Flexible electrode device for combining with SEEG electrode and manufacturing method thereof

Abstract

A flexible electrode device for use in combination with a SEEG electrode, comprising: at least one implantable and flexible electrode wire, wherein each electrode wire comprises: a wire located between a first insulating layer and a second insulating layer of the flexible electrode; and an electrode site located above the second insulating layer and electrically coupled to the wire via a through hole in the second insulating layer, wherein the at least one electrode wire is configured to be attached to the SEEG electrode and to contact biological tissue after the SEEG electrode is implanted.

Description

Technical Field

[0001] The present disclosure relates to a flexible electrode device for combining with stereotactic electroencephalography (SEEG) electrodes and a method for manufacturing the same, and in particular, to a flexible electrode device and a method for manufacturing the same that can achieve firm attachment without using a specific adhesive and without significantly affecting the SEEG electrodes. Background Art

[0002] For patients with medically refractory epilepsy, timely and accurate diagnosis allows physicians at all levels and epilepsy specialists to provide more effective treatment and services. SEEG technology utilizes a minimally invasive approach, requiring no surgical incisions. Instead, it requires only 2mm micro-holes drilled in the scalp and skull to place deep electrodes at specific locations deep within the brain. Therefore, this technology is suitable for epilepsy patients who require intracranial EEG localization.

[0003] SEEG technology introduces the positioning method from 2D to 3D level. It can be directly placed in the deep frontal lobe, medial side of the brain, cingulate gyrus, medial temporal lobe and other target areas in the skull that conventional cortical electrodes cannot reach, providing all-round three-dimensional coverage of the brain, thereby achieving the purpose of accurately locating lesions and improving treatment effects. It is a new epilepsy lesion localization technology that plays an important role in identifying lesions in epilepsy patients. Summary of the Invention

[0004] The present application proposes a flexible electrode device for combining with a SEEG electrode and a manufacturing method thereof.

[0005] According to a first aspect of an embodiment of the present disclosure, a flexible electrode device for use in combination with a SEEG electrode is provided, comprising: at least one implantable and flexible electrode wire, wherein each electrode wire comprises: a wire located between a first insulating layer and a second insulating layer of the flexible electrode; and an electrode site located above the second insulating layer and electrically coupled to the wire through a through hole in the second insulating layer, wherein the at least one electrode wire is configured to be attached to the SEEG electrode and to contact biological tissue after the SEEG electrode is implanted.

[0006] According to a second aspect of an embodiment of the present disclosure, a method for manufacturing a flexible electrode device is provided, which includes a flexible electrode for combining with a SEEG electrode as described in the first aspect, the method including: manufacturing a flexible separation layer on a substrate; manufacturing a first insulating layer, a wire layer, a second insulating 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 manufacturing the electrode site layer, through holes are manufactured by patterning at positions corresponding to the electrode sites in the second insulating layer.

[0007] According to a third aspect of an embodiment of the present disclosure, a method for processing a flexible electrode device is provided, which flexible electrode device includes a flexible electrode for combining with a SEEG electrode as described in the first aspect, and the method includes: contacting and fitting the SEEG electrode and the root of the flexible electrode in pure water; adjusting the fitting angle, and slowly pulling the combination of the SEEG electrode and the flexible electrode out of the water; and baking the combination to enhance the adhesion between the SEEG electrode and the flexible electrode.

[0008] The advantage of the embodiments disclosed herein is that the flexible film and the SEEG electrode can be firmly attached without using any adhesives and without affecting the size, physicochemical properties and surgical process of the SEEG electrode, thereby providing a basis for surgical implantation of the SEEG electrode and various flexible films, and expanding the application of the SEEG electrode. For example, when combined with a flexible electrode, it can have functions such as multi-channel, single-cell-level precise EEG signal acquisition and electrical stimulation.

[0009] It should be appreciated that the advantages described above need not all be realized in one or some specific embodiments, but may be partially dispersed across different embodiments according to the present disclosure. Embodiments according to the present disclosure may have one or some of the advantages described above, or may alternatively or additionally have other advantages.

[0010] Other features and advantages of the present invention will become more apparent from the following detailed description of exemplary embodiments of the present invention with reference to the accompanying drawings. BRIEF DESCRIPTION OF THE DRAWINGS

[0011] Figure 1 is an exploded schematic diagram showing a flexible electrode according to an embodiment of the present disclosure.

[0012] Figure 2 Schematic diagrams showing different perspectives of a flexible electrode device combined with a SEEG electrode according to an embodiment of the present disclosure.

[0013] Figure 3 is a schematic diagram illustrating an end portion of a flexible electrode device combined with a SEEG electrode according to an embodiment of the present disclosure.

[0014] Figure 4 is another schematic diagram illustrating a flexible electrode device combined with a SEEG electrode according to an embodiment of the present disclosure.

[0015] Figure 5 is a flowchart illustrating a method of manufacturing a flexible electrode according to an embodiment of the present disclosure.

[0016] Figure 6 is a schematic diagram illustrating a method for manufacturing a flexible electrode according to an embodiment of the present disclosure.

[0017] Figure 7 is a schematic diagram illustrating a method of attaching a flexible electrode to a SEEG electrode according to an embodiment of the present disclosure.

[0018] Figure 8 is a flow chart illustrating a method of attaching a flexible electrode to a SEEG electrode according to an embodiment of the present disclosure. DETAILED DESCRIPTION

[0019] Various exemplary embodiments of the present disclosure will be described in detail below with reference to the accompanying drawings. It should be noted that unless otherwise specifically stated, the relative arrangements of components and steps, numerical expressions and numerical values set forth in these embodiments do not limit the scope of the present disclosure.

[0020] The following description of at least one exemplary embodiment is merely illustrative and is not intended to limit the present disclosure, its application, or use. In other words, the structures and methods herein are presented in an exemplary manner to illustrate various embodiments of the structures and methods of the present disclosure. However, those skilled in the art will appreciate that these are merely exemplary of the present disclosure that may be implemented, and are not exhaustive. Furthermore, the drawings are not necessarily drawn to scale, and some features may be exaggerated to illustrate details of specific components.

[0021] Technologies, methods and equipment known to ordinary technicians in the relevant art may not be discussed in detail, but where appropriate, such technologies, methods and equipment should be considered part of the authorization specification.

[0022] The inventors of this application found in their research that the existing SEEG technology is limited by volume, number of channels, and size of electrode sites. Even if it can be used to determine the location of epileptic lesions, it is not possible to accurately collect EEG data, perform electrical stimulation, and monitor the brain microenvironment at the single-cell level. Specifically, a single SEEG electrode is limited by volume and original design. The number of channels is generally more than ten, and the electrode sites are large, at the millimeter scale. Therefore, the number of channels is small and the amount of channel information is large, resulting in low recording accuracy. The data usually obtained is a field potential signal (LFP), which is not suitable for single-cell level EEG signal acquisition. SEEG electrodes have a relatively single function and are often used for epileptic lesion location. They lack scalability in other functions. When used in combination with flexible electrodes, they can use the flexible electrodes to record action potential (spike) data, improve the precision and accuracy of epileptic lesion location, and also provide other medical or scientific research purposes.

[0023] Based on this, the technical solution of the present application attempts to attach an ultra-thin and ultra-flexible thin film electrode to the SEEG electrode to improve and expand the function of the SEEG electrode.

[0024] In summary, the technical solution disclosed in the present invention mainly relates to a flexible electrode for brain electrical stimulation and electrical signal collection, which has technical effects such as smaller size, better adhesion and multi-channel. The flexible electrode is combined with a SEEG electrode to cooperate with implantation into the brain area, thereby obtaining expanded comprehensive detection results, such as realizing multi-channel, single-cell-level precise EEG signal acquisition and electrical stimulation, physiological signal monitoring (ion concentration, pH value, etc.), etc.

[0025] Figure 1 FIG. 1 shows an exploded view of a flexible electrode according to an embodiment of the present disclosure. Figure 1 As shown, the shape of the flexible electrode can be a strip, which includes a wire portion connected to an external circuit, an electrode site, an attachment portion (rear end portion) attached to the SEEG electrode, and a contact portion with biological tissue. It should be noted that the actual shape of the electrode and / or individual components can be designed according to needs and are not limited to the shape and size relationship shown. Specifically, it can be clearly seen from the figure that the flexible electrode is a multi-layer structure, specifically, including a flexible separation layer 110, a first insulating layer 120, a layer 130 connected to the circuit board, a wire layer 140, a second insulating layer 150, an electrode site layer 160, etc. It should be understood that, Figure 1 The distribution of the layers of the flexible electrode shown in FIG is merely a non-limiting example. The flexible electrode in the present disclosure may omit one or more layers, or may include more other layers.

[0026] like Figure 1 As shown, the conductive wires in the flexible electrode include a plurality of conductive wires located in a conductive wire layer and spaced apart from one another. The electrode sites in the flexible electrode include a plurality of electrode sites each electrically coupled to one of the plurality of conductive wires via a corresponding through-hole in a bottom insulating layer. The flexible electrode has excellent flexibility and can be partially or fully implanted in biological tissue to collect or apply electrical signals to the biological tissue. Figure 1 The conductive layer of the flexible electrode shown in the figure includes a plurality of wires, however, it should be understood that in different embodiments, the electrode in the present disclosure may include a single wire or other specified number of wires. These wires may have a width and thickness of nanometers or micrometers, and a length that is several orders of magnitude (such as centimeters) larger than the width and thickness as needed. In the embodiments according to the present disclosure, the shape, size, etc. of these wires are not limited to the ranges listed above, but may vary according to design requirements.

[0027] Specifically, the flexible electrode may include a first insulating layer 120 located at the bottom of the electrode and a second insulating layer 150 located at the top of the electrode. The insulating layer in the flexible electrode may refer to the outer surface layer of the electrode that plays an insulating role. Since the insulating layer of the flexible electrode needs to contact the biological tissue after implantation, the material of the insulating layer is required to have good insulation and good biocompatibility. In the embodiment of the present disclosure, the material of the insulating layers 120 and 150 may include polyimide (PI), polydimethylsiloxane (PDMS), polyparaxylene (Parylene), epoxy resin, polyamideimide (PAI), etc. In addition, the insulating layers 120 and 150 are also the main part that provides strength in the flexible electrode. If the insulating layer is too thin, the strength of the electrode will be reduced, and if the insulating layer is too thick, the flexibility of the electrode will be reduced. Moreover, the implantation of an electrode including an overly thick insulating layer will cause greater damage to the organism. In the embodiment according to the present disclosure, the thickness of the insulating layers 120 , 150 may be 100 nm to 300 μm, preferably 300 nm to 3 μm, more preferably 1 μm to 2 μm, 500 nm to 1 μm, etc.

[0028] The conductive wire layer in the flexible electrode is distributed in the conductive wire layer 140 between the first insulating layer 120 and the second insulating layer 150. In an embodiment according to the present disclosure, each flexible electrode may include one or more conductive wires located in the same conductive wire layer 140. For example, Figure 1 As can be clearly seen in the figure, the conductive wire layer 140 of the flexible electrode includes a plurality of conductive wires, each of which includes an elongated main body and an end portion corresponding to a corresponding electrode site. The line width of the conductive wires and the spacing between the conductive wires can be, for example, 10 nm to 500 μm, and the spacing between the conductive wires can be as low as 10 nm, for example, preferably 100 nm to 3 μm. It should be understood that the shape, size, spacing, etc. of the conductive wires are not limited to the ranges listed above and can vary according to design requirements.

[0029] In an embodiment according to the present disclosure, the conductors in the conductor layer 140 can be a thin film structure including multiple layers stacked in the thickness direction. The materials of these layers can be materials that can enhance the properties of the conductors such as adhesion, ductility, and conductivity. As a non-limiting example, the conductor layer 140 can include a stacked conductive layer and an adhesion layer, wherein the adhesion layer in contact with the insulating layer 120 and / or 150 is a metal adhesion material or a non-metal adhesion material such as titanium (Ti), titanium nitride (TiN), chromium (Cr), tantalum (Ta) or tantalum nitride (TaN), and the conductive layer is a material with good conductivity such as gold (Au), platinum (Pt), iridium (Ir), tungsten (W), magnesium (Mg), molybdenum (Mo), platinum-iridium alloy, titanium alloy, graphite, carbon nanotubes, PEDOT, etc. It should be understood that the conductor layer can also be made of other conductive metal materials or non-metallic materials, or can be made of polymer conductive materials and composite conductive materials. In a non-limiting embodiment, the thickness of the conductive layer of these conductors is 5nm to 200μm, and the thickness of the adhesion layer is 1 to 50nm.

[0030] The flexible electrode may further include electrode sites in an electrode site layer 160 located above the first insulating layer 120. These electrode sites, after implantation of the flexible electrode, may contact biological tissue to directly collect or apply electrical signals. In the flexible electrode, an electrode site in the electrode site layer 160 may be electrically coupled to a corresponding wire via a through-hole in the first insulating layer 120 at a position corresponding to the electrode site. If the flexible electrode includes multiple wires, the flexible electrode may correspondingly include multiple electrode sites in the electrode site layer 160, and each of these electrode sites may be electrically coupled to one of the multiple wires via a corresponding through-hole in the first insulating layer 120.

[0031] In a non-limiting embodiment, each electrode site may have a corresponding wire in the wire layer 140. Each electrode site may have a planar dimension in the micrometer order and a thickness in the nanometer order. In an embodiment according to the present disclosure, the electrode sites may include sites with a diameter of 1 μm to 500 μm, and the spacing between each electrode site may be 1 μm to 5 mm. In an embodiment according to the present disclosure, 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 may be selected according to the conditions of the biological tissue area to be recorded.

[0032] In an embodiment according to the present disclosure, the electrode sites in the electrode site layer 160 may be a thin film structure including multiple layers stacked in the thickness direction. The material of the layer close to the wire layer 140 in the multiple layers may be a material that can enhance the adhesion of the electrode sites to the wire. As a non-limiting example, the electrode site layer 160 may be a metal film including two stacked layers, wherein the first layer close to the wire layer 140 is Ti, TiN, Cr, Ta or TaN, and the second layer exposed to the outside of the electrode site layer 260 is Au. It should be understood that the electrode site layer may also be similar to the wire layer, and may be made of other conductive metal materials or non-metallic materials, such as Pt, Ir, W, Mg, Mo, platinum-iridium alloy, titanium alloy, graphite, carbon nanotubes, PEDOT, etc.

[0033] In embodiments of the present disclosure, the surface of the electrode site exposed to contact biological tissue may also have a surface modification layer to improve the electrochemical properties of the electrode site. As a non-limiting example, the surface modification layer can be obtained by using a PEDOT:PSS electropolymerization coating, sputtering an iridium oxide film, or other methods. This layer is used to reduce impedance (such as electrochemical impedance at a 1 kHz operating frequency) when the flexible electrode collects electrical signals, and to improve charge injection capability when the flexible electrode applies electrical signal stimulation, thereby improving interaction efficiency.

[0034] In an embodiment according to the present disclosure, the flexible electrode may further include a bottom electrode site layer (not shown) located below the first insulating layer 120, and after the flexible electrode is implanted, the electrode site may contact biological tissue to directly collect or apply electrical signals. Specifically, the bottom electrode site layer is similar to the electrode sites in the electrode site layer 160, and in the flexible electrode, the electrode sites in the bottom electrode site layer may be electrically coupled to corresponding wires through through-holes at positions corresponding to the electrode sites in the bottom insulating layer. In an embodiment according to the present disclosure, the electrode sites in the bottom electrode site layer may be located at relative positions on both sides of the top and bottom of the flexible electrode as the electrode sites in the electrode site layer 160, and may be electrically coupled to the same wire in the wire layer 140 as the electrode sites in the electrode site layer 160 located at relative positions. In an embodiment according to the present disclosure, the electrode sites in the bottom electrode site layer may also be located at different positions on the top and bottom sides of the flexible electrode from the electrode sites in the electrode site layer 160 to collect or apply electrical signals in different areas of biological tissue; and in an embodiment according to the present disclosure, the electrode sites in the bottom electrode site layer may also be electrically coupled to wires in the wire layer 140 that are different from the electrode sites in the electrode site layer 160.

[0035] In an embodiment of the present disclosure, the flexible electrode may further include a flexible separation layer 110. The flexible separation layer 110 is primarily used in the manufacturing process of the flexible electrode. The flexible separation layer can be removed by a specific substance to separate portions of the flexible electrode and prevent damage to the flexible electrode. The flexible separation layer is provided with an adhesion layer. The material of the flexible separation layer is any one of nickel, chromium, and aluminum, or a combination thereof. The flexible separation layer 110 is also provided with an adhesion layer, the material of which includes chromium, tantalum, tantalum nitride, titanium, or titanium nitride.

[0036] It should be understood that the bottom electrode site layer is an optional and not essential part of the flexible electrode, e.g. Figure 1 In the decomposed structure shown in , the flexible electrode may include only the electrode site layer 160 but not the 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.

[0037] In an embodiment of the present disclosure, the rear end portion of the flexible electrode may include at least one rear end site, and the attachment portion of the flexible electrode attached to the optical device each extends from the rear end portion. The rear end site can be electrically coupled to one of the conductive wires and the rear end circuit via a through-hole in the first insulating layer 120 and / or the second insulating layer 150, thereby enabling bidirectional signal transmission between the electrode site electrically coupled to the conductive wire and the rear end circuit. Here, the rear end circuit may refer to a circuit at the rear end of the flexible electrode, such as a recording circuit, a processing circuit, etc. associated with the signal of the flexible electrode. In an embodiment of the present disclosure, the flexible electrode can be coupled to the rear end circuit by a connection. Specifically, the ball grid array (BGA) package site serving as the rear end site can be connected to a commercial signal recording system via a printed circuit board (PCB), a flexible printed circuit (FPC), etc. Connection methods include ball mounting and anisotropic conductive film bonding (ACF bonding). In the embodiments disclosed herein, the flexible electrode can also be integrated with the back-end circuit. Specifically, pre-processing functions such as signal amplification and filtering can be integrated on a dedicated chip, which is then connected and packaged with an integrated PCB at the back end of the flexible electrode through bonding or other methods, thereby achieving wireless transmission and charging. In this case, an independent flexible electrode and an independent dedicated chip serving as the back-end circuit can be used, with the electrical connection between the flexible electrode and the dedicated chip being achieved through methods such as ball implantation or ACF bonding. Alternatively, a certain amount of space can be reserved on a pre-taped wafer of the chip serving as the back-end circuit, and the electrodes can be directly fabricated on this basis, thereby enabling the combined or separate processing of the chip and electrode, achieving a higher level of integration.

[0038] The back-end site can have planar dimensions on the micrometer scale and thickness on the nanometer scale. As non-limiting examples, the back-end site can be a BGA package site with a diameter of 50 μm to 2000 μm, or a circular, elliptical, rectangular, rounded-corner rectangular, or chamfered rectangular site with a side length of 50 μm to 2000 μm. It should be understood that the shape and size of the back-end site are not limited to the ranges listed above and can vary according to design requirements.

[0039] The back-end site in a connected manner may include multiple layers in the thickness direction. The material of the adhesion layer near the wire layer 140 among the multiple layers may be a material that can enhance the adhesion between the electrode site and the wire. The material of the intermediate soldering layer among the multiple layers may be a soldering material. The conductive layer among the multiple layers may be other conductive metal materials or non-metallic materials such as the wire layer 140 described above. The outermost layer among the multiple layers that may be exposed through the insulating layers 120 and 150 is a protective layer for oxidation prevention. As a non-limiting example, the back-end site layer may include a stacked conductive layer and an adhesion layer, wherein the adhesion layer near the wire layer 140 may be a nano-scale layer to improve the adhesion between the back-end site layer and the wire layer 140. The adhesion layer as the intermediate soldering layer may be nickel (Ni), Pt, or palladium (Pd). The third layer as the outermost conductive layer may be Au, Pt, Ir, W, Mg, Mo, platinum-iridium alloy, titanium alloy, graphite, carbon nanotubes, PEDOT, etc. It should be understood that the back-end site layer may also be made of other conductive metal materials or non-metal materials. Figure 1 The back-end site layer serves as the connection to the back-end processing system or chip. The site size, spacing, shape, etc. can be changed to suit different back-end connection methods. In one non-limiting embodiment, the flexible electrode has 512 electrode sites, including four 128BGAs. It should be understood that other electrode sites with different channel numbers can be included as needed, such as 32, 36, 64, or 128 channels.

[0040] In an embodiment according to the present disclosure, the flexible electrode may not include site layers such as an electrode site layer (and / or a bottom electrode site layer), a back-end site layer, etc. In this case, the electrode sites of the flexible electrode and the back-end sites for switching in the back-end portion may both be parts of the wire layer and electrically coupled to corresponding wires in the wire layer. Furthermore, the electrode sites for sensing and applying electrical signals may be directly in contact with the tissue area into which the electrode wire is implanted. As a non-limiting example, each electrode site may be electrically coupled to a corresponding wire in the wire layer in the wire layer, and exposed to the outer surface of the electrode wire and in contact with biological tissue through corresponding through-holes in the top insulating layer or the bottom insulating layer.

[0041] Figure 2 Schematic diagrams illustrating a device combining a flexible electrode and a SEEG electrode according to the present disclosure from different perspectives, with (A) through (C) illustrating the combined state of the flexible electrode and SEEG electrode from the upper side, the side, and the top, respectively. In one non-limiting embodiment, as shown in the figure, the SEEG electrode 201 is generally cylindrical in shape, and the flexible electrode 202 is attached to the cylindrical outer wall of the SEEG electrode 201.

[0042] like Figure 2 As shown, the inner diameter of the SEEG electrode is generally 0.5mm to 2mm, and the inner diameter of the electrode shown in the figure is preferably 1mm. The commonly used thickness of the flexible electrode is 300nm-10μm, and the thickness shown in the figure is 10μm; the commonly used width is 100μm-500μm, and the specific width can be adjusted according to the usage scenario and function. In addition, close adhesion to the SEEG electrode can be achieved without the use of adhesives, which will be described later. Therefore, the flexible electrode itself has the characteristics of ultra-thinness, ultra-flexibility, good adhesion, and the size and position relationship of the flexible electrode compared to the SSEG electrode can be adjusted in actual applications. Therefore, combining the flexible electrode with the SEEG electrode will not significantly affect the size (such as cross-sectional area), physicochemical properties and / or implantation surgery of the SEEG electrode.

[0043] The device after combining the above flexible electrode with the SEEG electrode is further as follows Figure 3 As shown, Figure 3 (A) shows a front view of the device. Figure 3 (B) is an enlarged schematic diagram of region 300 (i.e., the end portion of the device) in (A). In one non-limiting embodiment, as shown, SEEG electrode sites 301 are made of a metal material, such as platinum-iridium alloy, platinum, silver, stainless steel, or any combination thereof. SEEG electrode rods 302 between the electrode sites are typically made of an insulating material. The electrode sites of flexible electrode 303 are partially attached to the outer sidewall of electrode rod 302, forming a relatively tightly attached assembly.

[0044] Alternatively, Figure 4 FIG is another schematic diagram showing a flexible electrode device combined with a SEEG electrode according to an embodiment of the present disclosure. That is, in addition to the adhesiveness of the flexible electrode itself, the flexible electrode can also be connected by mechanical means. Specifically, as Figure 4 As shown, the structure of the SEEG electrode 400 can be customized so that the SEEG electrode site 402 (usually a metal ring structure) or the rod material forms a gap for the flexible electrode 401 to pass through. Figure 4(A) and (B) show the metal ring of the customized electrode site 401 and its enlarged schematic diagram respectively. It should be noted that Figure 4 The gap in (B) is for illustration only; in practice, the relationship between the gap size and the diameter of the SSEG electrode is not the same. Furthermore, after the flexible electrode 402 passes through the metal ring gap at the electrode site 401, a secure connection between the flexible electrode and the SEEG electrode is formed by thermal contraction or thermal expansion. Alternatively, a groove can be customized in the structure of the SEEG electrode 400 to conform to the shape of the flexible electrode 401, thereby securing the flexible electrode 401 in the groove and preventing undesirable relative movement between the flexible electrode 401 and the SEEG electrode 400 during implantation.

[0045] Figure 5 is a flow chart showing a method for manufacturing a flexible electrode according to an embodiment of the present disclosure. In the present disclosure, a manufacturing method based on a micro-electromechanical system (MEMS) process can be adopted to manufacture a nano-scale flexible electrode. Figure 5 As shown, method 5000 may include: at S501, manufacturing a flexible separation layer on a substrate; at S502, manufacturing a first insulating layer, a wire layer, a second insulating layer and an electrode site layer layer by layer on the flexible separation layer, wherein, before manufacturing the electrode site, a through hole is manufactured at a position corresponding to the electrode site in the first insulating layer by patterning; and at S503, removing the flexible separation layer to separate the flexible electrode from the substrate.

[0046] Figure 6 Schematic diagram showing a method for manufacturing a flexible electrode according to an embodiment of the present disclosure. Figure 6 The manufacturing process and structure of the flexible separation layer, bottom insulating layer, wire layer, top insulating layer, electrode site layer and other parts of the flexible electrode are described in more detail.

[0047] Figure 6 The view (A) shows the substrate of the electrode. In the embodiment according to the present disclosure, a hard substrate such as glass, quartz, silicon wafer, etc. can be used. In the embodiment of the present disclosure, other soft materials can also be used as the substrate, such as the same material as the insulating layer.

[0048] Figure 6 The view (B) shows the step of making a flexible separation layer on the substrate. The flexible separation layer can be removed by applying a specific substance, thereby facilitating the separation of the flexible part of the electrode from the hard substrate. Figure 8The embodiment shown in uses Ni as the material of the flexible separation layer, and other materials such as Cr and Al may also be used. In an embodiment according to the present disclosure, when manufacturing a flexible separation layer on a substrate by evaporation, a portion of the exposed substrate may be etched first, thereby improving the flatness of the entire substrate after evaporation. It should be understood that the flexible separation layer is an optional but not necessary part of the flexible electrode. Depending on the characteristics of the selected material, the flexible electrode can also be conveniently separated without a flexible separation layer. In an embodiment according to the present disclosure, the flexible separation layer may also have a mark, which can be used for alignment of subsequent layers.

[0049] Figure 6 View (C) shows the manufacture of the bottom insulating layer on top of the flexible separation layer. As a non-limiting example, in the case where the insulating layer is made of polyimide material, the manufacture of the bottom insulating layer may include steps such as film forming process, film curing and enhanced curing to manufacture a thin film as the insulating layer. The film forming process may include coating polyimide on the flexible separation layer, such as spin coating a layer of polyimide at a segmented speed. Film curing may include gradually heating to a higher temperature and keeping the temperature to form a film, thereby performing subsequent processing steps. Enhanced curing may include performing multi-gradient temperature increases before manufacturing subsequent layers, preferably heating in a vacuum or nitrogen atmosphere, and baking for several hours. It should be understood that the above-mentioned manufacturing process is only a non-limiting example of the manufacturing process of the bottom insulating layer, and one or more steps may be omitted, or more other steps may be included.

[0050] It should be noted that the above manufacturing process is directed to an embodiment of manufacturing a bottom insulating layer in a flexible electrode without a bottom electrode site layer and without through holes corresponding to the electrode sites in the bottom insulating layer. If the flexible electrode includes a bottom electrode site layer, the bottom electrode site layer can be manufactured on the flexible separation layer before manufacturing the bottom insulating layer. For example, Au and Ti can be sequentially evaporated on the flexible separation layer. The patterning step of the bottom electrode site will be described in detail later with respect to the top electrode site. Accordingly, in the case where the flexible electrode includes a bottom electrode site, in addition to the above steps, a patterning step can be included in the process of manufacturing the bottom insulating layer for etching a through hole at a position corresponding to the bottom electrode site in the bottom insulating layer. The patterning step of the insulating layer will be described in detail later with respect to the top insulating layer.

[0051] Figure 6Views (D) to (G) show the manufacture of the conductor layer on the bottom insulating layer. As shown in view (D), a photoresist and a mask can be applied on top of the bottom insulating layer. It should be understood that other photolithographic means can also be used to prepare patterned thin films, such as laser direct writing and electron beam lithography. In an embodiment according to the present disclosure, for a metal film such as a conductor layer, a double layer of glue can be applied to facilitate the manufacture (evaporation or sputtering) and peeling of the patterned film. By setting the pattern of the mask associated with the conductor layer, for example, Figure 1 The pattern of the wire layer 140 shown in , that is, the outline of one or more wires in each electrode wire extending from the rear end portion. Then, exposure and development can be performed to obtain a structure as shown in view (E). In an embodiment according to the present disclosure, exposure can be performed by contact lithography, and the mask and the structure are exposed in a vacuum contact mode. In an embodiment according to the present disclosure, different developers and their concentrations can be used for graphics of different sizes. This step can also include alignment between layers. Then, film formation can be performed on the structure shown in view (E), such as using processes such as evaporation and sputtering to deposit metal thin film materials, such as Au, to obtain a structure as shown in view (F). Then, stripping can be performed to separate the thin film in the non-patterned area from the thin film in the patterned area by removing the photoresist in the non-patterned area, to obtain a structure as shown in view (G), that is, to manufacture a wire layer. In an embodiment according to the present disclosure, after stripping, debonding can be performed again to further remove residual glue on the surface of the structure.

[0052] In an embodiment of the present disclosure, a back-end site layer may be manufactured before the wire layer. As a non-limiting example, the manufacturing process of the back-end site layer may be similar to the manufacturing process of the metal film described above for the wire layer.

[0053] Figure 6Views (H) to (K) show the manufacture of the top insulating layer. For photosensitive films, patterning can generally be achieved directly through patterned exposure and development, while for the non-photosensitive material used in the insulating layer, patterning cannot be achieved by exposing and developing itself. Therefore, a sufficiently thick patterned anti-etching layer can be manufactured on the layer, and then the film in the area not covered by the anti-etching layer is removed by dry etching (the anti-etching layer will also become thinner, so it is necessary to ensure that the anti-etching layer is thick enough), and then the anti-etching layer is removed to achieve the patterning of the non-photosensitive layer. As a non-limiting example, the manufacture of the insulating layer can use photoresist as the anti-etching layer. The manufacture of the top insulating layer may include the steps of film forming process, film forming and curing, patterning, enhanced curing, etc., wherein view (H) shows the structure obtained after the top insulating layer is formed, view (I) shows the application of photoresist and mask on the top insulating layer after film formation, view (J) shows the structure including the anti-etching layer obtained after exposure and development, and view (K) shows the structure including the prepared top insulating layer. The film forming process, film curing and enhanced curing have been described in detail above for the bottom insulating layer and are omitted here for the sake of brevity. The patterning step can be performed after film curing or enhanced curing. After enhanced curing, the insulating layer has a stronger etching resistance. Specifically, in Figure (I), a sufficiently thick layer of photoresist is manufactured on the insulating layer through steps such as coating and baking. By setting the pattern of the mask related to the top insulating layer, for example, Figure 1 The pattern of the top insulating layer shown in FIG, that is, the outline of the top insulating layer implemented on one or more wires of each electrode wire extending from the rear end portion and the outline of the through hole implemented in the top insulating layer at a position corresponding to the electrode site. In view (J), the pattern is transferred to the photoresist on the insulating layer through exposure, development and other steps to obtain an etch-resistant layer, wherein the portion to be removed from the top insulating layer is exposed. The exposed portion of the top insulating layer can be removed by oxygen plasma etching to obtain the structure shown in view (K).

[0054] In an embodiment according to the present disclosure, the top insulating layer may be subjected to an adhesion enhancement treatment before being manufactured to improve the bonding force between the bottom insulating layer and the top insulating layer.

[0055] Figure 6 View (L) shows the fabrication of a top electrode site layer above the top insulating layer.

[0056] Next, we will combine Figure 7 Methods of attaching a flexible electrode to a SEEG electrode according to embodiments of the present disclosure are described.

[0057] Generally, when the flexible electrode according to the present disclosure is attached to the SEEG electrode, multiple forces are simultaneously generated between the two, and the combined force of these forces together creates the technical effect of tight attachment and resistance to peeling. These forces include but are not limited to the following:

[0058] (1) Mechanical bonding: Commonly seen in the bonding force between hot melt adhesive film and adherend, the friction force generated by drying and curing between the flexible electrode and the SEEG electrode forms a mechanical bonding force.

[0059] (2) Van der Waals force: When the distance between two materials is small enough, van der Waals force or hydrogen bond will be generated between the molecules, thus obtaining good adhesion. SEEG electrode rod material and flexible film material are both non-polar materials, which are easy to form this kind of molecular force.

[0060] (3) Mutual diffusion: The adhesion between polymer compounds is due to the diffusion of the macromolecules themselves or their chain segments caused by thermal motion. In essence, the interface dissolves into each other, thus forming a strong bond.

[0061] (4) Charge attraction: It comes from the attraction between positive and negative charges in the double layer. This attraction is proportional to the square of the charge density.

[0062] The aforementioned embodiments respectively illustrate common manifestations of the above-mentioned forces. Figure 2 and Figure 3 The device in the embodiment mainly shows an example of attaching a flexible electrode to the surface of a SEEG electrode, which achieves the attachment between the flexible electrode and the SEEG electrode without using adhesives and without relying on the constraints of mechanical structures. Alternatively, Figure 4 The device in shows another example of using mechanical structure to assist electrode attachment, where a gap through which a flexible electrode can pass is formed by customizing the structure of the SEEG electrode.

[0063] In a non-limiting embodiment, the method of attaching the flexible electrode to the SEEG electrode requires at least pure water (distilled water or above), an open container that can be used to hold water (including but not limited to a beaker, a culture dish, etc.), tools required to guide the flexible film (including but not limited to a thin tungsten wire, a toothpick, a syringe needle, etc.), and / or auxiliary tools such as an oven and a high-temperature resistant container (including but not limited to a glass culture dish, an enamel tank, etc.).

[0064] Experiments show that flexible electrodes are usually made of non-polar materials. If the end of the electrode that first contacts the brain surface or other substances (such as water) is attached to a metal SEEG electrode site made of polar material, it will easily detach due to insufficient binding force. Therefore, it is recommended to attach the end that first enters the brain area to a SEEG rod made of non-polar material.

[0065] Specifically, Figure 7 FIG. 7 shows a SEEG electrode 701 and a flexible electrode 702 being attached. Figure 7 (A) and (B) show the air 703 and liquid (such as pure water) 704 and the boundary between them at different viewing angles. The base of the flexible electrode 702 of the SEEG electrode 701 is in contact with and attached to the pure water. After adjusting the attachment angle, the flexible electrode 702 is moved along the Figure 7 Slowly pull the assembly out of the water in the direction indicated by the middle arrow. At this point, the remaining portion of flexible electrode 702 will adhere to the surface of SEEG electrode 701 under the action of the water's surface tension, with the end of flexible electrode 702 ultimately resting on the non-metallic portion of SEEG electrode 701. After the combined SEEG electrode 701 and flexible electrode 702 assembly is completely lifted out of the water, it is baked to enhance the adhesion between the two electrodes.

[0066] In one non-limiting embodiment, the combined SEEG electrode 701 and flexible electrode 702 are placed in a high-temperature resistant container and placed in an oven. The high-temperature resistant container preferably has a lid to prevent airflow interference in the oven. The oven baking temperature and time depend on the heat resistance of the flexible electrode 702 and the SEEG electrode 701. Generally, the temperature should be above 40°C, preferably between 60°C and 200°C, and the baking time should be at least 3 minutes.

[0067] It should be noted that the most advantageous technical effect of the technical solution of the present application is that the flexible electrode can be attached to the SEEG electrode without the need for adhesives. Alternatively, it can be attached to the SEEG electrode through a variety of adhesives including biodegradable materials, such as polyethylene glycol, polylactic acid, polylactic acid-glycolic acid copolymer, silk protein, etc.

[0068] Figure 8 is a flow chart illustrating a method for attaching a flexible electrode to a SEEG electrode according to the aforementioned embodiment. Specifically, in step S801, the SEEG electrode and the base of the flexible electrode are brought into contact and bonded in pure water. Subsequently, in step S802, the bonding angle is adjusted, and the SEEG electrode and flexible electrode combination is slowly pulled out of the water. Finally, in step S803, the combination is baked to enhance adhesion between the SEEG electrode and the flexible electrode.

[0069] Alternatively, the technical solution of the present application can also be used in other application scenarios. The flexible electrode disclosed in the present invention can be used in combination with a DBS electrode, or attached to an optical element for use in combination.

[0070] The terms "front," "back," "top," "bottom," "above," "below," and the like, if any, in the specification and claims, are used for descriptive purposes and are not necessarily intended to describe invariant relative positions. It is understood that the terms so used are interchangeable under appropriate circumstances such that the embodiments of the disclosure described herein, for example, are capable of operation in other orientations than those illustrated or otherwise described herein.

[0071] As used herein, the word "exemplary" means "serving as an example, instance, or illustration," rather than as a "model" to be precisely copied. Any implementation described as exemplary is not necessarily to be construed as preferred or advantageous over other implementations. Furthermore, the present disclosure is not to be bound by any expressed or implied theory presented in the preceding technical field, background, summary, or detailed description.

[0072] As used herein, the term "substantially" is intended to encompass any minor variations due to design or manufacturing imperfections, device or component tolerances, environmental influences, and / or other factors. The term "substantially" also allows for deviations from a perfect or ideal condition due to parasitic effects, noise, and other practical considerations that may be present in actual implementations.

[0073] The terms "first," "second," and the like may be used herein for reference purposes only and are not intended to be limiting. For example, the terms "first," "second," and other such numerical terms when referring to structures or elements do not imply a sequence or order unless the context clearly indicates otherwise.

[0074] It should also be understood that when the term “include / comprises” is used in this document, it indicates the presence of the specified features, integers, steps, operations, units and / or components, but does not exclude the presence or addition of one or more other features, integers, steps, operations, units and / or components and / or their combinations.

[0075] As used herein, the term "and / or" includes any and all combinations of one or more of the associated listed items. The terminology used herein is for the purpose of describing particular embodiments only and is not intended to limit the present disclosure. As used herein, the singular forms "a," "an," and "the" are intended to include the plural forms as well, unless the context clearly indicates otherwise.

[0076] Those skilled in the art will appreciate that the boundaries between the above-mentioned operations are merely illustrative. Multiple operations can be combined into a single operation, a single operation can be distributed among additional operations, and operations can be performed at least partially overlapping in time. Moreover, alternative embodiments can include multiple instances of specific operations, and the order of operations can be changed in various other embodiments. However, other modifications, variations, and replacements are also possible. Therefore, this specification and the accompanying drawings should be considered illustrative, not restrictive.

[0077] Although some specific embodiments of the present disclosure have been described in detail by way of examples, it should be understood by those skilled in the art that the above examples are for illustration only and are not intended to limit the scope of the present disclosure. The various embodiments disclosed herein may be combined in any manner without departing from the spirit and scope of the present disclosure. It should also be understood by those skilled in the art that various modifications may be made to the embodiments without departing from the scope and spirit of the present disclosure. The scope of the present disclosure is defined by the appended claims.

Claims

1. An implantable electrode device comprising: SEEG electrodes; as well as a flexible electrode attached to the SEEG electrode to be combined with the SEEG electrode, the flexible electrode comprising at least one electrode wire that is implantable and flexible, wherein each of the at least one electrode wire comprises: a wire, wherein the wire is located between the first insulating layer and the second insulating layer of the flexible electrode; as well as an electrode site located above the second insulating layer and electrically coupled to the conductive line through a through hole in the second insulating layer, wherein The at least one electrode wire is configured to contact biological tissue after the SEEG electrode is implanted.

2. The implantable electrode device according to claim 1, wherein: The conductive wires in each electrode wire include a plurality of conductive wires located in a conductive wire layer of the flexible electrode and spaced apart from each other, and The electrode sites in each electrode wire include a plurality of electrode sites each electrically coupled to one of the plurality of conductive wires through a corresponding through-hole in the second insulating layer.

3. The implantable electrode device according to claim 1, wherein a posterior portion, comprising at least one posterior site, in, The at least one electrode wire each extends from the rear end portion, and Each back-end site is electrically coupled to one of the wires and the back-end circuit through a through hole in the first insulating layer or the second insulating layer to achieve bidirectional signal transmission between the electrode site electrically coupled to one of the wires and the back-end circuit.

4. The implantable electrode device according to claim 1, wherein: The thickness of the electrode wire is between 300nm and 200μm.

5. The implantable electrode device according to claim 1 , further comprising: A flexible separation layer, wherein the flexible separation layer can be removed by a specific substance to separate parts of the flexible electrode and avoid damage to the flexible electrode.

6. The implantable electrode device according to claim 5, wherein: The flexible separation layer is made of any one of nickel, chromium, and aluminum, or a combination thereof.

7. The implantable electrode device according to claim 1, wherein: The material of the first insulating layer and the second insulating layer is any one of polyimide, polydimethylsiloxane, polyparaxylene, epoxy resin, polyamide-imide, polylactic acid, polylactic acid-glycolic acid copolymer, SU8 photoresist, silica gel, silicone rubber, or a combination thereof.

8. The implantable electrode device according to claim 1, wherein: The thickness of the first insulating layer and the second insulating layer is 100 nm to 300 μm.

9. The implantable electrode device according to claim 1, wherein: The electrode sites and the wires in each electrode wire include a conductive metal layer and an adhesion layer, respectively.

10. The implantable electrode device according to claim 9, wherein: The conductive metal layer is made of any one of gold, platinum, iridium, tungsten, magnesium, molybdenum, platinum-iridium alloy, titanium alloy, graphite, carbon nanotubes, PEDOT, or a combination thereof, and has a thickness of 5 nm to 200 μm. The adhesion layer is made of chromium, tantalum, tantalum nitride, titanium, or titanium nitride, and has a thickness of 1 to 50 nm.

11. The implantable electrode device according to claim 1 , wherein: The at least one electrode wire is attached to the SEEG electrode surface in the form of a patch.

12. The implantable electrode device of claim 1 , wherein: The at least one electrode wire is attached to the SEEG electrode surface by a mechanical structure.

13. The implantable electrode device according to claim 12, wherein: The mechanical structure includes forming a gap through which the flexible electrode can pass by customizing the structure of the SEEG electrode.

14. The implantable electrode device of claim 1 , wherein: The at least one electrode wire is attached to the surface of the SEEG electrode via a biodegradable material.

15. The implantable electrode device of claim 14, wherein: The biodegradable material includes any one of polyethylene glycol, polylactic acid, polylactic acid-glycolic acid copolymer, and silk protein, or a combination thereof.

16. The implantable electrode device of claim 1, wherein: The material of the SEEG electrode is any one of platinum-iridium alloy, platinum, silver, stainless steel, or a combination thereof, and the inner diameter of the SEEG electrode is 0.5 mm to 2 mm.

17. The implantable electrode device according to claim 1, wherein: The electrode site of the flexible electrode is a first electrode site, the SEEG electrode includes a second electrode site and an electrode connecting rod located between the second electrode sites, and the first electrode site of the flexible electrode is attached to the electrode connecting rod of the SEEG electrode.

18. The implantable electrode device according to claim 1, wherein: The SEEG electrodes can be configured to record field potential signal data, and the at least one electrode wire can be configured to record action potential data.

19. A method for manufacturing the implantable electrode device according to any one of claims 1 to 18, the method comprising: fabricating a flexible separation layer on top of a substrate; manufacturing a first insulating layer, a wire layer, a second insulating layer and an electrode site layer layer by layer on the flexible separation layer; removing the flexible separation layer to separate the flexible electrode from the substrate; as well as attaching the flexible electrode to the SEEG electrode to combine with the SEEG electrode, Before manufacturing the electrode site layer, through holes are manufactured at positions corresponding to the electrode sites in the second insulating layer by patterning.

20. The method according to claim 19, wherein Attaching the flexible electrode to the SEEG electrode to combine with the SEEG electrode includes: placing the SEEG electrode in contact with and fitting the root of the flexible electrode in the liquid; Adjusting the fitting angle, and slowly pulling the combination of the SEEG electrode and the flexible electrode out of the surface of the liquid; and The combination is baked to enhance the adhesion between the SEEG electrode and the flexible electrode.

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