A functionalized wide-width implantable microelectrode array and its preparation method and application

Abstract

The present invention relates to a functionalized wide-width implantable microelectrode array and a preparation method and application thereof. The functionalized wide-width microelectrode array comprises a functional layer, a substrate layer, a conductive layer, and an insulating layer arranged in sequence; the functional layer is a monomolecular layer, a polymer material layer and / or a polymer composite layer, and the thickness is 1nm-1000μm. The present invention also provides a preparation method for the above-mentioned functionalized wide-width implantable microelectrode array. The functionalized wide-width microelectrode array of the present invention can effectively adjust the microelectrode sites, circuits, spacing and other related parameters by increasing the size of the microelectrodes, thereby reducing the process complexity in the micro-machining process of the microelectrodes, greatly improving the yield of high-cost microelectrode arrays, and solving the design problems of high-density microelectrode arrays; through the functionalized wide-width design, the folding or curling function of the microelectrode array can be realized, thereby realizing minimally invasive implantation and greatly reducing surgical risks.

Description

Technical Field

[0001] The invention relates to a functionalized wide-width implantable microelectrode array and a preparation method thereof. Background Art

[0002] As the pace of life continues to accelerate, people are often in a state of high tension, resulting in an increasing number of neurological diseases such as retinitis pigmentosa, macular degeneration, depression, and epilepsy. At the same time, the global aging population has increased the probability of neurological diseases and has become a major social burden.

[0003] The rapid development of wearable or implantable neural stimulation therapy and the emergence of neural prostheses have brought new hope to a large number of patients. Neural stimulation therapy is a method of treatment that regulates nerves without destroying nerve tissue. It can treat or partially restore nerve function. Because this method is safe and effective, for some special nervous system diseases, the pacemakers, cochlear implants and artificial retinas involved in this method are irreplaceable and have been successfully applied in clinical practice.

[0004] With the continuous innovation and development of new technologies, more neural electrical stimulation prostheses have gradually been put into use, bringing new hope to people with Parkinson's disease, epilepsy, motor nerve disorders, stroke, depression and other diseases. Neural prostheses will help patients with nerve damage to repair and reconstruct damaged nerve functions and improve their quality of life. Along with the social demand for the treatment of neurological diseases, the research and development of functional electronic devices has become an objective requirement of the medical industry and the whole society.

[0005] Although the research on neural prostheses is developing rapidly, only a few implantable neural prostheses such as implantable cardiac pacemakers, cochlear implants, and artificial retinas have entered clinical applications. At present, the work in this field is facing many challenges brought by scientific and technological problems, one of which is the functional design of the device. For artificial retinal prostheses, since the existing electrodes are still designed by traditional methods and do not have special functions, it not only greatly increases the risk of surgical implantation, but also has a low resolution of image formation due to the small number of channels in the electrode array, and can only obtain a tubular field of view. In addition, the biocompatibility of neural electrodes is another major challenge. Neural electrodes with poor biocompatibility may damage multiple tissue parts, including capillaries, extracellular matrix, and cells when implanted into the human body. Moreover, macrophages will gather around the implanted electrodes and wrap the implant. Microglia are then 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 neural electrodes and failing to meet the purpose of long-term implantation.

[0006] At present, the work in this field is facing many challenges brought by scientific and technological problems. Taking artificial retina as an example, one of the difficulties is that it is difficult to obtain high-resolution microelectrode arrays. The main reason is that when the microelectrode array is implanted into the retina, the surgical incision must be guaranteed to be less than 5mm. Too large an incision will cause great damage to the normal function of biological tissues. Therefore, the design of the electrode size has strict requirements on the width. For this reason, the width of the microelectrode array has long been limited to less than 4.5mm in this field. It is difficult to obtain high-resolution microelectrodes on such a narrow area. At the same time, narrow electrodes will also cause difficulties in the design and production of microelectrode sites, lines, and spacing on the electrodes, greatly increasing the process complexity in the microelectrode micromachining process, and the yield rate is very low. In addition, the materials used in the current microelectrode arrays have poor biocompatibility, the body is prone to rejection or immune response, and they do not have anti-inflammatory functions, making it difficult to meet the effectiveness and safety of long-term implantation.

[0007] Therefore, there is an urgent need in this field to develop a high-resolution microelectrode array in order to effectively improve the image quality obtained by patients, reduce the process complexity of the microelectrode processing, improve the yield rate, and improve the long-term implantability of the microelectrode array. Summary of the invention

[0008] In view of this, one of the objectives of the present invention is to provide an implantable microelectrode array, in order to solve one or more of the above-mentioned technical problems.

[0009] Another object of the present invention is to provide applications of the above-mentioned implantable microelectrode array.

[0010] Another object of the present invention is to provide a method for preparing the above-mentioned implantable microelectrode array.

[0011] To achieve the above purpose, 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 a monomolecular layer, a polymer material layer, and / or a polymer composite layer, with a thickness of 1nm-1000μm. The functional layer and the conductive layer are respectively located on the two side surfaces of the base layer, and the insulating layer is located on the conductive layer. Its material is the same as that of the base layer. This insulating layer will expose the stimulation site (conductivity) of the electrode for stimulation.

[0012] By combining a layer of polymer material and / or polymer composite material behind the microelectrode array, the biocompatibility of the microelectrode array can be improved. Through the design of the polymer material layer and the polymer composite material layer, the electrode deformation can be driven by the triggering of the polymer, and by adding additional materials such as black phosphorus, the controllable deformation can be triggered by external fields such as NIR light.

[0013] According to a specific embodiment of the present invention, preferably, the functional layer is a monomolecular layer, and the monomolecular layer includes a monomolecular micro-nano structure layer formed by treating the surface of the substrate layer with alkanes, silanes or fluoroalkanes. In the functionalized wide-width microelectrode array of the present invention, the functional layer on the surface of the substrate layer is a monomolecular layer, and the monomolecular layer includes a monomolecular micro-nano structure layer formed by treating the surface of the substrate layer with alkanes, silanes or fluoroalkanes, that is, some microchannels, microarrays and other structures are designed behind the electrode substrate. In this way, the surface energy of the material on the back of the electrode can be reduced by the design of a monomolecular layer micro-nano structure, and the electrode can be deformed after encountering a liquid, so that the obtained implantable microelectrode array has a shape-adaptive change function, and can be folded or bent by hand or with the assistance of tools and then unfolded to achieve minimally invasive implantation, which can greatly reduce surgical risks.

[0014] According to a specific embodiment of the present invention, preferably, in the functionalized wide-width microelectrode array of the present invention, the number of stimulation channels in the functionalized wide-width microelectrode array is 60-2400, and the specific number can be selected as needed, such as 2000, 1024.

[0015] According to a specific embodiment of the present invention, preferably, the functionalized wide-width microelectrode array consists of a stimulation end, a lead portion and a pad end.

[0016] According to a specific embodiment of the present invention, the shape of the stimulation end can be any appropriate shape, preferably a rectangle, square, circle or irregular geometric shape. The size of the stimulation end is preferably 0.1cm-1.5cm, wherein, when the stimulation end is rectangular, its length is 0.1-1.5cm and its width is 0.1-1.5cm. The stimulation end includes a plurality of stimulation sites, each stimulation site corresponds to a stimulation channel, the size of a single stimulation site is 50nm-5mm (preferably 100μm), and the spacing between adjacent stimulation sites is 20μm-1mm (preferably 300μm). The shape of the stimulation site can be arbitrary, such as a rectangle, circle, square and other irregular geometric shapes. When the stimulation site is a rectangle, the above size range refers to its length and width of 50nm-5mm respectively; when the stimulation site is a circle or a square, the above size range refers to its diameter or side length of 50nm-5mm; when the stimulation site is an irregular shape, the above size range refers to its size in any direction of 50nm-5mm. The lead portion may be a rectangle; preferably, the length of the rectangle is 1cm-15cm and the width is 0.2cm-2cm. The lead portion may include a plurality of leads, and the spacing between adjacent leads is 1μm-1mm. The shape of the lead portion is the shape of a collection of leads, for example, the above-mentioned rectangle is a top view shape. The size of the pad end may 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 spacing between adjacent pads is 20μm-1mm. The shape of the pad end may be any appropriate shape, preferably a rectangle, a square, a circle or an irregular geometric shape. When the shape of the pad end is a rectangle, its length is 0.5mm-20cm and its width is 0.3mm-5cm; when the shape of the pad end is a square, its side length is 0.5mm-20cm; when the shape of the pad end is a circle, its diameter is 0.5mm-20cm. The shape of a single pad can be arbitrary, such as rectangular, circular, square and other irregular geometric shapes. When the pad is rectangular, the above size range refers to its length and width of 50nm-5mm respectively; when the pad is circular or square, the above size range refers to its diameter or side length of 50nm-5mm; when the pad is an irregular shape, the above size range refers to its size in any direction of 50nm-5mm.

[0017] On the one hand, the present invention breaks through the prejudice of the prior art that the width of the microelectrode array cannot be higher than 4.5 mm, and provides a wide-width microelectrode array. Due to its increased width, the resolution can be greatly improved, the process complexity of the microelectrode processing process can be reduced, and the yield rate can be improved; on the other hand, through the design of the functional layer, the minimally invasive implantation of traditional electrodes and the controllable deformation after implantation to fit the three-dimensional curved tissue surface can be achieved, which not only reduces the risk of surgical implantation, but also improves the efficiency of information transmission between the electrode and the biological tissue, thereby improving the reliability and effectiveness of long-term implantation of the device.

[0018] In the functionalized wide-width microelectrode array of the present invention, preferably, the thickness of the base layer is 3 μm-80 μm.

[0019] In the functionalized wide-width microelectrode array of the present invention, preferably, the material of the base layer is one or a combination of polyimide, polyparaxylene, polydimethylsiloxane, medical silicone, polyurethane, polyethylene terephthalate, polylactic acid, polycaprolactone and other materials and their derivatives.

[0020] In the functionalized wide-width microelectrode array of the present invention, preferably, the thickness of the conductive layer is 20 nm-10 μm.

[0021] In the functionalized wide-width microelectrode array of the present invention, preferably, 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, etc.

[0022] In the functionalized wide-width microelectrode array of the present invention, preferably, the polymer material in the polymer material layer and the polymer composite layer as the functional layer is poly(N-isopropylacrylamide), poly(N-n-propylacrylamide), poly(N-cyclopropylacrylamide), poly(N-isopropylmethacrylamide), poly(N-ethylacrylamide), poly(N-acryloxy-N-propylpiperazine), poly(N-(L)-(1-hydroxymethyl)propylmethacrylamide), poly[N-(2-methacryloxyethyl)pyrrolidone], poly[N-(3-acryloxypropyl)pyrrolidone], poly[N-(3-methacryloxypropyl)pyrrolidone], poly[N-(2-acryloxypropyl)pyrrolidone], poly[N-(1-methacryloxypropyl)pyrrolidone] [(2-acryloyloxyethyl)pyrrolidone], poly(2-alkyl-2-oxazoline), poly(2-ethyl-2-oxazoline), poly(2-isopropyl-2-oxazoline), poly(2-n-propyl-2-oxazoline), polydimethylaminoethyl methacrylate, poly(N-vinyl cyclohexanolactam), polyacrylpyrrolidine, polymethyl vinyl ether, polymethoxyethyl vinyl ether, polyethoxyethyl vinyl ether, polyethoxyethoxy vinyl ether, polypropylene oxide, poly(oligo(ethylene glycol) monomethyl ether methacrylate), polyorganophosphazene, protein, elastin-like polypeptide, agarose, polyvinyl alcohol, chitosan, starch, polyacrylamide, polyvinyl pyrrolidone, hyaluronic acid, sodium hyaluronate, sodium polystyrene sulfonate, poly(p-styrene sulfonic acid), polymethyl Hydroxyethyl acrylate, polyethylene glycol, polybutylene glycol, polyethylene glycol methacrylate, polyethylene glycol acrylate, matrigel, gelatin, alginate, collagen, poly L-lysine, poly L-glutamic acid, hydroxypropyl methylcellulose, hydroxyethyl cellulose, carboxymethyl cellulose, carboxyvinyl polymer, carrageenan, hyaluronic acid, polyvinyl alcohol, polymethyl methacrylate, polyethyl methacrylate, poly tert-butyl methacrylate, polymethyl acrylate, polyethyl acrylate, polyvinyl pyridine, polycarbonate, polyimide, cellulose acetate, nylon, poly (vinyl terephthalate), polyphosphazene, perfluorosulfonic acid, polyethylene, polystyrene, phenolic resin, polyacrylic acid, poly L-glutamic acid, polyhistidine, polyaspartic acid, poly [(2-dimethylamino) methyl acrylate [ethyl acrylate], polymethacrylic acid, polyethylacrylic acid, polypropylacrylic acid, polyvinyl benzoic acid, polyitaconic acid, polyethylene glycol acrylate phosphoric acid, polyethylene glycol methacrylate phosphoric acid, polyvinyl phosphoric acid, poly(4-vinyl-phenyl phosphoric acid), polyethylene sulfonic acid, poly(4-styrene sulfonic acid), polyethylene boronic acid, polydimethylaminoethyl methacrylate, polydiethylaminoethyl methacrylate, poly(N-ethylpyrrolidine methacrylate), poly(2-vinylpyridine), poly(N-acryloyl-N-alkenylpiperazine), polyacryloylmorpholine, poly(4-vinylpyridine), polyethyleneimine dendrimer, polyvinyl alcohol, preoxidized acrylonitrile, polyurethane, epoxy resin, ethylene-vinyl acetate copolymer, polyimide, polycaprolactone,One or a combination of polypyrrolidone, polydopamine, polylactic acid, polyglycolic acid, polylactic acid-glycolic acid copolymer and their derivatives.

[0023] According to a specific embodiment of the present invention, preferably, the polymer material is one or a combination of poly(N-isopropylacrylamide), polyvinyl alcohol, chitosan, polylactic acid, polyethylene glycol methacrylate, polyethylene glycol acrylate, matrigel, gelatin, alginate, collagen, etc. These materials have good biocompatibility and can be easily designed with related structures and functions.

[0024] In the functionalized wide-width microelectrode array of the present invention, preferably, 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 liposome, 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 、MnCo 0.98 Cr 0.02 One or a combination of Ge and its composite materials.

[0025] In the functionalized wide-width microelectrode array of the present invention, preferably, the polymer material layer and the polymer composite layer as the functional layer also contain anti-inflammatory drugs, which may include dexamethasone, prednisone, phenylbutazone or anti-inflammatory peptides, etc. The inclusion of anti-inflammatory drugs in the polymer material layer and the polymer composite layer can make the microelectrode array have anti-inflammatory function, reduce the immune inflammation problem after electrode implantation, and thereby improve the effectiveness and safety of long-term implantation of the device.

[0026] In the functionalized wide-width microelectrode array of the present invention, the thickness of the insulating layer and the like and the dimensions of other structures not limited thereto can be controlled as required.

[0027] The functionalized wide-width microelectrode array provided by the present invention has a larger stimulation area and has the function of adaptive shape change: by increasing the size of the microelectrodes, the number of arrays can be increased, greatly improving the patient resolution; by folding or curling the wide-width electrodes, minimally invasive implantation of the electrode array can be achieved, greatly reducing the surgical risk; designing a layer of polymer material or polymer composite behind the microelectrode array can improve the biocompatibility of the electrode, and can also realize the functionalization of the electrode, such as loading anti-inflammatory drugs, to improve the effectiveness and safety of long-term implantation of the device.

[0028] The present invention also provides a method for preparing the above functionalized wide-width microelectrode array, which comprises the following steps:

[0029] forming a microelectrode array on a substrate surface and separating the microelectrode array from the substrate;

[0030] The back side of the microelectrode array (the side where the substrate layer contacts the functional layer) is processed by laser, and then a polymer material layer or a polymer complex layer is formed on the back side of the microelectrode array to obtain the functionalized wide-width microelectrode array.

[0031] In the above preparation method, preferably, the step of forming a microelectrode array on the substrate surface is performed in the following manner:

[0032] (1) coating a base material on the surface of a base and curing the base material to form a base layer;

[0033] (2) coating a photoresist on the surface of the base layer and exposing and developing the layer to form a developing layer;

[0034] (3) forming a conductive layer on the surface of the developing layer and removing the developing layer at the same time;

[0035] (4) coating a second layer of base material on the surface of the conductive layer and curing it to form an insulating layer;

[0036] (5) The stimulation sites and pads are exposed by etching to obtain a microelectrode array.

[0037] The above steps (1) to (5) are to prepare the microelectrode array by micromachining. In addition, the microelectrode array can also be formed on the substrate by spraying, brushing or printing.

[0038] In the above preparation method, step (1) can form a base layer by spin coating, step (3) can form a conductive layer by magnetron sputtering / electron beam evaporation / printing / brushing, etc., step (4) can form an insulating layer by spin coating, step (5) can be etched by RIE to expose the stimulation sites and pads, and the Lift-Off method can be used to separate the microelectrode array from the substrate.

[0039] In the above preparation method, preferably, the monomolecular micro-nanostructure layer (ie, the monomolecular layer) is formed by treating the surface of the substrate layer with alkanes, silanes or fluoroalkanes.

[0040] In the above preparation method, preferably, the polymer material layer and the polymer composite layer are formed by chemical grafting or coating; wherein, the chemical grafting method may be to form a polymer layer on the surface of the electrode by means of a condensation reaction or a copolymerization reaction; the coating method may be to prepare a solution with a concentration of 0.1wt-50wt% of a polymer material or a composite of a polymer material and an additional material, and then coat the solution on the electrode surface and dry it to obtain a polymer material layer or a polymer composite layer.

[0041] The present invention also provides the use of the functionalized wide-width microelectrode array in the preparation of an implantable artificial retina, an implantable cochlear implant, an implantable heart pacemaker, and an implantable deep brain stimulator.

[0042] The present 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 implantable deep brain stimulator.

[0043] The functionalized wide-width microelectrode provided by the present invention can not only realize the ultra-high density design of the electrode, but also realize the minimally invasive implantation of the electrode (less than 5mm incision), and the electrode after implantation greatly increases the stimulation area, and can be widely used in brain-computer interface fields such as artificial retina, cochlear implant, cardiac pacemaker, deep brain stimulator, etc.

[0044] Due to the requirements of clinical ophthalmic surgery implantation, the scleral incision cannot be larger than 5mm, so there are specific restrictions on the size of the electrode during micro-processing, such as the width cannot be larger than 4.5mm. However, the existing photolithography technology can only be designed at a size of 4.5mm, and lower resolution (small number of stimulation sites) is easier to achieve. When the resolution is increased, for example, 1500 channels (large number of stimulation sites), designing so many stimulation sites in such a small area requires that the size of each stimulation site and the connection line is particularly small, and when the size is smaller than the processing accuracy of the equipment (in many cases, due to equipment performance limitations and operator experience, the size of nearly 10 times the processing accuracy cannot be designed), high-density design cannot be achieved. Therefore, due to the limitations of the processing method, the traditional electrode lacks the functional layer design in the present invention, so only lower-density electrodes can be obtained. The present invention designs a functionalized wide-width microelectrode array, and the main beneficial effects are as follows:

[0045] (1) By increasing the size of microelectrodes, the microelectrode sites, lines, spacing and other related parameters can be effectively adjusted, thereby reducing the process complexity of microelectrode micromachining, greatly improving the yield of high-cost microelectrode arrays, and solving the design problems of high-density microelectrode arrays.

[0046] (2) By increasing the size of the microelectrode, it is possible to effectively adjust the microelectrode site, circuit, spacing and other related parameters, optimize the electrode impedance, solve the crosstalk problem between stimulation sites, and achieve safe and effective electrophysiological stimulation.

[0047] (3) Through the functional wide-width design, the microelectrode array can be folded or curled, thereby achieving minimally invasive implantation and greatly reducing surgical risks.

[0048] (4) By designing a layer of polymer material or polymer composite layer behind the microelectrode array, the biocompatibility of the electrode can be improved, and the electrode can be functionalized, such as loading anti-inflammatory drugs, to improve the effectiveness and safety of long-term implantation of the device. BRIEF DESCRIPTION OF THE DRAWINGS

[0049] Figure 1 Schematic diagram of the structure of the functionalized wide-width microelectrode array of Examples 1 and 2.

[0050] Figure 2 This is a schematic diagram of the 126-channel flexible functional electrode array in Example 2.

[0051] Figure 3 This is a schematic diagram of a 1024-channel flexible electrode array in Example 6.

[0052] Figure 4 It is a self-expanding deformation image of the functional electrode array in Example 2 and a microscope image of the electrode circuit.

[0053] Figure 5 This is a diagram of the curled state of the functional electrode of Example 2 and its unfolding after implantation into the eyeball using 808nm near-infrared light. DETAILED DESCRIPTION

[0054] In order to have a clearer understanding of the technical features, purposes and beneficial effects of the present invention, the technical scheme of the present invention is described in detail below in conjunction with specific embodiments. It should be understood that these examples are only used to illustrate the present invention and are not used to limit the scope of the present invention. In the embodiments, each raw reagent material can be commercially obtained, and the experimental method without specifying the specific conditions is a conventional method and conventional conditions well known in the art, or according to the conditions recommended by the instrument manufacturer.

[0055] Example 1

[0056] This embodiment provides an implantable microelectrode array, and the preparation method thereof comprises the following steps:

[0057] A layer of polyimide with a thickness of 10 μm was spin-coated on the surface of a 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. Next, a layer of gold with a thickness of 150 nm was formed by magnetron sputtering, and then a second layer of polyimide was spin-coated and cured. The electrode stimulation sites and pads were exposed by RIE etching, and the electrodes were released from the substrate to obtain a 126-channel flexible electrode array.

[0058] The back of the obtained electrode was first treated with plasma for 3 minutes, and then exposed to a fluorosilane vapor atmosphere for 5 minutes to obtain a functionalized wide-width electrode treated with a fluorinated monolayer.

[0059] The structure of the implantable microelectrode array obtained in this embodiment is as follows Figure 1 As shown, the implantable microelectrode array includes a stimulation end, a lead part and a pad end. The stimulation end is rectangular, with a size of 1.2 cm wide × 0.5 cm long. The diameter of a single stimulation site in the stimulation end is 150 μm, the spacing between stimulation sites is 600 μm, and the number of stimulation channels is 126. The lead part is rectangular, with a length of 4 cm, a width of 0.4 cm, and a lead spacing of 8 μm. 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 μm, the pad site spacing is 400 μm, and the number of pads is 126.

[0060] Example 2

[0061] This embodiment provides an implantable microelectrode array, and the preparation method thereof comprises the following steps:

[0062] A layer of polyimide (base layer) was spin-coated on the surface of a 4-inch cleaned and dried silicon wafer (base), and then a layer of AZ5214 photoresist was spin-coated on its surface and exposed and developed. Next, a 120nm thick gold layer was formed by magnetron sputtering, and then a second layer of polyimide was spin-coated and cured. The electrode stimulation sites and pads were exposed by RIE etching, and the electrodes were released from the base to obtain a 126-channel flexible electrode array.

[0063] The back of the polyimide (base layer) obtained above was treated with vinyl silane, and the caprolactone monomer mixed with black phosphorus and vinyl silane were copolymerized for 30 minutes by gamma ray initiation, thereby achieving chemical grafting, and finally a layer of polycaprolactone copolymer was grafted on the back of the electrode to obtain a functional electrode array such as Figure 2 shown.

[0064] The structure of the implantable microelectrode array obtained in this embodiment is as follows Figure 1As shown, the implantable microelectrode array includes a stimulation end, a lead portion and a pad end. The stimulation end is rectangular, with a size of 1.2 cm wide × 0.5 cm long. The diameter of a single stimulation site in the stimulation end is 150 μm, the spacing between stimulation sites is 600 μm, and the number of stimulation channels is 126. The lead portion is rectangular, with a length of 4 cm, a width of 0.4 cm, and a lead spacing of 8 μm. 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 μm, the pad site spacing is 400 μm, and the number of pads is 126.

[0065] Figure 4 The self-expanding deformation diagram and the electrode circuit microscope diagram of the functional electrode array of this embodiment are shown. Among them, the two figures below are the corresponding metal circuit microscope diagrams when the stimulation end is curled and unfolded. It can be seen from the figure that the electrode circuit will not be lost during the curling process.

[0066] Figure 5 The curled state of the electrode and the effect of light-induced unfolding after implantation into the eyeball. Figure 5 It can be seen that the functional electrode is in a curled state before implantation, and is small in size, so it can be easily implanted in the eyeball. After implantation, the functional electrode can be automatically unfolded by irradiating it with 808nm near-infrared light.

[0067] The back of the microelectrode array is grafted with a copolymerized layer of polycaprolactone, which can improve the biocompatibility of the electrode.

[0068] Example 3

[0069] This embodiment provides an implantable microelectrode array, and the preparation method thereof comprises the following steps:

[0070] A layer of polyimide with a thickness of 10 μm was spin-coated on the surface of a 4-inch cleaned and dried silicon wafer, and then a layer of AZ5214 photoresist was spin-coated on the surface and exposed and developed. Next, a layer of platinum with a thickness of 120 nm was formed by magnetron sputtering, and then a second layer of polyimide with a thickness of 8 μm 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.

[0071] Furthermore, a polyethylene glycol functional layer with a thickness of 100 μm is coated on the back of the electrode.

[0072] 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, a single stimulation site in the stimulation end has a diameter of 145 μm, a stimulation site spacing of 600 μm, and a number of stimulation channels of 256. The lead part is a rectangle with a length of 4 cm, a width of 0.4 cm, and a lead spacing of 8 μm. 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 μm, the pad site spacing is 400 μm, and the number of pads is 256.

[0073] Example 4

[0074] This embodiment provides an implantable microelectrode array, and the preparation method thereof comprises the following steps:

[0075] A layer of polyimide with a thickness of 10 μm was spin-coated on the surface of a 4-inch cleaned and dried silicon wafer, and then a layer of AZ5214 photoresist was spin-coated on the surface and exposed and developed. Next, a layer of platinum with a thickness of 120 nm was formed by magnetron sputtering, and then a second layer of polyimide with a thickness of 8 μm 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.

[0076] The back of the electrode was treated with plasma, and the electrode was fixed on the LBL device using the LBL method. The process of immersion in sodium alginate solution-extraction-immersion in chitosan solution was repeated through programmed control, and then a sodium alginate / chitosan composite hydrogel layer with a thickness of 100 μm was grafted on the back of the electrode.

[0077] The structure of the implantable microelectrode array obtained in this embodiment includes a stimulation end, a lead portion and a pad end. The stimulation end is circular with a diameter of 0.8 cm, a single stimulation site in the stimulation end has a diameter of 145 μm, a stimulation site spacing of 600 μm, and a number of stimulation channels of 256. The lead portion is rectangular, for example, the length of the rectangle is 4 cm, the width is 0.4 cm, and the lead spacing is 8 μm. 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 μm, the pad site spacing is 400 μm, and the number of pads is 256.

[0078] Example 5

[0079] This embodiment provides an implantable microelectrode array, and the preparation method thereof comprises the following steps:

[0080] A layer of 20 μm thick polydimethylsiloxane was spin-coated on the surface of a 4-inch cleaned and dried silicon wafer, and then a layer of AZ5214 photoresist was spin-coated on the surface and exposed and developed. Next, a layer of 120 nm thick platinum was formed by magnetron sputtering, and then a second layer of 10 μm thick polydimethylsiloxane 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.

[0081] Furthermore, a polyvinyl alcohol functional layer with a thickness of 150 μm is coated on the back of the electrode.

[0082] The structure of the implantable microelectrode array obtained in this embodiment includes a stimulation end, a lead portion and a pad end. The stimulation end is circular with a diameter of 0.8 cm, a single stimulation site in the stimulation end has a diameter of 145 μm, a stimulation site spacing of 600 μm, and a number of stimulation channels of 256. The lead portion is a rectangle with a length of 4 cm, a width of 0.4 cm, and a lead spacing of 8 μm. The maximum side length of the pad end is 1.2 cm, the minimum side length is 0.6 cm, a single pad diameter is 100 μm, the pad site spacing is 400 μm, and the number of pads is 256.

[0083] Example 6

[0084] This embodiment provides an implantable microelectrode array, and the preparation method thereof comprises the following steps:

[0085] A layer of Parylene with a thickness of 10 μm was deposited on the surface of a 4-inch cleaned and dried silicon wafer, and then a layer of AZ5214 photoresist was spin-coated on the surface and exposed and developed. Next, a layer of platinum-iridium with a thickness of 160 nm was formed by magnetron sputtering, and then a second layer of Parylene with a thickness of 10 μm was deposited. After the electrode sites were exposed by RIE etching, the electrodes were released from the substrate to obtain a 1024-channel flexible electrode array.

[0086] Furthermore, the back of the electrode was plasma treated for 5 minutes, reacted with vinyl silane for 30 minutes, and then polymerized with N-isopropylacrylamide prepolymer solution under ultraviolet light for 60 minutes to obtain a poly N-isopropylacrylamide functional layer with a thickness of 150 μm.

[0087] The structure of the implantable microelectrode array obtained in this embodiment is as follows Figure 3As shown, the structure of the embedded microelectrode array includes a stimulation end, a lead part and a pad end. The stimulation end is rectangular, 1.2 cm long and 0.5 cm wide. The diameter of a single stimulation site in the stimulation end is 120 μm, the spacing between stimulation sites is 220 μm, and the number of stimulation channels is 1024. The lead part is rectangular, 4 cm long and 0.4 cm wide, and the lead spacing is 6 μm. 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 μm, the pad site spacing is 400 μm, and the number of pads is 1024.

[0088] Example 7

[0089] This embodiment provides an implantable microelectrode array, and the preparation method thereof comprises the following steps:

[0090] A layer of Parylene with a thickness of 10 μm was deposited on the surface of a 4-inch cleaned and dried silicon wafer, and then a layer of AZ5214 photoresist was spin-coated on the surface and exposed and developed. Next, a magnesium layer was formed by 3D printing, and then a second layer of Parylene with a thickness of 10 μm 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.

[0091] Furthermore, the back of the electrode was subjected to plasma treatment for 5 minutes, and then reacted with vinyl silane for 30 minutes, and then polymerized with sodium propylene sulfonate prepolymer solution under ultraviolet light for 60 minutes to obtain a sodium propylene sulfonate functional layer with a thickness of 150 μm.

[0092] The structure of the implantable microelectrode array obtained in this embodiment includes a stimulation end, a lead portion and a pad end. The stimulation end is rectangular, 0.7 cm long and 0.5 cm wide, the diameter of a single stimulation site in the stimulation end is 300 μm, the spacing between stimulation sites is 450 μm, and the number of stimulation channels is 60. The lead portion is a rectangle, the length of the rectangle is 4 cm, the width is 0.4 cm, and the lead spacing is 50 μm. 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 μm, the pad site spacing is 360 μm, and the number of pads is 60.

[0093] Example 8

[0094] This embodiment provides an implantable microelectrode array, and the preparation method thereof comprises the following steps:

[0095] A layer of polylactic acid with a thickness of 30 μm was spin-coated on the surface of a 4-inch cleaned and dried silicon wafer, and then a layer of AZ5214 photoresist was spin-coated on the surface and exposed and developed. Next, a layer of gallium indium was formed by brushing, and then a second layer of polylactic acid with a thickness of 10 μm was spin-coated. 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 electrode stimulation end was rectangular, 0.7 cm long and 0.5 cm wide.

[0096] Furthermore, the back of the electrode was subjected to plasma treatment for 5 minutes, and then reacted with vinyl silane for 30 minutes, and then polymerized with acrylic acid prepolymer solution under ultraviolet light for 60 minutes to obtain a polyacrylic acid functional layer with a thickness of 150 μm.

[0097] The structure of the implantable microelectrode array obtained in this embodiment includes a stimulation end, a lead portion and a pad end. The stimulation end is rectangular, 0.7 cm long and 0.5 cm wide, the diameter of a single stimulation site in the stimulation end is 300 μm, the spacing between stimulation sites is 450 μm, and the number of stimulation channels is 60. The lead portion is a rectangle, the length of the rectangle is 4 cm, the width is 0.4 cm, and the lead spacing is 50 μm. 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 μm, the pad site spacing is 360 μm, and the number of pads is 60.

[0098] Finally, it should be noted that the above embodiments are only used to illustrate the implementation process and features of the present invention, rather than to limit the technical solution of the present invention. Although the present invention is described in detail with reference to the above embodiments, ordinary technicians in this field should understand that the present invention can still be modified or replaced by equivalents, and any modification or partial replacement that does not depart from the spirit and scope of the present invention should be covered by the protection scope of the present invention.

Claims

1. A functionalized wide-width microelectrode array, characterized in that: The functionalized wide-width microelectrode array comprises a functional layer, a substrate layer, a conductive layer, and an insulating layer arranged in sequence; Wherein, the functional layer is a monomolecular layer, a polymer material layer and / or a polymer composite layer, and has a thickness of 100 μm-150 μm; Wherein, the monomolecular layer comprises a monomolecular micro-nano structure layer formed by treating the surface of the substrate layer with fluorosilane; The polymer material in the polymer material layer and the polymer composite layer as the functional layer is selected from one or a combination of poly(N-isopropylacrylamide), poly(N-n-propylacrylamide), poly(N-cyclopropylacrylamide), poly(N-isopropylmethacrylamide), poly(N-ethylacrylamide), polyvinyl alcohol, chitosan, hyaluronic acid, sodium polystyrene sulfonate, sodium polypropylene sulfonate, polyethylene glycol, polybutylene glycol, polyacrylic acid, polymethacrylic acid, polyethylacrylic acid, and polycaprolactone; The material of the conductive layer is one or a combination of magnesium, gold, platinum, platinum-iridium alloy, gallium-indium alloy, and gallium-indium-tin alloy; The thickness of the conductive layer is 20nm-160nm.

2. The functionalized wide-width microelectrode array according to claim 1, characterized in that: The number of stimulation channels in the functionalized wide-width microelectrode array ranges from 60 to 2400.

3. The functionalized wide-width microelectrode array according to claim 1, characterized in that: The functionalized wide-width microelectrode array consists of a stimulation end, a lead part and a pad end.

4. The functionalized wide-width microelectrode array according to claim 3, characterized in that: The size of the stimulation end is 0.1cm-1.5cm.

5. The functionalized wide-width microelectrode array according to claim 4, characterized in that: The stimulation end includes a plurality of stimulation sites, each stimulation site corresponds to a stimulation channel, the size of a single stimulation site is 50nm-5mm, and the distance between adjacent stimulation sites is 20μm-1mm.

6. The functionalized wide-width microelectrode array according to claim 4, characterized in that: The shape of the stimulation end is rectangular, square, circular or irregular geometric shape.

7. The functionalized wide-width microelectrode array according to claim 3, characterized in that: The lead part is rectangular.

8. The functionalized wide-width microelectrode array according to claim 7, characterized in that: The length of the rectangle is 1cm-15cm, and the width is 0.2cm-2cm.

9. The functionalized wide-width microelectrode array according to claim 7, characterized in that: The lead wire portion includes a plurality of lead wires, and the interval between adjacent lead wires is 1 μm-1 mm.

10. The functionalized wide-width microelectrode array according to any one of claims 3 to 9, characterized in that: The size of the pad end is 0.5-20 cm.

11. The functionalized wide-width microelectrode array according to claim 10, characterized in that: The pad end includes a plurality of pads, the size of a single pad is 0.2 mm-5 mm, and the spacing between adjacent pads is 20 μm-1 mm.

12. The functionalized wide-width microelectrode array according to claim 11, characterized in that: The pad end has a shape of a rectangle, a square, a circle or an irregular geometric shape.

13. The functionalized wide-width microelectrode array according to claim 12, characterized in that: When the shape of the pad end is rectangular, its length is 0.5mm-20cm and its 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 circular, its diameter is 0.5mm-20cm.

14. The functionalized wide-width microelectrode array according to any one of claims 1 to 9 and 11 to 13, characterized in that: The thickness of the base layer is 3 μm-80 μm.

15. The functionalized wide-width microelectrode array according to claim 14, characterized in that: The material of the base layer is one or a combination of polyimide, polyparaxylene, polydimethylsiloxane, medical silicone, polyurethane, polyethylene terephthalate, polylactic acid, polycaprolactone and derivatives thereof.

16. The functionalized wide-width microelectrode array according to claim 10, characterized in that: The thickness of the base layer is 3 μm-80 μm.

17. The functionalized wide-width microelectrode array according to claim 16, characterized in that: The material of the base layer is one or a combination of polyimide, polyparaxylene, polydimethylsiloxane, medical silicone, polyurethane, polyethylene terephthalate, polylactic acid, polycaprolactone and derivatives thereof.

18. The functionalized wide-width microelectrode array according to claim 1, characterized in that: Materials other than the polymer material in the polymer composite layer as the functional layer are 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 liposome, Fe2O3, Fe3O4, 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 、MnCo 0.98 Cr 0.02 One or a combination of Ge and its composite materials.

19. The functionalized wide-width microelectrode array according to claim 1, characterized in that: The polymer material layer and the polymer composite layer as the functional layer also contain anti-inflammatory drugs.

20. The functionalized wide-width microelectrode array according to claim 19, characterized in that: The anti-inflammatory drugs include dexamethasone, prednisone, phenylbutazone or anti-inflammatory polypeptides.

21. The method for preparing a functionalized wide-width microelectrode array according to any one of claims 1 to 20, characterized in that: The method comprises the following steps: forming a microelectrode array on a substrate surface and separating the microelectrode array from the substrate; The back of the microelectrode array is processed by laser, and then a monomolecular layer, a polymer material layer and / or a polymer complex layer are formed on the back of the microelectrode array to obtain the functionalized wide-width microelectrode array.

22. The method according to claim 21, characterized in that The steps of forming a microelectrode array on the substrate surface are performed as follows: (1) coating a base material on the surface of a base and curing the base material to form a base layer; (2) coating a photoresist on the surface of the base layer and exposing and developing the layer to form a developing layer; (3) forming a conductive layer on the surface of the developing layer and removing the developing layer at the same time; (4) coating a second layer of base material on the surface of the conductive layer and curing it to form an insulating layer; (5) Exposing the stimulation sites and pads by etching to obtain a microelectrode array; Alternatively, the microelectrode array is formed on the substrate by spraying, brushing or printing.

23. The method according to claim 21 or 22, characterized in that The monomolecular layer is formed by treating the surface of the substrate layer with fluorosilane; The polymer material layer and the polymer composite layer are formed by chemical grafting or coating.

24. The method according to claim 23, characterized in that The chemical grafting method is to form a polymer layer by grafting on the surface of the electrode through a condensation reaction or a copolymerization reaction.

25. The method according to claim 23, characterized in that The coating method is to prepare a solution with a concentration of 0.1wt% to 50wt% by polymer material or a composite of polymer material and additional material, and then coat it on the electrode surface and dry it to obtain a polymer material layer or a polymer composite layer.

26. Use of the functionalized wide-width microelectrode array according to any one of claims 1 to 20 in the preparation of an implantable artificial retina, an implantable cochlear implant, an implantable cardiac pacemaker, or an implantable deep brain stimulator.

27. A neural prosthesis comprising the functionalized wide-width microelectrode array according to any one of claims 1 to 20.

28. The neural prosthesis according to claim 27, characterized in that The neural prosthesis is preferably an implantable artificial retina, an implantable cochlear implant, an implantable cardiac pacemaker or an implantable deep brain stimulator.

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