Flexible neural electrode with planar biological interface and preparation method thereof

Abstract

The invention relates to a flexible neural electrode with a planar biological interface and a preparation method thereof. The method comprises the following steps: forming a first polymer insulating layer on a sacrificial layer; pre-defining a pit on the first polymer insulating layer by adopting an etching process; preparing a metal working electrode and a wire which fill the pit and have the lower surface flush with the lower surface of the first polymer insulating layer; after the second polymer insulation packaging layer is covered, the sacrificial layer is removed, and the flexible electrode is released; and finally, reversing the device to enable the lower surface of the original first polymer insulating layer to face upwards, so that the working electrode is exposed, and a step-free biological contact interface which is completely flush with the packaging layer is formed. Compared with the prior art, the flexible neural electrode fundamentally solves the problem that electrode steps are generated due to the fact that holes are formed in the packaging layer of a traditional flexible neural electrode, the fitting degree of the electrode and nervous tissue is remarkably improved, interface impedance can be reduced, signal quality can be improved, and long-term biocompatibility can be improved.

Description

Technical Field

[0001] This invention relates to the field of neural interface technology in biomedical engineering, and in particular to a flexible neural electrode with a planar biological interface and its preparation method. Background Technology

[0002] Flexible neural electrodes, as a key tool for brain-computer interfaces and neuroscience research, have attracted widespread attention due to their flexible mechanical properties, which can reduce damage to brain tissue and form a more stable long-term recording interface.

[0003] Traditional flexible neural electrodes are typically fabricated using a multilayer microfabrication process: a sacrificial layer is prepared on a rigid substrate (such as a silicon wafer); a first layer of polyimide is spin-coated and cured as a flexible substrate; metal wires and electrode points are formed through photolithography, coating, and etching; a second layer of polyimide is spin-coated as an encapsulation layer; and finally, the polyimide on the encapsulation layer is selectively removed using reactive ion etching technology to expose the electrode points for recording or stimulating electrophysiological activities.

[0004] However, this traditional method has a significant drawback: because reactive ion etching is isotropic, a micrometer-scale step is formed at the edge of the etching opening. This causes the electrode surface and the encapsulation layer surface to be out of plane. When the electrode is implanted into brain tissue, this step will: 1) hinder neurons and glial cells from forming a tight attachment with the electrode surface, leading to increased interfacial impedance and reducing the signal-to-noise ratio and stimulation efficiency of neural signal recording; 2) cause local stress concentration, exacerbating chronic foreign body reactions and glial scar formation, resulting in signal attenuation over time.

[0005] In existing technologies, many studies have attempted to optimize performance by improving electrode structure or materials. For example, the invention disclosed in CN117976294A relates to a microelectrode device for mapping the course of the tumor-bearing nerve during surgery for schwannomas. It employs a flexible base layer and an array of microelectrode points, designed to adapt to the complex interface between the nerve and the tumor, enabling real-time mapping of the nerve trajectory during surgery. This device captures the spatiotemporal patterns of nerve signals through high-density electrode points, but its fabrication process may still rely on traditional etching techniques, failing to address the step problem between the electrode surface and the encapsulation layer. Therefore, in long-term implantation scenarios, challenges related to interfacial impedance and biocompatibility remain, limiting its stability in broader neural interface applications. On the other hand, the invention disclosed in CN115054258A provides a flexible electrode for peripheral nerves, characterized by a porous structure that facilitates nerve reconstruction and close contact. This electrode employs a multilayer insulating and conductive layer design, emphasizing stretchability and biointegration. However, the fabrication method of this electrode may also involve RIE etching steps, resulting in step defects in the exposed electrode area. Although the technology optimizes fit for peripheral nerves, it does not address the perfect planarization of the electrode-tissue interface, thus failing to effectively reduce interfacial impedance or avoid chronic inflammatory responses, especially in applications to the central nervous system.

[0006] Furthermore, to reduce interfacial impedance, the electrode surface often needs to be modified with low-impedance functional materials (such as IrOx, PEDOT:PSS, and platinum black). Traditional processes can complete this by sputtering after the RIE (Residual Electrode) is opened. However, for flexible devices that need to be released from the sacrificial layer, modifying the fragile functional material layer before release can easily damage the layer during the release process.

[0007] Therefore, developing a new method for fabricating flexible neural electrodes that can achieve perfect planarization of the electrode-tissue interface and is compatible with efficient, stable, and low-impedance modification is of great significance to the development of technology in this field. Summary of the Invention

[0008] The purpose of this invention is to overcome the defects of the prior art by providing a flexible neural electrode with a planar biological interface and its preparation method. Through an innovative process sequence, the lower surface of the metal electrode point (the contact surface with the nerve tissue) and the lower surface of the polymer encapsulation layer are on the same plane, completely eliminating the step effect, thereby significantly improving the interface compatibility between the device and the nerve tissue, and being compatible with the electrochemical low impedance modification after release.

[0009] The objective of this invention can be achieved through the following technical solutions: A first aspect of the present invention provides a flexible neural electrode having a planarized biological interface, comprising: First polymer insulating layer; Multiple working electrodes are embedded in the first polymer insulating layer. The exposed biological contact surface of the working electrodes is at the same level as the surface of the corresponding side of the first polymer insulating layer, thereby forming a stepless planar biological interface. Adjacent working electrodes are connected by metal wires. A second polymer insulating layer covers the working electrode and the first polymer insulating layer.

[0010] Furthermore, the exposed surface of the working electrode is modified with a low-resistivity material layer, which is used to reduce the interface impedance. The flexible neural electrode also includes pads electrically connected to the metal wires, the pads being exposed outside the second polymer insulating layer for interconnection with an external circuit board via anisotropic conductive adhesive or solder.

[0011] Furthermore, the planarized bio-interface is used for contact with neural tissue to record neural signals or apply electrical stimulation.

[0012] A second aspect of the present invention provides a method for preparing a flexible neural electrode having a planarized biological interface as described above, comprising the following steps: S1, Provide a sacrificial layer; S2. A first polymer insulating layer is formed on the sacrificial layer; S3. Define and etch at least one pit on the first polymer insulating layer by an etching process; S4. A metal pattern layer is prepared on a first polymer insulating layer with etched pits. The metal pattern layer includes a wire and a working electrode electrically connected to the wire. The working electrode is filled in the pits, and the lower surface of the working electrode is flush with the lower surface of the first polymer insulating layer. S5. Cover the metal pattern layer and the first polymer insulating layer with a second polymer insulating layer; S6. Remove the sacrificial layer to release the flexible electrode structure; S7. Reverse the released flexible neural electrode so that the lower surface of the original first polymer insulating layer faces upward, thereby exposing the working electrode and forming a stepless planar biological contact interface.

[0013] Furthermore, in S6, after removing the sacrificial layer, the following steps are also included: The interfacial impedance is reduced by modifying the exposed lower surface of the working electrode with a low-resistivity material layer through electrochemical deposition.

[0014] Furthermore, the low-resistivity material layer is selected from one of conductive polymers, nano-metal particles, metal oxides, and bioactive molecules.

[0015] Furthermore, the material of the sacrificial layer is selected from one of metals, metal oxides, and soluble polymers.

[0016] Furthermore, the materials of the first polymer insulating layer and the second polymer insulating layer are selected from one of polyimide, parylene, benzocyclobutene, and SU-8 photoresist.

[0017] Furthermore, in S3, the pits are etched into the first polymer insulating layer using a reactive ion etching process.

[0018] Furthermore, in S4, during the fabrication of the metal pattern layer, pads for external connections are simultaneously formed, and the pads are electrically connected to the metal wires. After the second polymer insulating encapsulation layer is formed, the pads are exposed by selective etching or patterning processes. Furthermore, the exposed pads are interconnected with the printed circuit board using anisotropic conductive adhesive or solder to complete the external circuit connection.

[0019] Compared with the prior art, the present invention has the following beneficial effects: 1) A perfect planar interface was constructed: there is no height difference between the biological contact surface of the working electrode and the surface of the flexible encapsulation layer, realizing conformal contact with biological tissue, which greatly promotes the close attachment of neurons, reduces the formation of glial scars, and lays the foundation for long-term stable neural signal recording.

[0020] 2) Extremely low interfacial impedance: The tight cell-electrode contact and subsequent low-impedance material modification work together to significantly reduce interfacial impedance, thereby effectively improving the signal-to-noise ratio of neural signal recording and the efficiency of electrical stimulation.

[0021] 3) Wide range of applications: The preparation method and the resulting device are not only applicable to nerve electrodes, but can also be widely used in fields such as electrocardiogram (ECG) electrodes and electromyography (EMG) electrodes. Attached Figure Description

[0022] Figure 1 This is a schematic diagram comparing the structure of a traditional flexible electrode and the flexible electrode of this invention.

[0023] Figure 2 This is a process flow diagram (steps a to g) of a preferred embodiment of the present invention.

[0024] Figure 3 These are microscopic comparisons of traditional flexible electrodes and the flexible electrode of this invention.

[0025] Figure 4 This is a micrograph of the electrode prepared in Example 1 of the present invention. The electrode surface is coated with a platinum black coating by electrochemical deposition.

[0026] Figure 5 This is the frequency-impedance characteristic curve of the electrode prepared in Example 1 of the present invention.

[0027] Figure 6 This is a schematic flowchart of the method for preparing flexible neural electrodes with planar biological interfaces in this invention. Detailed Implementation

[0028] Overall, this invention discloses a flexible neural electrode with a planar bio-interface and its fabrication method, belonging to the field of biomedical engineering technology. The method includes: forming a first polymer insulating layer on a sacrificial layer; pre-defining pits on the first polymer insulating layer using an etching process; fabricating a metal working electrode and wires that fill the pits and have their lower surfaces flush with the lower surface of the first polymer insulating layer; covering with a second polymer insulating encapsulation layer, removing the sacrificial layer to release the flexible electrode; and finally, by inverting the device so that the lower surface of the original first polymer insulating layer faces upward, exposing the working electrode and forming a stepless bio-contact interface completely flush with the encapsulation layer. This invention, through innovative "pre-etched pits" and "device inversion" processes, fundamentally solves the electrode step problem caused by openings in the encapsulation layer in traditional flexible neural electrodes, significantly improving the adhesion between the electrode and nerve tissue, which is beneficial for reducing interface impedance, improving signal quality, and enhancing long-term biocompatibility. In specific implementation, the method for preparing the flexible neural electrode in this invention includes the following steps: S1. Provide a sacrifice layer; S2. A first polymer insulating layer is formed on the sacrificial layer; S3. Define and etch at least one pit on the first polymer insulating layer; S4. A metal pattern layer is prepared on a first polymer insulating layer with etched pits, the metal pattern layer including wires and electrode points electrically connected to the wires, wherein the electrode points fill the pits and their lower surfaces are flush with the lower surface of the first polymer insulating layer. S5. A second polymer insulating encapsulation layer is formed on the metal pattern layer and the electrode points; S6. Remove the sacrificial layer to release the flexible neural electrode structure, exposing the lower surface of the electrode point and placing it on the same plane as the lower surface of the first polymer insulating encapsulation layer, forming a stepless planar neural tissue contact interface.

[0029] In a specific implementation, after removing the sacrificial layer, the method further includes the step of modifying the lower surface of the exposed electrode points with a low-resistivity material layer by electrochemical deposition.

[0030] In specific implementations, the low-resistivity material layer is a conductive polymer PEDOT:PSS, platinum black, iridium oxide (IrOx), or a bioactive molecule.

[0031] The following specific embodiments illustrate the implementation of the present invention. Those skilled in the art can easily understand other advantages and effects of the present invention from the content disclosed in this specification. Although the description of the present invention will be presented in conjunction with preferred embodiments, this does not mean that the features of the invention are limited to these embodiments. On the contrary, the purpose of describing the invention in conjunction with embodiments is to cover other options or modifications that may be derived based on the claims of the present invention. To provide a thorough understanding of the invention, many specific details will be included in the following description. The invention may also be implemented without using these details. Furthermore, to avoid confusion or obscuring the focus of the invention, some specific details will be omitted in the description.

[0032] In the description of this invention, it should be noted that, unless otherwise explicitly specified and limited, the terms "installation," "connection," and "linking" should be interpreted broadly. For example, they can refer to a fixed connection, a detachable connection, or an integral connection; they can refer to a mechanical connection or an electrical connection; they can refer to a direct connection or an indirect connection through an intermediate medium; and they can refer to the internal connection of two components. Those skilled in the art can understand the specific meaning of the above terms in this invention based on the specific circumstances.

[0033] Furthermore, the terms "upper," "lower," "left," "right," "top," "bottom," "horizontal," and "vertical" used in the following description should be understood as the orientations shown in the relevant paragraphs and accompanying drawings. These relative terms are for illustrative purposes only and do not imply that the described apparatus must be manufactured or operated in a specific orientation, and therefore should not be construed as limiting the invention.

[0034] It is understood that although terms such as "first," "second," and "third" may be used herein to describe various components, regions, layers, and / or parts, these components, regions, layers, and / or parts should not be limited by these terms, and these terms are only used to distinguish different components, regions, layers, and / or parts. Therefore, the first components, regions, layers, and / or parts discussed below may be referred to as second components, regions, layers, and / or parts without departing from some embodiments of the present invention.

[0035] The implementation process of the technical solution of the present invention will be described in detail below with reference to the accompanying drawings and through multiple embodiments in a non-limiting manner. Those skilled in the art should understand that the specific embodiments described herein are only for explaining the present invention and are not intended to limit the scope of protection of the present invention.

[0036] Example 1: High-density flexible microfilament electrodes for intracortical neuronal recording This embodiment describes the fabrication of a flexible microfilament electrode (probe structure) with high impedance and high spatial resolution for recording action potentials of a single neuron.

[0037] Materials and Equipment: 4-inch silicon wafers as the carrier substrate; aluminum as the sacrificial layer material; polyimide (PI-2611, HDMicroSystems) as the flexible insulating layer; gold as the metal wire and electrode material; reactive ion etching (RIE); electrochemical workstation.

[0038] Preparation steps: (correspond Figure 2 a) Provide a sacrificial layer: A 200 nm thick aluminum film is deposited on the silicon wafer by electron beam evaporation as a sacrificial layer.

[0039] (correspond Figure 2 b) Preparation of the substrate PI layer: Polyimide PI-2611 was spin-coated onto the aluminum sacrificial layer, and after step soft baking (110°C / 2 min, 180°C / 5 min), it was cured at 300°C for 1 hour in a nitrogen atmosphere to form a first polymer insulating layer with a thickness of about 3 μm.

[0040] (correspond Figure 2 c) Predefined electrode site pits: Electrode point patterns are defined by photolithography on the first PI layer, and RIE is used to etch with a mixture of oxygen and carbon tetrafluoride gas until the sacrificial layer (depth > 2.5 μm) is reached, forming a 20 μm pit array.

[0041] (correspond Figure 2 d) Fabrication of metal lines and electrode points: Sputtering a Ti (10 nm) / Au (300 nm) double layer of metal, and using photolithography and lift-off processes to form metal wires and circular electrode points with a diameter of 23 μm (greater than the pit diameter), ensuring that the electrode points completely fill the pit and that their lower surface is flush with the lower surface of the first PI layer.

[0042] (correspond Figure 2 (e) Preparation of the encapsulation PI layer: Spin-coating a second layer of PI-2611 onto the entire structure, and curing it to form an encapsulation layer with a thickness of about 5 μm.

[0043] (correspond Figure 2f) Release and Low Impedance Modification: The device was immersed in an aluminum etching solution to dissolve the aluminum sacrificial layer, releasing the complete flexible neural electrode. Since the outermost layer of the exposed lower surface of the electrode is titanium (Ti), its natural oxides hinder electrochemical deposition. Therefore, after release, the electrode was briefly immersed in a diluted hydrofluoric acid (HF) solution for 5 seconds to remove surface oxides and expose the active gold layer; then immersed in a dilute sulfuric acid solution and subjected to more than 20 CV cycles to remove surface impurities and oxides. Finally, in a chloroplatinic acid electrolyte, a platinum black coating of approximately 500 nm thickness was electrochemically deposited on the electrode surface using constant current or cyclic voltammetry to significantly reduce interfacial impedance.

[0044] (correspond Figure 2 (g) After release, the electrode is reversed so that the exposed side faces upward. Microscopic observation confirms (see attached image). Figure 3 The electrode prepared by the method of the present invention has its lower surface at the electrode point on the same plane as the lower surface of the encapsulated PI layer, without any steps.

[0045] The effect verification is attached. Figure 4 and 5 As shown, Figure 4 Micrographs show that the platinum black coating uniformly covers the electrode points; Figure 5 The electrochemical impedance spectroscopy showed that the impedance of the electrode at a frequency of 1 kHz was less than 50 kΩ, which fully meets the requirements for high signal-to-noise ratio neuronal recording.

[0046] Example 2: Planar grid electrodes for cortical surface ECoG recording This embodiment aims to prepare a flexible planar grid electrode (ECoG electrode) that is attached to the surface of the cerebral cortex to record local field potentials and epileptiform discharges.

[0047] Materials and parameters: Basic materials: Same as in Example 1 (silicon wafer, aluminum sacrificial layer, PI-2611). First / second polymer insulating layer thickness: 3 μm each to provide sufficient mechanical support. Metal patterning layer: Sputtered Ti / Au (10 / 100 nm) and thickened to 500 nm by electroplating gold. Electrode points are designed as 100 μm diameter circles to accommodate the spatial characteristics of the ECoG signal and impedance is reduced using a PEDOT:PSS conductive polymer.

[0048] Preparation steps: The process steps are basically the same as those in Example 1.

[0049] Because ECoG electrodes have a large area, they are typically designed in a mesh pattern to enhance flexibility. Electrode points, interconnects, and external pads are formed simultaneously during the fabrication of the metal pattern layer.

[0050] It requires hydrofluoric acid treatment after release.

[0051] In an electrolyte containing EDOT monomer and PSS dispersant, a PEDOT:PSS coating of approximately 300 nm was electrochemically deposited on the surface of an electrode with a diameter of 100 μm using a potentiostatic method.

[0052] The electrode can be directly attached to the surface of the cerebral cortex. The PEDOT:PSS modified layer gives it extremely low impedance (<5kΩ, 1kHz) in the low-frequency range of 0.1-100 Hz, enabling clear recording of cortical EEG rhythms and epileptic seizure signals.

[0053] Example 3: Flexible microfilament electrodes for nerve stimulation This embodiment aims to prepare a flexible electrode for safe and effective electrical stimulation of nerve tissue, requiring the electrode to have a high charge injection capacity.

[0054] Materials and parameters: Basic materials: Same as in Example 1 (silicon wafer, aluminum sacrificial layer, PI-2611). First / second polymer insulating layer thickness: 3 μm for sufficient mechanical support. Metal patterning layer: sputtered Ti / Au (10 / 500 nm). Electrode points are designed as 50 μm diameter circles and impeded by IrOx plating.

[0055] Preparation steps: The process steps are basically the same as those in Example 1.

[0056] After release, an IrOx coating was electrochemically deposited on the gold electrode surface using a multi-cycle potential scan method in an iridium-containing electrolyte. This process forms a hydrated iridium oxide film on the electrode surface through the redox reaction of Ir(III) / Ir(IV).

[0057] The charge storage capacity of this IrOx-modified electrode was tested by cyclic voltammetry, and the value typically reached 5-10 mC / cm. 2 It is far superior to platinum black or bare gold electrodes, and can transmit a larger stimulation charge without hydrolysis. It remains stable even after more than 100 million cycles of stimulation (stimulation conditions 50mA, 100Hz), ensuring the effectiveness and biosafety of nerve stimulation.

[0058] The above description of the embodiments is provided to enable those skilled in the art to understand and use the invention. It will be apparent to those skilled in the art that various modifications can be made to these embodiments, and the general principles described herein can be applied to other embodiments without inventive effort. Therefore, the present invention is not limited to the above embodiments, and any improvements and modifications made by those skilled in the art based on the disclosure of the present invention without departing from the scope of the invention should be within the protection scope of the present invention.

Claims

1. A flexible neural electrode having a planarized biological interface, characterized by, The flexible neural electrode comprises: a first polymer insulation layer; a plurality of working electrodes embedded on the first polymer insulation layer, the exposed biological contact surface of the working electrodes being in the same horizontal plane as the surface of the corresponding side of the first polymer insulation layer, thereby forming a flat biological interface without steps, and the adjacent working electrodes being connected by metal wires; a second polymer insulation layer covering the working electrodes and the first polymer insulation layer.

2. The method for preparing a flexible neural electrode with a planarized biological interface according to claim 1, characterized in that, The exposed surface of the working electrode is modified with a low impedance material layer, which is used to reduce the interface impedance; The flexible neural electrode further comprises a pad electrically connected to the metal wire, the pad being exposed outside the second polymer insulation layer and used for interconnection with an external circuit board through anisotropic conductive adhesive or solder.

3. The method for preparing a flexible neural electrode with a planarized biological interface according to claim 1, characterized in that, The flat biological interface is used for nerve tissue contact to record neural signals or apply electrical stimulation.

4. A method of making a flexible neural electrode having a planarized biological interface as claimed in any one of claims 1 to 3, characterized in that, The method comprises the following steps: S1, providing a sacrificial layer; S2, forming a first polymer insulation layer on the sacrificial layer; S3, defining and etching at least one recess on the first polymer insulation layer by etching process; S4, preparing a metal pattern layer on the first polymer insulation layer etched with the recess, the metal pattern layer comprising wires and working electrodes electrically connected to the wires, wherein the working electrodes are filled in the recess, and the lower surface of the working electrodes is flush with the lower surface of the first polymer insulation layer; S5, covering the metal pattern layer and the first polymer insulation layer with a second polymer insulation layer; S6, removing the sacrificial layer to release a flexible electrode structure; S7, reversing the released flexible neural electrode so that the lower surface of the original first polymer insulation layer faces upwards, thereby exposing the working electrodes and forming a flat biological contact interface without steps.

5. The method for preparing a flexible neural electrode with a planarized biological interface according to claim 4, characterized in that, In S6, after removing the sacrificial layer, the following steps are further included: A low impedance material layer is modified on the exposed lower surface of the working electrode by electrochemical deposition, thereby reducing the interface impedance.

6. The method of claim 5, wherein the planarized biological interface is formed by a process comprising: The low impedance material layer is selected from one of conductive polymers, nano-metal particles, metal oxides, and biologically active molecules.

7. The method for preparing a flexible neural electrode with a planarized biological interface according to claim 4, characterized in that, The material of the sacrificial layer is selected from one of metals, metal oxides, and soluble polymers.

8. The method for preparing a flexible neural electrode with a planarized biological interface according to claim 4, characterized in that, The materials of the first polymer insulation layer and the second polymer insulation layer are selected from one of polyimide, parylene, benzocyclobutene, and SU-8 photoresist.

9. The method for preparing a flexible neural electrode with a planarized biological interface according to claim 4, characterized in that, In S3, a reactive ion etching process is used to etch the recess on the first polymer insulation layer.

10. A method for preparing a flexible neural electrode with a planarized biological interface according to claim 4, characterized in that, In S4, when the metal pattern layer is prepared, a pad for external connection is simultaneously formed, the pad being electrically connected to the metal wire; After the second polymer insulation encapsulation layer is formed, the pad is exposed by selective etching or patterning process, and the exposed pad is interconnected with a printed circuit board through anisotropic conductive adhesive or solder to complete the external circuit connection.

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