Anti-fatigue injectable adhesive conductive hydrogel, dynamic neural interface material and preparation method

Abstract

The application belongs to the field of flexible bioelectronic materials, and discloses an anti-fatigue injectable adhesive conductive hydrogel, a dynamic nerve interface material and a preparation method. The method comprises the following steps: mixing a first precursor solution, a second precursor solution and a complex dispersion liquid into a hydrogel precursor mixture, and performing gelation through a thiol-maleimide click chemistry reaction, a metal ion-tannic acid coordination action and a hydrogen bond action, so as to finally obtain a double network hydrogel. Through multiple design of the network structure of the hydrogel, the application prepares a conductive hydrogel which has the properties of injectability, tissue / electrode double adhesion and excellent anti-fatigue performance. As an interface buffer layer between a nerve electrode and a dynamic tissue, the hydrogel forms a seamless fitting interface between the electrode and the dynamic tissue through injectable filling and in-situ gelation of the precursor solution.

Description

Technical Field

[0001] This invention belongs to the field of biomedical materials and flexible bioelectronics technology, and more specifically, relates to an anti-fatigue injectable adhesive conductive hydrogel, a dynamic neural interface material, and a preparation method thereof. Background Technology

[0002] Neural interface technology holds immense promise for applications in brain-computer interfaces, neuromodulation, and neural repair. The reliability and long-term stability of the contact surface between neural electrodes and tissue (i.e., the neural interface) primarily depend on direct bidirectional communication between the electrode and the nerve. To mitigate the mismatch between neural tissue and rigid electrode materials, researchers have developed various conductive hydrogel materials. These materials possess tissue-like softness, high water content, and good conductivity, making them considered candidate materials for constructing ideal neural interfaces.

[0003] However, in the dynamic environment of the body, especially on the surface of organs that are constantly peristaltic or beating, such as the esophagus and heart, existing conductive hydrogels face severe challenges. Although many existing conductive hydrogels have certain conductivity and biocompatibility, they generally have the following problems: (1) lack of sufficient fatigue resistance: under long-term cyclic stretching or compression, the network structure of the hydrogel is prone to irreversible damage, resulting in performance degradation; (2) weak interfacial adhesion: the adhesion between the hydrogel and the tissue or electrode is insufficient, and delamination or slippage is prone to occur during dynamic deformation, resulting in micro gaps and electrical coupling failure; (3) single function: it is difficult to integrate multiple functions such as injectability, high conductivity, strong adhesion and excellent fatigue resistance at the same time.

[0004] In particular, the regulation of nerves surrounding the esophagus (such as the subphrenic vagus nerve) places extremely high demands on the interfacial stability of the nerve electrodes, as the esophagus periodically expands and contracts during eating. Traditional rigid or flexible encapsulation materials are difficult to adapt to this dynamic environment of large deformation, which can easily lead to electrode dislocation, electrochemical performance degradation, or even tissue damage.

[0005] Therefore, developing a multifunctional hydrogel that can simultaneously satisfy the requirements of injectability, strong tissue / electrode adhesion, high conductivity, and stable mechanical and electrochemical properties under long-term dynamic strain, and establishing a robust dynamic neural interface construction method based on this hydrogel, is crucial for the next generation of stable and reliable dynamic neural interfaces. Summary of the Invention

[0006] To address the above-mentioned deficiencies or improvement needs of existing technologies, this invention provides an anti-fatigue injectable adhesive conductive hydrogel, a dynamic neural interface material, and a preparation method thereof, aiming to solve the technical problem that existing conductive hydrogels cannot simultaneously satisfy the requirements of injectability, strong tissue / electrode adhesion, and maintain stable mechanical and electrochemical properties under long-term dynamic strain.

[0007] To achieve the above objectives, in one aspect of the present invention, a method for preparing an anti-fatigue injectable adhesive conductive hydrogel is provided, comprising: mixing a first precursor solution, a second precursor solution and the complex dispersion to form a hydrogel precursor mixture, and gelling it through a click chemical reaction of thiol groups and maleimide, coordination interaction of metal ions and tannic acid and hydrogen bonding, to finally obtain a dual-network hydrogel; The first precursor solution is a solution in which thiol-terminated multi-arm polyethylene glycol is dissolved in a dispersion containing conductive nanomaterials and conductive polymers; the second precursor solution is a solution in which maleimide-terminated multi-arm polyethylene glycol is dissolved in a dispersion containing conductive nanomaterials and conductive polymers; and the complex dispersion is a solution mixed with trivalent metal salts and tannic acid.

[0008] Preferably, the pH of the first precursor solution and the second precursor solution is adjusted to 7.0-7.4; the pH of the complex dispersion is adjusted to 5.0-6.0; and the pH of the hydrogel precursor mixture should be 6.5-7.5.

[0009] Preferably, the mass fraction of the thiol-terminated multi-arm polyethylene glycol in the first precursor solution is 10%-15%, and the mass fraction of the maleimide-terminated multi-arm polyethylene glycol in the second precursor solution is 10%-15%; the molar ratio of thiol in the first precursor solution to maleimide in the second precursor solution is (1-1.5):1.

[0010] Preferably, the metal ion in the trivalent metal salt is Fe. 3+ Al 3+ Ce 3+ At least one of the following, wherein the trivalent metal salt has a mass fraction of 0.1%-0.5% in the complex dispersion; and the volume ratio of the second precursor solution to the complex dispersion is (1-1.5):0.1.

[0011] Preferably, the tannic acid in the hydrogel precursor mixture has a mass fraction of 3%-10%.

[0012] Preferably, the thiol-terminated multi-arm polyethylene glycol is at least one of four-arm polyethylene glycol thiol, six-arm polyethylene glycol thiol, and eight-arm polyethylene glycol thiol; the maleimide-terminated multi-arm polyethylene glycol is two-arm polyethylene glycol maleimide.

[0013] Preferably, the conductive nanomaterial is at least one of MXene, carbon nanotubes, and graphene; and the conductive polymer is at least one of poly(3,4-ethylenedioxythiophene) polystyrene sulfonate, polypyrrole, and polyaniline.

[0014] Preferably, the gelation temperature is 20℃-50℃ and the time is 0.5 minutes-5 minutes.

[0015] In another aspect of the invention, a dual-network hydrogel prepared by the method for preparing an anti-fatigue injectable adhesive conductive hydrogel according to any one of the first aspects is provided.

[0016] In another aspect of the present invention, a dynamic neural interface material is provided, wherein the dynamic neural interface material is formed by mixing a first precursor solution, a second precursor solution and a complex dispersion to form a hydrogel precursor mixture, and then injecting the hydrogel precursor mixture into the surface of a polydopamine-modified flexible neural electrode, thereby forming a hydrogel material that exhibits viscosity in dynamic tissue interaction. The first precursor solution is a solution in which thiol-terminated multi-arm polyethylene glycol is dissolved in a dispersion containing conductive nanomaterials and conductive polymers; the second precursor solution is a solution in which maleimide-terminated multi-arm polyethylene glycol is dissolved in a dispersion containing conductive nanomaterials and conductive polymers; the complex dispersion is a solution mixed with trivalent metal salt and tannic acid; the first precursor solution, the second precursor solution, and the complex dispersion are mixed and gelled through click chemical reaction between thiol and maleimide, coordination interaction between metal ions and tannic acid, and hydrogen bonding to obtain a double network hydrogel.

[0017] In summary, compared with the prior art, the above-described technical solutions conceived by this invention mainly possess the following technical advantages: 1. The method for preparing anti-fatigue injectable adhesive conductive hydrogel provided by the present invention involves mixing a first precursor solution, a second precursor solution, and a complex dispersion to form a hydrogel precursor mixture. The mixture undergoes a gelation process in which a first covalent network is formed through a click chemical reaction between thiol groups and maleimide, and a second dynamic cross-linking network is formed through the coordination of metal ions and tannic acid with the rich hydrogen bond network of the hydrogel. Finally, a dual-network hydrogel is obtained. Specifically, on the one hand, the thiol groups of multi-arm polyethylene glycol in the first precursor solution and the maleimide groups of multi-arm polyethylene glycol in the second precursor solution form a first covalent network through a click chemical reaction between the thiol groups and maleimide, serving as the basic framework structure of the entire gel material. The thiol groups and the multi-arm structure of the maleimide-terminated multi-arm polyethylene glycol provide multiple cross-linking points for the hydrogel network, enhancing its overall strength. On the other hand, tannic acid in the complex dispersion forms a second, dynamically cross-linked network with metal ions through coordination, enabling the hydrogel network to effectively dissipate energy under external forces and dynamically reorganize after deformation, thus enhancing the hydrogel's fatigue resistance. Simultaneously, tannic acid competes with the maleimide-terminated multi-arm polyethylene glycol for reaction with the thiol-terminated multi-arm polyethylene glycol, slowing down the click chemical reaction between the thiol groups and maleimide, prolonging the gelation time, and achieving the injectability of the hydrogel. On the other hand, the conductive nanomaterials and conductive polymers in the first and second precursor solutions can form dynamic conductive and energy dissipation networks with tannic acid / metal ion complexes and polyethylene glycol networks through hydrogen bonds. Furthermore, the abundant phenolic hydroxyl groups, mercapto multi-arm polyethylene glycol, and other active groups in tannic acid endow the hydrogel with covalent (mercapto-mercapto, mercapto-phenolic hydroxyl) and non-covalent (hydrogen bond) bonds with tissues or polydopamine-modified devices during in-situ gelation, resulting in excellent tissue and device adhesion. Therefore, based on the molecular regulation of tannic acid (thiol / maleimide click chemistry regulation), the construction of dynamic dissipation networks (metal ion chelation and hydrogen bond networks between conductive phases), and the composition of adhesively active groups, the hydrogel possesses fatigue resistance, injectability, strong adhesion, and conductivity.

[0018] 2. In this invention, the pH of the first precursor solution is preferably adjusted to 7.0-7.4, the pH of the second precursor solution is adjusted to 7.0-7.4, and the pH of the complex dispersion is adjusted to 5.5-6.0, so that the final hydrogel precursor mixture has a pH of 6.5-7.5. This pH adjustment method ensures that the pH of the hydrogel precursor mixture after in-situ injection is close to the pH of the physiological environment, reducing the irritation of in-situ injection and improving the biocompatibility of the hydrogel. The click chemistry reaction between thiol groups and maleimide is relatively slow only under acidic conditions (3.0-5.0) (achieving injectability). The tannic acid in this invention acts as a molecular regulator of the click chemistry reaction, extending the injectable pH range of the thiol-maleimide click chemistry reaction to a safe physiological range. Furthermore, adjusting the pH based on the first precursor solution, the second precursor solution, and the complex dispersion avoids directly adjusting the pH of the hydrogel precursor mixture, which could affect injectability.

[0019] 3. The present invention preferably uses the following concentrations: thiol-terminated multi-arm polyethylene glycol in the first precursor solution, maleimide-terminated multi-arm polyethylene glycol in the second precursor solution, and controls the molar ratio of thiol in the first precursor solution to maleimide in the second precursor solution to be (1.5-1):1. This achieves the adjustment of the strength of the first covalent network of the hydrogel, directly determining the final modulus of the hydrogel to be in the kilopascal range, close to the tissue modulus, thus improving the safety of hydrogel implantation. Furthermore, it ensures that the proportion of thiol is slightly higher than that of maleimide, so that free thiol can form disulfide bonds with thiol in the tissue, providing tissue adhesion.

[0020] 4. This invention preferably adjusts the crosslinking density of the second dynamic crosslinking network by regulating the mass fraction of the trivalent metal salt in the hydrogel precursor mixture, thereby achieving the regulation of fatigue resistance. In the complex dispersion, the mass fraction of the trivalent metal salt is 0.1-0.5%, and the final concentration of the trivalent metal salt in the hydrogel precursor mixture is 0.005-0.025%. Under this adjustment of the trivalent metal salt, the resulting hydrogel exhibits significant fatigue resistance.

[0021] 5. This invention preferably adjusts the gelation rate of the click chemical reaction between thiol groups and maleimide under near-physiological conditions by regulating the tannic acid concentration of the hydrogel precursor mixture. The tannic acid concentration of the hydrogel precursor mixture is 0.3-1%. At this concentration, the gelation time of the click chemical reaction between thiol groups and maleimide under physiological pH conditions is controlled within 0.5-5 minutes, satisfying the injectability requirements.

[0022] 6. This invention provides a long-term stable dynamic neural interface material adapted to changes in the in vivo dynamic environment. By drop-feeding a hydrogel precursor mixture onto the surface of a polydopamine-modified flexible neural electrode, a hydrogel material exhibiting viscous interaction with dynamic tissue is formed, i.e., a dynamic neural interface. This hydrogel, on the one hand, utilizes its injectability (the hydrogel precursor mixture has good flowability) and in-situ gelation properties to construct a tightly adhered, seamless dynamic neural interface between the neural electrode and dynamic tissue; and on the other hand, it utilizes the polyphenolic structure of tannic acid in the hydrogel and the active thiol groups of the thiol-based multi-arm polyethylene glycol polymer to form multiple interactions with proteins on the tissue surface and the polydopamine (PDA) layer on the electrode surface, such as hydrogen bonds, π-π stacking, and disulfide bonds, thereby achieving efficient adhesion to biological tissue and neural electrodes, ensuring that the interface does not delaminate or slip during dynamic deformation. On the other hand, metal-phenolic coordination bonds are introduced as the main component of the second dynamic cross-linking network. These coordination bonds have higher bond energies than traditional hydrogen bonds, effectively dissipating energy under stress and dynamically recombining after deformation, thus significantly enhancing the fatigue resistance of the neural interface. The hydrogel layer acts as a protective layer, effectively isolating the flexible neural electrode from direct contact with the physiological environment and preventing electrochemical oxidation under electrical stimulation. Therefore, the long-term stability and electrochemical performance of the dynamic neural interface are significantly improved through the combined effects of seamless interface adhesion resulting from injectability and in-situ gelation, the dual high-efficiency adhesion imparted by multiple interactions between the hydrogel and tissue / electrode, the energy dissipation and fatigue resistance provided by the dynamic cross-linking network formed by metal-phenolic coordination bonds, and the electrochemical isolation of the neural electrode by the hydrogel protective layer. Attached Figure Description Figure 1 The graphs show the changes in storage modulus (G') and loss modulus (G') over time during the gelation process of the fatigue-resistant injectable adhesive conductive hydrogel prepared in Example 1 of this invention, as well as the statistical graphs of gelation time for Examples 1 and 4, and Comparative Examples 1-2 and 4; wherein... Figure 1 In Example 1, a is a graph showing the changes in storage modulus (G') and loss modulus (G") over time; b is a statistical graph of gelation time at different pH values ​​(5.0, 7.4, 9.0); and c is a statistical graph of gelation time at different TA concentrations (0 wt%, 0.14 wt%, 0.43 wt%).

[0023] Figure 2 The stress-strain curves of the fatigue-resistant injectable adhesive conductive hydrogels prepared in Examples 1-3 and Comparative Example 3 of this invention after 1,000 cyclic stretching cycles at 100% strain are shown. Figure 2 'a' in 'Fe' represents Fe. 3+ Stress-strain curves of a fatigue-resistant injectable adhesive conductive hydrogel prepared at a concentration of 0.56 mM after 1000 cycles of cyclic tensile stress at 100% strain, where b represents Fe. 3+Stress-strain curve of hydrogel prepared with a concentration of 0 mM after 1000 cycles of cyclic stretching at 100% strain, where c represents Fe. 3+ Stress-strain curves of a 0.19 mM hydrogel subjected to 1000 cyclic stretching cycles at 100% strain, where d represents Fe. 3+ Stress-strain curves of a 0.93 mM hydrogel subjected to 1,000 cyclic stretching cycles at 100% strain, where e represents different Fe values. 3+ A quantitative statistical chart of the maximum stress retention rate of hydrogels prepared at concentrations (0 mM, 0.19 mM, 0.56 mM, 0.93 mM) after 1000 cycles of cyclic stretching at 100% strain.

[0024] Figure 3 The image shows the adhesion strength-displacement curve of the anti-fatigue injectable conductive hydrogel prepared in Example 1 of this invention to a polydopamine (PDA) modified SBS substrate and esophageal tissue.

[0025] Figure 4 The image shown is a cross-sectional scanning electron microscope image (scale bar: 50 μm) of the LM@IAAC composite electrode in Application Example 1 of this invention, showing the three-layer structure of the hydrogel layer (IAAC), the liquid metal wetting layer (EGaIn@SBS), and the support layer (SBS), as well as the tightly bonded interfaces between each layer.

[0026] Figure 5 The image shows a dynamic conformal photograph (scale bar: 5 mm) of the hydrogel-liquid metal electrode composite with the rabbit esophagus and duodenum in Application Example 1 of this invention, which shows that the hydrogel-electrode composite remains closely attached to the tissue during tissue expansion and contraction.

[0027] Figure 6 This invention applies Example 1 to characterize the interfacial stability of the hydrogel-liquid metal electrode composite in an in vitro dynamic esophageal dilation-contraction model; wherein, Figure 6 In the figure, a is a photograph of the liquid metal electrode in an in vitro dynamic expansion-contraction model of the esophagus (with and without hydrogel) (scale bar: 1 cm), and b is a quantitative comparison of the offset distance of the liquid metal electrode with and without hydrogel after 1000 expansion-contraction cycles with 50% radial strain.

[0028] Figure 7 This is a comparison chart showing the charge injection capacity (CIC) retention rate of the LM@IAAC composite electrode prepared in Application Example 1 of the present invention and the unprotected liquid metal electrode (LM) after cyclic electrochemical testing.

[0029] Figure 8The graph shows the changes in impedance, charge storage capacity (CSC), and charge injection capacity (CIC) of the LM@IAAC composite electrode prepared in Application Example 1 of this invention after cyclic tensile testing. Detailed Implementation To make the objectives, technical solutions, and advantages of this invention clearer, the invention will be further described in detail below with reference to the accompanying drawings and embodiments. It should be understood that the specific embodiments described herein are merely illustrative and not intended to limit the invention. Furthermore, the technical features involved in the various embodiments of this invention described below can be combined with each other as long as they do not conflict with each other.

[0030] To achieve the above objectives, the following solutions are provided: The first aspect of the invention provides a method for preparing an anti-fatigue injectable strong adhesion conductive hydrogel, comprising: mixing a first precursor solution, a second precursor solution and a complex dispersion in a certain proportion, naturally gelling, and finally forming a hydrogel containing a first covalent network formed by the click chemical reaction of thiol groups and maleimide, and a second dynamic cross-linked network formed by the coordination of trivalent metal ions and tannic acid and the abundant hydrogen bonds in the hydrogel network. The first precursor solution is a solution in which thiol-terminated multi-arm polyethylene glycol is dissolved in a dispersion containing conductive nanomaterials and conductive polymers; the second precursor solution is a solution in which maleimide-terminated multi-arm polyethylene glycol is dissolved in a dispersion containing conductive nanomaterials and conductive polymers; and the complex dispersion is a solution mixed with trivalent metal salts and tannic acid.

[0031] Preferably, an example is a method for preparing a first precursor solution, a second precursor solution, and a complex dispersion: Preparation of the first precursor solution, the second precursor solution, and the complex dispersion: Preparation of the first precursor solution and the second precursor solution: Conductive nanomaterials and conductive polymers are mixed and dispersed in deionized water to obtain a dispersion solution; then, thiol-terminated multi-arm polyethylene glycol is dissolved in the dispersion solution to obtain the first precursor solution, and maleimide-terminated multi-arm polyethylene glycol is dissolved in the dispersion solution to obtain the second precursor solution; Preparation of complex dispersion: Trivalent metal salt and tannic acid were mixed in deionized water to obtain metal-phenolic complex dispersion.

[0032] In practice, tannic acid can be added in batches to the first precursor solution and the second precursor solution, and then the first precursor solution, the second precursor solution and the complex dispersion are mixed. In the end, it is only necessary to control the total amount of tannic acid in the hydrogel precursor mixture.

[0033] Preferably, the pH of the first precursor solution is adjusted to 7.0-7.4; the pH of the second precursor solution is adjusted to 7.0-7.4; the pH of the complex dispersion is adjusted to 5.5-6.0; the pH of the hydrogel precursor mixture should be 6.5-7.5; and the pH of the final hydrogel precursor mixture is 6.5-7.5, close to the pH of the physiological environment, reducing the irritation of in-situ injection and improving biocompatibility. The pH of the first and second precursor solutions being 7.0-7.4 facilitates adjusting the pH of the final hydrogel precursor mixture within a suitable range. The pH of the complex dispersion being adjusted to 5.5-6.0 is to ensure the pH is as close as possible while maintaining the metal complex structure and preventing precipitation.

[0034] Preferably, in the first precursor solution, the concentration of thiol-terminated multi-arm polyethylene glycol is 10-15 wt%; in the second precursor solution, the concentration of maleimide-terminated multi-arm polyethylene glycol is 10-15 wt%, and the mixing volume ratio of the first and second precursor solutions is 1:1. The resulting hydrogel has a Young's modulus in the kilopascal range, which is close to the tissue modulus, thus improving the safety of hydrogel implantation.

[0035] Preferably, in the complex dispersion, the metal ion in the trivalent metal salt is Fe. 3+ Al 3+ Ce 3+ At least one of the following is used: the mass fraction of the trivalent metal salt is 0.1%-0.5%, and the final concentration of the trivalent metal salt in the resulting hydrogel precursor mixture is 0.005%-0.025%. At lower trivalent metal salt concentrations, due to the extremely high tannin chelation effect of the trivalent metal salt, abundant metal-phenolic coordination bonds are obtained, giving the hydrogel significant anti-fatigue properties while maintaining extremely high safety. When the mass fraction of the trivalent metal salt is 0.1%-0.5%, the preferred mixing volume ratio of the first precursor solution, the second precursor solution, and the complex dispersion is 1:1:0.1, which ensures that the final hydrogel modulus matches the tissue structure and obtains a safe and effective anti-fatigue network.

[0036] Preferably, the tannic acid concentration in the final hydrogel precursor mixture is 0.3%-1%. At this concentration, the gelation time of the thiol / maleimide click chemistry reaction is controlled within 0.5-5 minutes under physiological pH conditions, matching the injectable properties.

[0037] Preferably, the thiol-terminated multi-arm polyethylene glycol is at least one of four-arm polyethylene glycol thiol, six-arm polyethylene glycol thiol, and eight-arm polyethylene glycol thiol (PEG-8SH); the maleimide-terminated multi-arm polyethylene glycol is two-arm polyethylene glycol maleimide (PEG-2Mal). The abundant branching structure of the multi-arm polyethylene glycol provides more tannic acid binding sites, which is beneficial for tannic acid to act as a molecular regulator to control the thiol / maleimide click chemistry reaction, while constructing a stable first-layer hydrogel network.

[0038] Preferably, the conductive nanomaterial is at least one of MXene, carbon nanotubes, and graphene; the conductive polymer is at least one of poly(3,4-ethylenedioxythiophene)polystyrene sulfonate (PEDOT:PSS), polypyrrole (Ppy), and polyaniline (PANI). Furthermore, the conductive nanomaterial, conductive polymer, and tannic acid further construct a stable conductive network through abundant hydroxyl groups and π-π stacking interactions, endowing the hydrogel with excellent conductivity and electrochemical properties.

[0039] Preferably, the natural gelation temperature of the hydrogel is 20℃-50℃, and especially under human body temperature conditions, the gelation time is 0.5 min-5 min, which meets the gelation requirements for in-situ injection into the human body.

[0040] In another aspect of the present invention, a hydrogel prepared according to any one of the first aspects of the present invention is provided, comprising a first covalent network formed by maleimide click chemistry and a second dynamic cross-linking network formed by coordination between trivalent metal ions and tannic acid and abundant hydrogen bonds in the hydrogel network, and a second dynamic cross-linking network formed by coordination between metal ions and tannic acid and abundant hydrogen bonds in the hydrogel network, and the prepared conductive hydrogel possessing injectability, tissue / electrode dual adhesion and excellent anti-fatigue properties.

[0041] In another aspect of the present invention, a dynamic neural interface material is provided, which is formed by mixing a first precursor solution, a second precursor solution and a complex dispersion to form a hydrogel precursor mixture, and then injecting the hydrogel precursor mixture into the surface of a polydopamine-modified flexible neural electrode to form a hydrogel material that exhibits viscosity in dynamic tissue interaction. The first precursor solution is prepared by dispersing conductive nanomaterials and conductive polymers in deionized water, and then dissolving thiol-terminated multi-arm polyethylene glycol in the dispersion solution. The second precursor solution is prepared by dispersing conductive nanomaterials and conductive polymers in deionized water, and then dissolving maleimide-terminated multi-arm polyethylene glycol in the dispersion solution. The complex dispersion is obtained by mixing a trivalent metal salt and tannic acid in deionized water. The first precursor solution, the second precursor solution, and the complex dispersion, when mixed, can gel through click chemical reactions between thiol groups and maleimide, coordination interactions between metal ions and tannic acid, and hydrogen bonding to obtain a double-network hydrogel.

[0042] The core of constructing the aforementioned dynamic neural interface material lies in using the hydrogel obtained by the above preparation method to modify neural electrodes and construct a dynamic neural interface, including the following steps: (1) The surface of the flexible neural electrode to be modified is modified with polydopamine to obtain a polydopamine-modified electrode; (2) Disperse conductive nanomaterials and conductive polymers in deionized water to prepare a dispersion solution; dissolve thiol-terminated multi-arm polyethylene glycol in the dispersion solution to obtain a first precursor solution, and dissolve maleimide-terminated multi-arm polyethylene glycol in the dispersion solution to obtain a second precursor solution; mix trivalent metal salt and tannic acid in deionized water to obtain a complex dispersion; then mix the first precursor solution, the second precursor solution and the complex dispersion to form a hydrogel precursor mixture; (3) The hydrogel precursor mixture is filled between the polydopamine modified electrode and the dynamic tissue, and the hydrogel precursor mixture is allowed to gel in situ at room temperature to form a hydrogel interface layer that is closely attached to the electrode and the tissue, thereby achieving a stable construction of the dynamic neural interface.

[0043] Preferably, the dynamic tissue is the esophagus, heart, intestines, or bladder.

[0044] Preferably, the neural electrode is a liquid metal electrode, a gold electrode, a platinum electrode, or a conductive polymer electrode, etc.

[0045] The following description, in conjunction with specific embodiments and accompanying drawings, further illustrates the solution of this application.

[0046] Example 1: The preparation of a fatigue-resistant, injectable, highly adhesive, conductive hydrogel includes the following steps: (a) Preparation of the first precursor solution: 4 wt% MXene and 0.3 wt% tannic acid (TA) were added to a 1% PEDOT:PSS aqueous dispersion and magnetically stirred for 2 hours to ensure uniform dispersion. The pH was then adjusted to 7.4 with NaOH to obtain an MXene / PEDOT:PSS / TA dispersion. 15 wt% octahedral polyethylene glycol thiol (PEG-8SH, molecular weight 8000) was dissolved in the above dispersion to obtain the first precursor solution.

[0047] (b) Preparation of the second precursor solution: 4 wt% MXene and 0.3 wt% tannic acid (TA) were added to a 1% PEDOT:PSS aqueous dispersion and magnetically stirred for 2 hours to ensure uniform dispersion. The pH was then adjusted to 7.4 with NaOH to obtain an MXene / PEDOT:PSS / TA dispersion. 9 wt% of two-arm polyethylene glycol maleimide (PEG-2Mal) with a molecular weight of 5,000 and 1 wt% of two-arm polyethylene glycol maleimide (PEG-2Mal) with a molecular weight of 20,000 were dissolved in the above dispersion to obtain the second precursor solution.

[0048] (c) Preparation of metal-phenolic coordination complex: 3 wt% tannic acid (TA) and 0.3 wt% FeCl3·6H2O were dissolved in deionized water, and the pH was adjusted to 6.0 to obtain TA / Fe 3+ Complex dispersion.

[0049] (d) Preparation of highly conductive, fatigue-resistant injectable hydrogel: The first precursor solution, the second precursor solution, and TA / Fe prepared above are mixed together. 3+ The complex dispersion was mixed uniformly at a volume ratio of 1:1:0.1 to form a hydrogel precursor mixture, at which point the concentration of tannic acid in the mixture was 0.43%. The mixture was then immediately injected into a mold or the desired interface. After standing at room temperature, the system gelled, yielding the highly conductive, fatigue-resistant injectable hydrogel of this invention.

[0050] Comparative Example 1: This comparative example is basically the same as Example 1, except that the pH of the first precursor solution and the second precursor solution in steps (a) and (b) is adjusted to 5.

[0051] Comparative Example 2: This comparative example is basically the same as Example 1, except that the pH of the first and second precursors in steps (a) and (b) is adjusted to 9.

[0052] Example 2: This embodiment is basically the same as Embodiment 1, except that the mass fraction of FeCl3·6H2O in step (c) is 0.1%.

[0053] Example 3: This comparative example is basically the same as Example 1, except that the mass fraction of FeCl3·6H2O in step (c) is 0.5%.

[0054] Comparative Example 3: This comparative example is basically the same as Example 1, except that FeCl3·6H2O is not added in step (c), that is, no metal-phenolic coordination complex is formed.

[0055] Example 4: This embodiment is basically the same as Example 1, except that the tannic acid concentrations in steps (a), (b), and (c) are 0.1 wt%, 0.1 wt%, and 1 wt%, respectively. At this time, the tannic acid concentration of the mixture in step (d) is approximately 0.14%.

[0056] Comparative Example 4: This comparative example is basically the same as Example 1, except that tannic acid is not added in steps (a), (b) and (c).

[0057] Characterization tests: The natural gelation process of the examples and comparative examples was observed, and the performance of the naturally gelled samples of the examples and comparative examples was tested. Details are as follows: (1) Gelation time: Observed in conjunction with the preparation processes of Example 1 and Comparative Examples 1-2. For example... Figure 1 As shown in b, the hydrogel precursor mixture in Example 1 gelled in approximately 1 minute; while the precursor mixtures in Comparative Examples 1-2 gelled in approximately 10 minutes at room temperature when the pH was 5, and in approximately 20 seconds at room temperature when the pH was 9. This indicates that the hydrogel system's natural gelation time under near-neutral pH conditions meets the requirements for in-situ gelation under physiological conditions. Too long or too short a gelation time is unsuitable for real-time injectable gelation. The preparation processes of Examples 1 and 4, as well as Comparative Example 4, were observed. Figure 1 As shown in c, the hydrogel precursor mixture in Example 1 gelled after about 1 minute; while in Example 4 and Comparative Example 4, when the tannic acid concentration of the precursor mixture was 0.1%, the system gelled after standing at room temperature for about 30 seconds, and when there was no tannic acid, it gelled after standing at room temperature for about 5 seconds.

[0058] Furthermore, the prepared material was subjected to time-oscillation scanning tests using a rheometer (MCR 102, Anton Paar, Austria, 0.5% amplitude, 1 Hz oscillation frequency). The specific gelation time of the material was determined by the intersection time of the storage modulus (G') and the loss modulus (G'). Figure 1As shown in a, the gelation time of Example 1 is about 1.06 minutes, and the mechanical properties (Young's modulus ~31.75 kPa) of the hydrogel prepared in Example 1 can deform in tandem with dynamic tissues and can adapt to complex tissue surface morphology; the gelation time of Example 2 is about 10 minutes, and the gelation time of Comparative Example 1 is about 20 seconds, which are not suitable for real-time injectable gel formation.

[0059] (2) Fatigue resistance: Cyclic tensile tests were conducted on the samples after natural gelation in Examples 1-3 and Comparative Example 3. For example... Figure 2 As shown, Fe was added in Example 1. 3+ The hydrogel formed at 0.3 wt% retained approximately 75% stress after 1000 cycles of cyclic stretching at 100% strain, while the hydrogel in Comparative Example 2, without the addition of Fe, showed a different stress. 3+ The hydrogel system fractured after 8 cycles of cyclic stretching, indicating that even with hydrogen bonds present, effective fatigue resistance cannot be achieved without the formation of a dynamic network in the hydrogel system due to the low bond energy of the hydrogen bonds. Example 2: Adding Fe 3+ The hydrogel formed at 0.1 wt% exhibited a stress retention of nearly 60%. While its fatigue resistance was slightly lower than that of the hydrogel system in Example 1, it was still better than that of the system in Comparative Example 2 with added Fe. 3+ The fatigue resistance of the hydrogel system is still significantly improved. In Example 3, the Fe... 3+ The hydrogel formed at 0.5% exhibited a maximum stress retention rate of approximately 75%, showing no significant difference from Example 1, and limited growth. These results indicate that Fe... 3+ The metal-phenolic coordination bonds formed with tannic acid, and the hydrogen bond network formed by the phenolic hydroxyl groups of tannic acid and the hydroxyl groups on the surface of conductive nanoparticles and conductive polymers, give the hydrogel system of this invention significantly enhanced fatigue resistance. Meanwhile, compared to Example 1, Example 3 further increases the iron ion concentration, but its maximum stress fatigue resistance increases only slightly. Considering the biosafety risks associated with excessively high iron ion concentrations, Fe... 3+ The concentration should be limited to below 0.5%.

[0060] (3) Adhesion performance: The adhesion strength of the hydrogel prepared in Example 1 to the PDA-modified polymer film (IAAC with PDA coated SBS film) and esophageal tissue (IAAC with esophageal tissue) was determined by lap shear test (20 mm / min) using a universal testing machine (CTM8000, Xieqiang Instrument Manufacturing Co., Ltd., China). Figure 3As shown, in Example 1, the adhesion strength of the SBS substrate was approximately 51.67 kPa, and the adhesion strength to esophageal tissue was approximately 18.14 kPa, indicating that the hydrogel system of Example 1 has dual adhesion to tissue and PDA-modified devices.

[0061] Application Example 1: A stable dynamic neural world based on hydrogel modified with liquid metal electrodes was developed.

[0062] In this embodiment, the fatigue-resistant injectable hydrogel prepared in Example 1 is used to construct a stable dynamic neural interface, which is then used to modify a liquid metal electrode to prepare an LM@IAAC composite electrode. The dynamic interface stability and electrochemical performance are then tested.

[0063] (1) Preparation of LM electrode: 12.5% ​​SBS was added to 1,2-dichloroethane and magnetically stirred overnight at 60℃ to obtain a transparent viscous solution. SBS fiber membrane was prepared by electrospinning at a spinning voltage of 13 kV and -3 kV, a solution propulsion speed of 0.3 mm / min, and a receiving distance of 15 cm, and collected on a rotating cylindrical collector. EGaIn was dropped onto the surface of the SBS fiber membrane, repeatedly rolled with a PTFE roller, and then subjected to 6 cycles of 200% strain stretching to fully embed the liquid metal into the fiber network, thus obtaining the LM electrode.

[0064] (2) Preparation of LM@PDA electrode: 1% DA·HCl was dissolved in Tris-HCl buffer at pH=8.5 and added dropwise to the surface of LM electrode. The reaction was carried out at room temperature for 6 hours. Excess solution was removed and the electrode was rinsed with deionized water to obtain polydopamine modified LM@PDA electrode.

[0065] (3) Construction and morphology characterization of LM@IAAC electrodes: Preparation of LM@IAAC electrode: Ungelled IAAC hydrogel was dropped onto the surface of IAAC@PDA electrode, and the LM@IAAC electrode was obtained after gelation.

[0066] The prepared LM@IAAC electrode was frozen in liquid nitrogen and then fractured to obtain a fresh cross-section, which was then freeze-dried. After sputtering with gold, the cross-sectional morphology of the sample was observed using a scanning electron microscope (SEM, model: SU8010, Hitachi, Japan).

[0067] like Figure 4As shown, the cross-sectional SEM image clearly reveals a three-layer structure: an upper IAAC hydrogel layer with a thickness of approximately 50 μm, a middle EGaIn-impregnated SBS fiber layer (approximately 25 μm thick), and a lower SBS support layer (approximately 25 μm thick). The interfaces between the layers are clear and well-bonded, with no obvious interfacial gaps or delamination observed. A tight connection is formed between the hydrogel layer and the EGaIn layer through a polydopamine (PDA) modification layer, confirming the effectiveness of the PDA layer as an adhesion bridge.

[0068] (4) Construction of a stable dynamic neural interface: The ungelled IAAC hydrogel precursor mixture from Example 1 was dropped onto the surface of the LM@PDA electrode, and then the electrode was wrapped around the surface of a dynamic tissue (such as rabbit esophagus or duodenum) so that the precursor mixture filled the gap between the electrode and the tissue. The mixture was allowed to gel at room temperature to obtain an integrated hydrogel-electrode-tissue composite structure.

[0069] (5) Dynamic conformal capability test: Fresh isolated rabbit esophagus and duodenum tissues were collected, and a hydrogel-electrode-tissue composite structure was constructed according to the method in step (3). The expansion and contraction of the tissue were simulated by injecting or withdrawing liquid into the esophageal lumen. Figure 5 As shown, during tissue expansion and contraction, the hydrogel-electrode composite can maintain a tight conformal fit with the esophageal and duodenal tissues without delamination or slippage.

[0070] (6) Dynamic interface stability test: Constructing an in vitro esophageal peristalsis simulation model: using Ecoflex TM 00-30 A hollow elastic tube (6 mm inner diameter, 12 mm outer diameter) was prepared to simulate the esophagus. The lumen was filled with glycerol, and a 10 mm diameter metal ball was moved reciprocally within the tube (1000 times) to simulate esophageal peristalsis. An LM@PDA electrode was wrapped around the outer wall of the simulated esophagus. In the experimental group, IAAC hydrogel was used to fill and fix the gap between the electrode and the tube wall, while the control group did not use hydrogel. Figure 6 As shown in a, after 1000 cycles of simulated peristalsis, the experimental group electrodes showed no significant displacement, while the control group electrodes exhibited significant slippage; Figure 6 As shown in b, quantitative analysis indicates that the electrode displacement in the experimental group was less than 1 mm, while the electrode displacement in the control group exceeded 5 mm.

[0071] (7) Electrochemical performance testing: The electrochemical performance of the prepared LM@IAAC composite electrode was compared with that of an unprotected LM electrode. Figure 7As shown, after 10,000 cycles of electrochemical testing, the charge injection capacity (CIC) retention rate of the LM@IAAC composite electrode still exceeded 95%, while the unprotected liquid metal electrode (LM) retained only about 25%. Figure 8 As shown, after 1000 cycles of 100% stretching, the impedance, CSC, and CIC of the LM@IAAC composite electrode remained stable with no significant changes.

[0072] This invention utilizes multiple designs of the hydrogel network structure to prepare a hydrogel that combines injectability, high conductivity, tissue / electrode dual adhesion, and excellent fatigue resistance. This hydrogel can serve as an interfacial buffer layer between neural electrodes and dynamic tissues, forming a seamless interface between the electrode and dynamic tissues through injectable filling and in-situ gelation of the precursor solution.

[0073] Specifically, the hydrogel prepared by this invention possesses the following excellent properties and application advantages: Injectability and in-situ adaptation: The hydrogel precursor mixture has good fluidity, allowing it to fill the tiny gaps between electrodes and tissues for in-situ gelation, forming a tightly adhered, seamless interface. Dual adhesion: Utilizing the polyphenol structure of TA, the hydrogel of this invention can form multiple interactions with proteins on the tissue surface and the polydopamine (PDA) layer on the electrode surface, achieving efficient adhesion to biological tissues and neural electrodes; Excellent fatigue resistance and dynamic adaptability: The hydrogel of this invention, through the introduction of Fe... 3+ The -TA metal-phenolic coordination bond serves as the main component of the second dynamic cross-linking network. This coordination bond has a higher bond energy than traditional hydrogen bonds, effectively dissipating energy under stress and dynamically recombining after deformation, thus significantly enhancing the fatigue resistance of the hydrogel. Stable dynamic neural interface construction capability: Based on the above characteristics, this hydrogel is used to construct dynamic neural interfaces. By filling the space between the polydopamine-modified liquid metal electrode and dynamic tissue with an ungelled precursor, in-situ gelation forms a seamless, highly adhesive interface, exhibiting long-term stability under dynamic physiological environments. Excellent electrochemical performance and interface protection: The hydrogel internally constructs a non-covalent conductive network composed of MXene and PEDOT:PSS, giving it low impedance, high charge storage capacity, and high charge injection capacity. The hydrogel layer acts as a protective layer, effectively isolating the liquid metal electrode from direct contact with the physiological environment, preventing electrochemical oxidation under electrical stimulation, and enabling it to adapt to dynamic, large-deformation neural interfaces.

[0074] Those skilled in the art will readily understand that the above description is merely a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, and improvements made within the spirit and principles of the present invention should be included within the scope of protection of the present invention.

Claims

1. A method for preparing a fatigue-resistant injectable adhesive conductive hydrogel, characterized in that, include: The first precursor solution, the second precursor solution, and the complex dispersion were mixed to form a hydrogel precursor mixture. The mixture was then gelled through click chemistry between thiol groups and maleimide, coordination between metal ions and tannic acid, and hydrogen bonding to finally obtain a dual-network hydrogel. The first precursor solution is a solution in which thiol-terminated multi-arm polyethylene glycol is dissolved in a dispersion containing conductive nanomaterials and conductive polymers. The second precursor solution is a solution in which maleimide-terminated multi-arm polyethylene glycol is dissolved in a dispersion containing conductive nanomaterials and conductive polymers; the complex dispersion is a solution mixed with trivalent metal salt and tannic acid.

2. The method for preparing the fatigue-resistant injectable adhesive conductive hydrogel according to claim 1, characterized in that, The pH of the first precursor solution and the second precursor solution is adjusted to 7.0-7.4; the pH of the complex dispersion is adjusted to 5.0-6.0; and the pH of the hydrogel precursor mixture is 6.5-7.

5.

3. The method for preparing the fatigue-resistant injectable adhesive conductive hydrogel according to claim 1, characterized in that, The mass fraction of the thiol-terminated multi-arm polyethylene glycol in the first precursor solution is 10%-15%, and the mass fraction of the maleimide-terminated multi-arm polyethylene glycol in the second precursor solution is 10%-15%; the molar ratio of thiol in the first precursor solution to maleimide in the second precursor solution is (1-1.5):

1.

4. The method for preparing the fatigue-resistant injectable adhesive conductive hydrogel according to claim 1, characterized in that, The metal ion in the trivalent metal salt is Fe. 3+ Al 3+ Ce 3+ At least one of the following, wherein the trivalent metal salt has a mass fraction of 0.1%-0.5% in the complex dispersion; and the volume ratio of the second precursor solution to the complex dispersion is (1-1.5):0.

1.

5. The method for preparing the fatigue-resistant injectable adhesive conductive hydrogel according to claim 1, characterized in that, The tannic acid has a mass fraction of 3%-10% in the hydrogel precursor mixture.

6. The method for preparing the fatigue-resistant injectable adhesive conductive hydrogel according to any one of claims 1-5, characterized in that, The thiol-terminated multi-arm polyethylene glycol is at least one of four-arm polyethylene glycol thiol, six-arm polyethylene glycol thiol, and eight-arm polyethylene glycol thiol; the maleimide-terminated multi-arm polyethylene glycol is two-arm polyethylene glycol maleimide.

7. The method for preparing the fatigue-resistant injectable adhesive conductive hydrogel according to any one of claims 1-5, characterized in that, The conductive nanomaterial is at least one of MXene, carbon nanotubes, and graphene; the conductive polymer is at least one of poly(3,4-ethylenedioxythiophene) polystyrene sulfonate, polypyrrole, and polyaniline.

8. The method for preparing the fatigue-resistant injectable adhesive conductive hydrogel according to claim 1, characterized in that, The gelation temperature is 20℃-50℃, and the time is 0.5 minutes-5 minutes.

9. The hydrogel prepared by the method for preparing the fatigue-resistant injectable adhesive conductive hydrogel according to any one of claims 1-8.

10. A dynamic neural interface material, characterized in that, The dynamic neural interface material is formed by mixing a first precursor solution, a second precursor solution, and a complex dispersion to form a hydrogel precursor mixture, and then injecting the hydrogel precursor mixture into the surface of a polydopamine-modified flexible neural electrode, thereby forming a hydrogel material that exhibits viscosity in dynamic tissue interaction. The first precursor solution is a solution in which thiol-terminated multi-arm polyethylene glycol is dissolved in a dispersion containing conductive nanomaterials and conductive polymers; the second precursor solution is a solution in which maleimide-terminated multi-arm polyethylene glycol is dissolved in a dispersion containing conductive nanomaterials and conductive polymers; the complex dispersion is a solution mixed with trivalent metal salt and tannic acid; the first precursor solution, the second precursor solution, and the complex dispersion are mixed and gelled through click chemical reaction between thiol and maleimide, coordination interaction between metal ions and tannic acid, and hydrogen bonding to obtain a double network hydrogel.

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