Multi-stage drug sustained-release coating system for nerve interface electrode, preparation method of multi-stage drug sustained-release coating system and nerve interface electrode

Abstract

The invention relates to the technical field of neural interface devices, and discloses a multi-stage drug sustained-release coating system for a neural interface electrode and a preparation method of the multi-stage drug sustained-release coating system. The coating system sequentially comprises a short-term sustained-release layer, a middle-term sustained-release layer and a long-term sustained-release layer from outside to inside, each of the short-term sustained-release layer and the middle-term sustained-release layer comprises a hydrogel matrix and drug-loading microspheres dispersed in the hydrogel matrix, and the crosslinking density of the hydrogel matrix in the short-term sustained-release layer is lower than that of the middle-term sustained-release layer; a gradient transition area with an interpenetrating network structure is arranged between every two adjacent coatings; and an adhesion transition layer is arranged between the electrode substrate and the long-term slow release layer. Through the three-layer structure, time sequence matching of drug release and neuroinflammation stages is achieved, the release rate and mechanical properties are cooperatively regulated and controlled through the cross-linking density gradient, the interlayer bonding stability is enhanced through the interpenetrating network structure, the interface adhesion is enhanced through the adhesion transition layer, and the drug delivery efficiency is improved. The problems of release time sequence mismatching, mechanical mismatching, interlayer layering, interface falling and the like of an existing coating are solved.

Description

Technical Field

[0001] This application relates to the field of neural interface technology, and in particular to a drug-releasing coating technology for neural interface electrodes. Background Technology

[0002] Neural interface technology is a key technology for enabling information interaction between the human brain and external devices, and it has significant application prospects in fields such as motor function rehabilitation, sensory function reconstruction, and diagnosis and treatment of neurological diseases. In typical application scenarios, such as decoding motor intentions in patients with spinal cord injuries, microelectrode arrays need to be implanted long-term in the cerebral motor cortex to collect neural signals; in lesion localization in patients with refractory epilepsy, cortical electroencephalography (EEG) electrodes need to be attached to the surface of the cerebral cortex for long-term monitoring; and in deep brain stimulation therapy for Parkinson's disease patients, stimulation electrodes need to be implanted long-term in specific brain nuclei. All of these application scenarios place extremely high demands on the long-term stability and biocompatibility of neural interface electrodes.

[0003] However, after neural interface electrodes are implanted into brain tissue, the interface between the electrode and the brain tissue undergoes a complex biological reaction process. In the initial stage of implantation, the mechanical damage caused by electrode puncture triggers an acute inflammatory response, releasing a large number of inflammatory factors and rapidly activating microglia that migrate towards the electrode interface. Subsequently, in the subacute phase, astrocytes begin to proliferate and gradually encapsulate the electrode. Finally, in the chronic phase, glial scars gradually mature and physically isolate the electrode from surrounding neurons, leading to a continuous decline or even complete loss of signal recording quality. This problem severely restricts the translation of neural interface technology into clinical applications.

[0004] To suppress the aforementioned inflammatory responses and glial scar formation, existing technologies include drug-release coatings on the surface of neuroelectrodes. However, these technologies and their corresponding drug-release coating techniques still have several shortcomings. First, existing coatings mostly employ a single release mode, making it difficult to provide differentiated drug release strategies for the different pathological characteristics of the acute, subacute, and chronic phases of neuroinflammation, resulting in a temporal mismatch between the drug release curve and the inflammatory process. Second, existing coatings lack sufficient consideration for the unique mechanical environment of brain tissue in their mechanical performance design. Modulus mismatch between the coating and brain tissue can cause interfacial stress concentration during brain tissue micromovement, exacerbating tissue damage and inflammatory responses. Furthermore, multilayered coating systems are prone to interlayer delamination or detachment under long-term implantation conditions, affecting the functional durability of the coating. In addition, insufficient adhesion between the coating and the electrode substrate is also a significant cause of coating failure.

[0005] Therefore, there is an urgent need for a neural interface electrode coating system and its preparation method that can achieve multi-stage drug release, has mechanical properties that match brain tissue, has a stable interlayer structure, and is firmly attached to the electrode substrate. Summary of the Invention

[0006] The purpose of this application is to provide a multi-stage drug sustained-release coating system for neural interface electrodes, a method for preparing the same, and the neural interface electrode, in order to solve the problems mentioned in the background art.

[0007] This application discloses a multi-stage drug sustained-release coating system for neural interface electrodes, comprising a short-term sustained-release layer, a medium-term sustained-release layer, and a long-term sustained-release layer arranged sequentially from the outside to the inside. The short-term sustained-release layer is configured to release drugs within 1-15 days after implantation to suppress acute inflammatory responses; The intermediate sustained-release layer is configured to continuously release drugs 1-6 weeks after implantation to suppress subacute inflammatory responses; The long-term sustained-release layer is configured to release a long-acting drug 1-12 months after implantation to inhibit the formation of glial scars in the chronic phase; Both the short-term sustained-release layer and the medium-term sustained-release layer comprise a hydrogel matrix and drug-loaded microspheres dispersed in the hydrogel matrix; The crosslinking density of the hydrogel matrix in the short-term sustained-release layer is lower than that in the medium-term sustained-release layer. A gradient transition region with an interpenetrating network structure is provided between adjacent coatings, in which the polymer molecular chains of adjacent layers interpenetrate and entangle with each other.

[0008] In a preferred embodiment, the thickness of the gradient transition region of the interpenetrating network structure is 5-30 μm.

[0009] In a preferred embodiment, the hydrogel matrix of both the short-term sustained-release layer and the medium-term sustained-release layer is a polyvinyl alcohol hydrogel; The short-term sustained-release layer contains 3-7% polyvinyl alcohol by mass, forming a loose network structure. The mass fraction of polyvinyl alcohol in the intermediate-release layer is 7-15%, forming a dense network structure.

[0010] In a preferred embodiment, the short-term sustained-release layer comprises, by mass fraction: 3-7% polyvinyl alcohol, 1-3% chitosan, 6-8% polyethylene glycol, 5-15% glycerol, 8-15% PLGA drug-loaded microspheres, 0.1-0.3% Tween, and the balance being ultrapure water.

[0011] In a preferred embodiment, the intermediate-release layer comprises, by mass fraction: 7-15% polyvinyl alcohol, 1-3% chitosan, 6-8% polyethylene glycol, 5-15% glycerol, 8-15% PLGA drug-loaded microspheres, 0.1% Tween, and the balance being ultrapure water.

[0012] In a preferred embodiment, the long-term sustained-release layer consists of a hydrophobic biodegradable polymer matrix and a drug or drug-loaded nanoparticles dispersed therein. The long-term sustained-release layer is a planar thin film layer covering the electrode surface with a thickness of 5-20 μm; or it is an end component located at the tip of the electrode, which has both puncture and sustained-release functions.

[0013] In a preferred embodiment, the long-term sustained-release layer is composed of a polymer matrix consisting of PLGA nanoparticles and PLA, wherein the mass ratio of PLGA nanoparticles to PLA is 2:1 to 3:1.

[0014] In a preferred embodiment, the carrier material of the drug-loaded microspheres is selected from at least one of PLGA, PLA, PCL, gelatin, and chitosan.

[0015] In a preferred embodiment, the drug loaded in the drug-loaded microspheres is selected from at least one of dexamethasone, rapamycin, ibuprofen, BDNF, and NGF.

[0016] In a preferred embodiment, the swelling rate of the coating system is less than 50%, and the hardness after swelling is 3-15 kPa.

[0017] In a preferred embodiment, the hydrogel matrix is ​​selected from at least one of polyvinyl alcohol, methacrylated gelatin, and polyethylene glycol diacrylate.

[0018] This application also discloses a neural interface electrode, including an electrode substrate and a coating system as described above disposed on the surface of the electrode substrate; An adhesion transition layer is provided between the electrode substrate and the long-term sustained-release layer of the coating system.

[0019] In a preferred embodiment, the adhesion transition layer is a polydopamine layer with a thickness of 50-200 nm; or, the adhesion transition layer is a silane coupling agent layer; or, the adhesion transition layer is a polyimide coating with a thickness of 3-10 μm.

[0020] In a preferred embodiment, the following steps are included: Step S1: Preparation of drug-loaded microspheres; Step S2: Prepare short-term sustained-release layer solution and medium-term sustained-release layer solution respectively, wherein the concentration of hydrophilic polymer in the short-term sustained-release layer solution is lower than the concentration of hydrophilic polymer in the medium-term sustained-release layer solution, and the drug-loaded microspheres prepared in step S1 are dispersed in both solutions; prepare long-term sustained-release layer solution. Step S3: Form a long-term sustained-release layer on the surface of the electrode substrate; Step S4: Coat the surface of the long-term sustained-release layer with the intermediate sustained-release layer solution to form the intermediate sustained-release layer; Step S5: Coat the surface of the intermediate sustained-release layer with the short-term sustained-release layer solution to form the short-term sustained-release layer; Step S6: Perform final drying treatment; In steps S4 and S5, before applying the next layer of coating solution, the previous layer of coating is controlled to be in a semi-dry state with a moisture content of 8-15%, and the next layer of coating solution is allowed to stand and penetrate on the surface of the previous layer of coating. After drying, a gradient transition region of the interpenetrating network structure is formed between adjacent coatings.

[0021] In a preferred embodiment, the static infiltration time is 5-15 minutes, and the temperature of the coating solution is 20-30°C.

[0022] In a preferred embodiment, the specific process for preparing drug-loaded microspheres in step S1 is as follows: Add the drug to an organic solvent and stir to dissolve; Add the carrier material to the solution and stir until completely dissolved to form an oil phase; The oil phase is added dropwise to a 1%-10% polyvinyl alcohol aqueous solution; Homogenize at 6000-15000 rpm for 3-15 min; After stirring to evaporate the solvent, the drug-loaded microspheres were obtained by centrifugation, washing, and freeze-drying. The mass ratio of the carrier material to the drug is 3:1 to 10:1, and the organic solvent is a mixture of acetone and dichloromethane, with a volume ratio of acetone to dichloromethane of 1:2 to 1:7.

[0023] In a preferred embodiment, prior to forming the long-term sustained-release layer in step S3, the step of preparing an adhesion transition layer on the surface of the electrode substrate is further included, using one of the following methods: Method A: Place the electrode substrate in a plasma cleaning chamber, introduce argon or oxygen, and perform plasma treatment for 1-10 minutes. The specific time depends on the electrode material and the power of the plasma treatment. Method B: Immerse the electrode substrate in a dopamine-Tris buffer solution with a concentration of 2-8 mg / mL and a pH of 8-9, react at room temperature for 12-24 h, remove, wash and dry to form a polydopamine adhesion transition layer with a thickness of 50-200 nm. Option C: Immerse the electrode substrate in a 2-4% polyimide solution, remove it and dry it for 5-15 minutes, then place it in an oven for 45-90 minutes to form a polyimide transition layer with a thickness of 3-10 μm.

[0024] In a preferred embodiment, steps S4 and S5 are performed using an dip-coating method with a coating speed of 0.5-5 mm / min.

[0025] In a preferred embodiment, when the long-term sustained-release layer is a planar thin film layer, step S3 adopts a spin coating method with a spin coating speed of 1500-3500 rpm and a time of 30-60 s; When the long-term sustained-release layer is a conical end component, step S3 adopts a mold forming method. The long-term sustained-release layer solution is poured into the conical mold cavity, allowed to stand to remove air bubbles, vacuum dried, and demolded. After plasma cleaning of the surface of the conical drug carrier, the electrode head is dipped in the coating solution and inserted into the conical drug carrier. After curing, the long-term sustained-release layer is formed.

[0026] In a preferred embodiment, when the long-term sustained-release layer is a planar thin film layer, the surface of the long-term sustained-release layer is subjected to oxygen plasma treatment to increase surface hydrophilicity before coating the intermediate sustained-release layer solution in step S4.

[0027] In a preferred embodiment, the crosslinking density of the hydrogel matrix in the short-term sustained-release layer and the medium-term sustained-release layer is controlled by one or a combination of the following methods: Method 1: Adjusting the polyvinyl alcohol concentration, wherein the polyvinyl alcohol concentration in the short-term slow-release layer solution is 3-7%, and the polyvinyl alcohol concentration in the medium-term slow-release layer solution is 7-15%; Method 2: Adjust the number of freeze-thaw cycles, performing 1-3 freeze-thaw cycles on the short-term slow-release layer and 4-6 freeze-thaw cycles on the medium-term slow-release layer.

[0028] In a preferred embodiment, in steps S4 and S5, the intermediate-term sustained-release layer and the short-term sustained-release layer are each coated 2-3 times, the number of times depending on the thickness of the sustained-release layer. After each coating, the layer is dried to a moisture content of 8-15% before the next coating or the next layer is applied. In step S6, the final drying time is at room temperature for more than 24 hours.

[0029] The multi-stage drug sustained-release coating system and its preparation method for neural interface electrodes provided in this application can solve the technical problems of existing neural interface electrode coatings, such as the mismatch between the drug release curve and the neuroinflammatory process, the mismatch between the mechanical properties of the coating and the mechanical environment of brain tissue, the easy delamination and peeling between the layers of the multilayer coating structure, and the insufficient adhesion between the coating and the electrode substrate.

[0030] Specifically, the coating system of this application employs a three-layer structure design, consisting of a short-term sustained-release layer, a medium-term sustained-release layer, and a long-term sustained-release layer arranged sequentially from the outside in. This allows the short-term sustained-release layer to rapidly release the drug during the acute phase after implantation, the medium-term sustained-release layer to continuously release the drug during the subacute phase after implantation, and the long-term sustained-release layer to release the drug over a long period during the chronic phase after implantation. This achieves a precise correspondence between the drug release sequence and the three stages of neuroinflammation: the acute phase, the subacute phase, and the chronic phase. This enables the anti-inflammatory drug to be released at appropriate doses and rates during each inflammatory stage, thereby maximizing the anti-inflammatory effect and effectively inhibiting the formation of glial scars.

[0031] Furthermore, both the short-term and medium-term sustained-release layers employ a composite structure of a hydrogel matrix and drug-loaded microspheres dispersed within it. A crosslinking density gradient is created by lowering the crosslinking density of the hydrogel matrix in the short-term sustained-release layer compared to the medium-term layer. This gradient design allows the short-term sustained-release layer to have a larger network pore size and a higher swelling tendency, enabling rapid absorption of tissue fluid and rapid drug diffusion and release after implantation. The medium-term sustained-release layer, on the other hand, forms a relatively dense network structure, delaying water penetration and drug diffusion, achieving sustained low-concentration release. Simultaneously, this crosslinking density gradient also regulates the macroscopic mechanical properties of the coating system, allowing the swelling rate and post-swelling hardness to be adjusted to match the low-modulus mechanical environment of brain tissue. This effectively alleviates interfacial stress concentration caused by mechanical mismatch between the coating and brain tissue during micromovement, reducing secondary inflammatory responses induced by mechanical stimulation.

[0032] When the hydrogel matrix is ​​a polyvinyl alcohol hydrogel, the aforementioned crosslinking density gradient can be achieved by adjusting the mass fraction of polyvinyl alcohol in the short-term and medium-term sustained-release layers. Specifically, the mass fraction of polyvinyl alcohol in the short-term sustained-release layer is controlled within a lower range to form a loose network structure, while the mass fraction in the medium-term sustained-release layer is controlled within a higher range to form a dense network structure. Chitosan added to the specific formulations of the short-term and medium-term sustained-release layers enhances the biocompatibility of the coating; polyethylene glycol and glycerol regulate the swelling properties and flexibility of the coating; and Tween improves the uniformity of drug-loaded microsphere dispersion in the hydrogel matrix. The synergistic effect of these components ensures that the coating system possesses excellent drug release performance, mechanical properties, and film-forming properties.

[0033] The long-term sustained-release layer utilizes a hydrophobic, biodegradable polymer matrix. Its degradation primarily relies on hydrolysis, and its degradation cycle is significantly longer than that of hydrophilic hydrogels, thus achieving drug sustained release for several months. The long-term sustained-release layer can be designed as a planar thin film layer or an end-component structure, depending on the electrode type. The planar thin film layer shape is suitable for non-invasive or minimally invasive electrodes such as surface patch electrodes, cortical EEG electrodes, or flexible thin film electrodes. The end-component shape (such as a cone shape) is suitable for invasive microelectrodes. In addition to providing long-term sustained-release functionality, this end-component structure can also utilize the polymer's high hardness to assist in puncture, achieving an integration of puncture and sustained-release functions.

[0034] This application incorporates an interpenetrating network structure with a gradient transition region between adjacent coatings. Within this gradient transition region, the polymer molecular chains of adjacent layers interpenetrate and entangle, thereby significantly enhancing interlayer bonding and avoiding the delamination and peeling failure problems that easily occur in traditional multilayer coating structures due to distinct interfaces between layers and reliance solely on physical contact, especially under long-term humid environments or conditions of micro-movement in brain tissue. Simultaneously, the interpenetrating network structure enables a continuous transition of drug release channels between layers, eliminating the "sudden release" or "cliff-like drop" phenomenon in the drug release curve that may occur due to interface barriers, resulting in a smoother and more continuous transition between stages of the release curve.

[0035] The preparation method of this application involves controlling the previous coating layer to a semi-dry state with a specific moisture content range before applying the next coating solution, and allowing the next coating solution to stand and penetrate the surface of the previous layer for a specific time. This allows a gradient transition region of the aforementioned interpenetrating network structure to naturally form during the drying and curing process. This moisture content range is a process window determined through systematic experiments: when the moisture content is below the lower limit, the polymer chains on the surface of the previous layer have lost their fluidity, and the polymer chains in the next solution cannot effectively penetrate, making it difficult to form an interpenetrating structure; when the moisture content is above the upper limit, the structure of the previous layer is still unstable, and applying the next layer may lead to layer collapse or interface confusion. Only by coating and allowing the solution to stand and penetrate within this specific moisture content window can a gradient transition region of appropriately thick interpenetrating network structure be formed between the layers.

[0036] In addition to regulating the crosslinking density gradient by varying the concentration of hydrophilic polymers, this application can further enhance the crosslinking density gradient effect by applying different numbers of freeze-thaw cycles to the short-term and medium-term sustained-release layers. Specifically, applying more freeze-thaw cycles to the medium-term sustained-release layer allows it to form more crystalline regions as physical crosslinking points, thereby further slowing down its release rate.

[0037] This application incorporates an adhesion transition layer between the electrode substrate and the long-term sustained-release layer of the coating system. This adhesion transition layer can form chemical bonds or strong physical interactions with both the electrode substrate surface and the coating polymer, thereby bridging and enhancing adhesion. When the adhesion transition layer is a polydopamine layer, its abundant catechol groups and amino groups can form chemical bonds with various substrate materials and polymers. Similarly, when the adhesion transition layer is a silane coupling agent layer, it can also achieve interfacial chemical bonding to enhance adhesion. The adhesion transition layer and the interlayer interpenetrating network structure together constitute a dual stabilization strategy of "substrate interface stability + interlayer interface stability," ensuring stability from the overall structure of the coating system to the interfaces at each level, thus ensuring that the coating system does not delaminate or detach under long-term implantation conditions.

[0038] For patch electrodes, oxygen plasma treatment of the surface of the hydrophobic long-term sustained-release layer before coating the hydrophilic intermediate sustained-release layer solution can increase the surface hydrophilicity of the long-term sustained-release layer, prevent "beading" or poor wetting of the subsequent hydrogel coating solution, and ensure that each coating layer uniformly and continuously covers the effective area of ​​the electrode.

[0039] The carrier material for drug-loaded microspheres can be selected from biodegradable biomaterials such as PLGA, PLA, PCL, gelatin, and chitosan, with PLGA being the preferred choice due to its tunable degradation rate and good biocompatibility. The drugs loaded into the drug-loaded microspheres can be selected according to clinical needs, such as dexamethasone, rapamycin, ibuprofen, or brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF). Dexamethasone, as a glucocorticoid anti-inflammatory drug, can effectively inhibit the activation of microglia and astrocytes; rapamycin can inhibit glial cell proliferation; and NGF can promote neuronal survival and axonal growth. Depending on the needs of different clinical scenarios, a single drug or a combination of multiple drugs can be selected, demonstrating the excellent drug compatibility and application flexibility of the coating system in this application.

[0040] In summary, the multi-stage drug sustained-release coating system and its preparation method of this application achieve all the technical goals of precise matching of the drug release curve of the coating system with the neuroinflammatory process, adaptation of mechanical properties to the mechanical environment of brain tissue, stable bonding of interlayer structure without delamination, and long-term stable adhesion of coating to electrode substrate through the synergistic combination of four technical features: precise correspondence between the three-layer structure and the neuroinflammatory stage, synergistic regulation of release rate and mechanical properties by cross-linking density gradient, stable bonding of interlayer structure without delamination, and long-term stable adhesion of coating to electrode substrate. This overcomes the above-mentioned technical defects of neural interface electrode coatings in the prior art and has significant technical progress.

[0041] The specification of this application contains numerous technical features distributed across various technical solutions. Listing all possible combinations of these technical features (i.e., technical solutions) would make the specification excessively lengthy. To avoid this problem, the various technical features disclosed in the above-described invention, the various technical features disclosed in the following embodiments and examples, and the various technical features disclosed in the accompanying drawings can be freely combined to form various new technical solutions (all of which are considered to have been described in this specification), unless such a combination of technical features is technically infeasible. For example, one example discloses feature A+B+C, and another example discloses feature A+B+D+E. Features C and D are equivalent technical means that serve the same function, and technically only one needs to be used; they cannot be used simultaneously. Feature E can technically be combined with feature C. Therefore, the solution A+B+C+D should not be considered as described because it is technically infeasible, while the solution A+B+C+E should be considered as described. Attached Figure Description

[0042] Figure 1 This is a schematic diagram of the structure of a multi-stage drug sustained-release coating system according to the first embodiment of this application.

[0043] Figure 2 This is a schematic flowchart of the coating system preparation method according to the second embodiment of this application.

[0044] in: Explanation of reference numerals in the attached figures: 10: Multi-stage drug sustained-release coating system 11: Short-term sustained-release layer 12: Mid-term sustained-release layer 13: Long-term sustained-release layer 14: Gradient transition region 15: Adhesion transition layer 16: Drug-loaded microspheres 17: Hydrogel matrix 20: Electrode substrate Detailed Implementation

[0045] In the following description, many technical details are presented to help the reader better understand this application. However, those skilled in the art will understand that the technical solutions claimed in this application can be implemented even without these technical details and various variations and modifications based on the following embodiments.

[0046] Explanation of some concepts: Neural interface electrodes are implantable devices used to establish signal transmission channels between the nervous system (especially the central nervous system) and external devices. These include, but are not limited to, microfilament electrodes for recording neuronal electrical activity, microelectrode arrays (such as the Utah array and Michigan probes), electrocorticography (ECoG) electrodes, and neuromodulation electrodes for applying electrical stimulation. Their applications span brain-computer interface signal acquisition, diagnosis of nervous system diseases, and neuromodulation therapy.

[0047] A multi-stage drug-sustained release coating system refers to a coating system composed of multiple functional layers with different release characteristics. Each functional layer is configured to release the drug at different time stages to achieve temporal regulation of drug release. In this application, it specifically refers to combinations of different release rates and durations corresponding to the acute, subacute, and chronic phases of neuroinflammatory responses.

[0048] A short-term release layer is a functional layer located on the outermost layer of a coating system, configured to rapidly release drugs within a short period after implantation (e.g., 1-15 days after implantation) to address acute inflammatory responses in the early stages of implantation.

[0049] The medium-term release layer is a functional layer located in the middle of the coating system, configured to continuously release drugs in the middle period after implantation (e.g., 1-6 weeks after implantation) to deal with the inflammatory response in the subacute phase.

[0050] The long-term release layer is a functional layer located at the innermost layer of the coating system, configured to release drugs for a long period of time (e.g., 1-12 months after implantation) after implantation, in order to inhibit the formation of chronic glial scars.

[0051] Hydrogel matrix refers to a three-dimensional network structure formed by physical or chemical cross-linking of hydrophilic polymers. It can absorb a large amount of water and swell but does not dissolve. In this application, it is used as the main material of the short-term sustained-release layer and the medium-term sustained-release layer to load drug-loaded microspheres and regulate the diffusion and release of drugs as well as the mechanical properties of the coating.

[0052] Cross-linking density refers to the number or density of cross-linking points per unit volume in a polymer network. Higher cross-linking density results in a denser polymer network, smaller pore size, lower swelling ratio, higher hardness, greater resistance to drug diffusion, and a slower release rate. In this application, cross-linking density can be controlled by polymer concentration, freeze-thaw cycles, etc.

[0053] Drug-loaded microspheres are micron-sized spherical particles made of biodegradable biomaterials, which are loaded with active pharmaceutical ingredients. In this application, they are dispersed in the hydrogel matrix of the short-term and medium-term sustained-release layers, and the controlled release of the drug is achieved through a dual mechanism of degradation of the carrier material and diffusion through the hydrogel network.

[0054] Drug-loaded nanoparticles are nanoscale spherical particles made of biodegradable biomaterials, loaded with active pharmaceutical ingredients. In this application, they are used as a long-term sustained-release layer, dispersed within a hydrophobic biodegradable polymer matrix.

[0055] The gradient transition region of an interpenetrating network (IPN) structure refers to a special interface structure formed between adjacent coatings. Within this region, the polymer chains of adjacent layers interpenetrate and entangle, forming a continuous interpenetrating network rather than a clearly defined physical contact. This structure enhances interlayer bonding and facilitates a smooth transition in drug release profiles. Its formation depends on the previous coating layer being in a specific semi-dry state during the coating process.

[0056] An adhesion transition layer is a thin layer structure placed between the electrode substrate and the coating system to enhance the adhesion between the coating and the electrode substrate. It can act as a "molecular bridge" through chemical bonding or strong physical action to prevent the coating from falling off.

[0057] A polydopamine layer is a thin film layer formed by the self-polymerization of dopamine monomers under alkaline conditions. It is rich in catechol groups and amino groups and can form chemical bonds with a variety of substrate materials and polymers. In this application, it can be used as an adhesion transition layer.

[0058] A silane coupling agent layer is an interface modification layer formed on the surface of a substrate by a silane coupling agent. It can bond with inorganic substrates (such as silicon or metal oxides) through silicon-oxygen bonds, or bond with organic flexible substrates such as polyimide after plasma activation treatment, and bond with polymer coatings through organic functional groups. In this application, it can be used as an adhesion transition layer.

[0059] Moisture content refers to the percentage of water content in a coating at a given moment during the drying process, relative to the total mass of the coating. It can be calculated by weighing, using the formula: Moisture content = (Wet weight - Dry weight) ÷ Wet weight × 100%. In this application, controlling the previous coating layer to be in a semi-dry state within a specific moisture content range is a key process condition for forming an interpenetrating network structure.

[0060] The semi-dry state refers to the intermediate state of the coating during the drying process, where the surface polymer chains still maintain a certain degree of fluidity and segment activity. In this application, it specifically refers to the state with a moisture content of 8-15%, at which point the coating surface is "slightly sticky but not tacky," allowing subsequent coating solutions to penetrate.

[0061] Hydrophobic biodegradable polymers are polymeric materials that have hydrophobic properties and can be gradually degraded through hydrolysis under physiological conditions, such as polylactic acid-glycolic acid copolymer (PLGA), polylactic acid (PLA), and polycaprolactone (PCL), which are used in this application as the matrix material for constituting the long-term sustained-release layer.

[0062] The conical end component refers to the conical drug-carrying structure set at the tip of an invasive microelectrode. It is made of hydrophobic and biodegradable polymer and has the dual functions of assisting puncture and long-acting drug release.

[0063] A planar thin film layer refers to a long-term sustained-release layer covering the surface of a patch electrode. It uniformly covers the effective area of ​​the electrode in the form of a thin film and is suitable for non-invasive or minimally invasive electrodes such as surface patch electrodes, cortical electroencephalography electrodes, or flexible thin film electrodes.

[0064] Dip coating is a coating method in which the substrate is immersed in a coating solution and then pulled out of the solution at a certain speed, so that the coating solution forms a film on the surface of the substrate. The pulling speed affects the thickness and uniformity of the coating.

[0065] Freeze-thaw cycle refers to the process of alternately freezing and thawing polyvinyl alcohol (PVA) aqueous solutions or coatings. During freezing, the PVA molecular chains rearrange to form crystalline regions, which act as physical crosslinking points and can increase the crosslinking density of the hydrogel.

[0066] The swelling ratio refers to the percentage increase in mass of a hydrogel after it has absorbed water and swelled to equilibrium in an aqueous medium. The formula is: Swelling ratio = (mass after swelling - dry weight) ÷ dry weight × 100%, which reflects the porosity and water absorption capacity of the hydrogel network.

[0067] Young's modulus is a physical quantity that describes the resistance of a solid material to deformation. In this application, it is used to characterize the hardness and softness of the coating after swelling, in order to assess its mechanical compatibility with brain tissue. The Young's modulus of brain tissue is approximately 1-10 kPa, which is much lower than that of peripheral tissues such as muscle and bone.

[0068] Brain micromotion refers to the periodic, minute displacements of brain tissue caused by physiological activities such as heartbeat and respiration. These micromotions generate periodic stress at the interface between the implanted electrode and the brain tissue, which is one of the important factors leading to coating delamination or detachment.

[0069] The LA:GA ratio in PLGA refers to the molar or mass ratio of lactic acid units to glycolic acid units in the polylactic acid-glycolic acid copolymer. A higher LA ratio results in stronger polymer crystallinity, higher hydrophobicity, and a slower degradation rate; a higher GA ratio results in stronger polymer hydrophilicity and a faster degradation rate. By adjusting the LA:GA ratio, the degradation cycle of PLGA can be controlled from several weeks to several months.

[0070] The following is a brief summary of some of the innovative aspects of this application: In summary, the core technical concept of the multi-stage drug-release coating system 10 for neural interface electrodes involved in this application lies in the following: After in-depth research, the inventors realized that the inflammatory response of neural tissue, especially brain tissue, to implants exhibits a distinctly different phased evolution pattern compared to peripheral tissues such as cardiovascular and skeletal tissues. Specifically, it sequentially experiences three phases—acute, subacute, and chronic—that differ significantly in both time span and pathological characteristics. However, existing drug-release coatings (whether multilayer coatings for cardiovascular stents or surface coatings for orthopedic implants) have not been specifically designed to address this unique temporal characteristic of neuroinflammation, resulting in a technical problem of temporal mismatch between the drug release curve and the neuroinflammation process.

[0071] Based on the above understanding, this application does not simply transplant the known multilayer sustained-release structure in the prior art to the field of neural interface electrodes. Instead, it creatively constructs a three-layer coating system 10 with a short-term sustained-release layer 11, a medium-term sustained-release layer 12, and a long-term sustained-release layer 13 arranged sequentially from the outside to the inside. The short-term sustained-release layer 11 and the medium-term sustained-release layer 12 both include a hydrogel matrix 17 and drug-loaded microspheres 16 dispersed in the hydrogel matrix 17. Furthermore, by designing a specific crosslinking density gradient such that the crosslinking density of the hydrogel matrix 17 in the short-term sustained-release layer 11 is lower than that in the medium-term sustained-release layer 12, a precise correspondence between the material structure and the stage process of neuroinflammation is established. It should be noted that the aforementioned crosslinking density gradient does not play an isolated role in regulating the release rate, but rather simultaneously exerts a synergistic regulatory effect on the macroscopic mechanical properties of the coating system 10. This allows the hardness of the coating system 10 in the swollen state to match the low-modulus mechanical environment of the brain tissue, thereby reducing the interfacial stress concentration problem caused by mechanical mismatch between the coating and the brain tissue while achieving phased drug release. This "synergistic optimization of release characteristics and mechanical properties" is a technical effect that is difficult for those skilled in the art to foresee based on existing technology.

[0072] Furthermore, this application recognizes that relying solely on gradient design of material composition is insufficient to ensure the structural integrity of a multilayer coating system under long-term implantation conditions. Therefore, it creatively introduces a gradient transition region 14 of interpenetrating network structure between adjacent coatings. The formation of this gradient transition region 14 depends on a specific process window determined through extensive experimental exploration. Specifically, before applying the next coating solution, the previous coating layer is controlled in a semi-dry state with a moisture content of 8-15%, and the next coating solution is allowed to stand and penetrate the surface of the previous layer for a specific time. The discovery of the aforementioned moisture content window is not a result obtained through conventional operation in the field or through a limited number of experiments, but rather a discovery made by the inventors through systematic experiments: when the moisture content is below the lower limit, the polymer chains on the surface of the previous layer lose fluidity and cannot form effective interpenetration with the next layer; when the moisture content is above the upper limit, it leads to unstable layer structure or interface confusion. Only within this specific window can the polymer molecular chains of adjacent layers interpenetrate and entangle to form a continuously transitioning interpenetrating network structure. The gradient transition region 14 of the interpenetrating network structure works in conjunction with the aforementioned crosslinking density gradient design, which not only enhances the interlayer bonding stability to resist the interfacial shear stress caused by brain tissue micromovement, but also makes the transition of the drug release curve between each stage smoother, avoiding the release mutation phenomenon that may occur in traditional layered structures due to distinct interfaces.

[0073] Furthermore, this application also provides an adhesion transition layer 15 between the electrode substrate 20 and the long-term sustained-release layer 13 of the coating system 10. This adhesion transition layer 15, together with the aforementioned interlayer interpenetrating structure, constitutes a dual stabilization strategy of "matrix interface stability + interlayer interface stability," achieving comprehensive stability assurance of the coating system from the overall structure to the interfaces of each layer. In summary, the technical solution of this application is a systematic solution in which four technical features are interconnected and synergistically cooperate: "precise correspondence between the three-layer structure and the neuroinflammatory stage + synergistic regulation of release rate and mechanical properties by the crosslinking density gradient + interlayer interpenetrating network structure formed by a specific moisture content process window + interface enhancement of the adhesion transition layer." The absence of any one of these technical features will prevent the coating system from simultaneously achieving all the technical objectives of precise staged release, mechanical property matching, stable interlayer bonding, and stable adhesion to the matrix interface. There is an inseparable internal connection between the various technical features, and the overall technical solution is non-obvious.

[0074] The technical solution of this application will now be clearly and completely described with reference to the accompanying drawings and specific embodiments. Obviously, the described embodiments are only a part of the embodiments of this application, and not all of them. All other embodiments obtained by those skilled in the art based on the embodiments of this application without creative effort are within the scope of protection of this application.

[0075] As stated above, the inventors of this application have discovered through long-term in-depth research that the reason why existing neural interface electrode coating technology is difficult to achieve satisfactory long-term effects in clinical applications is that there is a lack of systematic understanding and targeted design of the unique inflammatory response patterns of neural tissue and the unique mechanical microenvironment of brain tissue.

[0076] The inventors first conducted an in-depth analysis of the temporal characteristics of the inflammatory response after nerve tissue implantation, discovering that the inflammatory response of nerve tissue, especially brain tissue, to implants exhibits a distinctly different phased evolutionary pattern compared to peripheral tissues such as cardiovascular and skeletal tissues. Specifically, the acute phase after electrode implantation (approximately 1-15 days) is characterized by a burst of inflammatory factor release and rapid microglial activation, requiring high concentrations of anti-inflammatory drugs to take effect quickly. The subacute phase (approximately 1-6 weeks) is characterized by the inflammatory response transitioning to a chronic, low-level state and astrocyte proliferation, requiring the maintenance of stable drug concentrations to inhibit excessive glial cell activation. The chronic phase (over one month) is characterized by the gradual maturation of glial scars and the physical isolation of the electrodes, requiring long-acting, low-dose drug release to combat the continued formation of scars. Existing technologies, whether multilayer coatings used in cardiovascular stents or sustained-release coatings used in orthopedic implants, have not been specifically designed to address this unique temporal pattern of neuroinflammation. Simply transplanting these coating technologies to the field of neural interface electrodes cannot solve the problem of the mismatch between the drug release curve and the inflammatory process.

[0077] The inventors further recognized that simply achieving staged release is insufficient to solve all the problems faced by neural interface electrode coatings, because brain tissue has an extremely low Young's modulus (approximately one to ten kPa), far lower than that of peripheral tissues such as muscle and bone. If the coating's rigidity is too high, during the continuous micro-movements of brain tissue caused by heartbeat and respiration, interfacial stress concentration will occur between the coating and brain tissue due to modulus mismatch. This mechanical stimulation itself will exacerbate the inflammatory response and damage surrounding neural tissue. The inventors creatively proposed that the mechanical property design of the coating system should be synergistic with the drug release function design—by controlling the cross-linking density of the hydrogel matrix, both the pore size can be controlled to regulate the drug diffusion rate, and the swelling rate and hardness of the coating can be simultaneously controlled to match the mechanical environment of brain tissue, achieving synergistic optimization of release characteristics and mechanical properties.

[0078] Through in-depth analysis of existing multilayer coating failure cases, the inventors discovered that traditional multilayer coatings typically employ a process of "applying the next layer after the previous one is completely dry." This results in only physical contact interfaces between layers, rather than molecular chain-level bonding. Under long-term humid conditions, interfacial stress caused by differences in swelling coefficients between layers, as well as periodic shear forces from micromovements in brain tissue, all lead to gradual failure of the interlayer interfaces, ultimately causing coating delamination or even complete detachment. After systematic experimental exploration, the inventors discovered that controlling the previous coating layer to a specific semi-dry state (moisture content 8-15%) before applying the next coating solution, and allowing the next coating solution to stand and penetrate the surface of the previous layer for a certain period of time, allows the polymer molecular chains of adjacent layers to interpenetrate and entangle in the interfacial region, forming a gradient transition region of interpenetrating network structure. Determining this moisture content window is not a routine operation—when the moisture content is too low, the polymer chains on the surface of the previous layer lose fluidity and cannot form effective interpenetration; when the moisture content is too high, the layer structure becomes unstable, leading to interface confusion—the inventors determined this critical window through repeated experiments.

[0079] The inventors also noted that the interfacial stability between the coating and the electrode substrate is a key factor affecting the long-term performance of the coating. In existing technologies, the coating and electrode substrate mainly rely on physical adsorption for bonding, resulting in weak adhesion. This makes them prone to peeling under the mechanical forces during implantation or the interfacial degradation that occurs after long-term implantation. The inventors propose setting an adhesion transition layer between the electrode substrate and the coating system. This layer enhances the interfacial bonding strength through chemical bonding, forming a dual stabilization strategy of "substrate interface stability + interfacial interface stability" together with the interlayer interpenetrating network structure.

[0080] Based on the above in-depth research, the inventors of this application propose an innovative technical solution: a three-layer structure—comprising a short-term sustained-release layer, a medium-term sustained-release layer, and a long-term sustained-release layer—is used to achieve temporal matching between drug release and the neuroinflammatory stage; the crosslinking density gradient of the hydrogel matrix in the short-term and medium-term sustained-release layers is controlled to achieve synergistic regulation of release rate and mechanical properties; a gradient transition region of an interpenetrating network structure is constructed between adjacent coatings using a specific semi-dry interface permeation process to achieve stable interlayer bonding; and an adhesion transition layer is provided between the electrode substrate and the coating to achieve stable adhesion at the substrate interface. These four technical features are interconnected and synergistic, forming a systematic technical solution.

[0081] I. Overall Structure of the Coating System The multi-stage drug-release coating system provided in this application is suitable for neural interface electrodes. Its core design concept is to target the multi-stage temporal characteristics of the inflammatory response after neural tissue implantation. It should be noted that the inflammatory response of neural tissue, especially brain tissue, to implants exhibits a unique phased evolution: the acute phase after electrode implantation (approximately 1-15 days post-implantation) is characterized by an explosive release of inflammatory factors and rapid microglial activation triggered by implantation trauma and blood-brain barrier disruption; the subacute phase (approximately 1-6 weeks) sees the inflammatory response gradually transition to a chronic, low-level state, with astrocytes beginning to proliferate; and the chronic phase (over one month) sees glial scars gradually maturing, and the electrode gradually becoming physically isolated. This temporal characteristic of inflammation is a significant feature that distinguishes neural tissue from peripheral tissues such as cardiovascular and skeletal systems. Existing cardiovascular stent coatings or orthopedic implant coatings are not designed to address this specific pattern.

[0082] like Figure 1 As shown, the coating system of this application includes a short-term sustained-release layer, a medium-term sustained-release layer, and a long-term sustained-release layer arranged sequentially from the outside to the inside. Specifically, the short-term sustained-release layer is located at the outermost layer of the coating system, directly contacting the brain tissue, and is configured to rapidly release the drug within 1-15 days after implantation to suppress the acute inflammatory response; the medium-term sustained-release layer is located at the middle layer, configured to continuously release the drug within 1-6 weeks after implantation to suppress the subacute inflammatory response; and the long-term sustained-release layer is located at the innermost layer, closely adhering to the adhesion transition layer or electrode substrate, and is configured to release the drug for a long-term effect within 1-12 months after implantation to inhibit the formation of glial scars in the chronic phase.

[0083] Furthermore, both the short-term and medium-term sustained-release layers comprise a hydrogel matrix and drug-loaded microspheres dispersed within it, forming a composite structure. A key innovation of this application lies in the lower cross-linking density of the hydrogel matrix in the short-term sustained-release layer compared to the medium-term sustained-release layer. This cross-linking density gradient design results in a larger network pore size and higher swelling rate in the short-term sustained-release layer, enabling rapid absorption and swelling of tissue fluid after implantation, with low drug diffusion resistance, thus achieving rapid release. Conversely, the medium-term sustained-release layer, with its higher cross-linking density and moderate network pore size, exhibits a lower swelling rate and degree, resulting in slower drug diffusion through the dense network, thus achieving sustained low-concentration release. The long-term sustained-release layer utilizes a hydrophobic biodegradable polymer as its matrix, whose degradation primarily relies on hydrolysis. The degradation cycle is long, and drug release is mainly controlled by the polymer degradation rate, thereby achieving slow release over several months.

[0084] More specifically, a gradient transition region with an interpenetrating network structure is provided between adjacent coatings. Within this gradient transition region, the polymer molecular chains of adjacent layers interpenetrate and entangle, rather than through simple physical contact or interfacial superposition. The formation mechanism of this interpenetrating network structure is as follows: Before coating the next layer, the previous layer is controlled to be in a semi-dry state with a moisture content of 8-15%. At this time, the polymer chains on the surface of the previous layer still have a certain degree of fluidity and activity. The polymer chains in the new coating solution can penetrate into the surface of the previous layer to form molecular chain-level interpenetration, and after drying, an interpenetrating structure is formed. The thickness of the gradient transition region of the interpenetrating network structure is preferably 5 to 30 μm.

[0085] The interpenetrating network structure brings many technical benefits: First, the interlayer bonding force is significantly improved, avoiding the delamination failure problem common in traditional multilayer coatings, which is especially important for neural electrodes that need to be implanted for a long time and are subject to brain tissue micro-movements; Second, the drug release curve can smoothly transition between each stage, eliminating the "burst release" or "cliff drop" phenomenon that may be caused by distinct interlayer interfaces, making the anti-inflammatory effect more continuous and stable.

[0086] The determination of interpenetrating network structure can be achieved using cross-sectional scanning electron microscopy (SEM). The criteria are: in the SEM image, there is no obvious delamination interface between adjacent coatings, but rather a continuous transition morphology. Specific testing conditions for SEM are as follows: During sample preparation, the hydrogel sample is blotted with filter paper until no free water remains on the surface, then immersed in liquid nitrogen for three to five minutes to ensure complete freezing. The sample is then quickly broken in liquid nitrogen and immediately transferred to a freeze dryer for sublimation drying. During conductive treatment, conductive silver paste or carbon paste is used between the sample and the sample stage to ensure a good electrical path. During SEM observation, a lower accelerating voltage (three to five kilovolts) and a smaller beam current are used, with a working distance of eight to ten millimeters. The cross-sectional area is first located under low magnification, and then gradually magnified. The coating thickness is observed while ensuring the cross-section is perpendicular to the electron beam, and multiple measurements are taken at different locations to determine the thickness of the gradient transition region.

[0087] II. Material Composition of Each Sustained-Release Layer Short-term sustained-release layer The hydrogel matrix of the short-term sustained-release layer is preferably polyvinyl alcohol (PVA) hydrogel, with a PVA mass fraction of 3-7%, forming a loose network structure. PVA molecular chains entangle with each other in solution to form a physical cross-linked network. When the PVA concentration is low, the molecular chain density is low, there are fewer entanglement points, and the resulting network is relatively loose with larger pore sizes, which is beneficial for the rapid diffusion and release of the drug.

[0088] For example, the short-term sustained-release layer may include, by mass fraction: 3-7% polyvinyl alcohol, 1-3% chitosan, 6-8% polyethylene glycol, 5-15% glycerol, 8-15% PLGA drug-loaded microspheres, 0.1-0.3% Tween, and the balance being ultrapure water. The addition of chitosan enhances biocompatibility, polyethylene glycol regulates swelling properties, glycerol acts as a plasticizer to improve coating flexibility, and Tween 20 acts as a surfactant to improve the uniform dispersion of drug-loaded microspheres in the hydrogel matrix.

[0089] Intermediate-release layer The hydrogel matrix for the intermediate-release layer is also preferably polyvinyl alcohol (PVA) hydrogel, but the mass fraction of PVA is increased to 7-15%, forming a denser network structure. Compared with the short-release layer, the increased PVA concentration leads to increased molecular chain density, more entanglement points, a denser network, smaller pore size, and reduced swelling rate, thereby slowing down the drug release rate.

[0090] For example, the intermediate-release layer may include, by mass fraction: 7-10% polyvinyl alcohol, 1% chitosan, 2-4% polyethylene glycol, 10% glycerol, 15-18% PLGA drug-loaded microspheres, 0.1% Tween 20, and the balance being ultrapure water. It should be noted that, compared to the short-release layer, the polyethylene glycol content in the intermediate-release layer is reduced, which further increases the degree of cross-linking and slows down the degradation rate; simultaneously, the content of drug-loaded microspheres is increased to prolong the release time.

[0091] The relationship between polyvinyl alcohol (PVA) concentration and crosslinking density is a key control mechanism for achieving phased release in this application. It is well known in the art that PVA concentration is positively correlated with crosslinking density, while crosslinking density is negatively correlated with drug release rate. By controlling the gradient difference in PVA concentration between the short-term and medium-term sustained-release layers, gradient control of the release rate can be achieved. The table below exemplarily illustrates the relationship between PVA concentration and coating performance: Long-term sustained-release layer The long-term sustained-release layer consists of a hydrophobic biodegradable polymer matrix and drug or drug-loaded nanoparticles dispersed within it. The degradation of the hydrophobic biodegradable polymer mainly relies on hydrolysis, which has a long degradation cycle, thus achieving long-term release.

[0092] When preparing the long-term sustained-release layer, an organic solvent is required to formulate the coating solution. For example, the long-term sustained-release layer solution may include, by mass fraction: 25-40% PLGA nanoparticles, 5-15% PLA, 15-20% acetone, and 40-50% dichloromethane. It should be noted that the above formulation is for the coating solution; during the film-forming and drying process, acetone and dichloromethane, as organic solvents, will evaporate and be removed. The final long-term sustained-release layer mainly consists of a biodegradable polymer matrix composed of PLGA nanoparticles and PLA, wherein the mass ratio of PLGA nanoparticles to PLA is preferably about 2.5:1 to 3:1.

[0093] The morphology of the long-term sustained-release layer can be selected according to the type of electrode: when applied to non-invasive or minimally invasive electrodes such as surface patch electrodes, electrocorticography electrodes, or flexible thin-film electrodes, the long-term sustained-release layer is preferably a planar thin-film layer covering the electrode surface with a thickness of 5-20 μm; when applied to invasive microelectrodes, the long-term sustained-release layer is preferably a conical end member located at the tip of the electrode, which has both puncture and sustained-release functions, can assist in puncturing brain tissue during electrode implantation, and continuously release drugs after implantation.

[0094] Options for hydrogel matrices and drugs In addition to polyvinyl alcohol, the hydrogel matrix may also be selected from at least one of hyaluronic acid, alginate, cellulose and its derivatives, collagen, silk fibroin, polyethylene glycol and its derivatives, polyacrylic acid, polyether-polyester block copolymer, methacrylated gelatin, and polyethylene glycol diacrylate, or a combination of the above materials. These materials all have good biocompatibility and controllable crosslinking properties.

[0095] The carrier material in the drug-loaded microspheres can be selected from at least one of PLGA, PLA, PCL, gelatin, and chitosan. Among them, PLGA is preferred due to its tunable degradation rate and good biocompatibility, and its molecular weight is preferably between 20,000 and 80,000.

[0096] The drug loaded into the drug-loaded microspheres can be selected from at least one of dexamethasone, rapamycin, ibuprofen, brain-derived neurotrophic factor (BDNF), and nerve growth factor (NGF). Dexamethasone is widely used as a glucocorticoid anti-inflammatory drug; rapamycin can inhibit glial cell proliferation; BDNF and NGF can promote neuronal survival and axonal growth. Depending on clinical needs, a single drug or a combination of multiple drugs can be selected.

[0097] III. Mechanical Properties of the Coating System The mechanical properties of the coating system in this application are designed with full consideration of the special mechanical environment of brain tissue. The Young's modulus of brain tissue is only about 1-10 kPa, which is much lower than that of peripheral tissues such as muscles and bones. If the rigidity of the coating is too high, the interfacial stress concentration caused by the micromovement of brain tissue (periodic displacement caused by heartbeat and respiration) after implantation may lead to cracking and peeling of the coating, or even damage to the surrounding nerve tissue.

[0098] The coating system of this application, through optimized design of crosslinking density, achieves a swelling rate of less than 50% after coating swelling, and a hardness controlled within the range of 3-15 kPa. This range of mechanical properties matches the modulus of brain tissue, effectively reducing interfacial stress and minimizing inflammatory responses induced by mechanical stimulation.

[0099] For example, by adjusting the polyvinyl alcohol (PVA) concentration gradient, the mechanical properties of the coating can be controlled while achieving staged release: when the PVA concentration of the short-term slow-release layer is 5% and the PVA concentration of the medium-term slow-release layer is 7%, the swelling rate of the coating system is approximately 52%, and the hardness after swelling is approximately 8.5 kPa; when the PVA concentration of the short-term slow-release layer is increased to 7% and the PVA concentration of the medium-term slow-release layer is increased to 10%, the swelling rate decreases to approximately 38%, the hardness increases to approximately 15.2 kPa, and the toughness also improves accordingly. This indicates that the PVA concentration gradient not only affects the release rate but also influences the mechanical properties, and the two have a synergistic regulatory relationship.

[0100] Regarding the methods for determining swelling rate and hardness, the swelling rate can be determined as follows: The coated sample is placed in a simulated body fluid (such as phosphate buffer, pH approximately 7.4) and immersed at 37 degrees Celsius until equilibrium is reached. The mass change before and after swelling is measured, and the swelling rate is calculated using the formula: (mass after swelling minus dry weight) divided by the dry weight and then multiplied by 100%. The dry weight can be determined by vacuum drying to constant weight at an appropriate temperature.

[0101] Hardness can be determined by indentation or dynamic mechanical analysis. For specific test conditions, please refer to section "IX. Test Methods and Characterization" of this manual.

[0102] IV. Structure of Neural Interface Electrodes This application also provides a neural interface electrode, including an electrode substrate and the aforementioned coating system disposed on the surface of the electrode substrate. To enhance the adhesion between the coating system and the electrode substrate, an adhesion transition layer is provided between the electrode substrate and the long-term sustained-release layer of the coating system.

[0103] The inclusion of an adhesion transition layer is another significant innovation of this application. In existing technologies, the adhesion between the coating and the electrode substrate relies primarily on physical adsorption, resulting in weak bonding and a tendency to separate and fail after long-term implantation. This application achieves chemical bonding between the coating and the electrode substrate by incorporating an adhesion transition layer on the electrode substrate surface, significantly improving long-term stability.

[0104] The adhesion transition layer is preferably a polydopamine layer with a thickness of 50-200 nm. The polydopamine layer contains a large number of catechol groups and amino groups, which can form chemical bonds with both the electrode substrate surface and the coating, acting as a bridging layer like "double-sided tape." Alternatively, the adhesion transition layer can also be a silane coupling agent layer, which can similarly achieve the effect of enhanced adhesion through chemical bonding.

[0105] V. Preparation methods of coating systems like Figure 2 As shown, the preparation method of the coating system in this application includes the following main steps: Step 100: Preparation of drug-loaded microspheres Specifically, step 100 may further include the following sub-steps: Step 110: Add the drug to an organic solvent and stir to dissolve. The organic solvent is preferably a mixture of acetone and dichloromethane, with a volume ratio of acetone to dichloromethane preferably between 1:2 and 1:7. Acetone and dichloromethane are both commonly used solvents for drugs and polymers; their mixture provides suitable solubility and evaporation rates.

[0106] Step 120: Add the carrier material to the solution obtained in step 110 and stir until completely dissolved to form an oil phase. The preferred mass ratio of carrier material to drug is 3:1 to 10:1. The selection and ratio of carrier material will affect the particle size, drug loading, and release characteristics of the microspheres.

[0107] Step 130: Slowly add the oil phase obtained in step 120 dropwise to a polyvinyl alcohol aqueous solution with a concentration of 1% to 10%. The concentration of the polyvinyl alcohol aqueous solution, as the aqueous phase, will affect the emulsification effect and the microsphere particle size distribution.

[0108] Step 140: Homogenize and disperse the oil phase at a speed of 5,000 to 10,000 revolutions per minute for 3 to 15 minutes. High-speed homogenization disperses the oil phase into fine droplets in the aqueous phase, and the droplet size determines the final particle size of the microspheres.

[0109] Step 150: Continue stirring to allow the solvent to evaporate. During stirring, the organic solvent gradually evaporates, and the oil phase droplets solidify to form microspheres.

[0110] Step 160: Centrifuge, wash, and freeze-dry to collect the drug-loaded microsphere powder. Centrifugation is preferably performed at a speed of 1000 to 5000 rpm for 2 to 10 minutes. Washing is preferably performed three to four times to remove residual polyvinyl alcohol and unencapsulated drug from the surface.

[0111] Step 200: Prepare short-term sustained-release layer solutions, medium-term sustained-release layer solutions, and long-term sustained-release layer solutions respectively. The key to preparing short- and medium-term sustained-release layer solutions lies in controlling the concentration difference of the hydrophilic polymer (such as polyvinyl alcohol). The concentration of the hydrophilic polymer in the short-term sustained-release layer solution is lower than that in the medium-term sustained-release layer solution, and this concentration difference is the basis for forming the crosslinking density gradient.

[0112] Specifically, the preparation of the short-term sustained-release layer solution may include: adding an appropriate proportion of polyvinyl alcohol powder to ultrapure water, heating and stirring until completely dissolved; adding chitosan, polyethylene glycol, glycerin, Tween, and other additives and stirring evenly; adding the drug-loaded microspheres prepared in step 100, stirring evenly, and degassing. The preparation method of the medium-term sustained-release layer solution is similar to that of the short-term sustained-release layer, but the concentration of polyvinyl alcohol is higher and the concentration of polyethylene glycol is lower.

[0113] The preparation of the long-term sustained-release layer solution includes: adding PLGA nanoparticles and PLA to a mixed solvent of acetone and dichloromethane, stirring thoroughly to dissolve; adding the drug as needed, stirring evenly; and vacuum degassing.

[0114] Step 300: Prepare an adhesion transition layer on the surface of the electrode substrate This step is optional and its purpose is to enhance the adhesion between the coating and the electrode substrate. The adhesion transition layer can be prepared using one of the following methods: Method A (Plasma Pretreatment): Place the electrode substrate in a plasma cleaning chamber, evacuate, and then introduce argon and / or oxygen gas for plasma treatment at 80-500W power for three to ten minutes. Plasma treatment can generate active groups on the electrode surface, enhancing adhesion to subsequent coatings. Subsequent coating should be performed within thirty minutes after treatment to avoid deactivation of the active groups.

[0115] Method B (Polydopamine Coating): Prepare a dopamine-Tris buffer solution with a concentration of 2 mg / ml and a pH of 8.5; immerse the electrode substrate in the solution and react at room temperature for 12-24 hours; remove, wash with ultrapure water, and dry. Dopamine self-polymerizes under alkaline conditions to form a polydopamine layer with a thickness of approximately 50-200 nm.

[0116] Option C: Immerse the electrode substrate in a 2-4% polyimide solution, remove it and dry it for 5-15 minutes, then place it in an oven for 45-90 minutes to form a thickness of 3-10 μm.

[0117] Step 400: Form a long-term sustained-release layer on the surface of the electrode substrate (or the surface of the adhesion transition layer). When the long-term sustained-release layer is a planar thin film, spin coating can be used: the electrode is fixed to the suction cup of a spin coater, the long-term sustained-release layer solution is added dropwise, and spin coating is performed at a speed of 1,500 to 2,500 revolutions per minute for 30 to 60 seconds to form a dense film, which is then dried at room temperature for 24 hours. During the drying process, the organic solvents (acetone and dichloromethane) evaporate and are removed, ultimately forming a polymer matrix film composed of PLGA nanoparticles and PLA.

[0118] When the long-term sustained-release layer is a conical end component, a mold forming method can be used: pour the long-term sustained-release layer solution into the conical mold cavity, let it stand at room temperature for about four hours to remove air bubbles, and then perform vacuum drying (preferred conditions are 25 degrees Celsius, -0.1 MPa, and 72 hours). After demolding, perform plasma cleaning on the surface of the conical drug carrier, dip the electrode head into the coating solution and insert it into the conical drug carrier, and cure it at room temperature for about four hours.

[0119] Step 500: Coat the surface of the long-term sustained-release layer with the intermediate sustained-release layer solution to form the intermediate sustained-release layer. This step is one of the key steps in forming the interpenetrating network structure. Specifically, before coating the intermediate-release layer solution, the long-release layer needs to be kept in a semi-dry state with a moisture content of 8-15%.

[0120] For patch electrodes, since the long-term sustained-release layer is a hydrophobic polymer film, the surface of the long-term sustained-release layer needs to be treated with oxygen plasma before coating with a hydrophilic intermediate sustained-release layer solution to increase surface hydrophilicity and prevent "beading" phenomenon in subsequent coatings. For example, oxygen plasma treatment conditions of about 50-80W power and about 30 seconds can be used.

[0121] Moisture content can be determined by weighing, and the calculation formula is: Moisture content = (Wet weight - Dry weight) / Wet weight × 100%. Dry weight can be determined by vacuum drying to constant weight at an appropriate temperature. Alternatively, sensory evaluation can be used; a suitable semi-dry state is indicated when the surface is "slightly sticky but not sticky to the touch".

[0122] The technical reasons for controlling the moisture content within the range of 8-15% are as follows: When the moisture content is below 8%, the polymer chains on the surface of the previous layer have lost their fluidity, and the polymer chains in the solution of the next layer cannot effectively penetrate, making it difficult to form an interpenetrating structure; when the moisture content is above 15%, the structure of the previous layer is still unstable, and coating the next layer may lead to interface confusion or layer structure collapse.

[0123] After coating the intermediate-release layer solution, allow it to stand and permeate on the surface of the long-release layer for five to fifteen minutes. The purpose of this standing and permeation is to allow the polymer chains in the subsequent layer solution to fully penetrate the surface of the previous layer, creating conditions for the formation of an interpenetrating structure. The choice of standing time also requires a trade-off: too short a time will result in insufficient permeation, while too long a time may cause the solution to dry out and fail to permeate effectively. The temperature of the coating solution is preferably controlled between 20 and 25 degrees Celsius to ensure that the solution has appropriate fluidity and permeability.

[0124] For invasive electrodes, the intermediate-release layer can be applied using the dip-coating method: The electrode is suspended and fixed in the coating fixture, slowly immersed in the intermediate-release layer solution, allowed to stand and penetrate, and then pulled up at a speed of approximately 0.5 to 2 mm per minute, allowing it to dry at room temperature. The choice of pulling speed affects the uniformity of the coating thickness; too fast a speed results in a thin and uneven coating, while too slow a speed results in an overly thick coating. It is preferable to apply the intermediate-release layer twice to ensure complete coverage, drying each coat to a moisture content of 8-15% before applying the next coat.

[0125] For patch electrodes, a spraying method (such as an ultrasonic atomizing nozzle) can be used to coat the intermediate slow-release layer solution, and multiple sprayings can be applied until the thickness meets the requirements.

[0126] Step 600: Coat the surface of the intermediate-release layer with the short-release layer solution to form the short-release layer. The key points of this step are similar to those of step 500. Before applying the short-term sustained-release layer solution, it is also necessary to control the intermediate sustained-release layer to be in a semi-dry state with a moisture content of 8-15%, and allow the applied short-term sustained-release layer solution to stand and penetrate on the surface of the intermediate sustained-release layer for five to fifteen minutes, so as to form a gradient transition region of interpenetrating network structure between the intermediate and short-term sustained-release layers.

[0127] For invasive electrodes, the short-term sustained-release layer is also coated using the dip-coating method, with process parameters similar to those for the medium-term sustained-release layer. For patch electrodes, a soft buffer layer can be formed by adding the short-term sustained-release layer solution and then spin-coating at a low speed (approximately 500 rpm).

[0128] Step 700: Perform final drying treatment After the short-term sustained-release layer is applied, a final drying process is performed. Final drying is preferably carried out at room temperature for at least 24 hours to ensure that each coating layer is fully dried and cured, while avoiding high temperatures that could lead to loss of drug activity or damage to the coating structure.

[0129] Step 800 (optional): Further adjust the crosslinking density through freeze-thaw cycles. Besides controlling the crosslinking density through differences in polyvinyl alcohol concentration, it can also be further controlled by the number of freeze-thaw cycles. After freeze-thaw cycles, the molecular chains of the polyvinyl alcohol aqueous solution rearrange to form crystalline regions. These crystalline regions serve as physical crosslinking points; the more freeze-thaw cycles, the more crystalline regions there are, and the higher the crosslinking density.

[0130] Specifically, subjecting the short-term slow-release layer to one to three freeze-thaw cycles and the medium-term slow-release layer to four to six freeze-thaw cycles can create a crosslinking density gradient that superimposes on the polyvinyl alcohol concentration gradient, further enhancing the staged release effect. The preferred freeze-thaw cycle conditions are alternating between freezing at -20 degrees Celsius and thawing at 25 degrees Celsius. VI. Specific Implementation Methods Example 1: Preparation of an invasive electrode coating system (basic formulation) This embodiment prepares a coating system for use in invasive microelectrodes.

[0132] First, drug-loaded microspheres were prepared according to step 100. PLGA (molecular weight approximately 50,000) was selected as the carrier material, and dexamethasone as the drug, with a carrier-to-drug mass ratio of 5:1. It should be noted that the ratio of lactic acid (LA) to glycolic acid (GA) in PLGA affects its degradation rate and drug release cycle: for drug-loaded microspheres in short- and medium-term sustained-release layers, the LA:GA ratio is preferably 50:50 or 75:25, or a combination thereof; for drug-loaded nanoparticles in long-term sustained-release layers, the LA:GA ratio is preferably 75:25, 85:15, or 90:10, or a combination thereof, to achieve a longer degradation cycle and slower drug release.

[0133] Next, the coating solutions for each layer were prepared. The short-term sustained-release layer solution, by mass fraction, comprised 5% polyvinyl alcohol, 1% chitosan, 8% polyethylene glycol (molecular weight approximately 2000), 10% glycerol, 12% of the aforementioned PLGA drug-loaded microspheres, 0.1% Tween 20, and the remainder being ultrapure water. The medium-term sustained-release layer solution, by mass fraction, comprised 7% polyvinyl alcohol, 1% chitosan, 4% polyethylene glycol (molecular weight approximately 2000), 10% glycerol, 15% of the aforementioned PLGA drug-loaded microspheres, 0.1% Tween 20, and the remainder being ultrapure water. The long-term sustained-release layer solution, used to prepare the end-capsule of the electrode tip, comprised by mass fraction 30% PLGA nanoparticles, 10% PLA, 15% acetone, and 45% dichloromethane.

[0134] Then, a polydopamine adhesion transition layer was prepared on the surface of the electrode substrate. The electrode was immersed in a dopamine-Tris buffer solution with a concentration of 2 mg / ml and a pH of 8.5, and reacted at room temperature for about 18 h. After removal, washing and drying, a polydopamine layer with a thickness of about 100 nm was formed.

[0135] Next, a conical long-release layer was prepared according to step 400. The long-release layer solution was poured into the cavity of a conical mold, allowed to stand to remove air bubbles, and then vacuum dried. After demolding, the surface of the conical drug carrier was plasma cleaned. The electrode tip was dipped into the coating solution and inserted into the conical drug carrier for curing. During the drying process, the organic solvent evaporated, and the final long-release layer consisted of PLGA nanoparticles and a PLA polymer matrix.

[0136] Subsequently, apply the intermediate sustained-release layer according to step 500. When the long-term sustained-release layer dries to a moisture content of approximately 12%, apply the intermediate sustained-release layer solution using the dip-lift method. After allowing it to stand and penetrate for about ten minutes, lift it at a speed of 1 mm / min. Let it dry at room temperature for about three hours, and repeat the coating once.

[0137] Then, apply the short-term sustained-release layer according to step 600. When the intermediate sustained-release layer dries to a moisture content of about 12%, apply the short-term sustained-release layer solution using the dip-lift method. After standing and penetrating for about ten minutes, lift at a speed of 1 mm / min and dry at room temperature for about three hours. Repeat the coating once.

[0138] Finally, dry at room temperature for more than 24 hours to complete the final drying.

[0139] The coating system prepared in this embodiment has a swelling rate of approximately 52%, a hardness of approximately 8.5 kPa after swelling, and a toughness of approximately 420 J / m. 2 The appearance is uniform and free of condensation beads. Cross-sectional scanning electron microscopy shows that there are no obvious delamination interfaces between layers, confirming the formation of a gradient transition region of an interpenetrating network structure.

[0140] Example 2: Preparation of an invasive electrode coating system (optimized formulation) The difference between this embodiment and Embodiment 1 is that the concentrations of polyvinyl alcohol and polyethylene glycol in the short-term and medium-term sustained-release layers were adjusted.

[0141] Specifically, the concentration of polyvinyl alcohol in the short-term sustained-release layer was increased from 5% to 6%, and the content of polyethylene glycol was decreased from 8% to 6%; the concentration of polyvinyl alcohol in the medium-term sustained-release layer was increased from 7% to 8%, and the content of polyethylene glycol was decreased from 4% to 2%. The remaining formulation and process parameters were the same as in Example 1.

[0142] The coating system prepared in this embodiment has a swelling rate of approximately 45%, a hardness of approximately 12.8 kPa after swelling, and a toughness of approximately 680 J / m. 2 Compared with Example 1, by increasing the polyvinyl alcohol concentration, the swelling rate of the coating decreased, while the hardness and toughness improved, which confirms the regulatory effect of polyvinyl alcohol concentration on crosslinking density and mechanical properties.

[0143] Example 3: Preparation of an invasive electrode coating system (high mechanical property formulation) This embodiment further increases the polyvinyl alcohol concentration to obtain higher mechanical properties.

[0144] Specifically, the short-term sustained-release layer contains 7% polyvinyl alcohol, 4% polyethylene glycol, and 15% PLGA drug-loaded microspheres; the medium-term sustained-release layer contains 10% polyvinyl alcohol, 2% polyethylene glycol, and 18% PLGA drug-loaded microspheres. The remaining formulations and process parameters are the same as in Example 1.

[0145] The coating system prepared in this embodiment has a swelling rate of approximately 38%, a hardness of approximately 15.2 kPa after swelling, and a toughness of approximately 920 J / m. 2 .

[0146] A comparison of Examples 1 to 3 shows that, with the increase of polyvinyl alcohol concentration gradient, the swelling ratio decreases from about 52% to about 38%, the hardness increases from about 8.5 kPa to about 15.2 kPa, and the toughness increases from about 420 J / m. 2 Increased to approximately 920 J / m 2 This data demonstrates that by controlling the polyvinyl alcohol concentration gradient, this application can simultaneously regulate the mechanical properties of the coating to achieve staged release, thus realizing synergistic optimization of release characteristics and mechanical properties. Those skilled in the art can select appropriate formulation parameters within the above range based on the target electrode type and application scenario.

[0147] Example 4: Preparation of Patch Electrode Coating System The coating system prepared in this embodiment for use in patch electrodes differs from that in Examples 1 to 3 in that the long-term sustained-release layer adopts a planar thin film morphology.

[0148] First, the surface of the patch electrode is treated with oxygen plasma at 300W for about five minutes as a pretreatment to form an adhesion transition layer.

[0149] Secondly, a long-term sustained-release layer was formed on the electrode surface using spin coating. The long-term sustained-release layer solution contained approximately 25% PLGA (molecular weight approximately 60,000), approximately 2.5% dexamethasone, and the remainder was a mixture of acetone and dichloromethane solvent. The electrode was fixed in a spin coater, and the long-term sustained-release layer solution was added dropwise. Spin coating was performed at a speed of 3,000 rpm for approximately 30 seconds, followed by drying at room temperature for 24 hours. During the drying process, the organic solvent evaporated, forming a planar thin film with a thickness of approximately 8 μm.

[0150] Then, the surface of the long-term sustained-release layer is treated with oxygen plasma (approximately 80W power, approximately 30 seconds) to increase surface hydrophilicity and prevent subsequent coating from "beading". This step is one of the key steps in this embodiment. Since the long-term sustained-release layer is a hydrophobic polymer film and the intermediate sustained-release layer is a hydrophilic hydrogel, without surface treatment, the subsequent coating solution will be difficult to wet and spread evenly.

[0151] Next, an intermediate-release layer was applied using a spray coating method. The formulation of the intermediate-release layer was the same as in Example 2. After the intermediate-release layer was applied, a freeze-thaw cycle was performed four to six times to enhance cross-linking.

[0152] Then, a short-term sustained-release layer solution is added dropwise, and a soft buffer layer is formed by spin coating at a low speed of about 500 rpm. The layer is then air-dried to form a film or subjected to a freeze-thaw cycle. The formulation of the short-term sustained-release layer is the same as in Example 2.

[0153] For example, the coating system prepared in this embodiment has a coating thickness of about 25 μm, a swelling rate of about 48%, a hardness of about 11.5 kPa after swelling, and a uniform appearance covering the effective area of ​​the electrode.

[0154] Example 5: Preparation using a coating system with alternative drugs In this embodiment, rapamycin is used instead of dexamethasone as the sustained-release drug in the long-term sustained-release layer. Rapamycin can inhibit glial cell proliferation and has a more targeted inhibitory effect on the formation of chronic glial scars.

[0155] Specifically, the drug-loaded microspheres were prepared using PLA (molecular weight approximately 80,000) as the carrier material and rapamycin as the drug, with a carrier-to-drug mass ratio of 8:1. The remaining formulations and process parameters were the same as in Example 2.

[0156] This embodiment demonstrates that the coating system of this application can flexibly select different types of drugs according to clinical needs, and has good adaptability and scalability.

[0157] Example 6: Preparation of a coating system based on hyaluronic acid hydrogel In this embodiment, hyaluronic acid (HA) hydrogel is used instead of polyvinyl alcohol as the hydrogel matrix for the short-term and medium-term sustained-release layers to verify the universality of the crosslinking density gradient design in different hydrogel material systems.

[0158] In this embodiment, the crosslinking density of the hyaluronic acid hydrogel is controlled by the amount of chemical crosslinking agent (1,4-butanediol diglycidyl ether, i.e., BDDE). The higher the amount of BDDE, the more covalent crosslinking points are formed between the hyaluronic acid molecular chains, resulting in a higher crosslinking density and a denser network.

[0159] The short-term sustained-release layer solution was prepared as follows (by mass fraction): 2% hyaluronic acid (molecular weight approximately one million), 0.3% BDDE (mass ratio to hyaluronic acid 0.15:1), 12% PLGA drug-loaded microspheres (loaded with dexamethasone), 0.1% Tween 20, and the balance being phosphate buffer (pH approximately 7.4). The low BDDE content allows the hyaluronic acid to form a loose cross-linked network, which is beneficial for the rapid diffusion and release of the drug.

[0160] The intermediate-release layer solution was prepared as follows (by mass fraction): 5% hyaluronic acid (molecular weight approximately one million), 2% BDDE (mass ratio to hyaluronic acid 0.4:1), 15% PLGA drug-loaded microspheres (loaded with dexamethasone), 0.1% Tween 20, and the balance being phosphate buffer (pH approximately 7.4). The higher concentration of hyaluronic acid and the addition of BDDE resulted in a denser cross-linked network in the intermediate-release layer, thus slowing down the drug diffusion rate.

[0161] The formulation of the long-term sustained-release layer is the same as in Example 1, using a hydrophobic and biodegradable polymer matrix composed of PLGA nanoparticles and PLA. The adhesion transition layer is also prepared using the polydopamine method, with the same process parameters as in Example 1.

[0162] The preparation process of the coating system is basically the same as in Example 1. It should be noted that the hyaluronic acid hydrogel is cured using a chemical cross-linking method. Specifically, after the short-term and medium-term sustained-release layer solutions are prepared, BDDE begins to cross-link with the hydroxyl groups on the hyaluronic acid molecular chains. During the coating process, the previous layer should be applied in a semi-dry state with a moisture content of 8-15% before the next layer is applied, and the solution of the next layer should be allowed to stand and penetrate for about 10 minutes to form a gradient transition region in the interpenetrating network structure. After coating, the reaction continues at room temperature and drying for at least 24 hours to ensure the cross-linking reaction is fully completed.

[0163] The coating system prepared in this embodiment has a swelling rate of approximately 55% and a hardness of approximately 6.8 kPa after swelling. Cross-sectional scanning electron microscopy observation shows that there are continuous transition morphological features between the short-term and medium-term sustained-release layers, as well as between the medium-term and long-term sustained-release layers, with no obvious physical boundary observed, confirming the formation of a gradient transition region with an interpenetrating network structure.

[0164] In vitro release tests showed that the short-term sustained-release layer released approximately 80% of its total drug load within 1-12 days post-implantation, exhibiting a rapid release characteristic; the medium-term sustained-release layer continuously released the drug within 1-5 weeks post-implantation, with a release rate significantly lower than the short-term sustained-release layer, exhibiting a moderate-rate continuous release characteristic; and the long-term sustained-release layer slowly released the drug within 1-10 months post-implantation. These results confirm that the coating system based on a hyaluronic acid hydrogel matrix can also achieve a phased drug release characteristic of "fast-medium-slow," validating the applicability of the crosslinking density gradient design scheme of this application in hyaluronic acid material systems.

[0165] Compared with the polyvinyl alcohol-based Examples 1 to 3, the hyaluronic acid-based coating system has the following characteristics: hyaluronic acid itself is an important component of the extracellular matrix and has excellent biocompatibility and cell affinity; the hyaluronic acid hydrogel has a slightly higher swelling rate and slightly lower hardness, making it more suitable for application scenarios with extremely high mechanical matching requirements.

[0166] Example 7: Preparation of a coating system based on polyethylene glycol diacrylate hydrogel In this embodiment, polyethylene glycol diacrylate (PEGDA) hydrogel is used as the hydrogel matrix for the short-term and medium-term sustained-release layers to further verify the material universality of the technical solution of this application.

[0167] PEGDA hydrogels form a cross-linked network through a free radical polymerization reaction initiated by ultraviolet light. The cross-linking density can be controlled by the concentration and molecular weight of PEGDA: the higher the concentration of PEGDA, the greater the cross-linking density and the denser the network; the lower the molecular weight of PEGDA, the shorter the spacing between cross-linking points, and the denser the network.

[0168] The short-term sustained-release layer solution was prepared as follows (by mass fraction): 10% PEGDA (molecular weight approximately 6,000), 0.1% photoinitiator (2-hydroxy-2-methyl-1-phenyl-1-propanone, i.e., Irgacure 2959), 12% PLGA drug-loaded microspheres (loaded with dexamethasone), 0.1% Tween 20, and the balance being phosphate buffer. The lower PEGDA concentration, combined with the higher molecular weight, forms a loose network structure, which is beneficial for rapid drug release.

[0169] The intermediate-release layer solution was prepared as follows (by mass fraction): 20% PEGDA (molecular weight approximately 2000), 0.1% photoinitiator (Irgacure 2959), 15% PLGA drug-loaded microspheres (loaded with dexamethasone), 0.1% Tween 20, and the balance being phosphate buffer. The higher PEGDA concentration, combined with the lower molecular weight, forms a dense network structure, thus slowing the drug release rate.

[0170] The formulation and preparation method of the long-term sustained-release layer and the adhesive transition layer are the same as those in Example 1.

[0171] The preparation process of the coating system is largely the same as in Example 1, with the key difference being the crosslinking and curing methods for the short-term and medium-term sustained-release layers. In this example, after each hydrogel coating layer is applied and allowed to stand for penetration, it is then subjected to ultraviolet light (wavelength approximately 365 nm, light intensity approximately 10 mW / cm²). 2 Irradiate for about 5-15 minutes to initiate the cross-linking reaction. After coating the intermediate slow-release layer, control its moisture content after UV cross-linking to be within the range of 8-15%, then coat the short-term slow-release layer solution and let it stand to penetrate for about 10 minutes to form an interpenetrating network structure.

[0172] It should be noted that the formation mechanism of the interpenetrating network structure in the PEGDA system is slightly different from that in the polyvinyl alcohol system: when the first layer of PEGDA hydrogel is in a semi-dry state, the unreacted double bonds (acrylate groups) still have a certain degree of reactivity; after the second layer of PEGDA solution penetrates, under ultraviolet light irradiation, the PEGDA molecules in the second layer can undergo copolymerization reaction with the double bonds remaining on the surface of the first layer, thereby forming a chemically bonded interpenetrating network structure between the layers. The interlayer bonding strength is even higher than that of a purely physically entangled interpenetrating structure.

[0173] The coating system prepared in this embodiment showed a swelling rate of approximately 42% and a hardness of approximately 10.5 kPa after swelling. Cross-sectional scanning electron microscopy also confirmed the formation of a gradient transition region with an interpenetrating network structure.

[0174] In vitro release tests showed that the short-term sustained-release layer released approximately 75% of its total drug load within 1-10 days post-implantation; the medium-term sustained-release layer continuously released the drug within 1-5 weeks post-implantation; and the long-term sustained-release layer slowly released the drug within 1-10 months post-implantation. These results confirm that the coating system based on the PEGDA hydrogel matrix can also achieve a phased drug release characteristic of "fast-medium-slow".

[0175] A comprehensive comparison of Examples 1 to 7 shows that regardless of whether the hydrogel matrix uses polyvinyl alcohol (crosslinking density controlled by concentration), hyaluronic acid (crosslinking density controlled by the amount of chemical crosslinking agent), or polyethylene glycol diacrylate (crosslinking density controlled by concentration and molecular weight), as long as a gradient design with low crosslinking density in the short-term sustained-release layer and high crosslinking density in the medium-term sustained-release layer is used, combined with a long-term sustained-release layer of hydrophobic and biodegradable polymer and an interpenetrating network structure, a "fast-medium-slow" staged drug release characteristic matching the three stages of neuroinflammation can be achieved. This verifies that the core design concept of the technical solution of this application—staged release achieved by crosslinking density gradient—has good material universality.

[0176] Comparative Example 1: Single-layer coating system To verify the superiority of the three-layer staged structure of this application over the traditional single-layer coating, a single-layer drug sustained-release coating was prepared as a control in this comparative example.

[0177] Specifically, polyvinyl alcohol (7% by mass) was used as the hydrogel matrix, loaded with dexamethasone PLGA drug-loaded microspheres (15% by mass), with the remaining adjuvant proportions the same as those in the intermediate sustained-release layer of Example 1. This single-layer coating solution was applied in one pass to the surface of the polydopamine-treated electrode substrate using a dip-coating method and dried at room temperature for at least 24 hours. The total coating thickness was comparable to that of the three-layer coating system in Example 1.

[0178] In vitro release tests showed that the single-layer coating exhibited a significant "burst release" phenomenon within the first three days after implantation, releasing approximately 40-50% of the total drug amount. The release rate then rapidly decreased and was essentially depleted after about three to four weeks. This release curve showed a significant temporal mismatch with the three-stage progression of neuroinflammation: although there was high concentration release in the acute phase, the drug concentration fluctuated wildly and was uncontrollable; in the late subacute phase, the drug concentration had already decreased significantly, making it difficult to maintain an effective inhibitory concentration; and in the chronic phase, there was virtually no drug release. Compared to the three-layer coating system in Example 1, the single-layer coating cannot achieve precise, staged release and cannot provide differentiated drug supply for each stage of neuroinflammation.

[0179] Comparative Example 2: A coating system with three layers but no interpenetrating network structure To verify the contribution of the interpenetrating network structure to the smoothness of the release curve and the structural stability of the coating system, a three-layer coating system without the formation of an interpenetrating network structure was prepared as a control in this comparative example.

[0180] Specifically, the formulation of each coating layer is exactly the same as that in Example 1 (5% polyvinyl alcohol for short-term slow-release layer and 7% polyvinyl alcohol for medium-term slow-release layer). The only difference is the coating process: the traditional process of "coating the next layer after the previous layer is completely dry" is adopted, that is, each layer is completely dried at room temperature (moisture content is less than 3%) before coating the next layer, and no static penetration treatment is performed when coating the next layer.

[0181] Cross-sectional scanning electron microscopy observations showed that the coating system in this comparative example exhibited clear and straight physical boundaries between adjacent layers, and no continuous transition morphological features were observed, proving that no gradient transition region of interpenetrating network structure was formed.

[0182] In vitro release tests showed that while the comparative coating system exhibited a phased release trend overall, significant discontinuities in the release curves occurred at the transitions between stages. Specifically, when the short-term sustained-release layer degraded and the mid-term sustained-release layer began to be exposed to the release medium, the release curve experienced a brief "cliff-like drop" followed by a "secondary burst release," meaning the drug release rate initially decreased sharply and then increased. This discontinuous release behavior could lead to drastic fluctuations in drug concentration within the tissue microenvironment, which is detrimental to the stable suppression of inflammation. Compared to Example 1, the coating system of Example 1, due to its gradient transition region with an interpenetrating network structure, exhibited a smoother and more continuous transition between stages in its release curve, without the aforementioned discontinuities.

[0183] Furthermore, the coating systems of Comparative Example 2 and Example 1 were placed under accelerated aging test conditions simulating brain tissue micromovement (periodic micromovement at a frequency of approximately 1 Hz and an amplitude of approximately 30 μm in phosphate buffer at 37°C) to test the structural integrity of the coatings. The results showed that the coating of Comparative Example 2 exhibited visible interlayer separation after approximately four weeks, with some areas showing coating lifting or peeling; while the coating of Example 1 maintained structural integrity after eight weeks of testing under the same conditions, with no delamination or peeling observed. This comparative result confirms the crucial role of the interpenetrating network structure in enhancing the long-term structural stability of the coating system.

[0184] In vitro release comparative test and comprehensive comparative analysis In vitro drug release tests were conducted on the coating systems of Example 1 (polyvinyl alcohol matrix, three layers + interpenetrating network), Example 6 (hyaluronic acid matrix, three layers + interpenetrating network), Example 7 (PEGDA matrix, three layers + interpenetrating network), Comparative Example 1 (single-layer coating), and Comparative Example 2 (three-layer coating without interpenetrating network). The test conditions were standardized as follows: each coating sample was placed in 5 mL of phosphate buffer (pH approximately 7.4) and subjected to release testing in a constant-temperature shaker at 37°C (approximately 60 rpm). At preset time points, all released liquid was collected and replaced with an equal volume of fresh buffer. The drug concentration was detected using high-performance liquid chromatography (HPLC), and the cumulative release percentage at each time point was calculated based on the standard curve. Three parallel samples were used for each group, and the average value was taken.

[0185] The table below shows the cumulative drug release percentage (%) for each group at different time points: A comprehensive comparison of the table above and the release curves of each group shows that: First, Examples 1, 6, and 7 all exhibit an ideal "fast-medium-slow" three-stage release characteristic. During the acute phase (approximately 1-14 days), the release rate is high, with the cumulative release accounting for approximately 50-65% of the total drug amount, meeting the demand for high-concentration anti-inflammatory drugs in the acute phase. During the subacute phase (approximately 14 to 42 days), the release rate steadily decreases, with the release amount in this stage accounting for approximately 14-26% of the total drug amount, providing a stable drug concentration for sustained inflammation suppression during the subacute phase. During the chronic phase (after 42 days), the drug is released slowly at a low rate, providing a sustained drug supply for inhibiting the long-term formation of glial scars. The coating systems of the three different hydrogel matrix materials (polyvinyl alcohol, hyaluronic acid, and polyethylene glycol diacrylate) all achieved similar phased release patterns. The overall release curves exhibited a smooth and continuous three-stage characteristic, with natural transitions between stages, without abrupt changes or cliffs, further verifying the universality of the crosslinking density gradient strategy of this application.

[0186] Second, Comparative Example 1 (single-layer coating) exhibits a typical "burst release + rapid decay" pattern. This single-layer coating cumulatively released 56% within the first 3 days and 68% by day 7, demonstrating a significant burst release with drastic and uncontrollable fluctuations in drug concentration. After 28 days, the cumulative release reached 85%, with subsequent release becoming extremely slow, resulting in almost no effective drug replenishment during the chronic phase. In contrast, Example 1 achieved a cumulative release percentage of 45% within the first 7 days, with a more controllable release rate; after 28 days, approximately 32% of the drug remained to be released, enabling continuous anti-inflammatory drug delivery during the chronic phase. Therefore, it is evident that there is a severe temporal mismatch between the release curve of the single-layer coating and the three-stage process of neuroinflammation, failing to provide differentiated drug supply for each inflammatory stage.

[0187] Third, while Comparative Example 2 (three-layer coating but without an interpenetrating network) exhibited a phased trend overall, its release curve showed significant discontinuities at the transition points between each phase. Data showed that Comparative Example 2 had a cumulative release of 55% at 14 days, close to 58% in Example 1. However, during the transition from 14 to 28 days, the average daily release rate of Comparative Example 2 showed a fluctuation of first a sharp drop and then a rebound – this is precisely the release "gap" and "secondary burst release" caused by the distinct interlayer interfaces during the transition from the depletion of the short-term sustained-release layer to the medium-term sustained-release layer. Example 1, due to its gradient transition region with an interpenetrating network structure, showed a stable decreasing trend in the average daily release rate during the same period, without significant abrupt changes or gaps. Furthermore, Comparative Example 2's cumulative release at 9 months was only 82%, significantly lower than Example 1's 94%. This is because the interlayer interfaces without an interpenetrating network structure underwent a certain degree of stratification under long-term immersion and micro-motion conditions, resulting in some drug being trapped in the interlayer gaps and unable to be effectively released. Cross-sectional scanning electron microscopy also confirmed that Comparative Example 2 showed observable interlaminar microcracks 3 months after in vitro release testing, while no interlaminar delamination was observed in Example 1 at the same time point.

[0188] The above comparative results fully demonstrate that the three-layer structure design of this application significantly improves the matching between drug release timing and the neuroinflammatory process compared to a single-layer coating, avoiding the problems of initial burst release and subsequent drug insufficiency. The gradient transition region of the interpenetrating network structure significantly improves interlayer bonding stability and the smoothness and continuity of the release curve compared to the traditional layer-by-layer complete drying process. The crosslinking density gradient strategy is applicable to various hydrogel matrix material systems, exhibiting good universality and scalability. The three-layer structure design of this application, combined with the interlayer interpenetrating network structure, can achieve precise matching and smooth transition between the release curve and the three stages of neuroinflammatory processes, which is impossible to achieve with a single-layer coating or a multi-layer coating without an interpenetrating network structure.

[0189] VII. Description of Drug Release Characteristics The phased drug release characteristics of the coating system in this application are achieved through the synergistic design of a three-layer structure.

[0190] From the perspective of release mechanism, the short-term sustained-release layer uses a low-crosslink density hydrogel matrix (polyvinyl alcohol concentration 3-7%) with a large network pore size. After implantation, it rapidly absorbs tissue fluid and swells, and the hydrogel network expands. The drug diffusion resistance is small, and a large amount of drug can be released in the acute phase after implantation (about 1-15 days), which can promptly inhibit the explosive release of inflammatory factors in the acute phase.

[0191] The intermediate-release layer uses a hydrogel matrix with moderate cross-linking density (polyvinyl alcohol concentration 7-15%), resulting in a moderate network pore size and low swelling rate and degree. As the short-release layer gradually degrades, the intermediate-release layer is gradually exposed to the tissue fluid. The drug released by the drug-loaded microspheres diffuses more slowly through the denser network, enabling sustained low-concentration release during the subacute phase (approximately 1-6 weeks) after implantation, thus maintaining the inhibition of the subacute inflammatory response.

[0192] The long-term sustained-release layer uses hydrophobic and biodegradable polymers (such as PLGA and PLA), whose degradation mainly depends on hydrolysis and has a long degradation cycle. Drug release is mainly controlled by the polymer degradation rate, enabling slow release during the chronic phase after implantation (approximately 1-12 months) and inhibiting the continued formation of glial scars.

[0193] The gradient transition region of the interpenetrating network structure between layers allows the drug release curve to transition smoothly between stages, avoiding the release abrupt phenomenon that may be caused by distinct interlayer interfaces.

[0194] Regarding the methods for determining swelling rate and hardness, the swelling rate can be determined as follows: The coated sample is placed in a simulated body fluid (such as phosphate buffer, pH approximately 7.4) and immersed at 37 degrees Celsius until equilibrium is reached. The mass change before and after swelling is measured. The swelling rate is calculated using the formula: (mass after swelling minus dry weight) divided by the dry weight and then multiplied by 100%. The dry weight can be determined by vacuum drying to constant weight at an appropriate temperature. Specific test conditions are detailed in Section IX, "Test Methods and Characterization," of this manual.

[0195] VIII. Overall Technical Effects of the Coating System The coating system of this application achieves the following technical effects through the synergistic design of four innovative points: "three-layer structure + crosslinking density gradient + interlayer interpenetration + enhanced interfacial adhesion": First, the drug release curve is precisely matched with the neuroinflammatory process. Through the staged design of the three-layer structure and the gradient regulation of cross-linking density, a "fast-medium-slow" release sequence is achieved, corresponding to the acute, subacute, and chronic phases of neuroinflammatory disease, thus maximizing the anti-inflammatory efficacy.

[0196] Second, the integrity of the coating structure is significantly improved. The interpenetrating network structure and the interface adhesion enhancement design work synergistically to prevent the coating from delaminating or peeling off under long-term implantation conditions, overcoming the interlayer failure problem of existing multilayer coating technologies.

[0197] Third, the mechanical properties are matched with brain tissue. Through optimized design of cross-linking density, the hardness of the coating after swelling can be controlled within the range of 3-15 kPa, which matches the modulus of brain tissue, reducing interfacial stress and inflammatory responses induced by mechanical stimulation.

[0198] Fourth, it has a wide range of applications. The coating system of this application can be adapted to different types of neural interface devices, such as invasive electrodes and patch electrodes, by adjusting the morphology of the long-term sustained-release layer (planar thin film layer or conical end member).

[0199] The aforementioned technical effects are the result of the synergistic effect of the four innovative points of this application. No single technical means could achieve all of the above effects by using any one of them alone, which reflects the systematic and holistic nature of the technical solution of this application.

[0200] The above description is merely a preferred embodiment of this application and is not intended to limit this application. Various modifications and variations can be made to this application by those skilled in the art. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of this application should be included within the protection scope of this application.

[0201] The embodiments of this application have the following technical effects: The coating system of this application employs a three-layer structure design, consisting of a short-term sustained-release layer, a medium-term sustained-release layer, and a long-term sustained-release layer arranged sequentially from the outside in. This allows the short-term sustained-release layer to rapidly release the drug during the acute phase after implantation, the medium-term sustained-release layer to continuously release the drug during the subacute phase after implantation, and the long-term sustained-release layer to release the drug over a long period during the chronic phase after implantation. This achieves a precise correspondence between the drug release sequence and the three stages of neuroinflammation: the acute phase, the subacute phase, and the chronic phase. This enables anti-inflammatory drugs to be released at appropriate doses and rates during each inflammatory stage, thereby maximizing the anti-inflammatory effect and effectively inhibiting the formation of glial scars.

[0202] Furthermore, both the short-term and medium-term sustained-release layers employ a composite structure of a hydrogel matrix and drug-loaded microspheres dispersed within it. A crosslinking density gradient is created by lowering the crosslinking density of the hydrogel matrix in the short-term sustained-release layer compared to the medium-term layer. This gradient design allows the short-term sustained-release layer to have a larger network pore size and a higher swelling tendency, enabling rapid absorption of tissue fluid and rapid drug diffusion and release after implantation. The medium-term sustained-release layer, on the other hand, forms a relatively dense network structure, delaying water penetration and drug diffusion, achieving sustained low-concentration release. Simultaneously, this crosslinking density gradient also regulates the macroscopic mechanical properties of the coating system, allowing the swelling rate and post-swelling hardness to be adjusted to match the low-modulus mechanical environment of brain tissue. This effectively alleviates interfacial stress concentration caused by mechanical mismatch between the coating and brain tissue during micromovement, reducing secondary inflammatory responses induced by mechanical stimulation.

[0203] When the hydrogel matrix is ​​a polyvinyl alcohol hydrogel, the aforementioned crosslinking density gradient can be achieved by adjusting the mass fraction of polyvinyl alcohol in the short-term and medium-term sustained-release layers. Specifically, the mass fraction of polyvinyl alcohol in the short-term sustained-release layer is controlled within a lower range to form a loose network structure, while the mass fraction in the medium-term sustained-release layer is controlled within a higher range to form a dense network structure. Chitosan added to the specific formulations of the short-term and medium-term sustained-release layers enhances the biocompatibility of the coating; polyethylene glycol and glycerol regulate the swelling properties and flexibility of the coating; and Tween improves the uniformity of drug-loaded microsphere dispersion in the hydrogel matrix. The synergistic effect of these components ensures that the coating system possesses excellent drug release performance, mechanical properties, and film-forming properties.

[0204] The long-term sustained-release layer utilizes a hydrophobic, biodegradable polymer matrix. Its degradation primarily relies on hydrolysis, and its degradation cycle is significantly longer than that of hydrophilic hydrogels, thus achieving drug sustained release for several months. The long-term sustained-release layer can be designed as a planar thin film layer or a conical end member, depending on the electrode type. The planar thin film layer is suitable for non-invasive or minimally invasive electrodes such as surface patch electrodes, cortical EEG electrodes, or flexible thin film electrodes. The conical end member is suitable for invasive microelectrodes. In addition to providing long-term sustained-release functionality, this end member can also utilize the polymer's high hardness to assist in puncture, achieving an integration of puncture and sustained-release functions.

[0205] The embodiments of this application provide a gradient transition region with an interpenetrating network structure between adjacent coatings. Within this gradient transition region, the polymer molecular chains of adjacent layers interpenetrate and entangle, thereby significantly enhancing the interlayer bonding force. This avoids the delamination and peeling failure problems that easily occur in traditional multilayer coating structures due to distinct interfaces between layers and reliance solely on physical contact, which are prone to occur under long-term humid environments or brain tissue micro-movement conditions. Simultaneously, the interpenetrating network structure enables a continuous transition of drug release channels between layers, eliminating the "sudden release" or "cliff-like drop" phenomenon in the drug release curve that may occur due to interface barriers, making the transition between stages of the release curve smoother and more continuous.

[0206] The preparation method of this application involves controlling the previous coating layer to a semi-dry state with a specific moisture content range before applying the next coating solution, and allowing the next coating solution to stand and penetrate the surface of the previous layer for a specific time. This naturally forms a gradient transition region of the interpenetrating network structure during the drying and curing process. This moisture content range is a process window determined through systematic experiments: when the moisture content is below the lower limit, the polymer chains on the surface of the previous layer have lost their fluidity, and the polymer chains in the next solution cannot effectively penetrate, making it difficult to form an interpenetrating structure; when the moisture content is above the upper limit, the structure of the previous layer is still unstable, and applying the next layer may lead to layer collapse or interface confusion. Only by coating and allowing the solution to stand and penetrate within this specific moisture content window can a gradient transition region of appropriately thick interpenetrating network structure be formed between the layers.

[0207] In addition to regulating the crosslinking density gradient by varying the concentration of hydrophilic polymers, embodiments of this application can further enhance the crosslinking density gradient effect by applying different numbers of freeze-thaw cycles to the short-term and medium-term sustained-release layers. Specifically, applying more freeze-thaw cycles to the medium-term sustained-release layer allows it to form more crystalline regions as physical crosslinking points, thereby further slowing down its release rate.

[0208] In this application, an adhesion transition layer is provided between the electrode substrate and the long-term sustained-release layer of the coating system. This adhesion transition layer can form chemical bonds or strong physical interactions with the electrode substrate surface and the coating polymer, respectively, thus bridging and enhancing adhesion. When the adhesion transition layer is a polydopamine layer, its abundant catechol groups and amino groups can form chemical bonds with various substrate materials and polymers; when the adhesion transition layer is a silane coupling agent layer, the same effect of interfacial chemical bonding and enhanced adhesion can be achieved. The adhesion transition layer and the interlayer interpenetrating network structure together constitute a dual stabilization strategy of "substrate interface stability + interlayer interface stability," ensuring stability from the overall structure of the coating system to the interfaces of each layer, ensuring that the coating system does not delaminate or detach under long-term implantation conditions.

[0209] For patch electrodes, oxygen plasma treatment of the surface of the hydrophobic long-term sustained-release layer before coating the hydrophilic intermediate sustained-release layer solution can increase the surface hydrophilicity of the long-term sustained-release layer, prevent "beading" or poor wetting of the subsequent hydrogel coating solution, and ensure that each coating layer uniformly and continuously covers the effective area of ​​the electrode.

[0210] The carrier material for drug-loaded microspheres can be selected from biodegradable biomaterials such as PLGA, PLA, PCL, gelatin, and chitosan, with PLGA being the preferred choice due to its tunable degradation rate and good biocompatibility. The drugs loaded in the drug-loaded microspheres can be selected according to clinical needs, such as dexamethasone, rapamycin, ibuprofen, or brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF). Dexamethasone, as a glucocorticoid anti-inflammatory drug, can effectively inhibit the activation of microglia and astrocytes; rapamycin can inhibit glial cell proliferation; and NGF can promote neuronal survival and axonal growth. Depending on the needs of different clinical scenarios, a single drug or a combination of multiple drugs can be selected, demonstrating the good drug compatibility and application flexibility of the coating system in this application.

[0211] In summary, the multi-stage drug sustained-release coating system and its preparation method of the embodiments of this application achieve all the technical goals of precise matching of the drug release curve of the coating system with the neuroinflammatory process, adaptation of mechanical properties to the mechanical environment of brain tissue, stable bonding of interlayer structure without delamination, and long-term stable adhesion of coating to electrode substrate through the synergistic combination of four technical features: precise correspondence between the three-layer structure and the neuroinflammatory stage, synergistic regulation of release rate and mechanical properties by cross-linking density gradient, stable bonding of interlayer structure without delamination, and long-term stable adhesion of coating to electrode substrate. This overcomes the above-mentioned technical defects of neural interface electrode coatings in the prior art and has significant technical progress.

[0212] IX. Testing Methods and Characterization To verify the structural characteristics and performance parameters of the coating system of this application, the following test methods can be used for characterization.

[0213] (I) Determination and thickness measurement of gradient transition region in interpenetrating network structure To verify whether a gradient transition region with an interpenetrating network structure is formed between adjacent coatings, the cross-sectional morphology of the coating sample can be observed. For example, a coating cross-sectional sample can be prepared using the cryogenic fracture method: the prepared coating electrode is rapidly frozen in liquid nitrogen (e.g., for about 30 minutes), quickly broken to expose the coating cross-section, sputtered with gold, and then observed using a scanning electron microscope at a magnification of about 5,000 to 10,000 times.

[0214] When the interface between adjacent coatings in a cross-sectional image does not exhibit a clear, continuous layer boundary, but rather shows a gradual transition from one layer to another, a gradient transition region with an interpenetrating network structure can be identified. To determine the thickness of this gradient transition region, multiple locations along the interface normal in the cross-sectional image can be selected to measure the width of the transition morphology, and the statistical average can be used as the thickness characterization. If necessary, energy dispersive spectroscopy (EDS) line scans can be used to track the distribution changes of characteristic elements to help determine the extent of the gradient transition region.

[0215] In Embodiment 1 of this application, the coating cross-section was observed using the above method. The results showed that no obvious physical boundary lines or microcracks were observed between the short-term and medium-term sustained-release layers, or between the medium-term and long-term sustained-release layers. Instead, regions exhibited continuous transitions in component morphology. The thicknesses of the two gradient transition regions were measured to be approximately 15 and 20 μm, respectively, both falling within the range of 5 to 30 μm. In contrast, the cross-sectional image of the comparative sample prepared using the "coating the next layer after the previous layer is completely dried" process showed a clear and straight interlayer interface.

[0216] (II) Determination of Moisture Content and Semi-Dry State Before applying the next coating solution, the semi-dry state of the previous layer can be characterized by weighing. Specifically, the mass of the previous layer in its uncoated state is recorded as the wet weight, and the mass of a similar sample dried under vacuum drying conditions (e.g., approximately 60 degrees Celsius) until its mass no longer changes is recorded as the dry weight. The moisture content is then calculated using the following formula: Moisture content = (Wet weight - Dry weight) ÷ Wet weight × 100% When the moisture content is in the range of 8-15%, the previous layer can be considered to be in a semi-dry state that is conducive to maintaining a certain activity of polymer chain segments and allows the solution of the next layer to penetrate.

[0217] In addition to the weighing method, appearance and touch criteria can also be used to verify the semi-dry state: when the coating surface is slightly sticky, fingerprints are left when the finger touches it but no liquid residue transfers, and the overall shape has stabilized, it can be used as an operable condition for determining the semi-dry state.

[0218] (III) Method for determining swelling rate The coated sample was dried under vacuum until constant weight, weighed, and recorded as dry weight. The sample was then immersed in a simulated body fluid (e.g., phosphate buffer, pH approximately 7.4) at a constant temperature (e.g., approximately 37 degrees Celsius). The sample was removed at regular intervals, the surface moisture was blotted dry with filter paper, and the sample was weighed again until the sample mass stabilized over time (i.e., swelling equilibrium was reached), and this was recorded as the swollen mass. The swelling rate was calculated using the following formula: Swelling rate = (mass after swelling - dry weight) ÷ dry weight × 100% To improve the comparability of test results, sample size, immersion medium, temperature conditions, and the criteria for reaching equilibrium should be kept consistent.

[0219] (iv) Method for determining hardness after swelling After the sample reaches swelling equilibrium, its hardness can be characterized. For example, an indentation method can be used to perform load-unload tests at multiple locations on the sample surface: a spherical indenter is used, and the test is conducted in a liquid environment (e.g., phosphate buffer, approximately 37 degrees Celsius). The hardness or elastic modulus of the coating is calculated based on the load-displacement curve. Alternatively, dynamic mechanical analysis methods can be used to test the mechanical response of the swollen sample to obtain parameters characterizing its compatibility with the mechanical environment of brain tissue.

[0220] To ensure the stability of the results, the test location and number of repetitions can be set reasonably according to the sample area, and comparisons should be made under the same swelling state and the same test conditions.

[0221] (v) Test methods for in vitro drug release characteristics To characterize the phased release characteristics of the short-term, medium-term, and long-term sustained-release layers, an in vitro simulated release method can be used for testing. The coating sample is placed in a predetermined volume of release medium (e.g., phosphate buffer, pH approximately 7.4) and the release test is conducted under constant temperature conditions (e.g., approximately 37 degrees Celsius). A constant-temperature shaker can be used to maintain uniform flow of the medium.

[0222] At predetermined time points (e.g., one day, three days, seven days, fourteen days, twenty-eight days, two months, three months after implantation), all or part of the released fluid was collected for testing, and replenished with an equal volume of fresh medium. The drug concentration in the sample fluid was detected using high-performance liquid chromatography or ultraviolet spectrophotometry, and the release amount at each time point was calculated based on the standard curve, and a cumulative release curve was plotted accordingly.

[0223] The release medium type, medium volume, temperature, sampling time point, and liquid replacement strategy should be consistent to enable comparability analysis between samples with different formulations or structures.

[0224] It should be noted that in this patent application, relational terms such as "first" and "second" are used only to distinguish one entity or operation from another, and do not necessarily require or imply any such actual relationship or order between these entities or operations. Furthermore, the terms "comprising," "including," or any other variations thereof are intended to cover non-exclusive inclusion, such that a process, method, article, or apparatus that comprises a list of elements includes not only those elements but also other elements not expressly listed, or elements inherent to such a process, method, article, or apparatus. Without further limitations, an element defined by the phrase "comprising one" does not exclude the presence of other identical elements in the process, method, article, or apparatus that includes said element. In this patent application, if it refers to performing an action according to an element, it means performing the action at least according to that element, including two cases: performing the action only according to that element, and performing the action according to that element and other elements. Expressions such as "multiple," "repeatedly," and "various" include two, two times, two kinds, and more than two, more than two times, and more than two kinds.

[0225] All documents mentioned in this application are considered to be incorporated in their entirety into the disclosure of this application so that they can serve as a basis for modifications if necessary. Furthermore, it should be understood that after reading the foregoing disclosure of this application, those skilled in the art can make various alterations or modifications to this application, and these equivalent forms also fall within the scope of protection claimed in this application.

Claims

1. A multi-stage drug sustained-release coating system for neural interface electrodes, characterized in that, It includes a short-term sustained-release layer, a medium-term sustained-release layer, and a long-term sustained-release layer arranged sequentially from the outside to the inside; wherein the short-term sustained-release layer is configured to release the drug at a first rate, wherein the drug release rate of the short-term sustained-release layer is the highest, the drug release rate of the long-term sustained-release layer is the lowest, and the release rate of the medium-term sustained-release layer is between the two.

2. The coating system according to claim 1, characterized in that, The short-term sustained-release layer is configured to release most of its drug within 1-15 days after implantation; the medium-term sustained-release layer is configured to continuously release the drug within 1-6 weeks after implantation; and the long-term sustained-release layer is configured to release the drug over a long period of 1-12 months after implantation.

3. The coating system according to claim 1, characterized in that, Both the short-term sustained-release layer and the medium-term sustained-release layer include a hydrogel matrix and drug-loaded microspheres dispersed in the hydrogel matrix; and the crosslinking density of the hydrogel matrix in the short-term sustained-release layer is lower than that in the medium-term sustained-release layer. A gradient transition region with an interpenetrating network structure is provided between adjacent coatings, in which the polymer molecular chains of adjacent layers interpenetrate and entangle with each other.

4. The coating system according to claim 2, characterized in that, The hydrogel matrix is ​​selected from at least one of hyaluronic acid, alginate, cellulose and its derivatives, collagen, silk fibroin, polyethylene glycol and its derivatives, polyacrylic acid, polyether-polyester block copolymer, methacrylated gelatin, polyethylene glycol diacrylate, or any combination thereof.

5. The coating system as described in claim 2, characterized in that, The hydrogel matrix of the short-term sustained-release layer and the medium-term sustained-release layer is polyvinyl alcohol hydrogel; The short-term sustained-release layer contains 3-7% polyvinyl alcohol by mass, forming a loose network structure. The mass fraction of polyvinyl alcohol in the intermediate-release layer is 7-15%, forming a dense network structure.

6. The coating system as described in claim 2, characterized in that, The short-term sustained-release layer comprises (by mass fraction): 3-7% polyvinyl alcohol, 1-3% chitosan, 6-8% polyethylene glycol, 5-15% glycerol, 8-15% PLGA drug-loaded microspheres, 0.1-0.3% Tween, and the balance being ultrapure water; and / or, The intermediate sustained-release layer comprises (by mass fraction): 7-15% polyvinyl alcohol, 1-3% chitosan, 6-8% polyethylene glycol, 5-15% glycerol, 8-15% PLGA drug-loaded microspheres, 0.1% Tween, and the balance being ultrapure water.

7. The coating system as described in claim 1, characterized in that, The long-term sustained-release layer consists of a hydrophobic, biodegradable polymer matrix and a drug or drug-loaded nanoparticles dispersed therein.

8. The coating system as described in claim 6, characterized in that, The long-term sustained-release layer is composed of a polymer matrix of PLGA nanoparticles and PLA, wherein the mass ratio of PLGA nanoparticles to PLA is 2:1 to 3:1; and / or, The long-term sustained-release layer is a planar thin film layer covering the electrode surface with a thickness of 5-20 μm; or it is an end component located at the tip of the electrode, which has both puncture and sustained-release functions.

9. The coating system according to any one of claims 1-7, characterized in that, The carrier material for the drug-loaded microspheres is selected from at least one of PLGA, PLA, PCL, gelatin, and chitosan; and / or, The loaded drug is selected from at least one of dexamethasone, rapamycin, ibuprofen, BDNF, and NGF.

10. A method for preparing a multi-stage drug sustained-release coating system for neural interface electrodes as described in claim 1, characterized in that, Includes the following steps: Step S1: Preparation of drug-loaded microspheres; Step S2: Prepare short-term sustained-release layer solution and medium-term sustained-release layer solution respectively, wherein the concentration of hydrophilic polymer in the short-term sustained-release layer solution is lower than the concentration of hydrophilic polymer in the medium-term sustained-release layer solution, and the drug-loaded microspheres prepared in step S1 are dispersed in both solutions; prepare long-term sustained-release layer solution. Step S3: Form a long-term sustained-release layer on the surface of the electrode substrate; Step S4: Coat the surface of the long-term sustained-release layer with the intermediate sustained-release layer solution to form the intermediate sustained-release layer; Step S5: Coat the surface of the intermediate sustained-release layer with the short-term sustained-release layer solution to form the short-term sustained-release layer; Step S6: Perform final drying treatment; In steps S4 and S5, before applying the next layer of coating solution, the previous layer of coating is controlled to be in a semi-dry state with a moisture content of 8-15%, and the next layer of coating solution is allowed to stand and penetrate on the surface of the previous layer of coating to form a gradient transition region of interpenetrating network structure between adjacent coatings.

11. A neural interface electrode, characterized in that, Includes an electrode substrate and a coating system as described in any one of claims 1-9 disposed on the surface of the electrode substrate; An adhesion transition layer is provided between the electrode substrate and the long-term sustained-release layer of the coating system.

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