A neural electrode and a preparation method and application thereof

Abstract

This invention provides a neural electrode, its preparation method, and its application. The preparation method includes the following steps: placing a plasma-treated electrode body in an acid solution for cyclic voltammetry measurement until the cyclic voltammetry curve stabilizes, thus obtaining an activated electrode body; placing the activated electrode body in a gold electrolyte for electrochemical deposition to obtain a gold nanoparticle-modified electrode; placing the gold nanoparticle-modified electrode in a solution containing thiol-containing organic acid for self-assembly to obtain a second modified electrode; and placing the second modified electrode in a conductive polymer monomer solution for electrochemical polymerization to obtain the neural electrode. This invention, through the design of the preparation method, forms a stable and highly adhesive interface modification layer on the electrode body, resulting in a neural electrode with significantly reduced impedance, excellent biocompatibility and tissue friendliness, good mechanical and electrochemical stability, and the ability to meet the requirements for robustness, stability, and reliability for long-term electrode use.

Description

Technical Field

[0001] This invention belongs to the field of biomedical materials technology, specifically relating to a neural electrode, its preparation method, and its application. Background Technology

[0002] In the nervous system, numerous neurons constantly generate and transmit electrophysiological signals, communicating between neurons and brain regions. Implantable neural electrodes, serving as a bridge for two-way communication between the human body and external devices, are a crucial means of detecting and controlling neural activity. Their application has significantly enhanced our understanding of neuropsychiatric disorders and led to more effective treatments for brain diseases such as depression, Parkinson's disease, and epilepsy. Furthermore, implantable neural electrodes can monitor brain activity through neural recording and respond directly or indirectly to the brain's subjective intentions or objective events until the brain returns to a normal state. Implantable neural electrodes can promote the rehabilitation of patients with nerve damage or disease, playing a vital role in monitoring the state of the nervous system or influencing its treatment or functional recovery.

[0003] However, implantation of neural electrodes into the central nervous system triggers a host tissue response, leading to the formation of astrocytes that encapsulate the neuron. This inflammation results in the loss of neurons near the implanted electrode, increased electrode impedance, and consequently, increased background noise during recording. Rapid advancements in microelectrode fabrication technology have significantly reduced tissue damage during implantation and improved the spatial resolution of electrophysiological studies; however, smaller electrodes may increase electrochemical impedance at the interface and negatively impact the quality of the recorded signal. To effectively detect the dynamic characteristics of neural activity in vivo, microelectrodes with low impedance, biocompatibility, and long-term stability are required.

[0004] CN110742597A discloses a method for preparing a TPU / PDMS three-dimensional porous neural electrode, the steps of which are as follows: (1) a polyurethane solution and a polydimethylsiloxane solution are mixed to prepare an electrospinning solution, and then the electrospinning solution is loaded into an electrospinning device to prepare a three-dimensional spatial network film; (2) the three-dimensional spatial network film is cleaned in a plasma cleaner, and then placed in polydimethylsiloxane for adhesion treatment, and finally vacuum dried and cured to obtain a three-dimensional porous fiber membrane; (3) firstly, a gold layer is deposited in the porous structure of the three-dimensional porous fiber membrane using a chemical deposition method, and then a gold layer is deposited on the surface of the three-dimensional porous fiber membrane using an inorganic material evaporation coating device to obtain a conductive fiber membrane; (4) the conductive fiber membrane is connected to a wire and encapsulated to obtain a three-dimensional porous neural electrode. The TPU / PDMS three-dimensional porous neural electrode obtained by this method has good tensile and adhesion properties, which solves the problem of poor compatibility between implantable neural electrodes and biological tissues. However, its preparation process is complex, the material is relatively limited, and the adhesion between the fiber membrane and the gold layer is insufficient, posing a risk to the stability of long-term use.

[0005] Another approach to improving the interfacial impedance of implanted neural electrodes is to use conductive polymers (CPs), such as polypyrrole and poly(3,4-ethylenedioxythiophene), to enhance the performance of the electrode-nerve interface. Using these CPs as surface modifiers can significantly reduce the electrochemical impedance of the electrode, thereby improving ion exchange between the implanted electrode and neural tissue and increasing the signal-to-noise ratio during electrophysiological recording. Furthermore, these conductive polymer materials are generally biocompatible and conductive, which is beneficial for neuronal attachment and neurite growth, providing a favorable environment for neuronal growth and development. For example, CN103083725A discloses a neural electrode modified with an interface modification material. The preparation method is as follows: a gel polymer is coated on the surface of a neural electrode body with introduced hydrophilic groups, and after drying, a gel polymer film is formed. The gel polymer is a cross-linked polymer formed by polyacrylic acid and polyvinyl alcohol. The neural electrode body with the gel polymer film is immersed in an electrodeposition solution containing conductive polymer monomers, bioactive substances, and anti-inflammatory drugs, so that the electrodeposition solution is adsorbed into the gel polymer film. Then, electrotreatment is performed to polymerize the conductive polymer monomers adsorbed in the electrodeposition solution into a conductive polymer. The conductive polymer and the gel polymer form a cross-linked network, and the bioactive substances and anti-inflammatory drugs are interspersed in the cross-linked network, forming an interface modification layer on the surface of the neural electrode body, thereby improving the biocompatibility of the neural electrode.

[0006] Recent studies have revealed that conductive polymers and interface modification layers may experience mechanical and electrochemical instability, posing a risk to the long-term performance of modified surfaces. For example, conductive polymer modification layers formed on electrode substrates often delaminate and peel off. To enhance the adhesion between conductive polymers and substrates, researchers have attempted surface pretreatments such as laser irradiation and iodine etching, or electrodeposition of special functionalized conductive polymer monomers. While these techniques can enhance the bonding between conductive polymers and electrode surfaces, they also limit the choice of substrate materials and the types of monomers, thus restricting their applicability.

[0007] Therefore, developing neural electrodes with low impedance, tissue-friendly properties, and long-term stability to meet the application requirements of long-term in vivo neural recording is an urgent problem to be solved in this field. Summary of the Invention

[0008] To address the shortcomings of existing technologies, the present invention aims to provide a neural electrode, its preparation method, and its application. Through the design of the preparation method, a stable, reliable, and highly adhesive interface modification layer is formed on the electrode body, resulting in a neural electrode with significantly reduced impedance, excellent biocompatibility and tissue friendliness, good mechanical and electrochemical stability, and the ability to meet the requirements of robustness, stability, and reliability for long-term use of the electrode.

[0009] To achieve this objective, the present invention adopts the following technical solution:

[0010] In a first aspect, the present invention provides a method for preparing a neural electrode, the method comprising the following steps:

[0011] The plasma-treated electrode body was placed in an acid solution for cyclic voltammetry measurement until the cyclic voltammetry curve stabilized, thus obtaining the activated electrode body.

[0012] The activated electrode body was placed in a gold electrolyte for electrochemical deposition to obtain a gold nanoparticle-modified electrode.

[0013] The modified electrode made of gold nanoparticles was placed in a solution containing thiol-containing organic acid for self-assembly to obtain a second modified electrode.

[0014] The second modified electrode is placed in a conductive polymer monomer solution for electrochemical polymerization, thereby depositing the conductive polymer on the surface of the second modified electrode to obtain the neural electrode.

[0015] The method for preparing the neural electrode provided by the present invention includes four steps: (1) activating the electrode body, (2) depositing a layer of gold nanoparticles on the surface of the activated electrode body by in-situ electrochemical deposition, (3) introducing negatively charged organic acid groups (carboxyl groups) onto the surface of the gold nanoparticles by self-assembly, and (4) connecting the positively charged conductive polymer by electrochemical polymerization to form a neural interface modification layer, thereby obtaining the neural electrode.

[0016] In the neural electrodes prepared by the aforementioned method, the conductive polymer, serving as a surface modifier, significantly reduces the electrochemical impedance of the electrodes, improves ion exchange between the neural electrodes and neural tissue, and enhances the signal-to-noise ratio (SNR) during electrophysiological recording. Simultaneously, the conductive polymer exhibits good biocompatibility and conductivity, which is beneficial for neuronal attachment and neurite growth, providing a favorable environment for neuronal growth and development. Based on the construction of the neural interface modification layer, the biocompatibility and tissue friendliness of the neural electrodes are significantly improved, and the inflammatory response at the neural interface is significantly reduced, enabling long-term maintenance of implant performance and recording of more and stronger neural signals. Moreover, the specific preparation method designed in this invention forms an interface modification layer on the electrode body with high adhesion and resistance to detachment, resulting in superior mechanical and electrochemical stability of the neural electrodes. This meets the robustness and stability requirements for long-term use of the electrodes, allowing them to perform neural recording functions in vivo for extended periods.

[0017] Therefore, the preparation method provided by the present invention effectively solves the problems of poor biocompatibility and unstable recording stability of existing neural electrodes in chronic neural recording in live animals. The obtained neural electrodes can effectively improve the electrode-nerve interface, thereby maximizing the reliability of long-term recording of neural electrodes in live animals and meeting the application requirements of long-term in vivo neural recording.

[0018] The following are preferred technical solutions of the present invention, but are not intended to limit the technical solutions provided by the present invention. The purpose and beneficial effects of the present invention can be better achieved and realized through the following preferred technical solutions.

[0019] This invention does not impose any particular limitation on the type of electrode body; any electrode body known in the art that can be used for neural electrodes is applicable to this invention.

[0020] Preferably, the material of the electrode body includes any one of nickel-chromium alloy, platinum, and platinum-iridium alloy.

[0021] Preferably, the plasma treatment further includes a step of cleaning the electrode body.

[0022] Preferably, the cleaning agent includes any one or a combination of at least two of water, acetone, and ethanol, and more preferably water and / or acetone.

[0023] Preferably, the cleaning is performed under ultrasonic conditions.

[0024] Preferably, the cleaning method includes: placing the electrode body in an acetone solution and water, sequentially immersing the electrode sites of the electrode body completely and performing ultrasonic treatment to obtain a cleaned electrode body.

[0025] Preferably, the plasma treatment is an oxygen plasma treatment.

[0026] Preferably, the plasma treatment time is 60-300s, for example, it can be 80s, 100s, 120s, 150s, 180s, 200s, 220s, 250s or 280s, as well as specific values ​​between the above values. Due to space limitations and for the sake of brevity, the present invention will not exhaustively list the specific values ​​included in the range, but 60-180s is further preferred.

[0027] Preferably, the acid solution is a sulfuric acid solution.

[0028] Preferably, the concentration of the sulfuric acid solution is 0.2-0.8 mol / L, for example, it can be 0.25 mol / L, 0.3 mol / L, 0.35 mol / L, 0.4 mol / L, 0.45 mol / L, 0.5 mol / L, 0.55 mol / L, 0.6 mol / L, 0.65 mol / L, 0.7 mol / L or 0.75 mol / L, as well as specific values ​​between the above values. Due to space limitations and for the sake of brevity, the present invention will not exhaustively list the specific values ​​included in the range.

[0029] Preferably, the scanning voltage for the cyclic voltammetry measurement is from -0.2V to 1.5V; the lowest voltage for the cyclic voltammetry measurement can be -0.2V, -0.18V, -0.15V, -0.12V, -0.1V, -0.08V, -0.05V, -0.02V, and specific values ​​between the above values. Due to space limitations and for the sake of brevity, this invention will not exhaustively list the specific values ​​included in the range; the highest voltage for the cyclic voltammetry measurement can be 1.5V, 1.4V, 1.2V, 1V, 0.8V, 0.6V, or 0.5V, and specific values ​​between the above values. Due to space limitations and for the sake of brevity, this invention will not exhaustively list the specific values ​​included in the range.

[0030] As a preferred technical solution of the present invention, the electrode body is prone to passivation during use, resulting in a decrease in impedance. In step (1), after treating the electrode body with oxygen plasma, cyclic voltammetry is performed on the electrode in sulfuric acid solution, which can remove the oxide film on the surface of the electrode body, and also remove organic and inorganic substances from the surface of the electrode body. Therefore, before modification, oxygen plasma treatment and cyclic voltammetry are performed on the electrode in sulfuric acid to obtain an activated electrode body.

[0031] Preferably, the gold electrolyte comprises a combination of a gold electrolyte and an acidic compound.

[0032] Preferably, the gold electrolyte comprises any one or a combination of at least two of tetrachloroauric acid, sodium chloroaurate, potassium chloroaurate, and ammonium chloroaurate, with tetrachloroauric acid (HAuCl4) being more preferred.

[0033] Preferably, the concentration of gold electrolyte in the gold electrolyte solution is 5-30 mmol / L, for example, it can be 6 mmol / L, 8 mmol / L, 10 mmol / L, 12 mmol / L, 15 mmol / L, 18 mmol / L, 20 mmol / L, 22 mmol / L, 25 mmol / L or 28 mmol / L, as well as specific values ​​between the above values. Due to space limitations and for the sake of brevity, the present invention will not exhaustively list the specific values ​​included in the range.

[0034] Preferably, the acidic compound includes any one or a combination of at least two of perchloric acid, chloric acid, sulfuric acid, nitric acid, and hydrochloric acid, and more preferably perchloric acid (HClO4).

[0035] Preferably, the concentration of the acidic compound in the gold electrolyte is 0.01-0.5 mol / L, for example, it can be 0.02 mol / L, 0.05 mol / L, 0.08 mol / L, 0.1 mol / L, 0.12 mol / L, 0.15 mol / L, 0.18 mol / L, 0.2 mol / L, 0.25 mol / L, 0.3 mol / L, 0.35 mol / L, 0.4 mol / L, or 0.45 mol / L, as well as specific values ​​between the above values. Due to space limitations and for the sake of brevity, the present invention will not exhaustively list the specific values ​​included in the range.

[0036] Preferably, the voltage applied during the electrochemical deposition is from -0.1V to -0.5V, for example, it can be -0.12V, -0.15V, -0.18V, -0.2V, -0.22V, -0.25V, -0.28V, -0.3V, -0.32V, -0.35V, -0.38V, -0.4V, -0.42V, -0.45V, or -0.48V, as well as specific values ​​between the above values. Due to space limitations and for the sake of brevity, the present invention will not exhaustively list the specific values ​​included in the range.

[0037] Preferably, the electrochemical deposition time is 10-40s, for example, it can be 12s, 15s, 18s, 20s, 22s, 25s, 8s, 30s, 32s, 35s or 38s, as well as specific values ​​between the above values. Due to space limitations and for the sake of brevity, the present invention will not exhaustively list the specific values ​​included in the range, and 20-30s is further preferred.

[0038] As a preferred embodiment of the present invention, in step (2), the activated electrode body is placed in a tetrachloroauric acid (HAuCl4) perchloric acid (HClO4) solution and a voltage is applied to generate gold nanoparticles on the surface of the electrode body, completing the first modification and obtaining a gold nanoparticle-modified electrode. In this step, HAuCl4 undergoes in-situ electrochemical reduction to form gold nanoparticles that are deposited on the surface of the activated electrode body. In-situ electrochemical deposition allows for control over the particle size and thickness of the gold nanoparticles by adjusting the applied voltage and time, resulting in a relatively firm deposition on the surface of the activated electrode body.

[0039] Preferably, the voltage applied during the electrochemical deposition is -0.1V to -0.5V, and the deposition time is 20-30s, thereby obtaining a gold nanoparticle-modified electrode with optimal particle size, thickness, and distribution. If the deposition time is too short, insufficient gold nanoparticles will be generated, affecting the electrode impedance; if the deposition time is too long, the particle size and thickness of the formed gold nanoparticles will be too large, resulting in insufficient stability of the entire interface modification layer, poor adhesion to the electrode body, easy detachment of the modification layer, and affecting the stability of long-term use.

[0040] Preferably, the particle size of the gold nanoparticles is 10-200nm, for example, it can be 20nm, 30nm, 40nm, 50nm, 60nm, 70nm, 80nm, 90nm, 100nm, 120nm, 150nm or 180nm, as well as specific values ​​between the above values. Due to space limitations and for the sake of brevity, the present invention will not exhaustively list the specific values ​​included in the range.

[0041] Preferably, the thiol-containing organic acid is a compound containing a thiol group, a carboxyl group, and an aliphatic chain.

[0042] Preferably, the thiol-containing organic acid has the structure shown in Formula I:

[0043]

[0044] In Formula I, R is selected from C1-C20 straight-chain or branched alkylene groups, for example, straight-chain or branched alkylene groups of C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C12, C15, C18, etc., and is further preferably C2-C12 straight-chain or branched alkylene groups.

[0045] Preferably, the thiol-containing organic acid includes any one or a combination of at least two of 3-mercaptopropionic acid, mercaptooctanoic acid, and mercaptodecanoic acid.

[0046] Preferably, the solvent of the mercapto-containing organic acid solution includes any one or a combination of at least two of alcohol solvents, ketone solvents, ether solvents, and water, and more preferably a combination of alcohol solvents and water.

[0047] Preferably, the alcohol solvent includes any one or a combination of at least two of methanol, ethanol, n-propanol, and isopropanol, with ethanol being more preferred.

[0048] Preferably, the concentration of the thiol-containing organic acid in the solution is 1-10 mmol / L, for example, it can be 2 mmol / L, 3 mmol / L, 4 mmol / L, 5 mmol / L, 6 mmol / L, 7 mmol / L, 8 mmol / L or 9 mmol / L, as well as specific values ​​between the above values. Due to space limitations and for the sake of brevity, the present invention will not exhaustively list the specific values ​​included in the range.

[0049] Preferably, the self-assembly temperature is 4-30℃, for example, it can be 5℃, 6℃, 9℃, 10℃, 12℃, 15℃, 18℃, 20℃, 22℃, 25℃ or 28℃, as well as specific values ​​between the above points. Due to space limitations and for the sake of brevity, the present invention will not exhaustively list the specific values ​​included in the range, and room temperature / normal temperature is further preferred.

[0050] Preferably, the self-assembly time is 8-36 hours, for example, it can be 10 hours, 12 hours, 14 hours, 16 hours, 18 hours, 20 hours, 22 hours, 24 hours, 26 hours, 28 hours, 30 hours, 32 hours or 34 hours, as well as specific values ​​between the above values. Due to space limitations and for the sake of brevity, the present invention will not exhaustively list the specific values ​​included in the range, but 12-24 hours is further preferred.

[0051] As a preferred embodiment of the present invention, in step (3), the gold nanoparticle-modified electrode is immersed in an alcohol solution containing a thiol-containing organic acid. After self-assembly, carboxyl groups are introduced at the interface of the gold nanoparticles to obtain a second modified electrode. In this step, the gold nanoparticles can specifically form a strong "gold-sulfur bond" (Au-S) with the thiol (-SH) group in the thiol-containing organic acid, firmly grafting the thiol-containing organic acid onto the surface of the gold nanoparticles, thereby introducing negatively charged carboxyl groups at the interface of the gold nanoparticles modified with the electrode body.

[0052] Preferably, the conductive polymer monomer includes any one or a combination of at least two of 3,4-ethylenedioxythiophene, pyrrole, and aniline.

[0053] Preferably, the solvent of the conductive polymer monomer solution includes water.

[0054] Preferably, the concentration of the conductive polymer monomer in the conductive polymer monomer solution is 5-30 mmol / L, for example, it can be 6 mmol / L, 8 mmol / L, 10 mmol / L, 12 mmol / L, 15 mmol / L, 18 mmol / L, 20 mmol / L, 22 mmol / L, 25 mmol / L or 28 mmol / L, as well as specific values ​​between the above values. Due to space limitations and for the sake of brevity, the present invention will not exhaustively list the specific values ​​included in the range.

[0055] Preferably, the voltage for electrochemical polymerization is 0.9-2V, for example, it can be 0.9V, 1V, 1.1V, 1.2V, 1.3V, 1.4V, 1.5V, 1.6V, 1.7V, 1.8V or 1.9V, as well as specific values ​​between the above values. Due to space limitations and for the sake of brevity, the present invention will not exhaustively list the specific values ​​included in the range.

[0056] Preferably, the electrochemical polymerization time is 100-500s, for example, it can be 120s, 150s, 180s, 200s, 220s, 250s, 280s, 300s, 320s, 350s, 380s, 400s, 420s, 450s or 480s, as well as specific values ​​between the above values. Due to space limitations and for the sake of brevity, the present invention will not exhaustively list the specific values ​​included in the range.

[0057] To avoid the incorporation of other negatively charged ions into the polymerization of conductive polymer monomers, the electrochemical polymerization can preferably employ a two-electrode system or a three-electrode system.

[0058] Preferably, the two-electrode system is a working electrode + a counter electrode, and the counter electrode is a platinum electrode.

[0059] Preferably, the reference electrode in the three-electrode system is a double-salt-bridged saturated calomel electrode.

[0060] As a preferred embodiment of the present invention, in step (4), the second modified electrode is placed in a conductive polymer monomer solution, and an electrochemical oxidative polymerization is performed by applying a voltage. A conductive polymer is deposited on the surface of the second modified electrode to form a neural electrode with an interface modification layer covering its surface. In this step, since negatively charged carboxyl groups are introduced onto the surface of the second modified electrode, placing the second modified electrode in the conductive polymer monomer solution and applying a voltage allows the conductive polymer monomer to form a conductive polymer through electrodeposition. The conductive polymer carries a positive charge in a polaron state, and can combine with the negatively charged carboxyl groups through electrostatic attraction, thus constructing a stable interface modification layer.

[0061] Preferably, the preparation method includes the following steps:

[0062] (1) After treating the electrode body in plasma for 60-300s, place it in a 0.2-0.8mol / L sulfuric acid solution for cyclic voltammetry measurement. The scanning voltage is -0.2V to 1.5V. The cyclic voltammetry curve is scanned until it stabilizes to obtain the activated electrode body.

[0063] (2) The activated electrode body obtained in step (1) is placed in a perchloric acid solution of tetrachloroauric acid for electrochemical deposition. The applied voltage is -0.1V to -0.5V and the deposition time is 20-30s to obtain a nano-gold particle modified electrode.

[0064] The concentration of tetrachloroauric acid in the perchloric acid solution of the tetrachloroauric acid is 5-30 mmol / L, and the concentration of perchloric acid is 0.01-0.5 mol / L.

[0065] (3) The nano-gold particle modified electrode obtained in step (2) is placed in a solution containing thiol organic acid for 12-24 hours to self-assemble and obtain the second modified electrode;

[0066] The thiol-containing organic acid in the thiol-containing organic acid solution is selected from any one or a combination of at least two of 3-mercaptopropionic acid, mercaptooctanoic acid, and mercaptodecanoic acid, and the concentration is 1-10 mmol / L.

[0067] (4) The second modified electrode obtained in step (3) is placed in an aqueous solution of conductive polymer monomer for electrochemical polymerization. A voltage of 0.9-2V is applied and the polymerization time is 100-500s to deposit conductive polymer on the surface of the second modified electrode to obtain the neural electrode.

[0068] The conductive polymer monomer in the aqueous solution is selected from any one or a combination of at least two of 3,4-ethylenedioxythiophene, pyrrole, and aniline, with a concentration of 5-30 mmol / L.

[0069] In a second aspect, the present invention provides a neural electrode, which is prepared by the preparation method described in the first aspect.

[0070] Preferably, the electrochemical impedance of the neural electrode at 1 kHz is ≤20 kΩ, more preferably ≤18.5 kΩ, and can be 4.1-18.5 kΩ.

[0071] Thirdly, the present invention provides the application of the neural electrode as described in the second aspect in electrode arrays, biosensors, or implantable medical devices.

[0072] Compared with the prior art, the present invention has the following beneficial effects:

[0073] The method for preparing the neural electrode provided by this invention involves in-situ electrochemical deposition of a layer of gold nanoparticles, followed by self-assembly of negatively charged carboxyl groups onto the surface of the gold nanoparticles, and then electrochemical polymerization to connect a positively charged conductive polymer via electrostatic interaction, thus constructing an interface-modified neural electrode. This neural electrode exhibits significantly reduced electrochemical impedance, improved ion exchange between the neural electrode and nerve tissue, and enhanced signal-to-noise ratio (SNR) during electrophysiological recording, enabling the recording of more and stronger electrophysiological signals. It also demonstrates significantly improved biocompatibility and tissue friendliness, with significantly reduced inflammatory responses at the nerve interface, allowing for long-term maintenance of implant performance and the recording of more and stronger neural signals. Furthermore, the interface modification layer exhibits high adhesion and is not easily detached, giving the neural electrode excellent mechanical and electrochemical stability. This significantly improves the reliability and stability of long-term recording in live animals, maintaining good functionality even after prolonged use, thus meeting the requirements for long-term in vivo neural recording applications. Attached Figure Description

[0074] Figure 1 Impedance comparison diagram of the neural electrode provided in Example 1 and the electrode in Comparative Example 1;

[0075] Figure 2 A graph showing the long-term cyclic voltammetry impedance test results of the neural electrode provided in Example 1;

[0076] Figure 3 A graph showing the relationship between the glial fibrillary acidic protein reaction intensity and the implantation point distance between the neural electrode provided in Example 1 and the electrode in Comparative Example 1.

[0077] Figure 4 Electrophysiological signal test diagrams of the neural electrode provided in Example 1 and the electrode in Comparative Example 1. Detailed Implementation

[0078] The technical solution of the present invention will be further illustrated below through specific embodiments. Those skilled in the art should understand that the embodiments described are merely illustrative of the present invention and should not be construed as limiting the invention in any way.

[0079] The terms “comprising,” “including,” “having,” “containing,” or any other variations thereof, as used herein, are intended to cover non-exclusive inclusion. For example, a composition, step, method, article, or apparatus that includes the listed elements is not limited to those elements and may also include other elements not expressly listed or elements inherent to such composition, step, method, article, or apparatus.

[0080] "Optionally," "alternatively," or "any one" means that the matter or event described thereafter may or may not occur, and the description includes both the possibility that the event occurs and the possibility that the event does not occur.

[0081] In this invention, features specified as "first" and "second" may explicitly or implicitly include one or more of these features, used to distinguish and describe features, without any order or emphasis. In the description of this invention, unless otherwise stated, "multiple" means two or more.

[0082] Example 1

[0083] A neural electrode and its preparation method, the preparation method comprising the following steps:

[0084] (1) After cleaning the electrode body, it was treated in plasma for 180s and then placed in 0.5mol / L sulfuric acid solution for cyclic voltammetry measurement. The scanning voltage was from -0.2V to 1.5V until the cyclic voltammetry curve stabilized, and the activated electrode body was obtained.

[0085] (2) The activated electrode body obtained in step (1) is placed in a perchloric acid solution of tetrachloroauric acid (HAuCl4 concentration is 10 mmol / L, HClO4 concentration is 0.1 mol / L), and an electrochemical deposition is performed by applying a voltage of -0.5V for 30s. Nano gold particles are generated on the surface of the activated electrode body to obtain a nano gold particle modified electrode.

[0086] (3) The nano-gold particle modified electrode obtained in step (2) was immersed in 3-mercaptopropionic acid (3-MPA) solution (3-MPA concentration of 5 mmol / L, solvent of 95% ethanol). After self-assembly for 24 h, carboxyl groups were introduced into the nano-gold particle interface to obtain the second modified electrode.

[0087] (4) The second modified electrode obtained in step (3) is placed in an aqueous solution of 3,4-ethylenedioxythiophene (EDOT) (EDOT concentration is 10 mmol / L), and an electrochemical polymerization is carried out by applying a voltage of 1.3V. The counter electrode is a platinum electrode, and the polymerization time is 300s, so that a conductive polymer is deposited on the surface of the second modified electrode, and the neural electrode with an interface modification layer on the surface is obtained, which has an electrochemical impedance of 4.1kΩ at 1kHz.

[0088] Example 2

[0089] A neural electrode and its preparation method, the preparation method comprising the following steps:

[0090] (1) After cleaning the electrode body, it was treated in plasma for 180s and then placed in 0.5mol / L sulfuric acid solution for cyclic voltammetry measurement. The scanning voltage was from -0.2V to 1.5V until the cyclic voltammetry curve stabilized, and the activated electrode body was obtained.

[0091] (2) The activated electrode body obtained in step (1) is placed in a perchloric acid solution of tetrachloroauric acid (HAuCl4 concentration is 10 mmol / L, HClO4 concentration is 0.1 mol / L), and an electrochemical deposition is performed by applying a voltage of -0.5V for 30s. Nano gold particles are generated on the surface of the activated electrode body to obtain a nano gold particle modified electrode.

[0092] (3) The nano-gold particle modified electrode obtained in step (2) was immersed in 3-mercaptopropionic acid (3-MPA) solution (3-MPA concentration of 5 mmol / L, solvent of 95% ethanol). After self-assembly for 24 h, carboxyl groups were introduced into the nano-gold particle interface to obtain the second modified electrode.

[0093] (4) The second modified electrode obtained in step (3) was placed in an aqueous solution of 3,4-ethylenedioxythiophene (EDOT) (EDOT concentration of 10 mmol / L), and an electrochemical polymerization was carried out by applying a voltage of 1 V. The counter electrode was a platinum electrode, and the polymerization time was 300 s, so that a conductive polymer was deposited on the surface of the second modified electrode, resulting in the neural electrode with an interface modification layer on its surface. The electrochemical impedance at 1 kHz was measured to be 18.5 kΩ.

[0094] Comparative Example 1

[0095] The electrode body without any modification was used as Comparative Example 1.

[0096] Comparative Example 2

[0097] A neural electrode and its preparation method, the preparation method comprising the following steps:

[0098] (1) After cleaning the electrode body, it was treated in plasma for 180s and then placed in 0.5mol / L sulfuric acid solution for cyclic voltammetry measurement. The scanning voltage was from -0.2V to 1.5V until the cyclic voltammetry curve stabilized, and the activated electrode body was obtained.

[0099] (2) The activated electrode body obtained in step (1) is placed in a perchloric acid solution of tetrachloroauric acid (HAuCl4 concentration is 10 mmol / L, HClO4 concentration is 0.1 mol / L), and an electrochemical deposition is performed by applying a voltage of -0.5V for 30s. Nano gold particles are generated on the surface of the activated electrode body to obtain a nano gold particle modified electrode.

[0100] (3) The second modified electrode obtained in step (2) was placed in an aqueous solution of 3,4-ethylenedioxythiophene (EDOT) (EDOT concentration of 10 mmol / L), and electrochemical polymerization was carried out by applying a voltage of 1.3 V. The counter electrode was a platinum electrode, and the polymerization time was 300 s to obtain the neural electrode. The electrochemical impedance at 1 kHz was measured to be 28 kΩ. Since no 3-MPA was introduced for self-assembly during the preparation process of Comparative Example 3, and no negatively charged groups were introduced, the bonding between the conductive polymer PEDOT and the surface of the gold nanoparticles was relatively weakened, and the impedance of the neural electrode increased.

[0101] Comparative Example 3

[0102] A neural electrode and its preparation method, the preparation method comprising the following steps:

[0103] (1) After cleaning the electrode body, it was treated in plasma for 180s and then placed in 0.5mol / L sulfuric acid solution for cyclic voltammetry measurement. The scanning voltage was from -0.2V to 1.5V until the cyclic voltammetry curve stabilized, and the activated electrode body was obtained.

[0104] (2) The activated electrode body obtained in step (1) is placed in a perchloric acid solution of tetrachloroauric acid (HAuCl4 concentration is 10 mmol / L, HClO4 concentration is 0.1 mol / L), and an electrochemical deposition is performed by applying a voltage of -0.5V for 30s. Nano gold particles are generated on the surface of the activated electrode body, and a nano gold particle modified electrode is obtained, which is the neural electrode.

[0105] The performance of the neural electrodes provided in Examples 1-2 and Comparative Examples 1-3 was tested, as follows:

[0106] I. Electrochemical Performance

[0107] Electrochemical impedance and cyclic voltammetry tests were performed using a PBS buffer solution (phosphate buffered saline solution). Specifically, an electrochemical workstation (CHI660D, Shanghai Chenhua Instruments) was used with a three-electrode system. The electrode under test was used as the working electrode, the counter electrode was a platinum wire electrode, and the reference electrode was a saturated calomel electrode.

[0108] Figure 1 Impedance comparison diagram of the neural electrode provided in Example 1 and the electrode in Comparative Example 1; from Figure 1 As can be seen, compared to the unmodified electrode used as Comparative Example 1, the neural electrode with an interface modification layer provided in Example 1 exhibits better performance in the range of 1 Hz to 10 Hz. 5 It maintains low impedance at Hz and significantly reduces impedance at 1kHz to 4.1kΩ, which largely solves the problem of high impedance caused by small implanted electrodes.

[0109] Figure 2 The graph shows the long-term cyclic voltammetry impedance test results of the neural electrode provided in Example 1. Figure 2 As can be seen, after 100 cycles of cyclic voltammetry testing, the impedance of the neural electrode did not change significantly, indicating that the neural electrode containing the interface modification layer provided by the present invention has excellent electrochemical stability.

[0110] II. Biocompatibility Testing

[0111] The electrodes to be tested were implanted into the brains of mice for 12 weeks to observe and compare the condition of inflammatory capsules. The specific method is as follows:

[0112] The electrodes to be tested (the unmodified Pt electrode body of Comparative Example 1 and the neural electrode of Example 1) were implanted into the hippocampus of mice. Twelve weeks after implantation, brain tissue was extracted from the mice. The neural electrodes were characterized and evaluated using the relationship between the distance between implantation sites and the intensity of the glial fibrillary acidic protein (GFAP) response; a stronger response and a larger range indicated a stronger inflammatory response.

[0113] Figure 3 The graph shows the relationship between the glial fibrillary acidic protein response intensity and the implantation point distance between the neural electrode provided in Example 1 and the electrode in Comparative Example 1. Figure 3 As can be seen, after 12 weeks of chronic implantation, the inflammation around the neural electrode modified with the interface modification layer in Example 1 was significantly less than that of the unmodified neural electrode in Comparative Example 1, and the two showed significant differences within the range of 205 μm (P < 0.05).

[0114] The relationship between the glial fibrillary acidic protein reaction intensity and the implantation point distance of the neural electrode provided in Comparative Example 3 and that of the electrode in Comparative Example 1 was similar. However, compared to the neural electrode modified with conductive polymer in Example 1, the inflammation around the neural electrode in Comparative Example 3 was significantly more severe after 12 weeks of chronic implantation. This demonstrates that the neural electrode provided by the present invention, due to the modification effect of the bio-friendly conductive polymer interface modification layer, can significantly inhibit the growth of keratinocytes, thereby reducing the inflammatory response.

[0115] III. Electrophysiological Signal Testing

[0116] The electrodes to be tested were implanted into the hippocampus of mice for 12 weeks, and electrophysiological signals were collected and recorded. The specific method is as follows: After the electrodes to be tested were implanted into the hippocampus of mice for 12 weeks, neural signals were recorded using a multi-channel neural acquisition processor (Plexon, USA). The sampling frequency was 40 kHz, and the bandpass filter was set between 300 and 5000 Hz.

[0117] Figure 4Electrophysiological signal test diagrams of the neural electrode provided in Example 1 and the electrode in Comparative Example 1, from... Figure 4 As can be seen from the data, after 12 weeks of implantation in the hippocampus of rats, the interface-modified neural electrodes in Example 1 could record more signals and had higher signal intensity than those in Comparative Example 1.

[0118] The applicant declares that the present invention illustrates the neural electrode, its preparation method, and its application through the above embodiments. However, the present invention is not limited to the above-described process steps and application scope; that is, it does not mean that the present invention must rely on the above-described process steps to be implemented, nor does it mean that the above-described embodiments are the only ones. Those skilled in the art should understand that any improvements to the present invention, equivalent substitutions of the raw materials used in the present invention, additions of auxiliary components, and selection of specific methods, etc., all fall within the protection scope and disclosure scope of the present invention.

Claims

1. A method for preparing a neural electrode, characterized in that, The preparation method includes the following steps: The plasma-treated electrode body was placed in an acid solution for cyclic voltammetry measurement until the cyclic voltammetry curve stabilized, thus obtaining the activated electrode body. The activated electrode body was placed in a gold electrolyte for electrochemical deposition to obtain a gold nanoparticle-modified electrode. The modified electrode made of gold nanoparticles was placed in a solution containing thiol-containing organic acid for self-assembly to obtain a second modified electrode. The second modified electrode is placed in a conductive polymer monomer solution for electrochemical polymerization, thereby depositing the conductive polymer on the surface of the second modified electrode to obtain the neural electrode. The voltage applied during the electrochemical deposition is -0.1 V to -0.5 V; The electrochemical deposition time is 10-40 s.

2. The preparation method according to claim 1, characterized in that, The plasma treatment is an oxygen plasma treatment.

3. The preparation method according to claim 1, characterized in that, The plasma treatment time is 60-300 seconds.

4. The preparation method according to claim 3, characterized in that, The plasma treatment time is 60-180 seconds.

5. The preparation method according to claim 1, characterized in that, The acid solution is a sulfuric acid solution.

6. The preparation method according to claim 5, characterized in that, The concentration of the sulfuric acid solution is 0.2-0.8 mol / L.

7. The preparation method according to claim 1, characterized in that, The scanning voltage for the cyclic voltammetry measurement ranges from -0.2V to 1.5V.

8. The preparation method according to claim 1, characterized in that, The gold electrolyte comprises a combination of a gold electrolyte and an acidic compound.

9. The preparation method according to claim 8, characterized in that, The gold electrolyte includes any one or a combination of at least two of tetrachloroauric acid, sodium chloroaurate, potassium chloroaurate, and ammonium chloroaurate.

10. The preparation method according to claim 9, characterized in that, The gold electrolyte includes tetrachloroauric acid.

11. The preparation method according to claim 8, characterized in that, The concentration of gold electrolyte in the gold electrolyte solution is 5-30 mmol / L.

12. The preparation method according to claim 8, characterized in that, The acidic compound includes any one or a combination of at least two of perchloric acid, chloric acid, sulfuric acid, nitric acid, and hydrochloric acid.

13. The preparation method according to claim 8, characterized in that, The acidic compound includes perchloric acid.

14. The preparation method according to claim 8, characterized in that, The concentration of acidic compounds in the gold electrolyte is 0.01-0.5 mol / L.

15. The preparation method according to claim 1, characterized in that, The electrochemical deposition time is 20-30 s.

16. The preparation method according to claim 1, characterized in that, The particle size of the gold nanoparticles is 10-200 nm.

17. The preparation method according to claim 1, characterized in that, The thiol-containing organic acid has the structure shown in Formula I: ； R is selected from C1-C20 straight-chain or branched alkylene groups.

18. The preparation method according to claim 1, characterized in that, The thiol-containing organic acid includes any one or a combination of at least two of 3-mercaptopropionic acid, mercaptooctanoic acid, and mercaptodecanoic acid.

19. The preparation method according to claim 1, characterized in that, The solvent of the thiol-containing organic acid solution includes any one or a combination of at least two of the following: alcohol solvents, ketone solvents, ether solvents, and water.

20. The preparation method according to claim 1, characterized in that, The concentration of the thiol-containing organic acid in the solution is 1-10 mmol / L.

21. The preparation method according to claim 1, characterized in that, The self-assembly temperature is 4-30℃.

22. The preparation method according to claim 1, characterized in that, The self-assembly time is 8-36 hours.

23. The preparation method according to claim 22, characterized in that, The self-assembly time is 12-24 hours.

24. The preparation method according to claim 1, characterized in that, The conductive polymer monomer includes any one or a combination of at least two of 3,4-ethylenedioxythiophene, pyrrole, and aniline.

25. The preparation method according to claim 1, characterized in that, The solvent for the conductive polymer monomer solution includes water.

26. The preparation method according to claim 1, characterized in that, The concentration of the conductive polymer monomer in the conductive polymer monomer solution is 5-30 mmol / L.

27. The preparation method according to claim 1, characterized in that, The voltage for the electrochemical polymerization is 0.9-2 V.

28. The preparation method according to claim 1, characterized in that, The electrochemical polymerization time is 100-500 s.

29. The preparation method according to claim 1, characterized in that, The preparation method includes the following steps: (1) After treating the electrode body in plasma for 60-300 s, place it in a 0.2-0.8 mol / L sulfuric acid solution for cyclic voltammetry determination. The scanning voltage is -0.2 V to 1.5 V. The cyclic voltammetry curve is scanned until it stabilizes to obtain the activated electrode body. (2) The activated electrode body obtained in step (1) is placed in a perchloric acid solution of tetrachloroauric acid for electrochemical deposition. The applied voltage is -0.1 V to -0.5 V and the deposition time is 20-30 s to obtain a nano-gold particle modified electrode. The concentration of tetrachloroauric acid in the perchloric acid solution of the tetrachloroauric acid is 5-30 mmol / L, and the concentration of perchloric acid is 0.01-0.5 mol / L; (3) The nano-gold particle modified electrode obtained in step (2) is placed in a solution containing thiol organic acid for 12-24 h to self-assemble and obtain the second modified electrode; The thiol-containing organic acid in the solution is selected from any one or a combination of at least two of 3-mercaptopropionic acid, mercaptooctanoic acid, and mercaptodecanoic acid, with a concentration of 1-10 mmol / L; (4) The second modified electrode obtained in step (3) is placed in an aqueous solution of conductive polymer monomer for electrochemical polymerization. A voltage of 0.9-2 V is applied and the polymerization time is 100-500 s, so that conductive polymer is deposited on the surface of the second modified electrode to obtain the neural electrode. The conductive polymer monomer in the aqueous solution is selected from any one or a combination of at least two of 3,4-ethylenedioxythiophene, pyrrole, and aniline, with a concentration of 5-30 mmol / L.

30. A neural electrode, characterized in that, The neural electrode is prepared by the preparation method according to any one of claims 1-29.

31. The use of a neural electrode as described in claim 30 in an electrode array, a biosensor, or an implantable medical device.

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