A bionic flexible skin electrode and a preparation method and application thereof

Abstract

The present application relates to the technical field of flexible skin layer electrode, and particularly relates to a bionic flexible skin layer electrode, a preparation method and application thereof, the preparation method comprising the following steps: preparing a conductive hydrogel precursor solution and an adhesive hydrogel; preparing a flexible electrode substrate with conductive channels; injecting the conductive hydrogel precursor solution into the conductive channels of the flexible electrode substrate, and obtaining the flexible electrode substrate with conductive channels through ultraviolet cross-linking and curing; covering a layer of polydimethylsiloxane film on the entire flexible electrode substrate with conductive channels, and then arranging the adhesive hydrogel on the contact area of the flexible electrode to obtain the flexible skin layer electrode. The flexible skin layer electrode prepared by the above steps realizes high bionic matching with the brain tissue in modulus, water content and ion environment, has lower noise than the traditional metal electrode, significantly reduces the mechanical mismatch and immune response of the interface, and ensures efficient and stable transmission of the electrical signal between the interfaces.

Description

Technical Field

[0001] This invention relates to the field of flexible skin electrode technology, and in particular to a biomimetic flexible skin electrode, its preparation method, and its application. Background Technology

[0002] ECoG (electrocortical electroencephalography) is a neural signal acquisition technique that records the electrical activity of groups of neurons from underlying brain regions on the surface of the cerebral cortex. Compared to other electrophysiological techniques (penetrating electrodes), its main advantage is that it does not require penetration of brain tissue, resulting in less surgical trauma and extremely mild inflammatory responses. Thanks to this characteristic, ECoG technology has been widely used in neurosurgical diagnostic procedures such as localizing epileptic foci in human patients. Integrated neural interfaces that combine neurophysiology and optogenetics with medical neuroimaging (such as magnetic resonance imaging (MRI)) can overcome the spatiotemporal resolution limitations of individual techniques, providing neuroscientists with numerous opportunities to study the structure and function of neural circuits in the brain.

[0003] However, traditional metal electrode arrays, due to their opaque nature, obstruct the field of view in biological tissues. Furthermore, photoelectric artifacts—electrical noise generated when light shines on a metal surface—hinder the integration of electrophysiological recordings with optical modalities. Performing MRI on patients with implanted metal brain electrodes is extremely challenging. First, the metal electrodes absorb radiofrequency energy and generate local currents, leading to rapid local heating and damage to brain tissue. Second, the metal electrodes distort the homogeneity of the main magnetic field and interfere with the distribution of the radiofrequency field, resulting in signal loss and geometric distortion. Finally, the extremely high Young's modulus of the metal electrodes is mechanically mismatched with brain tissue, limiting their long-term monitoring after implantation.

[0004] Recently, hydrogel-neural interfaces based on multifunctional hydrogels have become a new trend in the field of neural electrodes due to their excellent mechanically tunable flexibility, biocompatibility, and ease of fabrication, providing an ideal platform for multimodal neural interfaces. However, many materials and technologies have been proposed for electrophysiological monitoring in recent years. For example, graphene, MXene, conductive polymers PEDOT:PSS, and indium tin oxide can be used to prepare conductive polymer hydrogels by mixing them with non-conductive hydrogels. They have shown potential in improving signal quality and multimodal integration, but still face a series of serious challenges. These materials are often expensive, and their transparency, conductivity, and mechanical properties are usually mutually restrictive and difficult to optimize simultaneously. To achieve specific functions, complex structural designs and tedious engineering optimizations must be followed, which further increases manufacturing costs. Moreover, research on these materials for long-term electrophysiological monitoring still needs further exploration. Therefore, obtaining transparent conductive hydrogels that are both long-term stable and maintain high conductivity and mechanical tunability remains a major challenge. Summary of the Invention

[0005] The purpose of this invention is to provide a biomimetic flexible cortical electrode, its preparation method, and its application. The prepared flexible cortical electrode achieves a high degree of biomimetic matching with brain tissue in terms of modulus, water content, and ionic environment. It has lower noise than traditional metal electrodes, which not only significantly reduces mechanical mismatch and immune response at the interface, but also ensures efficient and stable transmission of electrical signals between the interfaces.

[0006] To achieve the above objectives, the present invention provides a method for preparing a biomimetic flexible skin electrode, comprising the following steps: S1. Preparation of conductive hydrogel precursor solution and adhesive hydrogel; S2. Pour polydimethylsiloxane prepolymer into a multi-channel electrode mold, heat to cure, and then remove the multi-channel electrode mold to obtain a flexible electrode substrate with conductive channels. S3. Inject the conductive hydrogel precursor liquid of S1 into the conductive channel of the flexible electrode substrate obtained in S2, and then crosslink and cure it under ultraviolet light to obtain a flexible electrode substrate with conductive pathways. S4. A polydimethylsiloxane film is coated on the flexible electrode substrate with conductive pathways throughout S3. Then, the adhesive hydrogel of S1 is placed in the contact area of ​​the flexible electrode to obtain a flexible skin electrode.

[0007] Preferably, in S1, the conductive hydrogel precursor solution is prepared by: dissolving photocurable carboxymethyl cellulose in artificial cerebrospinal fluid, stirring until completely dissolved, adding N-acryloylglycine, continuing to stir until completely dissolved, adding a photoinitiator, and stirring until completely dissolved to obtain the conductive hydrogel precursor solution.

[0008] Preferably, in S1, the adhesive hydrogel is prepared by: completely dissolving photocurable carboxymethyl cellulose in deionized water, adding acrylic acid and N-hydroxysuccinimide acrylate in sequence, stirring until completely dissolved, adding 0.2wt% α-ketoglutaric acid and 0.05wt% polyethylene glycol diacrylate, continuing to stir until completely dissolved, and then UV curing for 100-150s to obtain the adhesive hydrogel.

[0009] Preferably, in S1, the components of the conductive hydrogel precursor solution are as follows by mass percentage: 1-6 wt% photocurable carboxymethyl cellulose, 10-20 wt% N-acryloylglycine, 0.1 wt% photoinitiator, and 10 mL artificial cerebrospinal fluid.

[0010] Preferably, in S1, the photoinitiator is 2-hydroxy-4′-(hydroxyethoxy)-2-methylphenylacetone.

[0011] Preferably, in S2, the multi-channel electrode mold has a mold cavity in the center, the upper width of the mold cavity is greater than the lower width of the mold cavity, and a number of electrode channels are provided in the lower end of the mold cavity. The middle part of the mold cavity connecting the upper and lower ends of the mold cavity is inclined.

[0012] Preferably, in S3, the UV cross-linking curing time is 80-120s.

[0013] The flexible skin electrode prepared by the above-mentioned biomimetic flexible skin electrode preparation method has several conductive channels, and conductive hydrogel is arranged inside the conductive channels.

[0014] Preferably, the diameter of the conductive channel is 300-800 μm, and the spacing between adjacent conductive channels is 300-900 μm.

[0015] The above-mentioned biomimetic flexible cortical electrode is used in the fabrication of brain-computer interfaces or nervous system monitoring devices.

[0016] Therefore, the present invention employs the above-mentioned biomimetic flexible cortical electrode, its preparation method, and its application, and its beneficial effects are as follows: 1. The conductive hydrogel prepared by this invention is a double-network interpenetrating hydrogel of N-acryloylglycine (NAGA) and methacryloxycarboxymethyl cellulose (CG) to simulate the chemical composition of the brain extracellular matrix, and artificial cerebrospinal fluid (ACSF) is used as a conductive medium to simulate the ion-conducting environment of the brain. 2. The ultra-soft, bioadhesive hydrogel interface layer (AA) prepared by this invention bridges the mechanical gradient between the encapsulation material polydimethylsiloxane (PDMS) film and brain tissue, thereby achieving stable and close adhesion between the flexible cortical electrode and the cortical surface. 3. The flexible cortical electrode prepared by this invention achieves a high degree of biomimetic matching with brain tissue in terms of modulus, water content and ionic environment. It has lower noise than traditional metal electrodes, which not only significantly reduces mechanical mismatch and immune response at the interface, but also ensures efficient and stable transmission of electrical signals between the interfaces.

[0017] The technical solution of the present invention will be further described in detail below with reference to the accompanying drawings and embodiments. Attached Figure Description

[0018] Figure 1 This is a schematic diagram of the five-channel electrode mold in Embodiment 1 of the present invention; Figure 2 This is a schematic diagram of the nine-channel electrode mold in Embodiment 2 of the present invention; Figure 3 This is a schematic diagram of the sixteen-channel electrode mold in Embodiment 3 of the present invention; Figure 4This is a diagram showing the electrochemical impedance spectroscopy (EIS) test setup of the flexible skin electrode in Embodiment 5 of the present invention. Figure 4 In the diagram, 'a' represents the electrochemical impedance spectroscopy of each conductive channel. Figure 4 In the diagram, b represents the electrochemical impedance spectroscopy of the flexible cortical electrode after 1000 bending cycles. Figure 4 In the figure, c represents the electrochemical impedance spectroscopy diagram of the flexible skin electrode after 1000 stretching cycles. Figure 5 This is a biocompatibility diagram of the flexible cortical electrode and the control group in Example 5 of the present invention, wherein... Figure 5 In the figure, 'a' represents the cell viability statistics. Figure 5 In the graph, b represents the cell survival rate statistics. Figure 6 These are cell staining results at different times for the flexible skin electrode and the control group in Example 5 of this invention; Figure 7 This is a statistical chart of cell viability and mortality staining rates for the flexible skin electrode and the control group in Example 5 of this invention; Figure 8 These are combined staining images of brain tissue at different times in the flexible cortical electrode and sham-operated group in Embodiment 5 of the present invention. Figure 8 In the image, 'a' represents the brain tissue staining images of the sham-operated group at different time points. Figure 8 b in the figure represents brain tissue staining images at different time points in Example 5; Figure 9 This is a combined fluorescence image of the flexible cortical electrode implantation one week after the procedure in Example 5 of this invention, and the sham surgery group. Figure 9 In the image, 'a' represents the fluorescence result after implantation. Figure 9 In the diagram, b represents the quantitative PCR chromatogram. Figure 10 This is a combined fluorescence image of the flexible cortical electrode implanted 6 months after the procedure in Example 5 of this invention and the sham surgery group. Figure 10 In the image, 'a' represents the fluorescence result after implantation. Figure 10 In the diagram, b represents the quantitative PCR chromatogram. Figure 11 This is a combined image of rat ECoG signals from the flexible cortical electrode in Example 5 of this invention at different isoflurane concentrations, wherein... Figure 11 In the figure, 'a' represents the electroencephalogram (EEG) signal of rats at different isoflurane concentrations. Figure 11 In the diagram, b represents the time-frequency spectrum of the electroencephalogram (ECoG) signal at different isoflurane concentrations. Figure 12 This is a power spectral density diagram of the flexible cortical electrode in Example 5 of the present invention under different isoflurane concentrations in rats; Figure 13 This is a time-domain diagram of the complete epileptic seizure process of a rat recorded by the flexible cortical electrode in Example 5 of the present invention and Comparative Example 2; Figure 14 This is a performance combination diagram of the electrodes in Embodiment 5, Comparative Example 1, and Comparative Example 2 of the present invention during an epileptic seizure, wherein... Figure 14 In the diagram, 'a' represents the time-domain signal map of late-stage epilepsy at different electrodes. Figure 14 In the diagram, b represents the late-stage epileptic spectrum of different electrodes. Figure 14 In the figure, c represents a comparison of the power spectral density of different electrodes in late-stage epilepsy. Figure 15 This is a graph showing the signal-to-noise ratio variation of the electrodes in Embodiment 5, Comparative Example 1, and Comparative Example 2 of the present invention. Figure 15 In the figure, 'a' represents the signal-to-noise ratio variation diagram of Example 5. Figure 15 In the diagram, b represents the signal-to-noise ratio variation of Comparative Example 1. Figure 15 In the figure, c represents the signal-to-noise ratio variation of Comparative Example 2. Detailed Implementation

[0019] The present invention will be further described below with reference to the accompanying drawings and embodiments. Unless otherwise defined, the technical or scientific terms used in this invention should be understood in their ordinary sense by those skilled in the art. The features mentioned above or in the specific examples mentioned in this invention can be combined arbitrarily, and these specific embodiments are only used to illustrate the invention and are not intended to limit the scope of the invention.

[0020] This invention provides a method for preparing a biomimetic flexible skin electrode, comprising the following steps: S1, preparing a conductive hydrogel precursor solution and an adhesive hydrogel; S2. Polydimethylsiloxane (PDMS) prepolymer is poured into the multi-channel electrode mold, and after heating and curing, the multi-channel electrode mold is removed to obtain a flexible electrode substrate with conductive channels; the PDMS flexible substrate provides structural support and encapsulation protection.

[0021] S3. Inject the conductive hydrogel precursor liquid of S1 into the conductive channel of the flexible electrode substrate obtained in S2, and then crosslink and cure it under ultraviolet light to obtain a flexible electrode substrate with conductive pathways. S4. A polydimethylsiloxane (PDMS) film is coated onto the flexible electrode substrate, which has conductive pathways throughout S3. Then, the adhesive hydrogel from S1 is deposited in the contact area of ​​the flexible electrode to obtain a flexible cortical electrode. The adhesive hydrogel is distributed around the electrode contacts. The carboxyl groups on the acrylic acid (PAA) chains adhere strongly to the amino groups on the brain tissue surface through covalent amide bonds and hydrogen bonds, allowing the flexible cortical electrode to fit seamlessly onto the cortical surface and bridging the modulus gradient between the material and tissue. The PDMS film encapsulation prevents the conductive hydrogel from dehydrating and swelling, and the overall structure exhibits no significant change in impedance after bending / stretching cycles.

[0022] In some embodiments of the present invention, in S1, the conductive hydrogel precursor solution is prepared by: dissolving photocurable carboxymethyl cellulose in artificial cerebrospinal fluid, stirring until completely dissolved, adding N-acryloylglycine, continuing to stir until completely dissolved, adding a photoinitiator, and stirring until completely dissolved to obtain the conductive hydrogel precursor solution.

[0023] A double-network interpenetrating hydrogel composed of N-acryloylglycine (NAGA) and methacryloxycarboxymethyl cellulose (CG) uses artificial cerebrospinal fluid (ACSF) as both solvent and conductive medium. Electrical signals are conducted via the migration of free ions within the ACSF, rather than through the electronic conduction of traditional metals. This ionic conductivity mechanism is essentially consistent with the ionic conduction of neural signals in vivo, significantly reducing impedance mismatch and electrical noise at the electrode-tissue interface. Ultimately, the conductive hydrogel modulus can be tuned to the same order of magnitude as brain tissue, eliminating micromotion damage and foreign body reactions.

[0024] In some embodiments of the present invention, in S1, the adhesive hydrogel is prepared by: completely dissolving photocurable carboxymethyl cellulose in deionized water, sequentially adding acrylic acid (PAA) and N-hydroxysuccinimide acrylate (PAA-NHS), stirring until completely dissolved, then adding 0.2wt% α-ketoglutarate and 0.05wt% polyethylene glycol diacrylate (PEGDA), continuing to stir until completely dissolved, and then UV curing for 100-150s to obtain the adhesive hydrogel.

[0025] In some embodiments of the present invention, in S1, the components of the conductive hydrogel precursor liquid are as follows by mass percentage: 1-6 wt% photocurable carboxymethyl cellulose, 10-20 wt% N-acryloylglycine, 0.1 wt% photoinitiator, and 10 mL artificial cerebrospinal fluid.

[0026] CG mimics the polysaccharide components of the brain's extracellular matrix (ECM), providing flexibility and high water content while ensuring low modulus. ACSF provides an ionic environment highly consistent with the interstitial fluid of brain tissue (Na+). + K + Ca 2+ Mg 2+ Cl - (e.g., through multiple hydrogen bonds to form reversible physical crosslinks, enhancing tensile and fatigue resistance.) NAGA provides a hydrogen-bonded enhanced physical crosslink network, endowing the hydrogel with high mechanical strength and toughness. The crosslinking of CG and NAGA forms a homogeneous amorphous polymer network with high visible light transmittance, allowing for synchronous optogenetic manipulation or optical imaging.

[0027] In some embodiments of the present invention, in S1, the photoinitiator is 2-hydroxy-4′-(hydroxyethoxy)-2-methylphenylacetone.

[0028] In some embodiments of the present invention, in S2, a mold cavity is provided in the center of the multi-channel electrode mold, the upper end of the mold cavity is wider than the lower end of the mold cavity, a plurality of electrode channels are provided in the lower end of the mold cavity, and the middle part of the mold cavity connecting the upper end and the lower end of the mold cavity is inclined.

[0029] In some embodiments of the present invention, in S2, the polydimethylsiloxane (PDMS) prepolymer liquid includes PDMS components and a curing agent, and the PDMS basic components and the curing agent are completely mixed at a weight ratio of 15:1 before use.

[0030] In some embodiments of the present invention, in S3, the UV crosslinking curing time is 80-120s.

[0031] In some embodiments of the present invention, the flexible skin electrode prepared by the above-described biomimetic flexible skin electrode preparation method has a plurality of conductive channels, and conductive hydrogel is disposed inside the conductive channels.

[0032] In some embodiments of the present invention, the diameter of the conductive channel is 300-800 μm, and the spacing between adjacent conductive channels is 300-900 μm.

[0033] In some embodiments of the present invention, the above-mentioned biomimetic flexible cortical electrode is applied to the fabrication of brain-computer interfaces or nervous system monitoring devices.

[0034] Example 1 S1. Preparation of conductive hydrogel precursor solution and adhesive hydrogel.

[0035] The conductive hydrogel precursor solution was prepared as follows: 1 wt% of photocurable carboxymethyl cellulose (CG) was dissolved in 10 mL of artificial cerebrospinal fluid (ACSF). After stirring until completely dissolved, 10 wt% of N-acryloylglycine (NAGA) was added. After stirring until completely dissolved, 0.1 wt% of photoinitiator (2-hydroxy-4′-(hydroxyethoxy)-2-methylphenylacetone) was added. After stirring until completely dissolved, the conductive hydrogel precursor solution was obtained.

[0036] The adhesive hydrogel was prepared as follows: Carboxymethyl cellulose that can be cured by light was completely dissolved in deionized water, PAA and PAA-NHS were added in sequence, and the mixture was stirred until completely dissolved. Then, 0.2 wt% α-ketoglutaric acid and 0.05 wt% polyethylene glycol diacrylate (PEGDA) were added, and the mixture was stirred until completely dissolved. After UV curing for 100-150 s, the adhesive hydrogel was obtained.

[0037] S2, such as Figure 1As shown, the five-channel electrode mold has a central mold cavity. The upper width of the mold cavity is greater than the lower width of the mold cavity. Several electrode channels are provided in the lower end of the mold cavity. The middle part of the mold cavity connecting the upper and lower ends is inclined. PDMS prepolymer liquid is poured into the multi-channel electrode mold, heated and cured, and then the multi-channel electrode mold is removed to obtain a flexible electrode substrate with conductive channels.

[0038] S3. Inject the conductive hydrogel precursor solution of S1 into the conductive channel of the flexible electrode substrate obtained in S2, and cure it under ultraviolet crosslinking for 90s to obtain a flexible electrode substrate with conductive pathways.

[0039] S4. A PDMS film is coated on the flexible electrode substrate with conductive pathways throughout S3. Then, the adhesive hydrogel of S1 is placed in the contact area of ​​the flexible electrode to obtain the flexible skin electrode ACGN-AA.

[0040] Example 2 S1. Preparation of conductive hydrogel precursor solution and adhesive hydrogel.

[0041] The conductive hydrogel precursor solution was prepared as follows: 1 wt% of photocurable carboxymethyl cellulose (CG) was dissolved in 10 mL of artificial cerebrospinal fluid (ACSF). After stirring until completely dissolved, 15 wt% of N-acryloylglycine (NAGA) was added. After stirring until completely dissolved, 0.1 wt% of photoinitiator (2-hydroxy-4′-(hydroxyethoxy)-2-methylphenylacetone) was added. After stirring until completely dissolved, the conductive hydrogel precursor solution was obtained.

[0042] The adhesive hydrogel was prepared as follows: Carboxymethyl cellulose that can be cured by light was completely dissolved in deionized water, PAA and PAA-NHS were added in sequence, and the mixture was stirred until completely dissolved. Then, 0.2 wt% α-ketoglutaric acid and 0.05 wt% polyethylene glycol diacrylate (PEGDA) were added, and the mixture was stirred until completely dissolved. After UV curing for 100-150 s, the adhesive hydrogel was obtained.

[0043] S2, such as Figure 2 As shown, the nine-channel electrode mold has a central mold cavity. The upper width of the mold cavity is greater than the lower width of the mold cavity. Several electrode channels are provided in the lower end of the mold cavity. The middle part of the mold cavity connecting the upper and lower ends is inclined. PDMS prepolymer liquid is poured into the multi-channel electrode mold, heated and cured, and then the multi-channel electrode mold is removed to obtain a flexible electrode substrate with conductive channels.

[0044] S3. Inject the conductive hydrogel precursor solution of S1 into the conductive channel of the flexible electrode substrate obtained in S2, and cure it under ultraviolet crosslinking for 90s to obtain a conductive path.

[0045] S4. A PDMS film is coated on the flexible electrode substrate with conductive pathways throughout S3. Then, the adhesive hydrogel of S1 is placed in the contact area of ​​the flexible electrode to obtain the flexible skin electrode ACGN-AA.

[0046] Example 3 S1. Preparation of conductive hydrogel precursor solution and adhesive hydrogel.

[0047] The conductive hydrogel precursor solution was prepared as follows: 1 wt% of photocurable carboxymethyl cellulose (CG) was dissolved in 10 mL of artificial cerebrospinal fluid (ACSF). After stirring until completely dissolved, 20 wt% of N-acryloylglycine (NAGA) was added. After stirring until completely dissolved, 0.1 wt% of photoinitiator (2-hydroxy-4′-(hydroxyethoxy)-2-methylphenylacetone) was added and stirred until completely dissolved to obtain the conductive hydrogel precursor solution.

[0048] The adhesive hydrogel was prepared as follows: Carboxymethyl cellulose that can be cured by light was completely dissolved in deionized water, PAA and PAA-NHS were added in sequence, and the mixture was stirred until completely dissolved. Then, 0.2 wt% α-ketoglutaric acid and 0.05 wt% polyethylene glycol diacrylate (PEGDA) were added, and the mixture was stirred until completely dissolved. After UV curing for 100-150 s, the adhesive hydrogel was obtained.

[0049] S2, such as Figure 3 As shown, a mold cavity is located in the center of the sixteen-channel electrode mold. The upper end of the mold cavity is wider than the lower end. Several electrode channels are located inside the lower end of the mold cavity. The middle part of the mold cavity, which connects the upper and lower ends, is inclined. PDMS prepolymer liquid is poured into the multi-channel electrode mold, and after heating and curing, the multi-channel electrode mold is removed to obtain a flexible electrode substrate with conductive channels.

[0050] S3. Inject the conductive hydrogel precursor solution of S1 into the conductive channel of the flexible electrode substrate obtained in S2, and cure it under ultraviolet crosslinking for 90s to obtain a conductive path.

[0051] S4. A PDMS film is coated on the flexible electrode substrate with conductive pathways throughout S3. Then, the adhesive hydrogel of S1 is placed in the contact area of ​​the flexible electrode to obtain the flexible skin electrode ACGN-AA.

[0052] Example 4 S1. Preparation of conductive hydrogel precursor solution and adhesive hydrogel.

[0053] The conductive hydrogel precursor solution was prepared as follows: 3 wt% of photocurable carboxymethyl cellulose (CG) was dissolved in 10 mL of artificial cerebrospinal fluid (ACSF). After stirring until completely dissolved, 15 wt% of N-acryloylglycine (NAGA) was added. After stirring until completely dissolved, 0.1 wt% of photoinitiator (2-hydroxy-4′-(hydroxyethoxy)-2-methylphenylacetone) was added and stirred until completely dissolved to obtain the conductive hydrogel precursor solution.

[0054] The adhesive hydrogel was prepared as follows: Carboxymethyl cellulose that can be cured by light was completely dissolved in deionized water, PAA and PAA-NHS were added in sequence, and the mixture was stirred until completely dissolved. Then, 0.2 wt% α-ketoglutaric acid and 0.05 wt% polyethylene glycol diacrylate (PEGDA) were added, and the mixture was stirred until completely dissolved. After UV curing for 100-150 s, the adhesive hydrogel was obtained.

[0055] S2, such as Figure 1 As shown, the five-channel electrode mold has a central mold cavity. The upper width of the mold cavity is greater than the lower width of the mold cavity. Several electrode channels are provided in the lower end of the mold cavity. The middle part of the mold cavity connecting the upper and lower ends is inclined. PDMS prepolymer liquid is poured into the multi-channel electrode mold, heated and cured, and then the multi-channel electrode mold is removed to obtain a flexible electrode substrate with conductive channels.

[0056] S3. Inject the conductive hydrogel precursor solution of S1 into the conductive channel of the flexible electrode substrate obtained in S2, and cure it under ultraviolet crosslinking for 90s to obtain a conductive path.

[0057] S4. A PDMS film is coated on the flexible electrode substrate with conductive pathways throughout S3. Then, the adhesive hydrogel of S1 is placed in the contact area of ​​the flexible electrode to obtain the flexible skin electrode ACGN-AA.

[0058] Example 5 S1. Preparation of conductive hydrogel precursor solution and adhesive hydrogel.

[0059] The conductive hydrogel precursor solution was prepared as follows: 3 wt% of photocurable carboxymethyl cellulose (CG) was dissolved in 10 mL of artificial cerebrospinal fluid (ACSF). After stirring until completely dissolved, 10 wt% of N-acryloylglycine (NAGA) was added. After stirring until completely dissolved, 0.1 wt% of photoinitiator (2-hydroxy-4′-(hydroxyethoxy)-2-methylphenylacetone) was added. After stirring until completely dissolved, the conductive hydrogel precursor solution was obtained.

[0060] The adhesive hydrogel was prepared as follows: Carboxymethyl cellulose that can be cured by light was completely dissolved in deionized water, PAA and PAA-NHS were added in sequence, and the mixture was stirred until completely dissolved. Then, 0.2 wt% α-ketoglutaric acid and 0.05 wt% polyethylene glycol diacrylate (PEGDA) were added, and the mixture was stirred until completely dissolved. After UV curing for 100-150 s, the adhesive hydrogel was obtained.

[0061] S2, such as Figure 1 As shown, the five-channel electrode mold has a central mold cavity. The upper width of the mold cavity is greater than the lower width of the mold cavity. Several electrode channels are provided in the lower end of the mold cavity. The middle part of the mold cavity connecting the upper and lower ends is inclined. PDMS prepolymer liquid is poured into the multi-channel electrode mold, heated and cured, and then the multi-channel electrode mold is removed to obtain a flexible electrode substrate with conductive channels.

[0062] S3. Inject the conductive hydrogel precursor solution of S1 into the conductive channel of the flexible electrode substrate obtained in S2, and cure it under ultraviolet crosslinking for 90s to obtain a conductive path.

[0063] S4. A PDMS film is coated on the flexible electrode substrate with conductive pathways throughout S3. Then, the adhesive hydrogel of S1 is placed in the contact area of ​​the flexible electrode to obtain the flexible skin electrode ACGN-AA.

[0064] Example 6 S1. Preparation of conductive hydrogel precursor solution and adhesive hydrogel.

[0065] The conductive hydrogel precursor solution was prepared as follows: 3 wt% of photocurable carboxymethyl cellulose (CG) was dissolved in 10 mL of artificial cerebrospinal fluid (ACSF). After stirring until completely dissolved, 20 wt% of N-acryloylglycine (NAGA) was added. After stirring until completely dissolved, 0.1 wt% of photoinitiator (2-hydroxy-4′-(hydroxyethoxy)-2-methylphenylacetone) was added and stirred until completely dissolved to obtain the conductive hydrogel precursor solution.

[0066] The adhesive hydrogel was prepared as follows: Carboxymethyl cellulose that can be cured by light was completely dissolved in deionized water, PAA and PAA-NHS were added in sequence, and the mixture was stirred until completely dissolved. Then, 0.2 wt% α-ketoglutaric acid and 0.05 wt% polyethylene glycol diacrylate (PEGDA) were added, and the mixture was stirred until completely dissolved. After UV curing for 100-150 s, the adhesive hydrogel was obtained.

[0067] S2, such as Figure 1As shown, the five-channel electrode mold has a central mold cavity. The upper width of the mold cavity is greater than the lower width of the mold cavity. Several electrode channels are provided in the lower end of the mold cavity. The middle part of the mold cavity connecting the upper and lower ends is inclined. PDMS prepolymer liquid is poured into the multi-channel electrode mold, heated and cured, and then the multi-channel electrode mold is removed to obtain a flexible electrode substrate with conductive channels.

[0068] S3. Inject the conductive hydrogel precursor solution of S1 into the conductive channel of the flexible electrode substrate obtained in S2, and cure it under ultraviolet crosslinking for 90s to obtain a conductive path.

[0069] S4. A PDMS film is coated on the flexible electrode substrate with conductive pathways throughout S3. Then, the adhesive hydrogel of S1 is placed in the contact area of ​​the flexible electrode to obtain the flexible skin electrode ACGN-AA.

[0070] Comparative Example 1 Commercial polyimide (PI) electrodes.

[0071] Comparative Example 2 Conductive silver paste electrode.

[0072] Performance testing a. Electrochemical impedance spectroscopy Electrochemical impedance spectroscopy was performed on the flexible skin electrode in Example 5, such as... Figure 4 As shown, each conductive channel of the electrode maintains low impedance throughout the overall frequency range, and each conductive channel exhibits good tensile properties. During the implantation of the flexible cortical electrode, twisting and deformation are inevitable; therefore, bending and tensile tests were also conducted on the flexible cortical electrode to verify its mechanical stability. When the flexible cortical electrode was repeatedly bent and stretched, changes in electrochemical impedance were observed. Even after more than 1000 cycles of bending, the impedance did not show significant changes.

[0073] b. The in vitro biocompatibility of the flexible cortical electrode in Example 5 was verified using the mouse hippocampal neuron cell line HT22. HT22 cells were cultured in a medium containing cell extract (flexible cortical electrode extract). Cell viability was quantitatively assessed using a CCK-8 assay, such as... Figure 5 As shown, the results indicate that cell viability was comparable to that of the control group (cultured in complete DMEM medium) on days 1, 3, and 7 of cell culture.

[0074] Live / dead staining results as follows Figure 6 As shown, HT22 cells cultured in conditioned medium exhibited significant proliferation, and the quantitative results are as follows: Figure 7As shown, cell proliferation was comparable to that of the control group, indicating that the hydrogel electrode has good cell compatibility.

[0075] c. The flexible cortical electrode from Example 5 was used to fix the right cerebral cortex surface of SD rats. As a control, a sham surgery was performed on the left brain of the same rat under the same conditions (craniotomy followed by skull repositioning without implantation of any device) to serve as the sham surgery group. Histological evaluations were performed at different time points within 6 months post-implantation to assess tissue response. Hemoglobin and isoflavone (HE) staining were performed, and the results are as follows: Figure 8 As shown, the brain tissue structure was intact after the flexible cortical electrode was implanted, with no obvious swelling, damage or collapse.

[0076] Immunohistochemistry (IHC) was performed to assess immune cell infiltration at the neural interface. Astrocytes and microglia were labeled with glial fibrillary acidic protein (GFAP, green) and ionized calcium-binding adaptor molecule-1 (Iba-1, red), respectively. Neuronal nucleoprotein (NeuN, green) was used to label neurons, and the nuclei were labeled with 4',6-diamidinyl-2-phenylindole (DAPI, blue). Within 6 months post-implantation, the mean fluorescence intensity of the experimental and sham-operated groups in Example 5 was quantitatively analyzed at different time points. The results are as follows: Figure 9 and Figure 10 As shown, compared with the sham surgery group, there was no significant difference in the number of astrocytes, microglia, and neurons in the experimental group of Example 5.

[0077] d. To evaluate the sensitivity and effectiveness of the flexible cortical electrode in Example 5 to electrical signals, an anesthesia model was constructed. Dynamic changes in neuronal activity were achieved by adjusting the isoflurane concentration within the range of 1% to 4%. A 20-second ECoG signal was analyzed, and the results are as follows: Figure 11 As shown, at a 2% isoflurane concentration (“standard anesthesia” state), the signal exhibited significant oscillatory activity; when the isoflurane concentration increased to 4% (“deep anesthesia” state), the signal intensity significantly decreased. The study observed enhanced low-frequency oscillations and significant attenuation of cortical signals, consistent with previously reported effects of deep isoflurane anesthesia. Cortical activity recovered as the depth of anesthesia was reduced; further reduction of the isoflurane concentration to 1% (“mild anesthesia” state) resulted in a significant increase in high-frequency activity. The corresponding normalized time-frequency power spectral density (PSD) results also exhibited the above trends, as shown in the figure. Figure 12 As shown above, the results demonstrate that ACGN-AA can simultaneously and accurately record the dynamic changes in electrical signals in the cerebral cortex.

[0078] e. Comparative Example 2 was used as a control to conduct a comparative study on the monitoring and recognition of epileptic electrical signals. Epilepsy seizures in rats were induced by intraperitoneal injection of (pentylenetetrazole) PTZ, and the recording performance of each electrode at different stages of the epileptic seizure was systematically evaluated. Results are as follows: Figure 13 As shown, the two types of electrodes, with a total of 10 channels, simultaneously recorded real-time representative LFP signals of rats under different states. The results showed that the prepared conductive hydrogel electrodes could completely record the neural electrical activity of rats in three consecutive phases, including the normal activity phase, the epileptiform activity phase, and the final resolution phase. The epileptiform activity phase could be further divided into early and late epileptic seizures.

[0079] During the first 100 seconds of normal activity, the rat's electrocortical signal (ECoG) remained relatively quiescent, and the amplitude of local field potentials (LFP) remained at a low level. Subsequently, after approximately 150 seconds of sustained epileptiform activity, the rat entered the early stage of an epileptic seizure, accompanied by low-level behavioral manifestations such as head nodding and mild twitching; this then developed into a generalized epileptic seizure, characterized by significantly enhanced EEG activity with characteristic frequencies and amplitudes, which eventually gradually weakened and entered the resolution phase.

[0080] Figure 14 The paper presents representative real-time recordings of ECoG activity during an epileptic seizure. In Example 5, the signal peak recorded by the flexible cortical electrode was significantly higher than that in Comparative Example 1. Typical ECoG signal fragments from single-channel recordings were also extracted for PSD analysis. As the seizure symptoms gradually intensified, the EEG energy recorded by the flexible cortical electrode was the strongest. Simultaneously, low-frequency signals in the EEG were gradually overwhelmed by high-frequency signals, ultimately reaching a peak in energy release. This indicates abnormally intense neuronal firing activity, consistent with the symptoms of an epileptic seizure.

[0081] f. To evaluate the effectiveness of the flexible cortical electrode in long-term neural recording, a 6-month rat ECoG recording experiment was conducted. ECoG signals recorded by the flexible cortical electrode in Example 5, compared with those recorded by electrodes in Comparative Examples 1 and 2, were recorded over 6 months. The signal quality recorded after long-term implantation of different electrodes was compared. Results are as follows: Figure 15 As shown, the flexible cortical electrode can continuously capture stable and detailed signals, while the signals acquired in Comparative Example 1 and Comparative Example 2 gradually weaken over time.

[0082] Therefore, the present invention employs the above-mentioned biomimetic flexible cortical electrode, its preparation method and application. The prepared flexible cortical electrode achieves a high degree of biomimetic matching with brain tissue in terms of modulus, water content and ionic environment. It has lower noise than traditional metal electrodes, which not only significantly reduces the mechanical mismatch and immune response at the interface, but also ensures the efficient and stable transmission of electrical signals between the interfaces.

[0083] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention and not to limit them. Although the present invention has been described in detail with reference to preferred embodiments, those skilled in the art should understand that modifications or equivalent substitutions can still be made to the technical solutions of the present invention, and these modifications or equivalent substitutions cannot cause the modified technical solutions to deviate from the spirit and scope of the technical solutions of the present invention.

Claims

1. A method for preparing a biomimetic flexible skin electrode, characterized in that: Includes the following steps: S1. Preparation of conductive hydrogel precursor solution and adhesive hydrogel; In S1, the conductive hydrogel precursor solution is prepared by dissolving photocurable carboxymethyl cellulose in artificial cerebrospinal fluid, stirring until completely dissolved, adding N-acryloylglycine, continuing to stir until completely dissolved, adding a photoinitiator, and stirring until completely dissolved to obtain the conductive hydrogel precursor solution. In S1, the components of the conductive hydrogel precursor solution are as follows by mass percentage: 1-6 wt% of photocurable carboxymethyl cellulose, 10-20 wt% of N-acryloylglycine, 0.1 wt% of photoinitiator, and 10 mL of artificial cerebrospinal fluid. S2. Pour polydimethylsiloxane prepolymer into a multi-channel electrode mold, heat to cure, and then remove the multi-channel electrode mold to obtain a flexible electrode substrate with conductive channels. In S2, a mold cavity is provided in the center of the multi-channel electrode mold. The upper width of the mold cavity is greater than the lower width of the mold cavity. Several electrode channels are provided in the lower end of the mold cavity. The middle part of the mold cavity connecting the upper and lower ends of the mold cavity is inclined. S3. Inject the conductive hydrogel precursor liquid of S1 into the conductive channel of the flexible electrode substrate obtained in S2, and then crosslink and cure it under ultraviolet light to obtain a flexible electrode substrate with conductive pathways. S4. A polydimethylsiloxane film is coated on the flexible electrode substrate with conductive pathways throughout S3. Then, the adhesive hydrogel of S1 is placed in the contact area of ​​the flexible electrode to obtain a flexible skin electrode.

2. The method for preparing a biomimetic flexible skin electrode according to claim 1, characterized in that: In S1, the adhesive hydrogel is prepared as follows: carboxymethyl cellulose that can be cured by light is completely dissolved in deionized water, acrylic acid and N-hydroxysuccinimide acrylate are added in sequence, and the mixture is stirred until completely dissolved. Then, 0.2 wt% α-ketoglutaric acid and 0.05 wt% polyethylene glycol diacrylate are added, and the mixture is stirred until completely dissolved. Finally, it is cured under ultraviolet light for 100-150 s to obtain the adhesive hydrogel.

3. The method for preparing a biomimetic flexible skin electrode according to claim 1, characterized in that: In S1, the photoinitiator is 2-hydroxy-4′-(hydroxyethoxy)-2-methylphenylacetone.

4. The method for preparing a biomimetic flexible skin electrode according to claim 1, characterized in that: In S3, the UV cross-linking curing time is 80-120s.

5. A biomimetic flexible skin electrode, characterized in that: The biomimetic flexible skin electrode is prepared according to any one of claims 1-4. The flexible skin electrode has a plurality of conductive channels, and conductive hydrogel is disposed inside the conductive channels.

6. The biomimetic flexible skin electrode according to claim 5, characterized in that: The diameter of the conductive channel is 300-800μm, and the spacing between adjacent conductive channels is 300-900μm.

7. An application of a biomimetic flexible cortical electrode, characterized in that: The biomimetic flexible cortical electrode according to claim 6 is used in the fabrication of brain-computer interfaces or devices for monitoring the nervous system.

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