Flexible neural electrode with multilayer bidirectional signal transmission structure and preparation method thereof

Abstract

The application discloses a flexible neural electrode with a multilayer bidirectional signal transmission structure and a preparation method thereof. The neural electrode comprises a substrate insulating layer, at least two signal transmission layers, an intermediate insulating layer and a packaging insulating layer. The intermediate insulating layer is located between the signal transmission layers. The signal transmission layers are stacked in a sandwich structure of an adhesive / seed layer-metal-conductive layer-metal-adhesive / seed layer-metal. The intermediate insulating layer and the packaging insulating layer are windowed at the insulating layer of the orthographic projection of signal detection sites and pads of all layers below. The application further discloses a preparation method of the flexible neural electrode with the multilayer signal transmission structure. The neural electrode adopts a 3D stacking structure of the signal transmission layers, reduces the implantation width of the electrode, increases the number of detection sites, reduces the damage to the implanted brain tissue, improves the detection flux, and is helpful to realize long-term collection of high-density and high-resolution neural signals of brains of rodents, primates and the like.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of brain-computer interface, and particularly relates to a flexible neural electrode with a multi-layer bidirectional signal transmission structure and a preparation method. BACKGROUND

[0002] A neural electrode is an effective tool for detecting neural signals. It can effectively capture signal abnormalities of nervous system diseases such as epilepsy, Parkinson's disease, and Alzheimer's disease; and it also greatly promotes the understanding of cognitive functions of the brain, especially the neural electrophysiological signal changes at the cell and neural network levels. At present, the electrodes used for detecting nervous system diseases and cognitive functions are mostly silicon-based neural electrodes, but the Young's modulus of the silicon-based electrodes deviates greatly from the brain tissue, which can easily cause persistent irreversible damage to the neural tissue. Therefore, a flexible neural electrode is the next advanced technology in the field of brain-computer interface. It has a Young's modulus closer to the brain tissue, can greatly reduce the inflammatory response caused by electrode implantation, and enables the long-term implantation of neural electrodes to move forward. In addition, the current flexible neural electrodes are mostly cortical electrodes, and the implantation depth is mostly limited to the cortex and only plays a role in detecting neural signals. Obviously, it cannot meet the requirements of detection and regulation in the treatment of deep brain nervous system diseases and spatial cognition. Therefore, the flexible neural electrode urgently needs to have the following conditions:

[0003] 1. High spatiotemporal resolution detection and regulation in the deep brain;

[0004] 2. Reduce implantation damage to achieve the purpose of long-term implantation;

[0005] 3. Achieve precise regulation at the cell or neural network level in the target detection brain area.

[0006] Obviously, when improving the spatiotemporal resolution of the deep brain neural electrode and increasing the number of detection or regulation sites, the number of channels increases, but the number of wires in the signal transmission also needs to increase. The increased wires increase the width of the implanted neural electrode. A larger electrode width will cause damage to the neural tissue and trigger inflammation, which is not conducive to long-term implantation of the electrode. Therefore, high throughput and minimal damage are a contradiction in the design of a neural electrode. Therefore, it is necessary to find a method to increase the detection throughput while minimizing the width of the implanted electrode. In addition, with the gradual deepening of the understanding of brain neural nuclei, the resolution of the neural electrode is further improved, and it is urgently needed to achieve more precise regulation of the neural nuclei target. Therefore, a structure that realizes precise electrical regulation of the detection area is also necessary.

[0007] Therefore, it is necessary to design a flexible neural electrode with a multi-layer bidirectional signal transmission layer structure to solve the above problems. SUMMARY

[0008] In view of the existing demand for brain-computer interface electrodes, the technical problem to be solved by the present application is how to reduce the implantation damage while ensuring high spatiotemporal resolution and increasing the number of electrode channels.

[0009] To achieve the above-mentioned purpose, the present application provides the following technical solutions.

[0010] The flexible neural electrode with a multilayer bidirectional signal transmission structure preferably includes but is not limited to 32 channels, and comprises a base insulating layer, at least two signal transmission layers, an intermediate insulating layer, and a packaging insulating layer.

[0011] The flexible neural electrode with a multilayer bidirectional signal transmission structure preferably includes but is not limited to 32 channels, and comprises a base insulating layer, at least two signal transmission layers, an intermediate insulating layer, and a packaging insulating layer.

[0012] The intermediate insulating layer is located between the signal transmission layers; the signal transmission layers are stacked in a sandwich structure of adhesive / seed layer metal-conductive layer metal-adhesive / seed layer metal; the intermediate insulating layer and the packaging insulating layer are windowed at the orthographic projections of the signal detection sites and pads of all the layers below. Preferably, the intermediate insulating layer and the packaging insulating layer are windowed at the orthographic projections of the signal reference sites, signal recording sites, electrical stimulation sites, and pads of all the layers below, the exposed signal reference sites and signal recording sites in the signal transmission layers are used to record neural electrical signals or electrochemical signals of the neural network implanted with the electrode, the exposed electrical stimulation sites are used to provide variable voltage or current electrical stimulation for the neural network implanted with the electrode, and the exposed pads are used to transmit the recorded neural signals.

[0013] Further, the signal detection sites include signal reference sites, signal recording sites, and electrical stimulation sites.

[0014] Further, the flexible material of the base insulating layer and the packaging insulating layer meets the biocompatibility requirements, has good insulating properties and flexibility, and includes but is not limited to polyimide PI, parylene, polyethylene terephthalate PET, polydimethylsiloxane PDMS, and other polymer materials.

[0015] Further, the adhesive / seed layer metal of the conductive layer has a thickness of 5-30 nm (e.g., a thickness of 5 nm, 6 nm, 7 nm, 8 nm, 9 nm, 10 nm, 12 nm, 14 nm, 16 nm, 18 nm, 20 nm, 22 nm, 24 nm, 26 nm, 28 nm, or 30 nm), and a metal capable of increasing the adhesion between the conductive layer metal and the insulating layer is selected as the adhesive / seed layer metal, including but not limited to chromium.

[0016] Further, the conductive layer metal thickness is 100 nm-500 nm (for example, 100 nm, 120 nm, 140 nm, 160 nm, 180 nm, 200 nm, 220 nm, 240 nm, 260 nm, 280 nm, 300 nm, 320 nm, 340 nm, 360 nm, 380 nm, 400 nm, 420 nm, 440 nm, 460 nm, 480 nm or 500 nm).

[0017] Further, the intermediate insulating layer thickness is less than the substrate insulating layer thickness. The intermediate insulating layer thickness is 2 nm-8 nm, for example, 2 nm, 3 nm, 4 nm, 5 nm, 6 nm, 7 nm or 8 nm.

[0018] Further, the site includes an electrical stimulation site and a recording site, and the two sites can be located in the same signal transmission layer.

[0019] Further, the recording site can be used as an electrophysiological recording site, and is modified by using nano materials such as platinum nanoparticles, carbon nanotubes or gold nanoparticles, and can be further modified by using biological functional materials such as enzymes for neurotransmitter detection as an electrochemical signal recording site.

[0020] Further, the electrical stimulation site is a multi-structure nest; the outer side is connected to ground through an electrical stimulation shielding ring, and the inner side is an electrical stimulation input pole with input voltage / current; the outer side structure can be plate-shaped, open ring-shaped or semi-ring-shaped, and the inner side structure can be plate-shaped, open ring-shaped or semi-ring-shaped.

[0021] Further, the plate-shaped structure of the electrical stimulation site can be oriented in different directions, and the recording site is located on the same side or the opposite side of the negative pole; the ring-shaped structure can have multiple different centers and different radii, and part or all of the recording sites are located in the ring.

[0022] The application also discloses a preparation method of the flexible neural electrode with the multi-layer bidirectional signal transmission structure.

[0023] (1) selecting a carrier with high temperature resistance and voltage resistance, such as glass and silicon wafer; in a vacuum chamber, a flexible substrate insulating layer is deposited on the carrier by chemical vapor deposition;

[0024] (2) using photolithography, evaporation and stripping process to prepare an adhesion / seed layer metal-conductive layer metal-adhesion / seed layer metal on the insulating layer as a signal transmission layer;

[0025] (3) in a vacuum chamber, an intermediate insulating layer is deposited on the signal transmission layer by chemical vapor deposition;

[0026] (4) Using photoetching, evaporation and stripping process, the adhering / seed layer metal-conductive layer metal-adhering / seed layer metal is prepared on the intermediate insulating layer as the signal transmission layer;

[0027] (5) Repeating step (3), the encapsulating insulating layer is deposited;

[0028] (6) Using photoresist as mask protection, using oxygen plasma etching process, the signal site and pad orthographic projection of the intermediate insulating layer and the encapsulating insulating layer and all the layers thereunder are windowed.

[0029] (7) Using photoresist as mask protection, using oxygen plasma etching process, all the insulating layers, including the substrate insulating layer, the intermediate insulating layer and the encapsulating insulating layer, are etched to determine the shape of the flexible electrode and release the flexible electrode;

[0030] Further, according to the requirements of the electrode involved and the production, the operation process of steps (2)-(4) can be repeated to form the electrode structure of the signal transmission layer with more than two layers of the signal transmission layer.

[0031] Compared with the prior art, the preparation method of the flexible neural electrode with the multilayer bidirectional signal transmission structure has the following beneficial effects:

[0032] 1. High spatiotemporal resolution brain deep detection and regulation;

[0033] 2. Reducing implantation damage to achieve long-term implantation;

[0034] 3. Achieving precise regulation at the cell or neural network level for target detection brain area; BRIEF DESCRIPTION OF DRAWINGS

[0035] Figure 1 is a schematic diagram of the multilayer stack of the flexible neural electrode with the multilayer bidirectional signal transmission structure;

[0036] Figure 2 is a front view of the flexible neural electrode with the multilayer bidirectional signal transmission structure;

[0037] Figure 3 is a local enlarged view of the electrical stimulation site and the recording site of the flexible neural electrode with the multilayer bidirectional signal transmission structure;

[0038] Figure 4 is a side view of the flexible neural stack structure with the multilayer bidirectional signal transmission structure;

[0039] Wherein: 1: insulating layer; 11: substrate insulating layer; 12: intermediate insulating layer; 13: encapsulating insulating layer; 2: signal transmission layer; 21: pad; 22: wire; 23: signal reference site; 24: signal recording site; 25: electrical stimulation site. DETAILED DESCRIPTION

[0040] The following description, with reference to the accompanying drawings, illustrates several preferred embodiments of the present invention to make its technical content clearer and easier to understand. The present invention can be embodied in many different forms, and the scope of protection of the present invention is not limited to the embodiments mentioned herein.

[0041] It should be noted that similar or identical parts are referred to by the same reference numerals in the accompanying drawings or description. Furthermore, embodiments are shown in the drawings for simplification or convenience. Moreover, elements or implementations not shown or described in the drawings are those known to those skilled in the art. Additionally, while this document may provide examples of parameters containing specific values, the parameters need not be exactly equal to the corresponding values, but rather approximate the corresponding values ​​within acceptable error tolerances or design constraints.

[0042] Figure 1 This is a schematic diagram of a multilayered, bidirectional signal transmission structure for flexible neural electrodes, as provided in an embodiment of the present invention. Figure 1 As shown, this embodiment of the invention provides a flexible neural electrode with a multilayer bidirectional signal transmission structure. The detection sites of the neuronal electrode array include, but are not limited to, 32 channels, wherein the number of detection channels is equal to the number of detection sites. The neural electrode structure includes: an electrode insulating layer 1 and a signal transmission layer 2; the electrode insulating layer 1 includes multiple insulating layers, namely a base insulating layer 11, at least one intermediate insulating layer 12, and an encapsulation insulating layer 13. Each insulating layer has a consistent outer contour and is used to isolate conductive signals transmitted between signal transmission layers. For example, the base insulating layer 11, one signal transmission layer 2, at least one intermediate insulating layer 12, another signal transmission layer 2, and the encapsulation insulating layer 13 are sequentially stacked.

[0043] Specifically, the electrode insulating layer 1 is a flexible material that meets biocompatibility requirements, possessing good insulation and flexibility. It can be a polymer material such as polyimide (PI), parylene, polyethylene terephthalate (PET), or polydimethylsiloxane (PDMS). Further, the intermediate insulating layer 12 is located between the signal transmission layers 2; further, the signal transmission layer 2 is formed by stacking adhesion / seed layer metal-conductive layer metal-adhesion / seed layer metal in a sandwich structure; further, the adhesion / seed layer metal thickness is 0 nm-50 nm, and a metal that can increase the adhesion between the conductive layer metal and the insulating layer is selected as the adhesion / seed layer metal, such as (including but not limited to) chromium. The conductive layer metal thickness is 100 nm-500 nm; further, the thickness of the intermediate insulating layer 12 is less than the thickness of the base insulating layer 11.

[0044] Specifically, such as Figures 2-4As shown, the signal transmission layer 2 comprises a plurality of signal transmission structures, namely the pads 21, the wires 22, the signal reference sites 23, the signal recording sites 24 and the electrical stimulation sites 25. The signal reference sites 23, the signal recording sites 24 and the electrical stimulation sites 25 are each independently connected to the pads 21 through the wires 22, wherein the pads have a reference size of 200 nm x 200 nm, and the wires have a line width greater than 3 μm. If the number of detection channels increases, the number of wires required also increases, resulting in a wider width of the electrode implantation part.

[0045] Specifically, the intermediate insulating layer 12 and the encapsulating insulating layer 13 in the electrode insulating layer 1 are windowed at the orthographic projections of the signal reference sites 23, the signal recording sites 24, the electrical stimulation sites 25 and the pads 21 of all the layers below, and the exposed signal reference sites 23 and signal recording sites 24 in the signal transmission layer 2 are used to record the neural electrical signals or electrochemical signals of the electrode-implanted neural network, the exposed electrical stimulation sites 25 are used to provide variable voltage or current electrical stimulation for the electrode-implanted neural network, and the exposed pads 21 are used to transmit the recorded neural signals out. Further, the signal reference sites 23, the signal recording sites 24 and the electrical stimulation sites 25 can be located in the same or different signal transmission layers.

[0046] Further, the recording sites 24 have a diameter greater than or equal to 1 μm, can be used as electrophysiological recording sites, can be modified with nanomaterials such as platinum nanoparticles, carbon nanotubes or gold nanoparticles, and organic polymer materials, and can also be modified with biological functional materials such as enzymes for neurotransmitter detection, as electrochemical signal recording sites, wherein the number of recording sites includes but is not limited to 32.

[0047] Further, the electrical stimulation sites 25 are multi-structure nested; the outer side is an electrical stimulation shielding ring connected to ground, and the inner side is an electrical stimulation input pole with input voltage / current; the outer side structure can be plate-shaped, open ring-shaped or semi-ring-shaped, and the inner side structure can be plate-shaped, open ring-shaped or semi-ring-shaped, wherein the inner diameter of the ring is greater than or equal to 30 μm, and the length of the plate is greater than or equal to 30 μm.

[0048] Further, the plate-shaped structure of the electrical stimulation sites 25 can be oriented in different directions, and the recording sites are located on the same side or the opposite side of the negative pole; the ring-shaped structure can have multiple different centers and different radii of the inner ring, and part or all of the recording sites are located in the ring.

[0049] The application also discloses a preparation method of the flexible neural electrode with the multi-layer bidirectional signal transmission structure, comprising the following steps:

[0050] (1) Select a high-temperature-resistant, pressure-resistant carrier such as glass, silicon wafer; in the vacuum chamber, chemical vapor deposition of flexible base insulating layer 11 on the carrier, wherein the thickness of the base insulating layer is 3-30 μm, and the base insulating layer is selected from polyimide PI, parylene, polyethylene terephthalate PET, polydimethylsiloxane PDMS and other polymer materials;

[0051] (2) Using photolithography, evaporation and stripping process, the adhesion / seed layer metal-conductive layer metal-adhesion / seed layer metal is prepared on the base insulating layer 11, which is the signal transmission layer 2, wherein the adhesion / seed layer metal-conductive layer metal-adhesion / seed layer metal can be selected from Cr-Au-Cr materials, the adhesion / seed layer metal is 0-50 nm thick, and the conductive layer metal is 100-500 nm thick;

[0052] (3) In the vacuum chamber, chemical vapor deposition of intermediate insulating layer 12 on the signal transmission layer 2, the thickness of the intermediate insulating layer is 1-10 μm, and the flexible material is selected from polyimide PI, parylene, polyethylene terephthalate PET or polydimethylsiloxane PDMS and other polymer materials;

[0053] (4) Using photolithography, evaporation and stripping process, the adhesion / seed layer metal-conductive layer metal-adhesion / seed layer metal is prepared on the intermediate insulating layer 12, which is the signal transmission layer 2, wherein the adhesion / seed layer metal-conductive layer metal-adhesion / seed layer metal can be selected from Cr-Au-Cr materials, the adhesion / seed layer metal is 0-50 nm thick, and the conductive layer metal is 100-500 nm thick;

[0054] (5) Repeat step 3 to deposit the encapsulation insulating layer 13, which is 3-30 μm thick, and the encapsulation insulating layer is selected from polyimide PI, parylene, polyethylene terephthalate PET, polydimethylsiloxane PDMS and other polymer materials;

[0055] (6) Using photoresist as a mask, the first adhesion / seed layer metal of the signal transmission layer protects the conductive metal layer of the signal transmission layer, and using oxygen plasma etching process, the signal reference site 23, signal recording site 24, electrical stimulation site 25 and pad 21 orthographic projection of all layers under the intermediate insulating layer 12 and encapsulation insulating layer 13 are windowed;

[0056] (7) Using photoresist as a mask protection, using oxygen plasma etching process to etch all electrode insulating layers 1, including base insulating layer 11, intermediate insulating layer 12 and encapsulation insulating layer 13, to determine the shape of the flexible electrode, and to release the flexible electrode;

[0057] Further, according to the requirements of electrode design and fabrication, the operation process of steps (2)-(4) can be repeated to form an electrode structure of the signal transmission layer with two or more layers of the signal transmission layer.

[0058] The rear end of the implantable electrode can be connected to a corresponding PCB circuit to realize filtering and amplification of the collected signals. By implanting the electrode into a specific brain area, bidirectional signal transmission can be realized through electrical stimulation regulation and detection, including electrophysiological and electrochemical signals. The implantable electrode has wide applications, including precise stimulation of specific brain areas for treatment of neurological diseases such as epilepsy and Parkinson's disease in the field of life and health; and spatial navigation signal reading and control of external devices in the field of brain-computer interaction, which is a new and emerging future cross-technology.

[0059] Finally, it should be noted that: all the above examples are only used to illustrate the technical solutions of the present application, but not to limit it; although the present application has been described in detail with reference to the foregoing examples, those skilled in the art should understand that: it can still modify the technical solutions recorded in the foregoing examples, or make equivalent replacement for part of the technical features; and these modifications or replacements do not make the essence of the corresponding technical solutions deviate from the spirit and scope of the technical solutions of the embodiments of the present application.

Claims

1. A flexible neural electrode with a multilayer bidirectional signal transmission structure, characterized in that, The neural electrode includes a base insulating layer, at least two signal transmission layers, an intermediate insulating layer, and an encapsulation insulating layer; The intermediate insulating layer is located between the signal transmission layers; the signal transmission layers are stacked in a sandwich structure of adhesion / seed layer metal-conductive layer metal-adhesion / seed layer metal; the intermediate insulating layer and the encapsulation insulating layer have windows at the signal detection sites and pad projections of all layers below them. The intermediate insulating layer and the encapsulation insulating layer have windows at the orthographic projection of the signal reference sites, signal recording sites, electrical stimulation sites, and pads in all layers below them. The exposed signal transmission layer's signal reference sites and signal recording sites are used to record the neural electrical or electrochemical signals of the electrode implanted in the neural network. The exposed electrical stimulation sites are used to provide variable voltage or current electrical stimulation to the electrode implanted in the neural network. The exposed pads are used to transmit the recorded neural signals. The electrical stimulation sites are multi-structure nested. The outer side is an electrical stimulation shielding ring grounded, and the inner side is an electrical stimulation input electrode for input voltage / current. The outer structure can be plate-shaped, open annular, or semi-annular, and the inner structure can be plate-shaped, open annular, or semi-annular. The plate-like structure of the electrical stimulation site can be oriented in different directions, and the recording site is located on the same side or opposite side of the negative electrode; the ring-like structure can have multiple inner rings or inner circles with different centers and radii, and some or all of the recording sites are located inside the ring.

2. The neural electrode according to claim 1, characterized in that, A flexible material matching the Young's modulus of brain tissue is selected as the base insulating layer and the encapsulation insulating layer, and meets the requirements of biocompatibility, possessing insulation and flexibility. The flexible material includes one or more of polyimide (PI), parylene (Parylene), polyethylene terephthalate (PET), and polydimethylsiloxane (PDMS).

3. The neural electrode according to claim 1, characterized in that, The thickness of the adhesion / seed layer metal of the conductive layer is 5 nm - 30 nm, and the metal that can increase the adhesion between the conductive layer metal and the insulating layer is selected as the adhesion / seed layer metal.

4. The neural electrode according to claim 1, characterized in that, The thickness of the conductive layer metal is 100 nm – 500 nm.

5. The neural electrode according to claim 1, characterized in that, The thickness of the intermediate insulating layer is 2 nm – 8 nm, which is less than the thickness of the base insulating layer.

6. The neural electrode according to claim 1, characterized in that, The signal recording site and the electrical stimulation site are both located in the same signal transmission layer.

7. The neural electrode according to claim 6, characterized in that, The recording sites can be used as electrophysiological recording sites, modified with platinum nanoparticles, carbon nanotubes or gold nanoparticles, or modified with enzyme biofunctional materials for neurotransmitter detection as electrochemical signal recording sites.

8. A method for preparing a neural electrode according to any one of claims 1-7, characterized in that, Includes the following steps: (1) Select glass or silicon wafer; in a vacuum chamber, chemically vapor-deposit a flexible substrate insulating layer on the carrier; (2) Using photolithography, evaporation or sputtering, and lift-off processes, an adhesion / seed layer metal-conductive layer metal-adhesion / seed layer metal is prepared on the insulating layer as a signal transmission layer; (3) In a vacuum chamber, an intermediate insulating layer is chemically vapor-deposited on the signal transmission layer; (4) Using photolithography, evaporation and lift-off processes, an adhesion / seed layer metal-conductive layer metal-adhesion / seed layer metal as a signal transmission layer is prepared on the intermediate insulating layer; (5) Repeat step (3) to deposit the encapsulation insulating layer; (6) Use photoresist as a mask for protection and use oxygen plasma etching process to open windows at the signal detection sites and pad projections of all layers below the intermediate insulating layer and the encapsulation insulating layer. (7) Use photoresist as a mask for protection, use oxygen plasma etching process to etch all insulating layers, including the base insulating layer, intermediate insulating layer and encapsulation insulating layer, determine the shape of the flexible electrode, and release the flexible electrode.

9. The preparation method according to claim 8, characterized in that, Repeat the operation process (2)-(4) multiple times to form an electrode structure of the signal transmission layer with two or more layers.

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