation sites is 450 ⁇ m, and the number of stimulation channels is 60.
  • the lead portion has a rectangular shape with a length of 4 cm, a width of 0.4 cm, and a lead pitch of 50 ⁇ m.
  • the maximum side length of the pad end is 1 cm, the minimum side length is 0.6 cm, the diameter of a single pad is 200 ⁇ m, the pad site spacing is 360 ⁇ m, and the number of pads is 60.

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Abstract

提供一种功能化宽幅植入式微电极阵列及其制备方法与应用。该功能化宽幅微电极阵列包括依次设置的功能层、基底层、导电层、绝缘层；所述功能层为单分子层、高分子材料层和/或高分子复合物层，厚度为1nm-1000μm。还提供了上述功能化宽幅植入式微电极阵列的制备方法及其在制备神经假体中的应用。

Description

一种功能化宽幅植入式微电极阵列及其制备方法与应用 技术领域
本发明涉及一种功能化宽幅植入式微电极阵列及其制备方法。
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的方法，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、有效等特点，对于某些特殊的神经系统疾病来说，该方法所涉及的心脏起搏器、人工耳蜗和人造视网膜等是无可替代的，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发展，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，其中困难之一就是器件的功能化设计。以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，因此不仅极大增大手术植入风险，同时由于电极阵列通道少，形成影像的分辨率较低，并且只能获得管状视野。另外，神经电极的生物相容性也是另一大挑战，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。而且，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。
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，以人造视网膜为例，其 中困难之一在于难以获得高分辨率微电极阵列，其主要原因在于将微电极阵列植入到视网膜时，手术切口必须保证在5mm以下，过大的切口会对生物组织的正常功能造成很大的破坏，因此，电极尺寸的设计对宽度有严格的要求，为此，本领域长期以来都是将微电极阵列的宽度限定在4.5mm以下，在如此窄幅的面积上很难获得高分辨率微电极，同时，窄幅电极还会造成电极上微电极位点、线路、间距设计及制作上的困难，大大增加了微电极微加工过程中的工艺复杂程度，良品率非常低。此外，目前微电极阵列所采用的材料生物相容性差，机体容易产生排斥或免疫反应，并且不具有抗炎功能，难以满足长期植入的有效性和安全性。
为此，本领域亟需开发一种高分辨率微电极阵列，以期有效改善患者获得的影像质量，降低微电极加工过程的工艺复杂程度，提高良品率，提高微电极阵列的长期植入性。
发明内容
有鉴于此，本发明的目的之一在于提供一种植入式微电极阵列，以期能解决上述技术问题中的一个或多个。
本发明的另一目的在于提供上述植入式微电极阵列的应用。
本发明的再一目的在于提供上述植入式微电极阵列的制备方法。
为实现上述目的，本发明提供了一种功能化宽幅微电极阵列，该功能化宽幅微电极阵列包括依次设置的功能层、基底层、导电层、绝缘层；其中，所述功能层为单分子层、高分子材料层和/或高分子复合物层，厚度为1nm-1000μm。功能层和导电层分别位于基底层的两侧表面，绝缘层位于导电层之上，其材料与基底层一样，这层绝缘层会把电极的刺激位点(导电)暴露出来用于刺激。
通过在微电极阵列背后结合一层高分子材料和/或高分子复合物材料，能够提高微电极阵列的生物相容性。通过高分子材料层、高分复合物材料层的设计，可以通过高分子的触发带动电极形变，而通过能附加材料如黑磷等的加入，可以实现通过类似NIR光等外场触发可控形变。
根据本发明的具体实施方案，优选地，所述功能层为单分子层，该单分子层包括对基底层表面进行烷烃、硅烷烃或氟烷烃处理形成的单分子微纳结构层。在本发明的功能化宽幅微电极阵列中，基底层表面的功能层为单分子层，该单分子层包括对基底层表面进行烷烃、硅烷烃或氟烷烃处理形成的单分子微纳结构层，即在电极基底背后设计一些微通道、微阵列等结构。通过这种方式通过单分子层微纳结构设计可以降低电极背面材质的表面能，可实现电极遇到液体后发生形变，使所获得的植入式微电极阵列具有形状 适应性改变功能，可通过手工或工具辅助将其折叠或弯曲后再展开，实现微创植入，这能够极大地降低手术风险。
根据本发明的具体实施方案，优选地，在本发明的功能化宽幅微电极阵列中，该功能化宽幅微电极阵列中的刺激通道的数量为60-2400，具体数量可以根据需要进行选择，例如2000、1024。
根据本发明的具体实施方案，优选地，该功能化宽幅微电极阵列由刺激端、引线部分和焊盘端组成。
根据本发明的具体实施方案，刺激端的形状可以是任何适当的形状，优选为长方形、正方形、圆形或不规则几何形状。刺激端的尺寸优选为0.1cm-1.5cm，其中，当刺激端为长方形时，其长度为0.1-1.5cm，宽度为0.1-1.5cm。刺激端包括多个刺激位点，每一个刺激位点对应一个刺激通道，单个刺激位点的尺寸为50nm-5mm(优选100μm)，相邻刺激位点的间距为20μm-1mm(优选300μm)。刺激位点的形状可以是任意的，例如长方形、圆形、正方形以及其他不规则的几何形状，当刺激位点为长方形时，上述尺寸范围指的是其长度、宽度分别为50nm-5mm；当刺激位点为圆形或正方形时，上述尺寸范围指的是其直径或边长为50nm-5mm；当刺激位点为不规则形状时，上述尺寸范围指的是其任一方向上的尺寸为50nm-5mm。引线部分可以为长方形；优选地，该长方形的长为1cm-15cm，宽为0.2cm-2cm。该引线部分可以包括多条引线，相邻引线的间距为1μm-1mm。引线部分的形状是指引线的集合体形状，例如，上述长方形是顶视图形状。焊盘端的尺寸可以为0.5mm-20cm。焊盘端可以包括多个焊盘，单个焊盘的尺寸为0.2mm-5mm，相邻焊盘的间距为20μm-1mm。焊盘端的形状可以是任何适当的形状，优选为长方形、正方形、圆形或不规则几何形状。当焊盘端的形状为长方形时，其长为0.5mm-20cm，宽为0.3mm-5cm；当焊盘端的形状为正方形时，其边长为0.5mm-20cm；当焊盘端的形状为圆形时，其直径为0.5mm-20cm。单个焊盘的形状可以是任意的，例如长方形、圆形、正方形以及其他不规则的几何形状，当焊盘为长方形时，上述尺寸范围指的是其长度、宽度分别为50nm-5mm；当焊盘为圆形或正方形时，上述尺寸范围指的是其直径或边长为50nm-5mm；当焊盘为不规则形状时，上述尺寸范围指的是其任一方向上的尺寸为50nm-5mm。
本发明一方面突破了现有技术对微电极阵列宽度不能高于4.5mm的偏见，提供了一种宽幅微电极阵列，由于其宽度增大，可极大的提高分辨率，降低微电极加工过程的工艺复杂程度，提高良品率；另一方面，通过功能层的设计，可以实现传统电极的微创 植入，及植入后的可控形变以贴合三维曲面组织表面，既降低了手术植入风险，又提高了电极与生物组织的信息传递效率，进而提高器件长期植入的可靠性与有效性。
在本发明的功能化宽幅微电极阵列中，优选地，所述基底层的厚度为3μm-80μm。
在本发明的功能化宽幅微电极阵列中，优选地，基底层的材料为聚酰亚胺、聚对二甲苯、聚二甲基硅氧烷、医用硅胶、聚氨酯、聚对苯二甲酸乙二醇酯、聚乳酸、聚己内酯等材料及其衍生物等中的一种或几种的组合。
在本发明的功能化宽幅微电极阵列中，优选地，所述导电层的厚度为20nm-10μm。
在本发明的功能化宽幅微电极阵列中，优选地，导电层的材料为镁、金、铂、铂铱合金、镓铟合金、镓铟锡合金等中的一种或几种的组合。
在本发明的功能化宽幅微电极阵列中，优选地，作为功能层的高分子材料层和高分子复合物层中的高分子材料为聚(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、聚乳酸、聚乙醇酸、聚乳酸-羟基乙酸共聚物等材料及其衍生物等中的一种或几种的组合。
根据本发明的具体实施方案，优选地，上述高分子材料为聚(N-异丙基丙烯酰胺)、聚乙烯醇、壳聚糖、聚乳酸、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、胶原等中的一种或几种的组合。这些材料有较好的生物相容特性，并能容易设计相关结构和功能。
在本发明的功能化宽幅微电极阵列中，优选地，作为功能层的高分子复合物层中的除高分子材料以外的附加材料为纳米金、纳米银、纳米铜、纳米铂、纳米钯、纳米锗、碳纳米管、炭黑、黑磷、硫化铜、二硫化钼、石墨烯、硒化铋、聚吡咯、聚苯胺、聚乙烯二氧噻吩、聚苯乙烯磺酸盐、吲哚菁绿、卟啉脂质体、Fe 2O 3、Fe 3O 4、FeCo、NiFe、CoFeO、NiFeO、MnFeO、LaFeCoSi、GdSiGe、LaFe 11.6Si 1.4C 0.2H 0.7、La(Fe,Si) 13、NiMnGa、MnCoGe 0.99In 0.01、MnCo 0.98Cr 0.02Ge及其复合材料等中的一种或几种的组合。
在本发明的功能化宽幅微电极阵列中，优选地，作为功能层的高分子材料层和高分子复合物层还含有含抗炎药物，该抗炎药物可以包括地塞米松、强的松、保泰松或抗炎性多肽等。在高分子材料层和高分子复合物层中含抗炎药物，可以使微电极阵列具有抗炎功能，降低电极植入后的免疫炎症问题，据此可提高器件长期植入的有效性和安全性。
在本发明的功能化宽幅微电极阵列中，绝缘层等的厚度以及未予以限定的其他结构的尺寸可以根据需要进行控制。
本发明提供的功能化宽幅微电极阵列具有较大的刺激区域，且具备形状适应性改变功能：通过增大微电极尺寸从而可以增加阵列数，极大提高患者分辨率；通过将宽幅电极折叠或卷曲，可以实现电极阵列的微创植入，极大降低手术风险；在微电极阵列背后设计上一层高分子材料或高分子复合物，可以提高电极的生物相容性，还可以实现电极的功能化，如负载抗炎症药物，提高器件长期植入的有效性和安全性。
本发明还提供了上述功能化宽幅微电极阵列的制备方法，其包括以下步骤：
在基底表面形成微电极阵列，并将微电极阵列与基底分离；
通过激光对微电极阵列的背面(基底层与功能层接触的那一侧表面)进行处理，然后在微电极阵列的背面形成高分子材料层或者高分子复合物层，得到所述功能化宽幅微 电极阵列。
在上述制备方法中，优选地，在基底表面形成微电极阵列的步骤按照以下方式进行：
(1)在基底表面涂布基底材料并固化，形成基底层；
(2)在基底层表面涂布光刻胶并曝光显影，形成显影层；
(3)在显影层表面形成导电层，同时去除显影层；
(4)在导电层表面涂布第二层基底材料并固化，形成绝缘层；
(5)通过刻蚀暴露出刺激位点和焊盘，得到微电极阵列。
上述步骤(1)-(5)是通过微加工的方式来制备微电极阵列，除此之外，还可以通过在基底上通过喷涂、刷涂或打印的方式形成微电极阵列。
在上述制备方法中，步骤(1)可以通过旋涂的方式形成基底层，步骤(3)中可以通过磁控溅射/电子束蒸发/打印/刷涂等方式形成导电层，步骤(4)中可以通过旋涂的方式形成绝缘层，步骤(5)中可以通过RIE进行刻蚀以暴露刺激位点和焊盘点，将微电极阵列与基底分离时可以采用Lift-Off法。
在上述制备方法中，优选地，所述单分子微纳结构层(即单分子层)是通过对基底层表面进行烷烃、硅烷烃或氟烷烃处理形成。
在上述制备方法中，优选地，所述高分子材料层和高分子复合物层是通过化学接枝法或涂覆法形成的；其中，所述化学接枝法可以是通过缩合反应或共聚反应的方式在电极的表面接枝形成高分子层；所述涂覆法可以是通过高分子材料或者高分子材料与附加材料的复合物配成浓度为0.1wt-50wt％的溶液，然后涂覆在电极表面并干燥而获得高分子材料层或高分子复合物层。
本发明还提供了上述功能化宽幅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。
本发明还提供了一种神经假体，其包括上述功能化宽幅微电极阵列；所述神经假体优选为植入式人造视网膜、植入式人工耳蜗、植入式心脏起博器或植入式深脑刺激器。
本发明提供的功能化宽幅微电极不仅可以实现电极的超高密度设计，同时还可以实现电极的微创植入(小于5mm切口)，以及植入后电极极大增大刺激区域，可广泛应用于人造视网膜、人工耳蜗、心脏起搏器、深脑刺激器等脑机接口领域。
由于临床眼科手术植入要求，巩膜切口不能大于5mm，因此对微加工过程中电极的尺寸有特定限制，例如宽度不能大于4.5mm。然而现有的光刻技术只能在4.5mm的尺寸上进行设计，较低分辨率(刺激位点数量少)比较容易实现，而当分辨率提高例如 1500通道(刺激位点数量多)时，在这么小的面积上设计这么多刺激位点，就要求每个刺激位点和连线的尺寸都特别小，而当尺寸小于设备的加工精度时(很多时候，由于设备性能限制及操作人员经验，在近10倍加工精度的尺寸都没法设计出来)，就无法实现高密度设计了。因此，传统电极由于加工方法限制，而又欠缺本发明中的功能层设计，因此只能获得较低密度电极。而本发明设计出一种功能化宽幅微电极阵列，主要有益效果如下：
(1)通过增大微电极尺寸，能够有效调节微电极位点、线路、间距等相关参数，从而降低微电极微加工过程中的工艺复杂程度，极大提高高成本微电极阵列的良品率，解决高密度微电极阵列的设计难题。
(2)通过增大微电极尺寸，能够有效调节微电极位点、线路、间距等相关参数，优化电极阻抗，解决刺激位点间的串扰问题，实现安全、有效电生理刺激。
(3)通过功能化宽幅设计，能够实现微电极阵列折叠或卷曲功能，从而实现微创植入，极大降低手术风险。
(4)通过在微电极阵列背后设计上一层高分子材料层或高分子复合物层，能够提高电极的生物相容性，还能够实现电极的功能化，例如负载抗炎症药物，提高器件长期植入的有效性和安全性。
附图说明
图1是实施例1和2的功能化宽幅微电极阵列的结构示意图。
图2是实施例2中的126通道的柔性功能电极阵列示意图。
图3是实施例6中的1024通道的柔性电极阵列示意图。
图4是实施例2中的功能电极阵列的自展开形变图及电极线路显微镜图。
图5是实施例2的功能电极卷曲状态及植入眼球后采用808nm近红外光照致展开图。
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
本实施例提供一种植入式微电极阵列，其制备方法包括如下步骤：
在4寸清洗并烘干后的硅片(基底)表面旋涂一层厚度为10μm的聚酰亚胺，随后在其表面旋涂上一层AZ5214光刻胶，并曝光显影。紧接着，通过磁控溅射形成一层厚度为150nm的金层，随后旋涂上第二层聚酰亚胺并固化，通过RIE刻蚀暴露出电极刺激位点和焊盘点，将电极从基底上释放下来，获得126通道柔性电极阵列。
将所得到电极背面先采用plasma处理3min，然后将其暴露在氟硅烷的蒸汽氛围中5min，即获得氟化单分子层处理的功能化宽幅电极。
本实施例获得的植入式微电极阵列的结构如图1所示，该植入式微电极阵列包括刺激端、引线部分及焊盘端。刺激端为长方形，尺寸为宽1.2cm×长0.5cm，在刺激端内的单个刺激位点直径为150μm，刺激位点间距为600μm，刺激通道数为126。引线部分为长方形，该长方形的长为4cm，宽为0.4cm，引线间距为8μm。电极焊盘端的最大边长为1.1cm，最小边长为0.6cm，单个焊盘直径为100μm，焊盘位点间距为400μm，焊盘数量为126。
实施例2
本实施例提供一种植入式微电极阵列，其制备方法包括如下步骤：
在4寸清洗并烘干后的硅片(基底)表面旋涂一层聚酰亚胺(基底层)，随后在其表面旋涂上一层AZ5214光刻胶，并曝光显影。紧接着，通过磁控溅射形成一层厚度为120nm的金层，随后旋涂上第二层聚酰亚胺并固化，通过RIE刻蚀暴露出电极刺激位点和焊盘点，将电极从基底上释放下来，获得126通道柔性电极阵列。
将上述所得到的微电极阵列通过乙烯基硅烷处理聚酰亚胺(基底层)背面，通过伽玛射线引发混有黑磷的己内酯单体与乙烯基硅烷共聚30min，进而实现化学接枝，最终在电极背面上接枝共聚一层聚己内酯共聚物层，所获得功能电极阵列如图2所示。
本实施例获得的植入式微电极阵列的结构如图1所示，该植入式微电极阵列包括刺激端、引线部分及焊盘端。刺激端为长方形，尺寸为宽1.2cm×长0.5cm，在刺激端内的单个刺激位点直径为150μm，刺激位点间距为600μm，刺激通道数为126。引线部分为长方形，该长方形的长为4cm，宽为0.4cm，引线间距为8μm。焊盘端的最大边长为1.1cm，最小边长为0.6cm，单个焊盘直径为100μm，焊盘位点间距为400μm，焊盘数量为126。
图4为本实施例的功能电极阵列的自展开形变图及电极线路显微镜图，其中，下面的两幅图是刺激端卷曲与展开时对应的金属线路显微镜图，由该图可以看出卷曲过程不会损失电极线路。
图5为电极卷曲状态与植入眼球后采用光照致展开的效果图。由图5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，通过采用808nm近红外光进行照射，可以使功能电极自动展开。
该微电极阵列的背面接枝有共聚一层聚己内酯共聚物层，能够提高电极的生物相容性。
实施例3
本实施例提供一种植入式微电极阵列，其制备方法包括如下步骤：
在4寸清洗并烘干后的硅片表面旋涂一层厚度为10μm的聚酰亚胺，随后在其表面旋涂上一层AZ5214光刻胶，并曝光显影。紧接着，通过磁控溅射形成一层厚度为120nm的铂层，随后旋涂上第二层厚度为8μm的聚酰亚胺并固化，通过RIE刻蚀暴露出电极位点后，将电极从基底上释放下来，获得256通道柔性电极阵列。
进一步地，在电极背面涂覆上一层厚度为100μm的聚乙二醇功能层。
本实施例获得的植入式微电极阵列的结构包括刺激端、引线部分及焊盘端。刺激端为圆形，直径为0.8cm，在刺激端内的单个刺激位点直径为145μm，刺激位点间距为600μm，刺激通道数为256。引线部分为长方形，该长方形的长为4cm，宽为0.4cm，引线间距为8μm。电极焊盘端的最大边长为1.2cm，最小边长为0.6cm，单个焊盘直径为100μm，焊盘位点间距为400μm，焊盘数量为256。
实施例4
本实施例提供一种植入式微电极阵列，其制备方法包括如下步骤：
在4寸清洗并烘干后的硅片表面旋涂一层厚度为10μm的聚酰亚胺，随后在其表面旋涂上一层AZ5214光刻胶，并曝光显影。紧接着，通过磁控溅射形成一层厚度为120nm的铂层，随后旋涂上第二层厚度为8μm的聚酰亚胺并固化，通过RIE刻蚀暴露出电极位点后，将电极从基底上释放下来，获得256通道柔性电极阵列。
将电极背面通过plasma处理，采用LBL方法将电极固定在LBL设备上，通过程序化控制重复浸入海藻酸钠溶液-提取-浸入壳聚糖溶液过程，进而在电极背面上接枝一层厚度为100μm的海藻酸钠/壳聚糖复合水凝胶层。
本实施例获得的植入式微电极阵列的结构包括刺激端、引线部分及焊盘端。刺激端为圆形，直径为0.8cm，在刺激端内的单个刺激位点直径为145μm，刺激位点间距为600μm，刺激通道数为256。所述引线部分为长方形，例如，该长方形的长为4cm，宽为0.4cm，引线间距为8μm。焊盘端的最大边长为1.2cm，最小边长为0.6cm，单个焊盘直径为100μm，焊盘位点间距为400μm，焊盘数量为256。
实施例5
本实施例提供一种植入式微电极阵列，其制备方法包括如下步骤：
在4寸清洗并烘干后的硅片表面旋涂一层厚度为20μm的聚二甲基硅氧烷，随后在其表面旋涂上一层AZ5214光刻胶，并曝光显影。紧接着，通过磁控溅射形成一层厚度为120nm的铂层，随后旋涂上第二层厚度为10μm的聚二甲基硅氧烷并固化，通过RIE刻蚀暴露出电极位点后，将电极从基底上释放下来，获得256通道柔性电极阵列。
进一步地，在电极背面涂覆上一层厚度为150μm的聚乙烯醇功能层。
本实施例获得的植入式微电极阵列的结构包括刺激端、引线部分及焊盘端。刺激端为圆形，直径为0.8cm，在刺激端内的单个刺激位点直径为145μm，刺激位点间距为600μm，刺激通道数为256。引线部分为长方形，该长方形的长为4cm，宽为0.4cm，引线间距为8μm。焊盘端的最大边长为1.2cm，最小边长为0.6cm，单个焊盘直径为100μm，焊盘位点间距为400μm，焊盘数量为256。
实施例6
本实施例提供一种植入式微电极阵列，其制备方法包括如下步骤：
在4寸清洗并烘干后的硅片表面沉积上一层厚度为10μm的聚对二甲苯(Parylene)，随后在其表面旋涂上一层AZ5214光刻胶，并曝光显影。紧接着，通过磁控溅射形成一层厚度为160nm的铂铱层，随后沉积上第二层厚度为10μm的Parylene，通过RIE刻蚀暴露出电极位点后，将电极从基底上释放下来，获得1024通道柔性电极阵列。
进一步地，对电极背面进行plasma处理5min，再与乙烯基硅烷反应30min后，将其与N-异丙基丙烯酰胺预聚液至于紫外光下聚合60min，即可获得一层厚度为150μm的聚N-异丙基丙烯酰胺功能层。
本实施例获得的植入式微电极阵列的结构如图3所示，该入式微电极阵列的结构包括刺激端、引线部分及焊盘端。刺激端为长方形，长为1.2cm，宽为0.5cm，在刺激端内的单个刺激位点直径为120μm，刺激位点间距为220μm，刺激通道数为1024。引线部分为长方形，该长方形的长为4cm，宽为0.4cm，引线间距为6μm。焊盘端的最大边长为1.2cm，最小边长为0.6cm，单个焊盘直径为100μm，焊盘位点间距为400μm，焊盘数量为1024。
实施例7
本实施例提供一种植入式微电极阵列，其制备方法包括如下步骤：
在4寸清洗并烘干后的硅片表面沉积上一层厚度为10μm的Parylene，随后在其表 面旋涂上一层AZ5214光刻胶，并曝光显影。紧接着，通过3D打印形成一层镁层，随后沉积上第二层厚度为10μm的Parylene，通过RIE刻蚀暴露出电极位点后，将电极从基底上释放下来，获得60通道柔性电极阵列。
进一步地，对电极背面进行plasma处理5min，再与乙烯基硅烷反应30min后，将其与丙烯磺酸钠预聚液至于紫外光下聚合60min，即可获得一层厚度为150μm的聚丙烯磺酸钠功能层。
本实施例获得的植入式微电极阵列的结构包括刺激端、引线部分及焊盘端。刺激端为长方形，长为0.7cm，宽为0.5cm，在刺激端内的单个刺激位点直径为300μm，刺激位点间距为450μm，刺激通道数为60。引线部分为长方形，该长方形的长为4cm，宽为0.4cm，引线间距为50μm。焊盘端的最大边长为1cm，最小边长为0.6cm，单个焊盘直径为200μm，焊盘位点间距为360μm，焊盘数量为60。
实施例8
本实施例提供一种植入式微电极阵列，其制备方法包括如下步骤：
在4寸清洗并烘干后的硅片表面旋涂上一层厚度为30μm的聚乳酸，随后在其表面旋涂上一层AZ5214光刻胶，并曝光显影。紧接着，通过刷涂形成一层镓铟，随后旋涂上第二层厚度为10μm的聚乳酸，通过RIE刻蚀暴露出电极位点后，将电极从基底上释放下来，获得60通道柔性电极阵列，电极刺激端为长方形，长为0.7cm，宽为0.5cm。
进一步地，对电极背面进行plasma处理5min，再与乙烯基硅烷反应30min后，将其与丙烯酸预聚液至于紫外光下聚合60min，即可获得一层厚度为150μm的聚丙烯酸功能层。
本实施例获得的植入式微电极阵列的结构包括刺激端、引线部分及焊盘端。刺激端为长方形，长为0.7cm，宽为0.5cm，在刺激端内的单个刺激位点直径为300μm，刺激位点间距为450μm，刺激通道数为60。引线部分为长方形，该长方形的长为4cm，宽为0.4cm，引线间距为50μm。焊盘端的最大边长为1cm，最小边长为0.6cm，单个焊盘直径为200μm，焊盘位点间距为360μm，焊盘数量为60。
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 (17)

  1. 一种功能化宽幅微电极阵列，其特征在于，该功能化宽幅微电极阵列包括依次设置的功能层、基底层、导电层、绝缘层；
    其中，所述功能层为单分子层、高分子材料层和/或高分子复合物层，厚度为1nm-1000μm。
  2. 根据权利要求1所述的功能化宽幅微电极阵列，其特征在于，该功能化宽幅微电极阵列中的刺激通道的数量为60-2400。
  3. 根据权利要求1所述的功能化宽幅微电极阵列，其特征在于，该功能化宽幅微电极阵列由刺激端、引线部分和焊盘端组成。
  4. 根据权利要求3所述的功能化宽幅微电极阵列，其特征在于，所述刺激端的尺寸为0.1cm-1.5cm；
    优选地，所述刺激端包括多个刺激位点，每一个刺激位点对应一个刺激通道，单个刺激位点的尺寸为50nm-5mm，相邻刺激位点的间距为20μm-1mm；
    优选地，所述刺激端的形状为长方形、正方形、圆形或不规则几何形状。
  5. 根据权利要求3所述的功能化宽幅微电极阵列，其特征在于，所述引线部分为长方形；
    优选地，所述长方形的长为1cm-15cm，宽为0.2cm-2cm；
    优选地，所述引线部分包括多条引线，相邻引线的间距为1μm-1mm。
  6. 根据权利要求3所述的功能化宽幅微电极阵列，其特征在于，所述焊盘端的尺寸为0.5-20cm；
    优选地，所述焊盘端包括多个焊盘，单个焊盘的尺寸为0.2mm-5mm，相邻焊盘的间距为20μm-1mm；
    优选地，所述焊盘端的形状为长方形、正方形、圆形或不规则几何形状；更优选地，当所述焊盘端的形状为长方形时，其长为0.5mm-20cm，宽为0.3mm-5cm；当所述焊盘端的形状为正方形时，其边长为0.5mm-20cm；当焊盘端的形状为圆形时，其直径为0.5mm-20cm。
  7. 根据权利要求1所述的功能化宽幅微电极阵列，其特征在于，所述基底层的厚度为3μm-80μm；优选地，所述基底层的材料为聚酰亚胺、聚对二甲苯、聚二甲基硅氧烷、医用硅胶、聚氨酯、聚对苯二甲酸乙二醇酯、聚乳酸、聚己内酯及其衍生物中的一种或几种的组合。
  8. 根据权利要求1所述的功能化宽幅微电极阵列，其特征在于，所述导电层的厚度为20nm-10μm；优选地，所述导电层的材料为镁、金、铂、铂铱合金、镓铟合金、镓铟锡合金中的一种或几种的组合。
  9. 根据权利要求1所述的功能化宽幅微电极阵列，其特征在于，所述功能层为单分子层，该单分子层包括对基底层表面进行烷烃、硅烷烃或氟烷烃处理形成的单分子微纳结构层。
  10. 根据权利要求1所述的功能化宽幅微电极阵列，其特征在于，作为功能层的高分子材料层和高分子复合物层中的高分子材料，其厚度为1nm-1000μm；优选地，所述高分子材料选自聚(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、聚乳酸、聚乙醇酸、聚乳酸-羟基乙酸共聚物及其衍生物中的一种或几种的组合。
  11. 根据权利要求1所述的功能化宽幅微电极阵列，其特征在于，作为功能层的高分子复合物层中的除高分子材料以外的材料为纳米金、纳米银、纳米铜、纳米铂、纳米钯、纳米锗、碳纳米管、炭黑、黑磷、硫化铜、二硫化钼、石墨烯、硒化铋、聚吡咯、聚苯胺、聚乙烯二氧噻吩、聚苯乙烯磺酸盐、吲哚菁绿、卟啉脂质体、Fe 2O 3、Fe 3O 4、FeCo、NiFe、CoFeO、NiFeO、MnFeO、LaFeCoSi、GdSiGe、LaFe 11.6Si 1.4C 0.2H 0.7、La(Fe,Si) 13、NiMnGa、MnCoGe 0.99In 0.01、MnCo 0.98Cr 0.02Ge及其复合材料中的一种或几种的组合。
  12. 根据权利要求1所述的功能化宽幅微电极阵列，其特征在于，作为功能层的高分子材料层和高分子复合物层还含有抗炎药物，优选地，所述抗炎药物包括地塞米松、强的松、保泰松或抗炎性多肽。
  13. 权利要求1所述的功能化宽幅微电极阵列的制备方法，其特征在于，该方法包括以下步骤：
    在基底表面形成微电极阵列，并将微电极阵列与基底分离；
    通过激光对微电极阵列的背面进行处理，然后在微电极阵列的背面形成单分子层、高分子材料层和/或高分子复合物层，得到所述功能化宽幅微电极阵列。
  14. 根据权利要求13所述的方法，其中，在基底表面形成微电极阵列的步骤按照以下方式进行：
    (1)在基底表面涂布基底材料并固化，形成基底层；
    (2)在基底层表面涂布光刻胶并曝光显影，形成显影层；
    (3)在显影层表面形成导电层，同时去除显影层；
    (4)在导电层表面涂布第二层基底材料并固化，形成绝缘层；
    (5)通过刻蚀暴露出刺激位点和焊盘，得到微电极阵列；
    或者，在基底上通过喷涂、刷涂或打印的方式形成微电极阵列。
  15. 根据权利要求13所述的方法，其中，所述单分子层通过对基底层表面进行烷烃、硅烷烃或氟烷烃处理形成；
    所述高分子材料层和高分子复合物层通过化学接枝法或涂覆法形成；
    优选地，所述化学接枝法是通过缩合反应或共聚反应的方式在电极的表面接枝形成高分子层；
    优选地，所述涂覆法是通过高分子材料或者高分子材料与附加材料的复合物配成浓度为0.1wt-50wt％的溶液，然后涂覆在电极表面并干燥而获得高分子材料层或高分子复合物层。
  16. 权利要求1所述的功能化宽幅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。
  17. 一种神经假体，其包括权利要求1所述的功能化宽幅微电极阵列；所述神经假体优选为植入式人造视网膜、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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