WO2023240700A1 - Appareil d'électrode flexible pour liaison avec un dispositif optique implantable et procédé de fabrication dudit appareil - Google Patents

Appareil d'électrode flexible pour liaison avec un dispositif optique implantable et procédé de fabrication dudit appareil Download PDF

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WO2023240700A1
WO2023240700A1 PCT/CN2022/102566 CN2022102566W WO2023240700A1 WO 2023240700 A1 WO2023240700 A1 WO 2023240700A1 CN 2022102566 W CN2022102566 W CN 2022102566W WO 2023240700 A1 WO2023240700 A1 WO 2023240700A1
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electrode
layer
flexible
flexible electrode
insulating layer
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PCT/CN2022/102566
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English (en)
Chinese (zh)
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李雪
赵郑拓
李肖城
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中国科学院脑科学与智能技术卓越创新中心
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Publication of WO2023240700A1 publication Critical patent/WO2023240700A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/24—Detecting, measuring or recording bioelectric or biomagnetic signals of the body or parts thereof
    • A61B5/25—Bioelectric electrodes therefor
    • A61B5/263—Bioelectric electrodes therefor characterised by the electrode materials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/0059—Measuring for diagnostic purposes; Identification of persons using light, e.g. diagnosis by transillumination, diascopy, fluorescence
    • A61B5/0082—Measuring for diagnostic purposes; Identification of persons using light, e.g. diagnosis by transillumination, diascopy, fluorescence adapted for particular medical purposes
    • A61B5/0084—Measuring for diagnostic purposes; Identification of persons using light, e.g. diagnosis by transillumination, diascopy, fluorescence adapted for particular medical purposes for introduction into the body, e.g. by catheters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/24—Detecting, measuring or recording bioelectric or biomagnetic signals of the body or parts thereof
    • A61B5/25—Bioelectric electrodes therefor
    • A61B5/279—Bioelectric electrodes therefor specially adapted for particular uses
    • A61B5/291—Bioelectric electrodes therefor specially adapted for particular uses for electroencephalography [EEG]
    • A61B5/293—Invasive
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/24—Detecting, measuring or recording bioelectric or biomagnetic signals of the body or parts thereof
    • A61B5/316—Modalities, i.e. specific diagnostic methods
    • A61B5/369—Electroencephalography [EEG]
    • A61B5/37—Intracranial electroencephalography [IC-EEG], e.g. electrocorticography [ECoG]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/68—Arrangements of detecting, measuring or recording means, e.g. sensors, in relation to patient
    • A61B5/6846—Arrangements of detecting, measuring or recording means, e.g. sensors, in relation to patient specially adapted to be brought in contact with an internal body part, i.e. invasive
    • A61B5/6867—Arrangements of detecting, measuring or recording means, e.g. sensors, in relation to patient specially adapted to be brought in contact with an internal body part, i.e. invasive specially adapted to be attached or implanted in a specific body part
    • A61B5/6868—Brain
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B2562/00—Details of sensors; Constructional details of sensor housings or probes; Accessories for sensors
    • A61B2562/02—Details of sensors specially adapted for in-vivo measurements
    • A61B2562/0209—Special features of electrodes classified in A61B5/24, A61B5/25, A61B5/283, A61B5/291, A61B5/296, A61B5/053
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B2562/00—Details of sensors; Constructional details of sensor housings or probes; Accessories for sensors
    • A61B2562/02—Details of sensors specially adapted for in-vivo measurements
    • A61B2562/0233—Special features of optical sensors or probes classified in A61B5/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B2562/00—Details of sensors; Constructional details of sensor housings or probes; Accessories for sensors
    • A61B2562/12—Manufacturing methods specially adapted for producing sensors for in-vivo measurements
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B2562/00—Details of sensors; Constructional details of sensor housings or probes; Accessories for sensors
    • A61B2562/12—Manufacturing methods specially adapted for producing sensors for in-vivo measurements
    • A61B2562/125—Manufacturing methods specially adapted for producing sensors for in-vivo measurements characterised by the manufacture of electrodes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B2562/00—Details of sensors; Constructional details of sensor housings or probes; Accessories for sensors
    • A61B2562/16—Details of sensor housings or probes; Details of structural supports for sensors
    • A61B2562/164—Details of sensor housings or probes; Details of structural supports for sensors the sensor is mounted in or on a conformable substrate or carrier

Definitions

  • the present disclosure relates to flexible electrode devices and manufacturing methods for use in combination with implantable optical devices, and specifically relates to being able to be matched with prisms for optical signal acquisition in deep brain regions, thereby achieving real-time synchronization of optical and electrical signals in the same area. Collected flexible electrode devices and manufacturing methods.
  • BCI Brain-Computer Interface
  • BMI Brain-Machine Interface
  • existing flexible electrodes are in contact with biological tissues such as brain tissue to receive electrical signals from the biological tissue for further processing, or to transmit external electrical signals to the biological tissue to, for example, apply Stimulate.
  • biological tissues such as brain tissue
  • optical devices for observing macroscopic changes in cell signals over time such as prisms for optical signal collection in deep brain areas.
  • Current techniques for measuring neural signals either acquire broad areas at low temporal resolution (such as calcium imaging) or record discrete regions at high temporal resolution (such as electrophysiology).
  • flexible electrodes need to be implanted in the brain together with prisms.
  • Electrodes combined with optical devices such as prisms need to be implanted into biological tissues and in long-term contact with the tissues.
  • electrodes In addition to transmitting as many signals as possible while being as small as possible, electrodes also need to be capable of simultaneous optical imaging and electrophysiological recording. without producing any light-induced artifacts in electrical recordings. Therefore, the electrode needs to have relatively good stability, biocompatibility, etc. to achieve long-term signal interaction; on the other hand, the electrode also needs to meet various requirements such as flexibility and light transmittance.
  • this application proposes a flexible electrode device and manufacturing method for combination with implantable optical devices.
  • a flexible electrode device for combination with an implantable optical device including an implantable and flexible high transmittance multi-channel mesh electrode, the multi-channel mesh
  • the mesh-shaped electrode is attached to the surface of the optical device and comes into contact with the biological tissue after the optical device is implanted, wherein the attachment portion of the multi-channel mesh electrode attached to the optical device includes: a wire located on the first insulating layer of the flexible electrode and between the second insulating layer; and electrode sites located on the second insulating layer and electrically coupled to the conductive wires through the through holes in the second insulating layer, wherein the flexible electrode device is configured to achieve the operation performed by the optical device Optical interaction is performed simultaneously with electrophysiological signal recording and electrical stimulation of neural activity by flexible electrodes.
  • an implantable electrode device including: a high transmittance multi-channel mesh electrode and an implantable optical device, wherein the multi-channel mesh electrode is attached to the optical device surface, and in contact with biological tissue after the optical device is implanted, wherein the attachment portion of the multi-channel mesh electrode to which the optical device is attached includes: a wire located between the first insulating layer and the second insulating layer of the flexible electrode; and electrode sites located over the second insulating layer and electrically coupled to the wires through the vias in the second insulating layer, wherein the electrode device is configured to enable neural activity by the flexible electrode while optical interaction is by the optical device Electrophysiological signal recording and electrical stimulation.
  • a method of manufacturing a flexible electrode device including a flexible electrode for combination with an implantable optical device as in the first aspect, the method comprising: Manufacturing a flexible separation layer on the substrate; manufacturing a first insulation layer, a conductor layer, a second insulation layer and an electrode site layer layer by layer on the flexible separation layer; and removing the flexible separation layer to separate the flexible electrode from the substrate; wherein, Before fabricating the electrode site layer, via holes are formed in the second insulating layer at positions corresponding to the electrode sites by patterning.
  • an implantation method of a flexible electrode device including a flexible electrode for combination with an implantable optical device as in the first aspect, the method comprising: Adjust the position of the flexible electrode so that the wire is aligned with the optical device; fix the optical device, drop pure water on the upper surface of the optical device, and move the electrode site of the flexible electrode into the water droplets on the upper surface of the optical device; blot the water droplets dry
  • the flexible electrode is brought into contact with the upper surface of the optical device; and the attached flexible electrode and the optical device are surgically implanted so that the attached part is in contact with the biological tissue.
  • an advantage of embodiments according to the present disclosure is that the flexible electrodes can be matched with prisms used for optical signal collection in deep brain areas, thereby achieving real-time synchronous collection of optical signals and electrical signals in the same area. Based on the observation of changes in macroscopic cell optical signals over time, local high-temporal resolution electrical signal information can be provided, which is conducive to in-depth analysis of dynamic network information in the later stage, thereby helping to understand network-level information. encoding mechanism.
  • FIG. 1 is a schematic diagram illustrating at least a portion of a flexible electrode device according to an embodiment of the present disclosure.
  • FIG. 2 is an exploded view illustrating at least a portion of a flexible electrode device according to an embodiment of the present disclosure.
  • FIG. 3 is a schematic diagram illustrating electrode sites of a flexible electrode device according to an embodiment of the present disclosure.
  • FIG. 4 is a schematic diagram showing a configuration of a flexible electrode device according to an embodiment of the present disclosure.
  • FIG. 5 is a schematic diagram showing another configuration of a flexible electrode device according to an embodiment of the present disclosure.
  • FIG. 6 is a diagram illustrating imaging effects obtained after implantation of a flexible electrode device according to an embodiment of the present disclosure.
  • FIG. 7 is a flowchart illustrating a method of manufacturing a flexible electrode according to an embodiment of the present disclosure.
  • FIG. 8 is a schematic diagram illustrating a method of manufacturing a flexible electrode according to an embodiment of the present disclosure.
  • FIG. 9 is a flowchart illustrating a method of implanting a flexible electrode device according to an embodiment of the present disclosure.
  • the technical solution of the present disclosure is mainly directed to flexible electrodes combined with optical devices.
  • the field requires applications that simultaneously collect optical signals and electrophysiological signals.
  • This requires the integration of invasive electrodes for electrical stimulation and electrical signal collection into the brain with optical devices such as prisms for collecting optical signals, which in addition to having the flexible characteristics of general brain implant electrodes , it also has adhesion to the surface of optical devices and light transmittance that is conducive to optical imaging.
  • Transparent graphene electrodes enable simultaneous optical imaging and electrophysiological recording without producing any light-induced artifacts in electrical recordings.
  • Stretchable carbon nanotube (CNT) transparent electrode arrays can simultaneously measure photoelectric signals in a mechanical deformation environment.
  • the flexible transparent array of 32 double-layered nanomesh microelectrodes allows simultaneous coupling of large, time-resolved electrophysiological data with optically measured, spatially resolved, and type-resolved single neuron activity with a high degree of uniformity and good biological Compatibility with state-of-the-art wireless recording and real-time artifact suppression systems.
  • the highly transparent double-layer nanomesh microelectrode array can perform in vivo two-photon imaging of single neurons in layer 2/3 of the visual cortex of awake mice, while performing high-fidelity simultaneous electrical recording of visual evoked activity through time-domain visual evoked potentials.
  • the measurements are at multiple unit activity bands and at lower frequencies.
  • the overall structure of the flexible electrode can be a strip-shaped high-transmittance multi-channel mesh electrode, which includes a wire portion connected to an external circuit, an electrode site, and an attachment portion attached to an optical device ( back-end part) and parts in contact with biological tissue, etc.
  • the flexible electrode has a multi-layer structure, specifically including a flexible separation layer 210, a first insulating layer 220, a circuit board connection layer 230, a wire layer 240, and a second insulating layer. 250, electrode site layer 260, etc.
  • the layers of the flexible electrode shown in Figures 1 and 2 are only non-limiting examples, and the flexible electrode in the present disclosure may omit one or more of the layers, and may also include more other layers.
  • the conductors in the multi-channel mesh electrode include a plurality of conductors located in the conductor layer and spaced apart from each other, wherein the electrode sites in the multi-channel mesh electrode include respective vias in the bottom insulating layer.
  • a hole is a plurality of electrode sites electrically coupled to one of the plurality of conductors.
  • Multi-channel mesh electrodes have good flexibility and can be partially or fully implanted in biological tissues to collect electrical signals from or apply electrical signals to biological tissues.
  • the conductive layer of the multi-channel mesh electrode shown in Figure 1 includes a plurality of conductors, however it should be understood that in different embodiments, the electrodes in the present disclosure may include a single conductor or other specified number of conductors.
  • These wires may have widths and thicknesses on the nanometer or micrometer scale, and lengths that are orders of magnitude greater than the width and thickness, such as centimeters, as desired.
  • the shapes, sizes, etc. of these wires are not limited to the ranges listed above, but can be changed according to design needs.
  • the multi-channel mesh electrode may include a first insulating layer 220 at the bottom of the electrode and a second insulating layer 250 at the top of the electrode.
  • the insulating layer in the multi-channel mesh electrode may refer to the outer surface layer in the electrode that plays an insulating role. Since the insulating layer of the flexible electrode needs to be in contact with biological tissue after implantation, the material of the insulating layer is required to have good insulation and good biocompatibility.
  • the materials of the insulating layers 220 and 250 may include polyimide (PI), polydimethylsiloxane (PDMS), parylene (Parylene), epoxy resin, Polyamide-imide (PAI), SU-8 photoresist, silicone, silicone rubber, etc.
  • the insulating layers 220, 250 are also a major portion of the multi-channel mesh electrode providing strength. An insulating layer that is too thin will reduce the strength of the electrode, and an insulating layer that is too thick will reduce the flexibility of the electrode. Moreover, the implantation of an electrode including an insulating layer that is too thick will cause greater damage to the living body.
  • the thickness of the insulating layers 220, 250 may be 100 nm to 300 ⁇ m, preferably 300 nm to 20 ⁇ m, more preferably 1 ⁇ m to 2 ⁇ m, 500 nm to 1 ⁇ m, or the like.
  • each multi-channel mesh electrode may include one or more conductive wires located in the same conductive wire layer 240 .
  • the wire layer 240 of the multi-channel mesh electrode includes a plurality of wires, wherein each wire includes an elongated body portion and an end portion corresponding to a corresponding electrode site.
  • the line width of the wires and the spacing between the wires may be, for example, 10 nm to 500 ⁇ m, and the spacing between the wires may be as low as 10 nm, for example, preferably 100 nm to 30 ⁇ m. It should be understood that the shape, size, spacing, etc. of the conductors are not limited to the ranges listed above, but can be changed according to design needs.
  • the wires in the wire layer 240 may be a film structure including a plurality of superimposed layers in the thickness direction. These layered materials may be materials that enhance the wire's properties such as adhesion, ductility, and conductivity.
  • the wire layer 240 may include a superimposed conductive layer and an adhesion layer, wherein the adhesion layer in contact with the insulating layer 220 and/or 250 is titanium (Ti), titanium nitride (TiN), chromium (Cr).
  • the conductive layer is gold (Au), platinum (Pt), iridium (Ir), tungsten (W) , magnesium (Mg), molybdenum (Mo), platinum-iridium alloy, titanium alloy, graphite, carbon nanotubes, PEDOT and other materials with good conductivity.
  • the conductor layer can also be made of other conductive metal materials or non-metal materials, or can also be made of polymer conductive materials and composite conductive materials.
  • the thickness of the conductive layer of these wires is 5 nm to 200 ⁇ m, and the thickness of the adhesion layer is 1 to 50 nm.
  • the multi-channel mesh electrode may also include electrode sites in the electrode site layer 260 located above the first insulating layer 220. These electrode sites may be in contact with biological tissue to directly collect or apply electrical signals after the flexible electrode is implanted. .
  • the electrode sites in the electrode site layer 260 can be electrically coupled to corresponding wires through through holes in the first insulation layer 220 at positions corresponding to the electrode sites.
  • the multi-channel mesh electrode may correspondingly include a plurality of electrode sites in the electrode site layer 260 , and each of these electrode sites passes through the first insulating layer 220 A corresponding via is electrically coupled to one of the plurality of conductors.
  • Figure 3 shows a schematic diagram of an electrode site of a flexible electrode device according to an embodiment of the present disclosure. Specifically, (A) of FIG. 3 shows an enlarged view of the end of the wire corresponding to the electrode site in the conductor layer, and (B) of FIG. 3 shows an enlarged view of the end of the insulating layer corresponding to the electrode site, where respectively schematically One electrode site 310 and one via site 320 are shown.
  • each electrode site may have a corresponding conductor in conductor layer 240 .
  • Each electrode site may have planar dimensions on the micron scale and thickness on the nanoscale.
  • the electrode sites may include sites with a diameter of 1 ⁇ m to 500 ⁇ m, and a spacing between electrode sites may be 1 ⁇ m to 5 mm.
  • the electrode sites may take the shape of a circle, an ellipse, a rectangle, a rounded rectangle, a chamfered rectangle, etc. It should be understood that the shape, size and spacing of the electrode sites can be selected according to the conditions of the biological tissue area to be recorded.
  • the electrode sites in the electrode site layer 260 may be a thin film structure including a plurality of stacked layers in the thickness direction.
  • the material of the layer close to the wire layer 240 among the plurality of layers may be a material that can enhance the adhesion of the electrode site to the wire.
  • the electrode site layer 260 may be a metal film including two superimposed layers, wherein the first layer close to the wire layer 240 is Ti, TiN, Cr, Ta or TaN, and the electrode site layer The exposed second layer of 260 is Au.
  • the electrode site layer can also be made of other conductive metallic materials or non-metallic materials, such as Pt, Ir, W, Mg, Mo, platinum-iridium alloy, titanium alloy, and graphite, similar to the wire layer. , carbon nanotubes, PEDOT, etc.
  • the surface of the electrode site that is exposed in contact with the biological tissue may also have a surface modification layer to improve the electrochemical characteristics of the electrode site.
  • the surface modification layer can be obtained by electrically initiated polymerization coatings using PEDOT:PSS, sputtering iridium oxide films, etc., for reducing impedance in the case of flexible electrodes collecting electrical signals (such as 1kHz operation electrochemical impedance at frequency), as well as improved charge injection capabilities under electrical signal stimulation applied by flexible electrodes, thereby improving interaction efficiency.
  • the multi-channel mesh electrode may further include a bottom electrode site layer (not shown) located under the first insulating layer 220, which electrode site may be in contact with the biological body after the flexible electrode is implanted. Tissue contact to directly collect or apply electrical signals.
  • the bottom electrode site layer is similar to the electrode sites in the electrode site layer 260.
  • the electrode sites in the bottom electrode site layer can be connected to the electrode through the bottom insulating layer. Vias at corresponding locations of the sites are electrically coupled to corresponding conductors.
  • the electrode sites in the bottom electrode site layer may be located at opposite positions to the electrode sites in the electrode site layer 260 on both sides of the top and bottom of the multi-channel mesh electrode, and with Electrode sites in the oppositely located electrode site layer 260 are electrically coupled to the same conductor in the conductor layer 240 .
  • the electrode sites in the bottom electrode site layer may also be located at different positions on the top and bottom sides of the multi-channel mesh electrode from the electrode sites in the electrode site layer 260, so as to Electrical signals are collected or applied in different areas of the biological tissue; and in embodiments according to the present disclosure, the electrode sites in the bottom electrode site layer can also be electrically coupled to the electrode sites in the conductor layer 240 and the electrode site layer 260 Wires with different electrode locations.
  • the multi-channel mesh electrode may further include a flexible separation layer 210 .
  • the flexible separation layer 210 is mainly used in the manufacturing process of multi-channel mesh electrodes, and is made of metal or non-metal materials such as nickel (Ni), chromium (Cr), aluminum (Al).
  • the flexible separation layer 210 is also provided with an adhesion layer, the material of which includes any one of Ti, TiN, Cr, Ta or TaN or a combination thereof.
  • the bottom electrode site layer is an optional but not essential part of the multi-channel mesh electrode.
  • the multi-channel mesh electrode may only include the electrode site layer 260. Excludes bottom electrode site layer.
  • the shape, size, material, etc. of the bottom electrode site may be similar to the top electrode site, and will not be described in detail here.
  • the rear end portion of the multi-channel mesh electrode may include at least one rear end site, the attachment portions of the multi-channel mesh electrode attached to the optical device each extend from the rear end portion, and the rear end portion
  • the site may be electrically coupled to one of the conductors and the back-end circuit through a through hole in the first insulating layer 220 and/or the second insulating layer 250 to achieve communication between the electrode site electrically coupled to the conductor and the back-end circuit.
  • Bidirectional signal transmission may refer to the circuit at the rear end of the multi-channel mesh electrode, such as a recording circuit, a processing circuit, etc. associated with the signal of the multi-channel mesh electrode.
  • the multi-channel mesh electrode can be coupled to the back-end circuit in a connected manner.
  • the Ball Gate Array (BGA) packaging site as the back-end site can be printed by
  • the flexible electrode can be released from the substrate before transfer (for example, by directly connecting the flexible electrode Peel it off from the base, or separate the flexible electrode from the base by removing the flexible separation layer), and connect the back end part through ball mounting patches and Anisotropic Conductive Film Bonding (ACF Bonding). Connect to the back-end circuit and then encapsulate using silicone etc.
  • BGA Ball Gate Array
  • PCB Printed Circuit Board
  • FPC Flexible Printed Circuit
  • ACF Bonding Anisotropic Conductive Film Bonding
  • the backend sites can have planar dimensions on the micron scale and thicknesses on the nanoscale.
  • the back-end site may be a BGA package site with a diameter of 50 ⁇ m to 2000 ⁇ m, or may be a circular, oval, rectangular, rounded rectangle, or chamfered rectangular site with a side length of 50 ⁇ m to 2000 ⁇ m. point.
  • shape, size, etc. of the rear end site are not limited to the ranges listed above, but can be changed according to design needs.
  • the back-end site in the connection mode may include multiple layers in the thickness direction, and the material of the adhesive layer close to the wire layer 240 in the multiple layers may be a material that can enhance the adhesion between the electrode site and the wire.
  • the material of the soldering flux layer in the middle of the multiple layers can be a soldering flux material
  • the conductive layer in the multiple layers can be other conductive metal materials or non-conducting materials such as the conductor layer 240 mentioned above.
  • Metal material, and the outermost layer among the multiple layers that may be exposed through the insulating layers 220 and 250 is an anti-oxidation protective layer.
  • the back-end site layer may include a superimposed conductive layer and an adhesive layer, wherein the adhesion layer close to the conductor layer 240 may be nanometer-scale layered to improve the connection between the back-end site layer and the conductor layer.
  • the adhesion layer as the middle layer of the soldering flux can be nickel (Ni), Pt or palladium (Pd), and the third layer as the outermost conductive layer can be Au, Pt, Ir, W, Mg, Mo, platinum-iridium alloy, titanium alloy, graphite, carbon nanotube, PEDOT, etc.
  • the backend site layer can also be made of other conductive metallic materials or non-metallic materials.
  • the back-end site layer in Figure 1 is a part connected to the back-end processing system or chip.
  • the size, spacing, shape, etc. of the sites can be changed according to the different connection methods of the back-end.
  • the multi-channel mesh electrode used has 512-channel electrode sites, including 4 128BGAs. It should be understood that other channel numbers of electrode sites may be included as desired, such as 32, 36, 64, 128 channels, etc.
  • the multi-channel mesh electrode may not include a site layer such as an electrode site layer (and/or a bottom electrode site layer), a rear end site layer, or the like.
  • the electrode sites of the multi-channel mesh electrode and the back-end sites for switching in the back-end portion can both be parts in the wire layer and be electrically coupled to corresponding wires in the wire layer.
  • the electrode sites for sensing and applying electrical signals can be in direct contact with the tissue area into which the electrode wire is implanted.
  • each electrode site can be electrically coupled to the conductor layer in the conductor layer.
  • Corresponding wires are exposed to the outer surface of the electrode wire through corresponding through holes in the top insulating layer or the bottom insulating layer and are in contact with the biological tissue.
  • FIG. 4 is a schematic diagram showing a configuration of a flexible electrode device according to an embodiment of the present disclosure.
  • the optical device that needs to be implanted in the brain is the prism 410 as an example.
  • the multi-channel mesh electrode 420 is attached to the end of the prism 410 as shown in Figure 4 (A), so that the multi-channel mesh electrode 420 is included in the patch.
  • the electrode sites in the attached portion 430 are combined with the prism 410 to produce an effect as shown in (B) of FIG. 4 .
  • FIG. 5 is a schematic diagram showing another configuration of a flexible electrode device according to an embodiment of the present disclosure.
  • FIG. 5(A) shows the arrangement state after the optical device (prism) attached with the flexible electrode is implanted in the brain. It can be seen that the end of the prism is connected to the brain via the attached part of the electrode. Direct contact with biological tissue.
  • FIG. 5(B) shows the arrangement state after the prism to which the flexible electrode is attached has been removed from the brain implantation site.
  • the multi-channel mesh electrode is attached to the surface of the optical device through van der Waals forces, thereby forming a strong adhesion between the electrode and the prism, so that the flexible electrode device is integrally implanted in the brain. It has friction with the surface of the cortex and will not fall off after being taken out.
  • the aforementioned flexible electrode device as a whole can be attached to the cerebral sulcus.
  • FIG. 6 is a diagram illustrating imaging effects obtained after implantation of a flexible electrode device according to an embodiment of the present disclosure. As shown in the figure, after imaging the brain, the electrode sites at the ends of the flexible electrodes according to the present disclosure can be seen, and the part in the wire spacing is not blocked, that is, the optical imaging of the prism can still be achieved even with the flexible electrodes attached. can be delivered effectively.
  • method 7000 may include: at S701, manufacturing a flexible separation layer on the substrate; at S702, manufacturing a first insulation layer, a conductor layer, a second insulation layer and a second insulation layer on the flexible separation layer layer by layer.
  • the electrode site layer wherein, before manufacturing the electrode sites, through holes are formed in the first insulating layer at positions corresponding to the electrode sites by patterning; and at S703, the flexible separation layer is removed to separate from the substrate Flexible electrodes.
  • FIG. 8 is a schematic diagram illustrating a method of manufacturing a flexible electrode according to an embodiment of the present disclosure. The manufacturing process and structure of the flexible separation layer, bottom insulation layer, conductor layer, top insulation layer, electrode site layer and other parts of the flexible electrode will be described in more detail with reference to FIG. 8 .
  • View (A) of Figure 8 shows the base of the electrode.
  • a hard substrate may be employed, such as glass, quartz, silicon wafer, etc.
  • other soft materials may also be used as the base, such as the same material as the insulating layer.
  • View (B) of Figure 8 illustrates the steps of fabricating a flexible release layer over a substrate.
  • the flexible separation layer can be removed by applying specific substances, thereby facilitating the separation of the flexible part of the electrode from the hard substrate.
  • the embodiment shown in Figure 8 uses Ni as the material of the flexible separation layer, but other materials such as Cr and Al can also be used.
  • the flexible separation layer when the flexible separation layer is manufactured on the substrate by evaporation, a portion of the exposed substrate may be etched first, thereby improving the flatness of the entire substrate after evaporation.
  • the flexible separation layer is an optional but not required part of the flexible electrode. Depending on the properties of the chosen material, flexible electrodes can be easily separated without a flexible separation layer.
  • the flexible separation layer may also have markings, which may be used for alignment of subsequent layers.
  • View (C) of Figure 8 shows the fabrication of the bottom insulating layer over the flexible separation layer.
  • the manufacturing of the bottom insulating layer may include steps such as a film forming process, film forming curing, and strengthened curing to produce a thin film as an insulating layer.
  • the film forming process may include coating polyimide on the flexible separation layer, for example, a layer of polyimide may be spin-coated at a stepped rotation speed.
  • Film-forming curing may include gradually increasing the temperature to a higher temperature and maintaining the temperature to form a film for subsequent processing steps.
  • Enhanced curing may include multiple temperature ramps, preferably in a vacuum or nitrogen atmosphere, and baking for several hours before fabricating subsequent layers. It should be understood that the above-mentioned manufacturing process is only a non-limiting example of the manufacturing process of the bottom insulation layer, and one or more steps may be omitted, or more other steps may be included.
  • the above manufacturing process is directed to an embodiment in which the bottom insulating layer in the flexible electrode without the bottom electrode site layer is manufactured and the bottom insulating layer has no through holes corresponding to the electrode sites.
  • the bottom electrode site layer may be fabricated over the flexible separation layer prior to fabricating the bottom insulating layer. For example, Au and Ti can be evaporated sequentially on the flexible separation layer.
  • the patterning steps for the bottom electrode sites will be detailed later for the top electrode sites.
  • a patterning step may also be included for forming the bottom insulating layer corresponding to the bottom electrode site. A through hole is etched at the location. The patterning steps for the insulating layer will be detailed later with respect to the top insulating layer.
  • Views (D) to (G) of Figure 8 show the fabrication of conductor layers on the bottom insulating layer.
  • photoresist and mask can be applied over the bottom insulating layer.
  • other photolithography methods can also be used to prepare patterned films, such as laser direct writing and electron beam lithography.
  • a double layer of glue may be applied to facilitate fabrication (evaporation or sputtering) and peeling off of the patterned film.
  • the exposure may take the form of contact lithography, in which the mask and the structure are exposed in a vacuum contact mode.
  • different developing solutions and their concentrations may be adopted for graphics of different sizes.
  • This step may also include layer-to-layer alignment.
  • a film can be formed on the structure as shown in view (E), such as evaporation, sputtering and other processes can be used to deposit a metal thin film material, such as Au, to obtain the structure as shown in view (F).
  • peeling can be performed to separate the film in the non-patterned area from the film in the patterned area by removing the photoresist in the non-patterned area, thereby obtaining a structure as shown in view (G), that is, the conductor layer is manufactured.
  • the glue removal process may be performed again after the glue removal stripping to further remove residual glue on the surface of the structure.
  • the backend site layer may also be manufactured.
  • the fabrication process of the backend site layer may be similar to the fabrication process of the metal film described above with respect to the conductor layer.
  • Views (H) to (K) of Figure 8 illustrate the fabrication of the top insulating layer.
  • patterning can generally be achieved directly through patterned exposure and development.
  • patterning cannot be achieved through exposure and development of the insulating layer. Therefore, it can be patterned on top of this layer. Create a thick enough patterned anti-etching layer, and then remove the film in the areas not covered by the anti-etching layer by dry etching (the anti-etching layer will also become thinner, so the anti-etching layer needs to be ensured Thick enough), and then remove the etching resist layer to achieve patterning of the non-photosensitive layer.
  • the insulating layer may be manufactured using photoresist as an etching-resistant layer.
  • the manufacturing of the top insulating layer may include film forming processes, film forming and curing, patterning, enhanced curing and other steps.
  • View (H) shows the structure obtained after the top insulating layer is formed
  • view (I) shows the structure obtained after the top insulating layer is formed.
  • Photoresist and mask are applied on the top insulating layer after film formation.
  • View (J) shows the structure including the etching resist layer obtained after exposure and development.
  • View (K) shows the structure including the prepared The structure of the top insulation layer.
  • the film-forming process, film-forming curing and enhanced curing have been described in detail above for the bottom insulation layer, and are omitted here for the sake of brevity.
  • the patterning step can be performed after film formation and curing, or after enhanced curing.
  • the insulating layer has stronger etching resistance.
  • a sufficiently thick layer of photoresist is created on the insulating layer through steps such as glue spreading and baking.
  • the outline of the top insulating layer is realized and the outline of the through hole is realized in the position of the top insulating layer corresponding to the electrode site.
  • the pattern is transferred to the photoresist on the insulating layer through steps such as exposure and development to obtain an etching-resistant layer, in which the portion that needs to be removed from the top insulating layer is exposed.
  • the exposed part of the top insulating layer can be removed by oxygen plasma etching, and then the remaining photoresist on the top insulating layer can be removed with a developer or acetone after flood exposure to obtain the structure shown in view (K) .
  • the top insulating layer may also undergo an adhesion-promoting treatment before manufacturing to improve the bonding force between the bottom insulating layer and the top insulating layer.
  • View (L) of Figure 8 shows the fabrication of the top electrode site layer over the top insulating layer.
  • the method 9000 may include: at S901, adjusting the position of the flexible electrode to align the conductor with the optical device, including making the conductor longitudinally a first distance lower than the upper end face of the optical device, and adjusting the position of the electrode laterally so that the conductor at the rear end of the electrode spreads out.
  • the first distance is 0mm-2.5mm
  • the flexible electrode is laterally 3mm-20mm away from the edge of the optical device.
  • the optical device is fixed, pure water is dropped on the upper surface of the optical device, and the electrode site of the flexible electrode is moved into the water droplets on the upper surface of the optical device, including exposing the optical device to a second distance for clamping and fixing. , the electrode sites are adjusted in the water droplet so that the electrode sites are flat on the upper surface of the optical device. Preferably, the second distance is 3-10mm.
  • the water droplets are sucked dry so that the flexible electrode is attached to the upper surface of the optical device; and at step S904, the attached flexible electrode and the optical device are surgically implanted so that the attached part is in contact with the biological tissue.
  • a transparent adhesive may be dripped on the upper surface of the optical device to attach the electrode site portion of the flexible electrode to the upper surface of the optical device.
  • the electrode wire and the circular site at the front end are first detached from the flexible separation layer, and then the electrode site area is moved to the water droplet on the upper surface of the prism, and the electrode site area is adjusted in the water droplet Lay it flat on the upper surface of the prism, and then absorb the water.
  • the electrode array will be closely attached to the upper surface of the prism. Then, attach the rear wire to the side wall of the prism, and the assembly is completed.
  • the assembled prism with flexible electrode attached use the following steps to implant it into the corresponding area of the brain: First, determine the implantation area of the brain, place the assembled electrodes and prism above the implantation area, and pass the prism through the prism. The support device adjusts the position of the prism so that it faces the hole to be implanted, thereby pressing the prism into the corresponding area. It should be noted that the conductor must have a certain degree of freedom of movement during the operation to avoid breakage of the conductor or movement of the site area. Then, lay the back-end wire flat on the surface of the skull so that the prism is tightly combined with the skull, and move the supporting device upward to separate it from the prism. Thereafter, electrical signal recording can be carried out after the prism and electrode are completely implanted, and the field potential signal can be recorded relatively stably. Calcium signal recording requires waiting time to allow the tissue to fully recover.
  • the flexible electrode array using stretchable carbon nanotubes can have, for example, 16 recording sites, the electrode recording site size is 100 ⁇ m ⁇ 100 ⁇ m, and the lead width is 50 ⁇ m.
  • the flexible electrode array using transparent graphene can have, for example, 8-16 recording sites, and the recording site size is 300m ⁇ 300 ⁇ m.
  • Stretchable carbon nanotubes and graphene use PDMS as the substrate and have a thickness of more than 100 ⁇ m, so the preparation process is more complex and the adhesion is insufficient.
  • the flexible electrodes in the embodiments of the present disclosure have electrode sites with smaller sizes, and the line widths can be less than 1.5 ⁇ m or even hundreds of nanometers, allowing for a higher number of channels with the same electrode size.
  • the line widths can be less than 1.5 ⁇ m or even hundreds of nanometers, allowing for a higher number of channels with the same electrode size.
  • a 64-channel electrode can be realized, and hundreds or thousands of channels can be realized; on the other hand, the thickness of the electrode is only 1 ⁇ m, so it can achieve technical effects of being thinner, more transparent, and better adherent.
  • the word "exemplary” means “serving as an example, instance, or illustration” rather than as a “model” that will be accurately reproduced. Any implementation illustratively described herein is not necessarily to be construed as preferred or advantageous over other implementations. Furthermore, the disclosure is not bound by any expressed or implied theory presented in the above technical field, background, brief summary or detailed description.
  • the word “substantially” is meant to include any minor variations resulting from design or manufacturing defects, device or component tolerances, environmental effects, and/or other factors.
  • the word “substantially” also allows for differences from perfect or ideal conditions due to parasitic effects, noise, and other practical considerations that may be present in actual implementations.

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Abstract

L'invention concerne un appareil d'électrode flexible pour la liaison avec un dispositif optique implantable, qui comprend : une électrode à mailles implantable, flexible, à transmittance élevée et à canaux multiples, l'électrode à mailles étant fixée à la surface du dispositif optique et étant en contact avec un tissu biologique après l'implantation du dispositif optique, et une partie de fixation de l'électrode à mailles à canaux multiples fixée au dispositif optique comprenant : un fil, situé entre une première couche isolante (220) et une seconde couche isolante (250) de l'électrode ; et un site d'électrode (310), situé au-dessus de la seconde couche isolante (250) et couplé électriquement au fil au moyen d'un trou traversant dans la seconde couche isolante (250). L'appareil d'électrode flexible peut enregistrer un signal électrophysiologique d'activité nerveuse et effectuer une stimulation électrique par l'électrode tandis que le dispositif optique réalise une interaction optique.
PCT/CN2022/102566 2022-06-17 2022-06-30 Appareil d'électrode flexible pour liaison avec un dispositif optique implantable et procédé de fabrication dudit appareil WO2023240700A1 (fr)

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CN110786846A (zh) * 2019-12-11 2020-02-14 中国科学院深圳先进技术研究院 一种柔性记录电极及其制备方法与植入方法
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US20150157862A1 (en) * 2013-12-06 2015-06-11 Second Sight Medical Products, Inc. Cortical Implant System for Brain Stimulation and Recording
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