Functionally integrated drug-loaded tip members for invasive neural electrodes, methods of making, and invasive neural electrodes

Abstract

The application relates to the technical field of biomedical engineering, and discloses a function-integrated drug-loaded end component of an invasive neural electrode, a preparation method and the invasive neural electrode. The end component is integrally formed by a drug-loaded degradable material through a mold and is configured to simultaneously undertake a puncture structure and a long-term drug slow-release carrier; the drug-loaded degradable material comprises a compound system of drug-loaded PLGA nanoparticles and polylactic acid, wherein the polylactic acid serves as a continuous phase to provide mechanical support, and the drug-loaded PLGA nanoparticles serve as a filling phase to provide slow-release function; the end component has a gradient pore structure formed by gradient volatilization of a double-solvent system; and the end component is connected with an electrode matrix in a molecular level fusion connection through interface solvent induction. The application fundamentally eliminates the risk of peeling of a coating due to interface failure in a traditional separated design, realizes synergistic optimization of puncture performance and slow-release performance, and endows the end component with multi-stage drug release characteristics matched with a neural inflammatory reaction stage.

Description

Technical Field

[0001] This application relates to the field of biomedical engineering technology, and in particular to the drug sustained-release structure of invasive neural electrodes and its preparation technology. Background Technology

[0002] Invasive neural electrodes are core components of brain-computer interface (BCI) technology. They are implanted within brain tissue to achieve high-precision, high-spatiotemporal resolution acquisition of neural signals or precise control of neural activity. In deep brain stimulation (DBS) therapy for Parkinson's disease, electrodes need to be implanted long-term in the subthalamic nucleus or medial part of the globus pallidus to continuously deliver electrical pulses to the target nucleus to alleviate motor symptoms. In epileptic focus localization and monitoring, deep electrodes need to be punctured into the temporal lobe or hippocampus to record abnormal discharge signals during epileptic seizures in real time to guide the subsequent surgical resection range. In motor intention decoding and neuroprosthetic control, microelectrode arrays need to be implanted in the motor cortex to stably acquire action potential signals from neuronal clusters over a long period to drive precise movement of external prostheses or computer cursors. All of these applications require invasive neural electrodes to have good puncture capabilities for successful entry into brain tissue, as well as long-term stable signal acquisition performance to meet the needs of clinical treatment or scientific research.

[0003] However, invasive neural electrodes face significant biological challenges during and after implantation. When electrodes are inserted into brain tissue, local mechanical damage is unavoidable, activating microglia and astrocytes and triggering an acute inflammatory response. As implantation time increases, the inflammatory response gradually transitions to a chronic phase, with glial scars thickening around the electrode, forming a high-impedance insulating barrier. This leads to a gradual decrease in signal coupling efficiency between the electrode and the target neuron, ultimately severely impacting the quality of neural signal acquisition and stimulation effectiveness. To mitigate these foreign body reactions, current technologies commonly employ methods such as altering the electrode morphology (e.g., using flexible electrodes) to improve long-term safety, and / or coating the electrode surface with drug-eluting agents to slowly release anti-inflammatory or neuroprotective drugs to suppress local inflammation and glial scar formation.

[0004] However, despite the promising theoretical prospects of flexible electrode + drug-loaded coating technology, several technical problems remain to be solved in practical applications. First, existing coating materials struggle to simultaneously meet the mechanical properties required for puncture and the biodegradability required for sustained release. High-rigidity materials degrade slowly, resulting in excessively long drug release cycles, while easily degradable materials lack sufficient mechanical strength to withstand the mechanical loads during puncture. Second, the connection between existing coatings and the electrode substrate often employs separate design and manufacturing. The interface bonding relies on limited physical adhesion strength, making the coating susceptible to scraping or peeling off due to tissue shear forces during electrode insertion into brain tissue. This prevents the coating from reaching the intended implantation depth intact, severely impairing its function in relieving inflammation at the target site. Third, the drug release kinetics of existing coatings lack effective matching with the temporal evolution of neuroinflammatory responses, making it difficult to provide appropriate drug concentration levels at different stages of inflammation.

[0005] Therefore, there is an urgent need for a new technological solution to address the above problems. Summary of the Invention

[0006] The purpose of this application is to provide a functional integrated drug-loaded end component for invasive neural electrodes, a preparation method thereof, and an invasive neural electrode, so as to solve the problems mentioned in the background art.

[0007] This application discloses a drug-loaded end component for an invasive neural electrode, the component being integrally molded from a drug-loaded biodegradable material, the component being configured to simultaneously serve as a puncture structure for the electrode and a long-term drug sustained-release carrier.

[0008] In a preferred embodiment, the component includes a tip segment and a connecting segment disposed along the axial direction; the tip segment has a geometry suitable for puncturing biological tissue, and the connecting segment is used for connection to an electrode substrate.

[0009] In a preferred embodiment, the connecting segment is provided with a connecting cavity for accommodating the end of the electrode substrate. The inner wall of the connecting cavity is configured to activate the contact interface under the action of a solvent, thereby forming an integrated connection with molecular-level fusion through interdiffusion and entanglement of molecular chains with the end of the electrode substrate.

[0010] In a preferred embodiment, the component has an AFM apparent hardness of not less than 0.1 GPa in a dry state, and its material degradation cycle in vivo or simulated body fluid is 1 to 12 months.

[0011] In a preferred embodiment, the component has a gradient pore structure with increasing porosity from the outside to the inside to achieve multi-stage drug release that matches the tissue response phase.

[0012] In a preferred embodiment, the drug-loaded biodegradable material comprises a polymer continuous phase and drug-loaded microparticles dispersed in the continuous phase; the polymer continuous phase is used to provide mechanical support, and the drug-loaded microparticles are used to provide sustained drug release.

[0013] In a preferred embodiment, the polymer continuous phase comprises polylactic acid (PLA), and the drug-loaded microparticles comprise drug-loaded PLGA nanoparticles.

[0014] In a preferred embodiment, the content of the drug-loaded PLGA nanoparticles is 25-40 wt% and the content of the polylactic acid (PLA) is 8-18 wt% based on the total solid mass of the drug-loaded biodegradable material.

[0015] In a preferred embodiment, the component has an AFM apparent hardness of 0.1-2 GPa in a dry state and a toughness of not less than 750 J / m. 2 ; and / or, the component has any one of the following geometric configurations: conical, cap-shaped, bullet-shaped, wedge-shaped, needle-shaped, pyramidal, streamlined, or wedge-shaped.

[0016] In a preferred embodiment, the following steps are included: S1. Preparation of drug-loaded polymer solution: Dissolve or disperse the components of the drug-loaded biodegradable material in a dual-solvent system containing a fast-evaporating solvent and a slow-evaporating solvent; S2. Injection molding and gradient drying: The drug-loaded polymer solution is injected into the mold cavity and subjected to gradient evaporation drying; the rapid evaporation of the fast-evaporating solvent forms an initial solidified layer on the surface, and the slow evaporation of the slow-evaporating solvent causes phase separation or densification inside, forming a drug-loaded end component after demolding. S3. Connection: An electrode substrate is provided, and the connection interface of the end surface of the electrode substrate and / or the drug-loaded end component is activated by a solvent, so that the two come into contact and form an integrated connection through the interdiffusion and entanglement of molecular chain segments.

[0017] In a preferred embodiment, step S3 specifically includes: S31. Dip the end of the electrode substrate into the drug-loaded polymer solution or its compatible solvent to form a wetted adhesive medium layer on its surface; S32. Insert the dipped end of the electrode substrate into the connecting cavity of the drug-loaded end component, and use the solvent in the adhesive medium layer to produce a micro-dissolving effect on the inner wall of the connecting cavity; S33. Maintain the connection state and solidify to form a molecular-level interpenetrating network at the interface between the electrode substrate end and the drug-loaded end component.

[0018] In a preferred embodiment, after step S2, the surface activation treatment of the drug-loaded end member is further included, the surface activation treatment including plasma treatment, ultraviolet irradiation or chemical reagent treatment.

[0019] This application also discloses an invasive neural electrode, comprising: an electrode substrate; and a drug-loaded end member as described above, connected to the end of the electrode substrate.

[0020] By implementing the above technical solution, the following technical effects can be achieved.

[0021] To address the challenge of independent implantation of flexible electrodes and to achieve both puncture and sustained-release functions, this application employs a composite structure of "nanoparticle-filled reinforced matrix" by compounding drug-loaded PLGA nanoparticles with polylactic acid (PLA) in a specific ratio. PLA serves as the continuous phase providing mechanical support, while the drug-loaded PLGA nanoparticles act as the filler phase to provide sustained-release functionality. This composite structure enables the end component to achieve the required puncture threshold level in its AFM (Augmented Surface Hardness) under dry conditions, while maintaining the overall biodegradable and sustained-release properties of the material. This effectively overcomes the technical contradiction in existing technologies where "high-rigidity materials degrade slowly, while easily degradable materials have low hardness." By reducing the overall size of the device coating, it achieves synergistic optimization of puncture and sustained-release performance within the same material system.

[0022] To address the issue of coating detachment, the functionally integrated drug-loaded end component of this application is integrally molded from a drug-degradable material and configured to simultaneously serve as the puncture structure for invasive neural electrodes and a long-term drug release carrier. This design makes the end component itself a puncture structure, eliminating the weak interface between the coating and the substrate present in traditional "puncture structure + surface coating" designs during puncture. This fundamentally eliminates the risk of the coating being scraped off or peeled off due to shear forces, ensuring that the drug-loaded material can reach the predetermined implantation depth intact with the electrode and exert its sustained-release function in situ.

[0023] To improve molding quality, this application employs a dual-solvent system comprising a fast-evaporating solvent and a slow-evaporating solvent. The rapid evaporation of the fast-evaporating solvent forms an initial solidified layer on the solution surface for shaping, while the slow evaporation of the slow-evaporating solvent densifies the interior. This gradient evaporation drying process maintains accurate replication of the tip's geometry while avoiding porosity, collapse, or structural defects caused by rapid solvent escape, significantly improving the molding integrity and appearance consistency of the micron-level tip structure. Furthermore, by controlling the liquid level of the drug-loaded polymer solution after injection into the mold cavity to be slightly higher than the top of the cavity, the volume shrinkage caused by solvent evaporation can be effectively compensated, further reducing the risk of tip underfilling or top collapse.

[0024] In achieving multi-stage drug release, the gradient porosity structure formed inside the end member of this application, from the outside in, complements the differences in the degradation rates of the drug-loaded biodegradable material components, jointly endowing the end member with multi-stage drug release characteristics. The dense outer layer bears the main mechanical load during the puncture stage and provides a high initial drug concentration through diffusion in the early stages of implantation. The inner layer, with a higher porosity than the outer layer, is gradually exposed and releases deep drugs as the material degrades, forming a "faster in the early stage + slower in the later stage" release pattern. This release pattern matches the trend of the inflammatory response after nerve implantation from high to low, which is conducive to providing appropriate drug concentration levels at different stages, achieving precise pharmacokinetics of rapid early inhibition of inflammation, continuous intervention in the middle stage, and long-term prevention of scarring.

[0025] To further improve connection reliability, the connection segment of this application has a connection cavity inside, with the opening of the connection cavity facing away from the tip segment, allowing for a larger contact area after the electrode substrate end is inserted into the connection cavity. Combined with the surface-active groups introduced by plasma surface activation treatment and the molecular-level interpenetrating network structure formed by the interface solvent-induced dissolution further activates the contact interface, the bonding interface between the electrode substrate and the drug-loaded end component has a significantly higher bonding strength than physical adhesion. This effectively withstands axial pressure and shear force during puncture, as well as periodic stress caused by brain tissue micromovement after long-term implantation, ensuring the long-term stability of the invasive neural electrode in practical applications.

[0026] In terms of process synergy, there is an organic synergistic relationship between the various steps in the preparation method of this application: the solution obtained in the step of preparing the drug-loaded polymer solution is not only used for injection molding, but also used as an adhesive medium in the subsequent connection step, realizing the process synergy of "homologous material-homologous solvent" and reducing the risk of interface incompatibility; the result of the plasma surface activation treatment step directly serves the subsequent interface solvent-induced dissolution to form the connection step, and the inner wall of the activated connection cavity is more easily wetted by the adhesive medium and undergoes interface micro-dissolution, which improves the reliability and consistency of the connection; the mold adopts a flexible material and is cooled before demolding, and the thermal expansion and contraction characteristics of the material are used to achieve flexible demolding, reducing the risk of damage to the micron-level tip structure during the demolding process.

[0027] Regarding the adaptability of materials and geometry, the drug-loaded end component of this application can be selected in various geometric shapes such as conical, cap-shaped, bullet-shaped, wedge-shaped, needle-shaped, and pyramidal according to actual application needs, in order to adapt to different types of electrode substrates and different implantation requirements; the drugs loaded on the drug-loaded PLGA nanoparticles may include anti-inflammatory drugs, neuroprotective drugs, or anti-proliferative drugs, in order to provide corresponding drug treatment for different pathological reactions; the material degradation cycle can be controlled within a certain range by adjusting the formula to cover different time windows from the acute inflammatory phase to the chronic phase, reflecting the flexibility and wide applicability of the technical solution of this application.

[0028] 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

[0029] Figure 1 This is a schematic diagram of a functionally integrated drug-loaded end component for an invasive neural electrode according to the first embodiment of this application.

[0030] Figure 2 This is a schematic flowchart of the preparation method of the invasive neural electrode according to the second embodiment of this application.

[0031] Explanation of reference numerals in the attached figures: 10-Integrated drug-carrying end component; 11-Tip segment; 12-Connecting segment; 121-Connecting cavity; 13-Outer dense region; 14-Inner porous region; 20-Electrode substrate; 30-Interface fusion zone. Detailed Implementation

[0032] 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.

[0033] Explanation of some concepts: The integrated drug-loaded end component refers to an independent solid structure integrally formed by molding a drug-loaded biodegradable material. It is not a thin film coating attached to the surface of the electrode substrate, but directly serves as the tip of the nerve electrode. In terms of physical structure, this component simultaneously undertakes the mechanical puncture function of penetrating biological tissue and the therapeutic function of releasing active drugs after implantation, and has the characteristics of "structure-function integration".

[0034] An end component refers to a component located at the tip of an invasive neural electrode, used for puncture into biological tissue and to achieve sustained drug release, including a tip segment and a connecting segment arranged along the axial direction.

[0035] The tip segment refers to the front end portion of the end component arranged along the axial direction. It has a geometric shape suitable for puncturing into biological tissue and can be selected from at least one of any geometric shapes with puncture capability, such as conical, cap-shaped, bullet-shaped, wedge-shaped, needle-shaped, pyramidal, etc.

[0036] The connecting section refers to the part of the end component that is axially arranged and located behind the tip section, and is used to connect with the electrode substrate; it may have a connecting cavity inside to accommodate the end of the electrode substrate.

[0037] A connecting cavity is a cavity structure located inside the connecting section to accommodate the end of the electrode substrate. Its opening is away from the tip section, so that a larger contact area can be formed after the end of the electrode substrate is inserted.

[0038] The electrode substrate refers to the conductive structure in an invasive neural electrode that performs signal transmission, with its end housed within the connecting cavity of a functionally integrated drug-carrying end component.

[0039] Drug-loaded biodegradable materials refer to material systems that can degrade in living organisms and release drugs during the degradation process. In this application, it specifically refers to a material system formed by combining drug-loaded PLGA nanoparticles with polylactic acid (PLA).

[0040] Drug-loaded PLGA nanoparticles refer to nanoscale drug carriers prepared using polylactic-co-glycolic acid copolymer (PLGA) as the carrier material, which are loaded with at least one of anti-inflammatory drugs, neuroprotective drugs, or antiproliferative drugs.

[0041] A dual-solvent system refers to a mixed solvent system consisting of a fast-evaporating solvent and a slow-evaporating solvent, wherein the evaporation rate of the fast-evaporating solvent is higher than that of the slow-evaporating solvent; in a preferred embodiment, the fast-evaporating solvent is acetone and the slow-evaporating solvent is ethyl acetate.

[0042] Fast-evaporating solvents refer to organic solvents that evaporate relatively quickly under normal room temperature and pressure conditions, such as acetone, chloroform, tetrahydrofuran, and dichloromethane.

[0043] Slow-evaporating solvents refer to organic solvents that evaporate at relatively slow rates under normal room temperature and pressure conditions, such as ethyl acetate, DMF, and DMSO.

[0044] Gradient porosity structure refers to the porosity gradient distribution characteristic from the outside to the inside of the end component, including a dense outer layer region and an inner layer region with higher porosity than the outer layer region. This structure is spontaneously formed by the difference in evaporation rate of the dual solvent system during the molding process, and usually exhibits a morphology of dense outer layer structure with few pores and relatively loose inner layer structure with more pores.

[0045] Interfacial solvent-induced (dissolution, formation) bonding refers to the use of drug-loaded polymer solutions as adhesive media, where the solvent in the solution causes micro-dissolution of the inner wall surface of the bonding cavity of the pre-formed end component, causing the polymer chain segments at the interface to swell, relax, and rearrange. As the solvent evaporates, the polymer molecular chains on both sides of the interface diffuse and entangle with each other, forming an interpenetrating network structure or recrystallization structure, thereby achieving a molecular-level fusion integrated bonding method.

[0046] Interpenetrating network structure refers to a molecular-level fusion structure formed at the interface between the electrode substrate end and the drug-carrying end component through the mutual diffusion, entanglement and recrystallization of polymer chain segments. In this structure, the polymer molecular chains of the two materials interpenetrate and entangle with each other to form a continuous polymer network, so that there is no obvious physical boundary at the connection interface.

[0047] AFM apparent hardness refers to the local apparent elastic modulus calculated by using atomic force microscopy (AFM) force spectrum mode, employing a spherical probe to perform indentation tests on the microscopic areas of the material surface in a dry state, and fitting a force-displacement curve based on the Hertz contact model. This index is used to characterize the surface contact stiffness of end component materials at the microscale, and it differs from the macroscopic Young's modulus of the entire material in terms of physical meaning and numerical magnitude.

[0048] Toughness refers to the fracture energy measured using the one-sided notch tensile test, and its unit is J / m. 2 This indicator reflects the material's ability to resist crack propagation; a higher toughness value indicates that the material is less prone to brittle fracture.

[0049] The degradation cycle refers to the time required for the end component to complete degradation in a simulated in vivo environment; the test conditions are that the degradation medium is PBS buffer (pH 7.4) or artificial cerebrospinal fluid, and the temperature is controlled at 37±0.5℃.

[0050] The following is a brief summary of some of the innovative aspects of this application: In summary, the technical concept of this application does not originate from a simple improvement or parameter optimization of existing neural electrode coating technology, but rather is a systematic solution proposed based on a re-examination of the fundamental contradictions faced by the two functional carriers, "puncture structure" and "sustained-release carrier," in the process of invasive neural electrode implantation. Specifically, the "flexible electrode + surface sustained-release coating" design mode commonly used in the prior art is difficult to simultaneously meet the requirements of rigid puncture and drug sustained-release function. Moreover, during the process of the electrode entering the brain tissue, the interfacial bonding strength between the electrode and the coating may be insufficient to withstand the shear force exerted by the tissue on the coating, causing the coating to be scraped off or peeled off layer by layer along the puncture path. As a result, the coating cannot reach the predetermined implantation depth with the electrode, and the sustained-release function is severely impaired. This application addresses this long-standing technical bottleneck in the field by creatively proposing the integrated design concept of "coating as tip". This concept involves constructing the drug-loaded end component 10 as an integrated solid structure that serves as both a puncture structure and a long-term drug release carrier. This completely eliminates the interface between the puncture structure and the coating that is inherent in traditional separate designs, thereby fundamentally avoiding the technical risk of the coating falling off due to interface failure.

[0051] First, the integrated design concept of the above-mentioned functions resolves the irreconcilable technical contradiction between the "mechanical properties required for puncture" and the "degradable properties required for sustained release": if high-rigidity materials are used to meet the puncture requirements, the material degradation rate is too slow and the drug release cycle is too long; if easily degradable materials are used to meet the sustained release requirements, the material's apparent hardness at AFM is insufficient, making puncture impossible. This application introduces a specific compound system of drug-loaded PLGA nanoparticles and polylactic acid (PLA) into the formulation design of drug-loaded biodegradable materials, and utilizes a composite structure design of "nanoparticle-filled reinforced matrix"—using polylactic acid (PLA) as the continuous phase 11 to provide mechanical support and drug-loaded PLGA nanoparticles as the filler phase 12 to provide sustained release function—to synergistically achieve the technical goal of reaching the AFM apparent hardness puncture threshold in a biodegradable material system. It should be noted that the reason why the end component with an apparent hardness of GPa in this application can puncture brain tissue is not solely due to the single parameter of material "hardness". Rather, it is the result of the coupled and synergistic effect of multiple factors under specific formulation and process conditions, including geometric factors (the outer dense structure 13 formed by the gradient evaporation of the dual solvent system bears the main mechanical load), size factors (the high aspect ratio geometry with a micron-level diameter is not prone to buckling instability), material factors (the enhanced composite structure formed by the combination of PLGA nanoparticles and PLA), process factors (the outer dense structure 13 formed by the gradient evaporation of the dual solvent system bears the main mechanical load), and state factors (rigid puncture in the dry state and flexible matching in the hydrated state after implantation). Such a multi-factor synergistic mechanism has no clear technical inspiration in the prior art.

[0052] Furthermore, the dual-solvent system (a combination of fast-evaporating solvent and slow-evaporating solvent) used in the preparation method of this application is not a simple solvent selection based on solubility considerations, but a deliberate design to serve the dual process goals of "defect-free molding of the tip segment" and "gradient pore structure formation" in the same molding process: the rapid evaporation of the fast-evaporating solvent forms an initial solidified layer on the solution surface to fix the shape, thereby perfectly replicating the sharp shape of the mold cavity and preventing collapse and deformation; the slow-evaporating solvent slowly escapes from the inside after the formation of the dense layer on the surface, giving the polymer chain segments sufficient rearrangement time to densify the internal structure. This gradient evaporation mechanism of "fast evaporation for shaping + slow evaporation for densification" not only ensures the molding quality of the end component, but also spontaneously forms a gradient pore structure inside the end component, including a dense outer layer region 13 and an inner layer region 14 with a higher porosity than the outer layer region. This gradient pore structure works in conjunction with the difference in degradation rate of the drug-loaded biodegradable materials (PLGA degrades faster than PLA) to give the end component multi-stage drug release characteristics that match the neuroinflammatory response stage. That is, it provides a high initial drug concentration in the acute inflammatory phase, maintains a moderate drug concentration in the subacute phase, and provides a low concentration but continuous drug supply in the chronic phase. This technical path of coupling molding quality control and multi-stage release characteristics in the same process chain is unprecedented in the existing technology.

[0053] Furthermore, the interface solvent-induced connection technology used in this application for the connection between the electrode substrate 20 and the drug-loaded end component 10 is not a simple improvement of the adhesive process, but a systematic connection scheme design based on the concept of "homogeneous materials and homogeneous solvents": using the same drug-loaded polymer solution as injection molding as the adhesive medium, the solvent in the adhesive medium layer produces a micro-dissolution effect on the inner wall of the connection cavity 102 after plasma surface activation treatment, thereby causing the polymer chain segments at the interface between the electrode substrate end and the drug-loaded end component to diffuse, entangle, and recrystallize, ultimately forming a molecular-level interpenetrating network (IPN) structure 30. This molecular-level integrated connection method is fundamentally different in connection mechanism from the traditional mechanical interlocking or van der Waals force adhesive method that relies on adhesives. The achieved bonding strength can withstand the axial pressure and shear force during puncture and the stress caused by micro-movement of brain tissue after long-term implantation, thus complementing the aforementioned functionally integrated end component design and jointly ensuring the reliability of the invasive neural electrode of this application in practical applications.

[0054] In summary, the technical solution of this application is an organic whole in which four elements—"functional integrated structural design," "PLGA nanoparticle / PLA composite material system," "gradient evaporation molding process driven by dual solvent system," and "interfacial solvent-induced molecular-level connection technology"—are interdependent and synergistic under the guidance of a specific technical concept. There is a close internal relationship between the technical features. The absence or replacement of any technical feature will lead to a significant deterioration of the overall effect of the technical solution. Such a systematic technical solution cannot be obviously obtained by those skilled in the art based on the prior art.

[0055] To make the objectives, technical solutions, and advantages of this application clearer, the embodiments of this application will be described in further detail below with reference to the accompanying drawings.

[0056] As stated above, the inventors of this application have discovered through long-term in-depth research that the reason why existing invasive neuroelectrode drug-loaded coating technology is difficult to achieve ideal results in practical applications is not due to defects in a single technical aspect, but rather to the structural contradiction between the two functional carriers, "puncture structure" and "sustaining release carrier," in the traditional design paradigm.

[0057] Through in-depth analysis of existing "flexible electrode + surface sustained-release coating" designs, the inventors discovered an inherent structural flaw in this design: when the electrode punctures brain tissue, the coating, located on the outermost layer of the puncture path, directly bears the shear and frictional forces exerted by the brain tissue; and the interface between the coating and the puncture structure—regardless of the surface treatment or bonding technology used—is always the weakest link in the entire structure in terms of mechanical strength. Further research revealed that even with surface modification methods such as plasma treatment, chemical coupling agents, or roughening treatment, the interfacial bonding strength between the coating and the substrate is still difficult to reach the level of the coating material's intrinsic strength; this means that during puncture, stress concentration at the interface will inevitably lead to the coating peeling or cracking along the interface, and subsequently being scraped off layer by layer by the brain tissue. The inventors deeply understand that the essence of this problem is not insufficient coating material performance or improper bonding process, but rather inherent in the separate design itself—as long as there is an interface between the puncture structure and the sustained-release coating, that interface will inevitably become a potential failure point. Based on this understanding, the inventors creatively proposed the functional integration design concept of "coating as tip". This means that by constructing the drug-carrying end component itself as an integrated solid structure that undertakes both puncture and sustained release functions, the interface that is inevitable in traditional separate designs is completely eliminated from the structural design level, thereby fundamentally avoiding the technical risk of coating peeling off due to interface failure.

[0058] However, the inventors encountered new technical obstacles in realizing the aforementioned integrated design concept. Through extensive experimental research, the inventors discovered an irreconcilable contradiction between the "mechanical properties required for puncture" and the "degradable properties required for sustained release": if a high-rigidity, non-degradable material is used to meet the puncture requirements, the material cannot degrade, and the drug cannot be released; if a readily degradable, flexible material is used to meet the sustained release requirements, the material's mechanical strength is insufficient, and it bends during puncture. After repeated experiments and theoretical derivations, the inventors realized that the key to overcoming this contradiction lies in constructing a specific "micro-nano composite reinforced" material system—using polylactic acid (PLA) as a continuous phase to provide a mechanical support framework, and using drug-loaded PLGA nanoparticles as a filler phase to provide sustained release functionality. The two, in a specific ratio, form a composite structure of "nanoparticle-filled reinforced matrix," thereby achieving a significant improvement in mechanical properties within the degradable material system. More importantly, the inventors also discovered that the puncture capability of the end component is not determined by the single parameter of material "hardness", but is the result of the coupled and synergistic effect of multiple factors such as geometric factors, size factors, material factors, process factors and state factors under specific formulation and process conditions.

[0059] Furthermore, the inventors made unexpected technological discoveries during their research on solving molding quality problems. Through systematic research on different solvent systems, the inventors discovered that using a dual-solvent system containing both fast-evaporating and slow-evaporating solvents for molding can simultaneously achieve the dual process goals of "defect-free molding of the tip segment" and "formation of a gradient porous structure" in the same molding process: the rapid evaporation of the fast-evaporating solvent forms an initial solidification layer on the solution surface for shaping, perfectly replicating the sharp shape of the mold cavity and preventing collapse and deformation; the slow-evaporating solvent slowly escapes from the inside after the formation of the dense surface layer, giving the polymer chain segments sufficient rearrangement time to densify the internal structure while retaining relatively porous characteristics. The inventors further discovered that this gradient porous structure, combined with the difference in the degradation rate of the components in the drug-loaded biodegradable material, can jointly endow the end component with multi-stage drug release characteristics that match the neuroinflammatory response stage—this technical path of coupling molding quality control and multi-stage release characteristics in the same process chain is an important technological discovery obtained by the inventors during their long-term research.

[0060] Furthermore, when studying the connection between the end component and the electrode substrate, the inventors proposed the concept of "homogeneous material and homogenous solvent." They discovered that using the same drug-loaded polymer solution as the injection molding process as the adhesive medium allows the solvent to micro-dissolve the inner wall of the connection cavity after plasma surface activation treatment. This induces diffusion, entanglement, and recrystallization of polymer chains at the interface, ultimately forming a molecular-level interpenetrating network structure. This connection method differs fundamentally from traditional adhesive-based mechanical interlocking or van der Waals force bonding in its connection mechanism. The resulting bond strength can withstand the axial pressure and shear force during puncture, as well as the stress caused by micro-movements in the brain tissue after long-term implantation.

[0061] Based on the above in-depth research, the inventors of this application have proposed an innovative technical solution—systematically solving the above-mentioned technical problems through the synergistic combination of "functionally integrated structural design", "PLGA nanoparticle / PLA composite material system", "gradient evaporation molding process driven by dual solvent system" and "interfacial solvent-induced molecular-level connection technology".

[0062] The present application will be further described in detail below with reference to the accompanying drawings and specific embodiments. The following embodiments are only used to illustrate the technical solutions of the present application and are not intended to limit the scope of protection of the present application. Those skilled in the art should understand that modifications or equivalent substitutions can be made to the technical solutions of the present application without departing from the spirit and scope of the present application, and such modifications or equivalent substitutions should all fall within the scope of protection of the present application.

[0063] I. Terminology Definitions and Testing Methods To make the technical solution of this application clearer, the key terms and test methods used in the specification are defined hereby.

[0064] Regarding the apparent hardness of AFM The "AFM apparent hardness" mentioned in this application refers to the local apparent elastic modulus measured using atomic force microscopy (AFM) force spectroscopy mode, used to characterize the relative mechanical properties of end component materials. Specifically, the AFM apparent hardness refers to the local apparent elastic modulus calculated by testing the surface of the end component in a dry state using an atomic force microscopy (AFM) force spectroscopy mode with a spherical probe and fitting it with a Hertz contact model.

[0065] A spherical probe is used for testing, with a diameter selectable within the range of 5-20 μm. During sample preparation, the sample is firmly and smoothly attached to a glass slide substrate treated with oxygen plasma, ensuring no displacement during testing. Data processing involves fitting force-displacement curves using the Hertz contact model, and calculating the local elastic modulus based on probe geometry and contact mechanics theory.

[0066] It should be noted that AFM force spectroscopy measures the local elastic response of a microscopic region on the material surface, and its numerical magnitude (GPa level) differs from that of macroscopic compressive modulus or Young's modulus (typically MPa-GPa level). The technical reasons for adopting this testing method in this application are as follows: First, the end component of this application is a fine structure with micrometer-level dimensions, which is difficult to directly test using traditional macroscopic mechanical testing methods, while AFM force spectroscopy can perform non-destructive characterization of the end component at the microscopic scale; second, under the same testing conditions, AFM apparent hardness can accurately reflect the relative mechanical property change trend of end components with different formulations, providing quantitative indicators for formulation optimization; third, AFM apparent hardness is positively correlated with actual puncture performance. Example data shows that end components with an AFM apparent hardness ≥ 0.1 GPa can successfully puncture simulated brain tissue, while end components with an AFM apparent hardness < 0.1 GPa experience bending failure during puncture.

[0067] Regarding toughness testing methods The "toughness" mentioned in this application refers to the fracture energy measured using the single-sided notch tensile method, with units of J / m. 2 During testing, dumbbell-shaped or rectangular tensile specimens are prepared. A sharp notch of known depth is pre-cut at the center of one edge of the specimen, with the notch depth being approximately one-third to one-half of the specimen width. A universal testing machine is used to subject the specimen to uniaxial tension at a constant rate until complete fracture. The complete load-displacement curve is recorded. The fracture energy is calculated using the formula: the total area under the curve divided by the product of the initial cross-sectional area of ​​the specimen and the ligament width. This indicator reflects the material's resistance to crack propagation; a higher toughness value indicates that the material is less prone to brittle fracture.

[0068] Methods for determining degradation period The "degradation cycle" described in this application refers to the time required for the end component to complete degradation in a simulated in vivo environment. The test conditions were as follows: the degradation medium used was PBS buffer (pH 7.4) or artificial cerebrospinal fluid (aCSF); the temperature was controlled at 37±0.5℃; the oscillation frequency was approximately 100 rpm; and the degradation medium was replaced every 2 hours on the first day, every 24 hours thereafter until the end of the first week, and weekly thereafter. Degradation was considered complete when any of the following conditions were met: a high level of mass loss, a decrease in molecular weight to a lower level than the initial value, complete disintegration of the macroscopic morphology, or loss of mechanical strength preventing the maintenance of the original shape.

[0069] Methods for verifying puncture performance To verify the puncture function of the end effector, a simulated medium was used for testing. For example, approximately 0.6% (w / v) agarose gel was used as the simulated medium, as its mechanical properties are similar to brain tissue, with an elastic modulus of approximately 1-10 kPa. During testing, the prepared electrode with the drug-loaded end effector was vertically inserted into the agarose gel, and the puncture speed was controlled within an appropriate range. The judgment criteria were: if the end effector successfully penetrated the gel without bending, twisting, or breaking during the puncture, it was considered a successful puncture; if the end effector bent or failed during the puncture or could not complete the puncture due to molding defects, it was considered a failed puncture.

[0070] Methods for evaluating connection performance The “connection effect” described in this application is characterized by the following three-level evaluation system to systematically reflect the integrity, reliability and bonding strength of the connection between the drug-loaded end component 10 and the electrode substrate 20.

[0071] Initial screening (observation with an optical microscope): After the connection and curing are completed, the prepared electrode array is observed using an optical microscope (magnification 40×) and the following indicators are recorded: (a) Array connection rate, that is, the percentage of the number of drug-loaded end components in the array that are successfully connected to the electrode substrate out of the total number of array electrodes; (b) Single electrode connection integrity, that is, whether the connection interface between a single electrode and the drug-loaded end component is complete and without obvious gaps or deviations; (c) Connection coaxiality, that is, whether the drug-loaded end component is connected in a straight line along the axis of the electrode substrate and whether there is any observable offset or tilt.

[0072] Second screening (ultrasonic testing): The electrode array after the initial screening is placed in an ultrasonic cleaner, submerged in an aqueous solution, and treated at an ultrasonic power of 80-200W (100W for example) for 3-10 minutes (5 minutes for example). After ultrasonic treatment, it is removed and dried, and then observed again using an optical microscope according to the initial screening standards. The changes in array connectivity, single electrode connection integrity, and connection coaxiality after ultrasonic treatment are recorded. This step is used to simulate the reliability of the connection under harsh stress conditions. The higher the connection retention rate after ultrasonic treatment, the better the connection reliability.

[0073] Peel strength test: The prepared electrode sample with drug-loaded end components was adhered to 3M tape (Scotch® High Performance Kraft Tape 250), with both ends of the tape clamped in the fixtures of a universal testing machine. Peeling was performed at a constant speed (50 mm / min), and the load-displacement curves during the peeling process were recorded. The average peel force was calculated. The adhesive failure force was calculated using the following formula: Adhesive failure force = Measured total peel force - Tape self-adhesive force, where the tape self-adhesive force was obtained by separately measuring the force of peeling a blank tape from an inert, smooth surface (such as a mirrored aluminum plate). Peel strength is expressed in N / m or N / cm; a higher value indicates a stronger bond.

[0074] II. Functionally Integrated Drug-Loading End Component This application provides a functional integrated drug-loaded end component 10 for invasive neural electrodes. Its core design concept is "coating as tip": the drug-loaded end component 10 is both the puncture structure of the electrode and a long-term sustained-release carrier. It is configured to simultaneously serve as the puncture structure of the invasive neural electrode and the long-term sustained-release carrier of the drug, fundamentally solving the problem of coating peeling caused by the traditional "puncture structure + sustained-release coating" separate design.

[0075] Overall structure like Figure 1 As shown, the functionally integrated drug-loaded end component 10 of this application is integrally molded from a drug-loaded biodegradable material. The end component 10 includes a tip segment 11 and a connecting segment 12 arranged axially. The tip segment 11 has a geometric shape suitable for puncturing into biological tissue, and can be selected from at least one of any geometric shape with puncture capability, such as conical, cap-shaped, bullet-shaped, wedge-shaped, needle-shaped, or pyramidal, depending on application requirements. The connecting segment 12 is located behind the tip segment 11 and is used to connect to the electrode substrate 20.

[0076] Furthermore, the connecting segment 12 has a connecting cavity 121 inside for accommodating the end of the electrode substrate 20, and the opening of the connecting cavity 121 faces away from the tip segment 11. This structural design allows the end of the electrode substrate 20 to form a large contact area after being inserted into the connecting cavity 121. The inner wall of the connecting cavity 121 is constructed to form an integrated connection with the end of the electrode substrate 20 inserted therein through interfacial solvent induction, which significantly improves the connection reliability.

[0077] For example, when using a conical geometry, the puncture resistance is low and the preparation process is simple, making it one of the preferred shapes. The bullet-shaped streamlined design minimizes lateral compression of surrounding tissues and reduces the risk of microvascular rupture, also making it a preferred shape. Cap-shaped designs are suitable for covering the end of a blunt electrode, wedge-shaped designs are suitable for specific puncture angle requirements, and needle-shaped designs with a large aspect ratio are suitable for deep implantation.

[0078] Key performance parameters The apparent hardness (AFM) of the end member 10 in a dry state should be no less than 0.1 GPa, exemplarily reaching the range of 0.1-2 GPa, and preferably reaching 0.2-0.7 GPa. Simultaneously, the toughness of the end member 10 should be no less than 750 J / m. 2 The optimal value can reach 850 J / m 2 The material degradation period of the end member 10 is 1-12 months, preferably 3-12 months, to cover the acute and chronic phases after nerve electrode implantation.

[0079] It should be noted that although the AFM apparent hardness of the end component 10 in this application is at the GPa level, it can still achieve puncture functionality. Its technical principle involves the synergy of multiple factors. Geometrically, the end component 10 adopts a sharp conical or similar shape with an extremely small radius of curvature at the tip. During puncture, stress is highly concentrated in a tiny area at the tip. According to the principle of stress concentration, the local stress at the tip can reach tens of times the average stress. In terms of size, the typical diameter of the end component 10 is on the micrometer scale. Its slender geometry has a high aspect ratio, making it less prone to buckling instability according to Euler buckling theory. From a material perspective, the combination of PLGA nanoparticles and PLA forms a reinforced composite structure. PLA acts as a continuous phase, providing skeletal support, while PLGA nanoparticles act as a filler phase, improving density and rigidity. From a process perspective, the gradient evaporation of the dual-solvent system forms a dense structure on the outer layer of the end component 10. This outer dense layer bears the main mechanical load during puncture. From the perspective of state factors, the end component 10 has high rigidity in the dry state and can complete the puncture; after implantation, it gradually hydrates in the tissue fluid environment, the elastic modulus decreases, and it tends to match the mechanical properties of the surrounding brain tissue, reducing chronic damage caused by mechanical mismatch.

[0080] In summary, the puncture capability of the end member 10 of this application is the result of the combined effects of geometric design, size effect, material ratio and molding process, rather than being determined by a single "hardness" parameter.

[0081] Material composition The drug-loaded biodegradable material is formulated from a mixture of drug-loaded PLGA nanoparticles, polylactic acid (PLA), and a dual-solvent system. Specifically, in the formulation, the content of drug-loaded PLGA nanoparticles is 25-40 wt%, preferably 30 wt%; and the content of polylactic acid (PLA) is 8-18 wt%, preferably 10 wt%.

[0082] In the material formulation design, polylactic acid (PLA) is used as a continuous phase to provide mechanical support, while drug-loaded PLGA nanoparticles are used as a filler phase to provide sustained-release function. The two form a composite structure of "nanoparticle-filled reinforced matrix", which synergistically achieves the technical goal of "achieving the required AFM apparent hardness and having a long-term sustained-release period".

[0083] More specifically, the roles of PLGA nanoparticles include: providing a controllable degradation rate and drug release kinetics as a drug carrier; uniformly dispersing the nanoparticles in the matrix to form a continuous drug-loaded network; and allowing the degradation products of PLGA (lactic acid, glycolic acid) to be metabolized and absorbed by the body. The roles of PLA include: PLA has higher crystallinity and a higher glass transition temperature than PLGA, providing rigid support as a continuous phase; simultaneously, PLA degrades more slowly than PLGA, maintaining the structural integrity of the end components 10 during degradation. The synergistic effect of both solves the problems of insufficient hardness when using PLGA alone and excessively slow degradation when using PLA alone.

[0084] Regarding the dual-solvent system, the dual-solvent system includes a fast-evaporating solvent and a slow-evaporating solvent. In a preferred embodiment, the fast-evaporating solvent is acetone, and the slow-evaporating solvent is ethyl acetate. Based on the total weight of the drug-loaded polymer solution, the content of acetone is 10-25 wt%, and the content of ethyl acetate is 35-50 wt%. More preferably, the content of acetone is 15 wt%, and the content of ethyl acetate is 45 wt%.

[0085] The technical advantage of the dual-solvent system lies in achieving both defect-free molding of the end component 10 and optimization of the gradient pore structure. Acetone has a low boiling point (approximately 56°C) and evaporates rapidly at room temperature, quickly forming a dense initial solidified layer on the solution surface. This perfectly replicates the sharp shape of the mold cavity and prevents collapse and deformation during subsequent evaporation. Ethyl acetate has a high boiling point (approximately 77°C) and evaporates more slowly than acetone. After the dense surface layer is formed, it slowly escapes from the interior, giving the polymer chain segments sufficient time for rearrangement, allowing the internal structure to gradually become denser and avoiding pores and stress concentration caused by rapid solvent escape. When the acetone ratio is too high, the surface solidifies too quickly, forming an "outer shell," preventing the internal solvent from escaping and leading to pores and structural defects. When the acetone ratio is too low, the overall solidification is too slow, and the end component 10 is prone to collapse and deformation.

[0086] Optionally, the drug loaded onto the drug-loaded PLGA nanoparticles may include at least one of anti-inflammatory drugs, neuroprotective drugs, or antiproliferative drugs. For example, anti-inflammatory drugs may be glucocorticoids such as dexamethasone or minocycline, or tetracyclines; neuroprotective drugs may be selected according to specific needs; and antiproliferative drugs may be mTOR inhibitors such as rapamycin. The drug-loaded PLGA nanoparticles can be prepared using conventional methods in the art, such as emulsification-solvent evaporation or nanoprecipitation. The molecular weight of PLGA can be selected from 10-100 kDa, and the LA / GA ratio can be selected from 50:50 to 85:15, adjusted according to the desired degradation rate and drug release profile.

[0087] Gradient pore structure and multi-stage release Furthermore, the end member 10 has a gradient porosity structure from the outside in, including a dense outer region 13 and an inner region 14 with a porosity higher than that of the outer region 13. This gradient porosity structure is formed by the differentiated evaporation of a dual-solvent system: the fast-evaporating solvent evaporates rapidly at room temperature, causing a dense initial solidified layer to form quickly on the solution surface; the slow-evaporating solvent slowly escapes from the inside after the dense surface layer is formed, giving the polymer chain segments sufficient rearrangement time, so that the internal structure gradually densifies but retains the characteristics of relative porosity.

[0088] Based on the differences in degradation rates of the components and the gradient pore structure of the drug-loaded biodegradable material, the end-member 10 exhibits multi-stage drug release characteristics that match the stages of the neuroinflammatory response. In the first post-implantation stage (acute inflammatory phase, approximately 1-7 days), the drug adsorbed on the surface of the PLGA nanoparticles and released through diffusion in the outer dense region 13 of the end-member 10 provide a high initial drug concentration to address the acute inflammatory storm. In the second stage (subacute phase, approximately 1-4 weeks), the PLGA nanoparticles continuously release the drug through surface erosion, with the release rate gradually decreasing to maintain a moderate drug concentration. In the third stage (chronic phase, approximately 1-6 months), the inner porous region 14 of the end-member 10 is gradually exposed as the PLA matrix degrades, and the deep PLGA nanoparticles slowly release the drug through bulk degradation, providing a low-concentration but continuous drug supply, effectively inhibiting the formation of chronic glial scars. This "rapid early release + gradual later release" pattern matches the trend of the inflammatory response from high to low.

[0089] III. Preparation Methods of Invasive Nerve Electrodes like Figure 2 As shown, this application also provides a method for preparing an invasive neural electrode, including the following steps.

[0090] Step 100: Mold Preparation Before injection molding, the mold must first be cleaned. Immerse the mold in anhydrous ethanol for ultrasonic cleaning. The cleaning time can be selected within the range of 8-15 minutes, and the ultrasonic power can be selected within the range of 80-120W. For example, 100W power can be used for cleaning for 10 minutes. After cleaning, remove the mold, wipe it dry, and place it horizontally so that the cavity axis is perpendicular, facilitating subsequent injection molding operations. This treatment helps reduce cavity contamination and residue, thereby improving the appearance consistency and defect control level of the injection molded product.

[0091] The mold is made of a flexible material, selected from PDMS or silicone. The purpose of using a flexible material is twofold: firstly, it facilitates subsequent demolding and reduces the risk of damage to the tip 11; secondly, it facilitates the formation of a complex cavity structure including the connecting cavity 121. The cavity shape matches the geometry of the required end component 10 and can be a single-cavity or multi-cavity design, with multi-cavity designs suitable for mass production. To form the connecting cavity 121 structure, a mandrel or mandrel can be placed within the cavity.

[0092] Step 200: Prepare drug-loaded polymer solution Drug-loaded PLGA nanoparticles and PLA are dissolved in a dual-solvent system to form a drug-loaded polymer solution. The dual-solvent system includes a fast-evaporating solvent and a slow-evaporating solvent, with the fast-evaporating solvent having a higher evaporation rate than the slow-evaporating solvent.

[0093] Specifically, acetone is preferably used as the fast-evaporating solvent, and ethyl acetate is preferably used as the slow-evaporating solvent. Based on the total weight of the drug-loaded polymer solution, the content of acetone can be selected in the range of 10-25 wt%, and the content of ethyl acetate can be selected in the range of 35-50 wt%. For example, a preferred ratio is 15 wt% acetone and 45 wt% ethyl acetate.

[0094] Meanwhile, based on the total weight of the drug-loaded polymer solution, the content of drug-loaded PLGA nanoparticles can be selected in the range of 25-40 wt%, and the content of PLA can be selected in the range of 8-18 wt%. For example, a preferred ratio is 30 wt% drug-loaded PLGA nanoparticles and 10 wt% PLA.

[0095] During preparation, weigh out the PLGA nanoparticles and PLA and add them to the mixed solvent. Dissolve them evenly using magnetic stirring. Place the solution in a vacuum environment to remove air bubbles. The degassing time can be adjusted according to the actual situation; for example, degassing can be performed for 10-20 minutes.

[0096] It should be noted that the design of the dual-solvent system has significant technical implications. The combined use of acetone (fast evaporation) and ethyl acetate (slow evaporation) avoids both surface collapse and porosity caused by rapid evaporation, and internal stress concentration caused by slow evaporation. When the acetone ratio is too high, the surface solidifies too quickly, forming an "outer shell," preventing the internal solvent from escaping and leading to porosity and structural defects. When the acetone ratio is too low, the overall solidification is too slow, and the end components 10 are prone to collapse and deformation.

[0097] It should be emphasized that the drug-loaded polymer solution obtained in step 200 is not only used for subsequent injection molding, but also as an adhesive medium in subsequent bonding steps, thereby achieving synergistic cooperation of "homogeneous materials and homogenous solvents" in the process chain and reducing the risk of interface incompatibility.

[0098] Step 300: Injection molding The drug-loaded polymer solution obtained in step 200 is injected into the mold cavity with the end member 10 prepared in step 100. The solution is drawn up using a microsyringe, and the air inside the cavity is expelled first. The needle is placed close to the bottom of the mold cavity, and the solution is slowly injected so that the cavity is gradually filled from the bottom up, thereby reducing the probability of air bubbles and local voids in the tip segment 11.

[0099] Furthermore, after the drug-loaded polymer solution is injected into the mold cavity, the liquid level should be a certain height above the top of the mold cavity to compensate for volume shrinkage caused by solvent evaporation. For example, the liquid level can be 0.5-3 mm above the top of the cavity, preferably 1.5 mm, to ensure complete filling. This excess liquid level helps maintain the integrity of the tip segment 11 and the connecting segment 12 during subsequent gradient evaporation, reducing the risk of top collapse or underfilling of the tip.

[0100] Step 400: Drying and curing The drug-loaded polymer solution after injection molding in step 300 is subjected to gradient evaporation drying. This step utilizes the rapid evaporation of fast-evaporating solvents to form an initial solidified layer on the solution surface for shaping, and the slow escape of slow-evaporating solvents to densify the interior. After degassing and vacuum drying, the solution is demolded to form the drug-loaded end component 10.

[0101] More specifically, gradient evaporation drying may include the following sub-steps.

[0102] Step 410: Initial shaping. Let it stand at room temperature for a period of time, for example 15-30 minutes, preferably 20 minutes. During this time, acetone evaporates rapidly, and an initial solidified layer forms on the surface of the solution, maintaining the shape of the end member 10, perfectly replicating the sharp shape of the mold cavity, and preventing collapse and deformation during the subsequent evaporation process.

[0103] Step 420: Initial curing. Continue to let it stand at room temperature for a longer period of time, for example, 3-5 hours, preferably 4 hours, to allow the slowly evaporating solvent to begin to slowly escape, and the internal polymer to gradually precipitate and accumulate, resulting in initial curing of the whole.

[0104] Step 430: Vacuum Drying. Transfer the mold to a vacuum drying oven and dry it for a sufficient time under suitable temperature and pressure conditions to completely remove the solvent. For example, the temperature can be selected in the range of 20-30°C, the pressure in the range of -0.05 to -0.2 MPa, and the time in the range of 48-96 hours. Preferred conditions are a temperature of 25°C, a pressure of -0.1 MPa, and a time of 72 hours. Vacuum drying thoroughly removes residual solvent, eliminates biotoxicity, and allows the end component 10 to achieve its final mechanical properties. Insufficient drying time may result in solvent residue, affecting biocompatibility and mechanical properties.

[0105] The aforementioned synergistic process of "fast evaporation and shaping + slow evaporation and densification + vacuum drying and desolventizing" not only helps to obtain a complete tip segment 11 structure without obvious pores and collapse, but also provides a process basis for the formation of a gradient pore structure with "relatively dense outer layer and relatively porous inner layer" inside the end component 10, thereby coupling the molding quality control and multi-stage release characteristics in the same process chain.

[0106] Step 500: Demolding Before demolding, cool the mold to a low temperature, exemplarily in the range of 10-20°C, preferably 15°C. The low temperature causes the end component 10 to shrink slightly. Utilizing the brittle shrinkage of PLA at low temperatures and the difference in thermal expansion and contraction of the PDMS mold, a slight separation occurs between the drug-loaded end component 10 and the mold cavity wall, facilitating demolding. Slightly bend the flexible mold edge and slowly remove the molded end component 10 using tweezers or other tools, avoiding damage to the tip. If there is any flash, it can be gently trimmed with a scalpel.

[0107] Step 600: Surface Treatment The drug-loaded end component 10 obtained in step 500 is subjected to plasma surface activation treatment to introduce surface-active groups. The end component 10 is placed in a plasma cleaning device and surface activation treatment is performed using argon or oxygen. The treatment time can be selected in the range of 3-10 minutes; for example, argon treatment for 5 minutes can be used.

[0108] Plasma treatment introduces active groups (such as -OH, -COOH, etc.) onto the surface of the end member 10, enhancing surface activity, increasing surface energy and wettability, promoting solvent penetration and polymer chain diffusion during subsequent bonding, and further strengthening interfacial bonding. The results of this step will be directly utilized in subsequent bonding steps: the inner wall of the surface-activated bonding cavity 121 is more easily wetted by the adhesive medium and undergoes interfacial micro-dissolution, which is beneficial to improving the reliability and consistency of interfacial solvent-induced bonding.

[0109] Step 700: Connection Using the drug-loaded polymer solution prepared in step 200 as an adhesive medium, the drug-loaded end component 10 treated in step 600 is connected to the end of the electrode substrate 20 by interfacial solvent induction.

[0110] Interfacial solvent-induced bonding is a key technical feature of this application. The bonding mechanism is as follows: the solvent in the polymer solution absorbed by the end of the electrode substrate 20 has a micro-dissolving effect on the inner wall surface of the connecting cavity 121 of the molded end member 10, causing the polymer chain segments at the interface to swell, relax, and rearrange. As the solvent evaporates, the polymer molecular chains on the end surface of the electrode substrate 20 and the end member 10 diffuse and entangle with each other, forming an "interpenetrating network (IPN)" structure or a recrystallized structure, achieving molecular-level fusion. Unlike traditional adhesives that rely on the mechanical interlocking or van der Waals forces of adhesives, the interfacial solvent-induced bonding of this application forms a continuous polymer network on both sides, significantly improving the bonding strength and enabling it to withstand axial pressure and shear force during puncture.

[0111] More specifically, interfacial solvent-induced linkage may include the following sub-steps.

[0112] Step 710: Positioning of the end component. The drug-loaded end component 10, which has undergone surface activation treatment, is placed into the coating fixture for fixation and positioning. The opening end of the connecting cavity 121 of the end component 10 faces upward to facilitate electrode insertion.

[0113] Step 720: Electrode tip dipping. The end of the electrode substrate 20 is dipped in the drug-loaded polymer solution described in step 200, forming a wetted adhesive medium layer on the surface of the end of the electrode substrate 20. To precisely control the bonding area, the dipping depth can be selected in the range of 0.1-0.5 mm, preferably 0.2 mm. The solution layer will serve as the adhesive medium and interface inducer between the electrode substrate 20 and the end member 10.

[0114] Step 730: Alignment and Insertion. Quickly insert the dipped end of the electrode substrate 20 vertically into the connecting cavity 121 of the drug-loaded end member 10 treated in step 600. The solvent in the adhesive medium layer produces a micro-dissolving effect on the inner wall of the connecting cavity 121, causing the polymer chain segments at the interface to swell and relax. Control the insertion depth to avoid crushing the tip of the end member 10.

[0115] Step 740: Interface-induced curing. Curing is performed while maintaining the connection, causing the polymer chain segments at the interface between the electrode substrate 20 and the drug-loaded end component 10 to diffuse, entangle, and recrystallize, forming an integrated connection. The curing time can be selected in the range of 2-6 hours, with 4 hours being preferred by example. The electrode is kept vertical during the curing process.

[0116] Step 750: Remove and Trim. After curing, slowly remove the connected electrodes from the coating fixture. If there are any burrs, gently trim them with a scalpel. Check the connections; if there are any poorly connected electrodes (such as individual electrodes in an array), use tweezers dipped in solution to manually reconnect them.

[0117] Through the synergistic combination of "plasma surface activation + homologous solvent bonding medium + connection cavity 121 to increase contact area", a molecular-level fusion structure, namely the interface fusion region 30, can be formed at the interface, thereby improving the failure resistance of the connection interface under puncture load and long-term fretting environment.

[0118] It should be noted that the aforementioned interface solvent-induced molecular-level fusion connection and its specific process parameters (such as dipping depth, curing time, plasma treatment time, etc.) are a preferred embodiment for achieving a reliable connection between the end component 10 and the electrode substrate 20. Their purpose is to further improve the reliability and consistency of the connection, but they are not prerequisites for the establishment of the core technical concept of "the end component 10 simultaneously serving as a puncture structure and a sustained-release carrier" in this application. For different types of electrode substrate materials and processing conditions, those skilled in the art can also use other methods to achieve a stable connection, such as interference fit, mechanical locking, thermocompression, short-time solvent vapor activation, or setting microstructures to enhance interlocking within the connection cavity 121. These alternative connection methods do not change the basic technical idea of ​​the end component 10 as a drug-loaded biodegradable entity tip, simultaneously undertaking puncture and sustained-release functions, and should all be considered reasonable variations of the technical solution in this application. The step parameters such as dipping depth and curing time given in the above embodiments are exemplary process windows that are easy for those skilled in the art to reproduce. Under the premise of not deviating from the connection mechanism of "homogeneous material / solvent activation promotes interdiffusion of interfacial segments", those skilled in the art can make equivalent adjustments to the above parameters according to factors such as electrode substrate diameter, connection cavity size, solvent evaporation rate and ambient temperature and humidity.

[0119] IV. Invasive neural electrodes This application also provides an invasive neural electrode, including an electrode substrate 20 and a functionally integrated drug-carrying end component 10 connected to the end of the electrode substrate 20.

[0120] The electrode substrate 20 can be made of conventional conductive materials in the art, such as metal wires or silicon-based materials, and performs signal transmission functions. The end of the electrode substrate 20 is housed in the connecting cavity 121 of the functionally integrated drug-carrying end component 10, and the interface between the electrode substrate 20 and the functionally integrated drug-carrying end component 10 is induced by an interface solvent to form a molecular-level interpenetrating network, i.e., an interface fusion region 30.

[0121] This structural design allows the drug-loaded end component 10 to simultaneously perform both puncture and sustained-release functions. The end component 10 itself is the puncture structure, eliminating the problem of coating scraping off and fundamentally solving the detachment issue caused by coating separation from the puncture structure in traditional designs. Simultaneously, the interface solvent-induced bonding enables the electrode substrate 20 and the end component 10 to form a molecular-level fused, integrated connection. This bonding strength far exceeds that of physical adhesion, enabling it to withstand axial pressure and shear force during puncture, as well as stress caused by micromovements in the brain tissue after long-term implantation.

[0122] V. Examples and Comparative Examples To verify the effectiveness of the technical solution of this application, comparative experiments were conducted using the following embodiments and comparative examples.

[0123] Comparative Example 1 Prepare a drug-loaded polymer solution according to the following formula: 20 wt% drug-loaded PLGA nanoparticles, 0 wt% PLA, 40 wt% acetone, and 40 wt% ethyl acetate. Prepare a conical drug-loaded end component according to the above process.

[0124] Test results: AFM has an apparent hardness of only about 25.8 MPa and a toughness of about 132 J / m. 2 Molding quality: Numerous defects and pores; Electrode connection: Initial screening showed an array connection rate of approximately 55%, with some end components showing significant misalignment; After ultrasonic testing, the array connection rate dropped to approximately 25%, with most connections detaching during the ultrasonic process; Peel strength was approximately 1.2 N / mm; Puncture verification: Failed (bending).

[0125] Analysis: The lack of PLA resulted in insufficient apparent hardness of AFM, which could not meet the puncture requirements; the excessive acetone ratio caused the surface to solidify too quickly, and the internal solvent could not escape, resulting in a large number of pores; the insufficient PLGA nanoparticle content led to incomplete molding.

[0126] Comparative Example 2 Prepare a drug-loaded polymer solution according to the following formula: 15 wt% drug-loaded PLGA nanoparticles, 5 wt% PLA, 40 wt% acetone, and 40 wt% ethyl acetate. Prepare a conical drug-loaded end component according to the above process.

[0127] Test results: AFM apparent hardness is approximately 51.3 MPa, and toughness is approximately 253 J / m. 2 Molding quality: still has defects; Electrode connection: the initial screening array connection rate is about 62%, with gaps in some connections; after ultrasonic testing, the array connection rate drops to about 37%; Peel strength is about 2.5 N / mm; Puncture verification: failed (bending).

[0128] Analysis: The addition of PLA improved the apparent hardness and toughness of AFM, proving the reinforcing effect of PLA. However, the PLGA nanoparticle content was too low; the acetone ratio was still too high.

[0129] Comparative Example 3 Prepare a drug-loaded polymer solution according to the following formula: 20 wt% drug-loaded PLGA nanoparticles, 5 wt% PLA, 25 wt% acetone, and 50 wt% ethyl acetate. Prepare a conical drug-loaded end component according to the above process.

[0130] Test results: AFM apparent hardness is approximately 89.9 MPa, and toughness is approximately 521 J / m. 2 Molding quality: improved integrity; Electrode connection: initial screening array connection rate was about 87%, and connection coaxiality was improved; after ultrasonic testing, the array connection rate dropped to about 73%; Peel strength was about 5.2 N / mm; Puncture verification: failed (bending).

[0131] Analysis: Reducing the acetone ratio and increasing the ethyl acetate ratio significantly improved the molding quality and reduced porosity; however, the apparent hardness of AFM still did not reach the puncture threshold of 0.1 GPa.

[0132] Comparative Example 4 Prepare the drug-loaded polymer solution according to the following formula: 25wt% drug-loaded PLGA nanoparticles, 10wt% PLA, 15wt% acetone, and 50wt% ethyl acetate. Perform plasma treatment for 3 minutes. Prepare a conical drug-loaded end component according to the above process.

[0133] Test results: AFM apparent hardness is approximately 115.6 MPa, and toughness is approximately 765 J / m. 2 Molding quality: Mostly intact; Electrode connection: Initial screening array connection rate is about 90%, most connections are complete but there are still a few offsets; After ultrasonic testing, the array connection rate drops to about 79%, and some connections fall off after ultrasonication; Peel strength is about 7.9 N / mm; Puncture verification: Successful.

[0134] Analysis: The apparent hardness of AFM reached the puncture threshold (> 0.1 GPa) for the first time; the content of PLGA nanoparticles and PLA both reached the appropriate range; however, the plasma treatment time was relatively short, and the bonding effect still needs to be optimized.

[0135] Example 1 Prepare the drug-loaded polymer solution according to the following formula: 30 wt% drug-loaded PLGA nanoparticles, 10 wt% PLA, 15 wt% acetone, and 45 wt% ethyl acetate. Extend the plasma treatment time to 5 min. Other process conditions use the aforementioned preferred parameters.

[0136] Test results: AFM apparent hardness is approximately 0.137 GPa, and toughness is approximately 778 J / m. 2Molding quality: basically intact; Electrode connection: initial screening array connection rate is about 99%, connection coaxiality is good; after ultrasonic testing, array connection rate is about 97%; peel strength is about 10.1 N / mm; puncture verification: successful.

[0137] Analysis: All performance parameters are close to the optimal values; the connection effect is improved by extending the plasma treatment time.

[0138] Example 2 (Preferred Example) The drug-loaded polymer solution was prepared according to the following formula: 30wt% drug-loaded PLGA nanoparticles, 10wt% PLA, 15wt% acetone, and 45wt% ethyl acetate. All the aforementioned optimized process parameters were used: ultrasonic cleaning of the mold with a power of 100W and a cleaning time of 10min; vacuum degassing of the solution for 15min; the injection liquid level exceeding the cavity by 1.5mm; standing at room temperature for 20min followed by standing for another 4h; vacuum drying conditions of 25℃, -0.1MPa, and 72h; demolding temperature of 15℃; plasma argon treatment for 5min; electrode dipping depth of 0.2mm; and connection curing time of 4h.

[0139] Test results: AFM apparent hardness is approximately 0.178 GPa, and toughness is approximately 886 J / m. 2 Molding quality: The shape is intact, without air holes, collapses, or defects; Electrode connection: The initial screening array connection rate is about 100%, all connections are complete and coaxial, and no observable offset is found; After ultrasonic testing, the array connection rate is about 99.8%, and the interface fusion zone is complete; Peel strength is about 11.3 N / mm; Puncture verification: Successful.

[0140] The end component 10 obtained in this embodiment meets all design requirements and can satisfy the puncture and long-term sustained release needs of invasive nerve electrodes.

[0141] Summary of Formula Optimization Rules The following patterns can be observed from the data of the above embodiments: First, the integrity of the molding is significantly improved when the PLGA nanoparticle content reaches a certain level (≥25wt%), with the best effect achieved at 35wt%. Too low a PLGA nanoparticle content leads to insufficient drug loading and is also unfavorable for forming a uniform composite structure. Second, when the PLA content reaches a suitable level (≥10wt%), the apparent hardness of the AFM meets the puncture requirement. PLA, as a reinforcing phase, plays a skeletal supporting role; without PLA, the apparent hardness of the end component at 10AFM is severely insufficient. Third, the best overall effect is achieved when the ratio of acetone to ethyl acetate is within a suitable range (approximately 15:45), realizing a gradient molding effect of "rapid shaping - slow densification," ensuring the integrity of the tip shape while avoiding internal porosity. Fourth, a plasma treatment time of a certain duration (≥5min) results in good bonding. Plasma treatment enhances surface activity, and combined with the interface solvent-induced process, achieves molecular-level interface fusion.

[0142] Based on the three-level evaluation data of the connection effect, with the gradual optimization of the formulation and process parameters, the connection rate of the initial screening array gradually increased from 55% in Comparative Example 1 to 100% in Example 2 (preferred example); the array connection retention rate after ultrasonic testing increased from 25% in Comparative Example 1 to 99.8% in Example 2; and the peel strength increased from approximately 1.2 N / m in Comparative Example 1 to approximately 11.3 N / m in Example 2. These data indicate that the synergistic effect of achieving a suitable range of drug-loaded PLGA nanoparticle and PLA content, optimizing the dual-solvent system ratio, and ensuring sufficient plasma treatment time significantly promotes the connection reliability between the drug-loaded end component 10 and the electrode substrate 20.

[0143] More importantly, there is a clear correlation between the apparent hardness of the AFM and the puncture test results: puncture tests failed when the apparent hardness of the AFM was below 0.1 GPa, and succeeded when the apparent hardness of the AFM reached 0.1 GPa or above. This indicates that an apparent hardness of 0.1 GPa is the critical threshold for the end component 10 of this application to achieve the puncture function.

[0144] VI. Other Implementation Methods Those skilled in the art will understand that, without departing from the spirit and scope of this application, the following substitutions or modifications can be made to the technical solution of this application.

[0145] In terms of materials, a combination of PLGA and PCL (polycaprolactone) can be used instead of a combination of PLGA and PLA to obtain different degradation characteristics and release curves to meet different clinical application needs.

[0146] Solid PLGA and dispersed drugs can be used to replace drug-loaded PLGA nanoparticles to simplify the nanoparticle preparation process; dimethylformamide and acetone can be used to replace acetone and ethyl acetate as a dual solvent system, and dimethylformamide has a moderate evaporation rate.

[0147] In terms of geometry, using the same formula and process as in Example 2, other geometric end components 10 can be prepared by changing the mold cavity of different shapes. For example, the end cap shape is suitable for blunt electrodes, covering the electrode end and forming a relatively blunt front end shape. The bullet-shaped streamlined design reduces puncture resistance and tissue damage compared to the conical shape. The wedge shape is suitable for specific puncture angle requirements, and the needle shape has a large length-to-diameter ratio, which is suitable for deep implantation.

[0148] All such substitutions or modifications shall fall within the scope of protection of this application.

[0149] 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.

[0150] The above embodiments have the following technical effects: To address the issue of coating detachment, the functionally integrated drug-loaded end member 10 of the above embodiment is integrally molded from a drug-degradable material and configured to simultaneously serve as the puncture structure for the invasive neural electrode and a long-term drug-releasing carrier. This design makes the end member 10 itself a puncture structure, eliminating the weak interface between the coating and the substrate present in traditional "puncture structure + surface coating" designs during puncture. This fundamentally eliminates the risk of the coating being scraped off or peeled off due to shear forces, ensuring that the drug-loaded material can reach the predetermined implantation depth intact with the electrode and exert its sustained-release function in situ.

[0151] In achieving both puncture and sustained-release functions, the above embodiments combine drug-loaded PLGA nanoparticles with polylactic acid (PLA) in a specific ratio. PLA serves as the continuous phase providing mechanical support, while the drug-loaded PLGA nanoparticles act as the filler phase to provide sustained-release functionality, forming a composite structure of "nanoparticle-filled reinforced matrix." This composite structure enables the end component 10 to achieve the required threshold hardness for puncture in its dry state via AFM, while maintaining the overall biodegradable and sustained-release properties of the material. This effectively overcomes the technical contradiction in existing technologies where "high-rigidity materials degrade slowly, while easily degradable materials have low hardness," achieving synergistic optimization of puncture and sustained-release performance within the same material system.

[0152] To improve molding quality, the dual-solvent system used in the above embodiments includes a fast-evaporating solvent and a slow-evaporating solvent. The rapid evaporation of the fast-evaporating solvent forms an initial solidified layer on the solution surface for shaping, while the slow evaporation of the slow-evaporating solvent densifies the interior. This gradient evaporation drying process can maintain the accurate replication of the geometry of the tip segment 11 while avoiding porosity, collapse, or structural defects caused by rapid solvent escape, significantly improving the molding integrity and appearance consistency of the micron-level tip structure. Furthermore, by controlling the liquid level of the drug-loaded polymer solution after injection into the mold cavity to be slightly higher than the top of the cavity, the volume shrinkage caused by solvent evaporation can be effectively compensated, further reducing the risk of tip underfilling or top collapse.

[0153] Regarding multi-stage drug release, the gradient porosity structure formed inside the end member 10 in the above embodiment, from the outside to the inside, works in conjunction with the differences in the degradation rates of the drug-loaded biodegradable material components to jointly endow the end member 10 with multi-stage drug release characteristics. The dense outer layer region 13 bears the main mechanical load during the puncture stage and provides a high initial drug concentration through diffusion in the early stages of implantation. The inner layer region 14, with a higher porosity than the outer layer region 13, is gradually exposed and releases deep drugs as the material degrades, forming a "faster in the early stage + slower in the later stage" release pattern. This release pattern matches the trend of the inflammatory response after nerve implantation from high to low, which is beneficial for providing appropriate drug concentration levels at different stages.

[0154] To improve connection reliability, the connecting segment 12 in the above embodiment has a connecting cavity 121 inside. The opening of the connecting cavity 121 faces away from the tip segment 11, so that a larger contact area can be formed after the end of the electrode substrate 20 is inserted into the connecting cavity 121. Combined with the surface-active groups introduced by the plasma surface activation treatment and the molecular-level interpenetrating network structure formed by the interface solvent-induced connection, namely the interface fusion region 30, the bonding interface between the electrode substrate 20 and the drug-loaded end component 10 has a bonding strength significantly higher than that of physical adhesion. It can effectively withstand the axial pressure and shear force during the puncture process, as well as the periodic stress caused by brain tissue micromovement after long-term implantation, ensuring the long-term stability of the invasive neural electrode in practical applications.

[0155] In terms of process synergy, there is an organic synergistic relationship between the steps in the preparation method of the above embodiments: the solution obtained in the step of preparing the drug-loaded polymer solution is not only used for injection molding, but also used as an adhesive medium in the subsequent connection step, realizing the process synergy of "homologous material-homologous solvent" and reducing the risk of interface incompatibility; the result of the plasma surface activation treatment step directly serves the subsequent interface solvent-induced connection step, and the inner wall of the activated connection cavity 121 is more easily wetted by the adhesive medium and undergoes interface micro-dissolution, improving the reliability and consistency of the connection; the mold adopts a flexible material and is cooled before demolding, and the thermal expansion and contraction characteristics of the material are used to achieve flexible demolding, reducing the risk of damage to the micron-level tip segment 11 structure during the demolding process.

[0156] Regarding the adaptability of materials and geometry, the drug-loaded end component 10 of the above embodiments can be selected in various geometric shapes such as conical, cap-shaped, bullet-shaped, wedge-shaped, needle-shaped, and pyramidal according to actual application needs, in order to adapt to different types of electrode substrates 20 and different implantation requirements; the drugs loaded on the drug-loaded PLGA nanoparticles may include anti-inflammatory drugs, neuroprotective drugs, or anti-proliferative drugs, in order to provide corresponding drug treatment for different pathological reactions; the material degradation cycle can be controlled within a certain range by adjusting the formula to cover different time windows from the acute inflammatory phase to the chronic phase, reflecting the flexibility and wide applicability of the technical solutions of the above embodiments.

[0157] VII. Supplementary Explanation and Verification Examples Further explanation regarding multi-stage drug release characteristics To avoid misunderstandings regarding the "multi-stage drug release characteristics" and its implementation mechanism, it should be clarified that the multi-stage drug release characteristics described in this application are not defined by a single parameter threshold, but rather refer to the relatively differentiated release behavior of the end member 10 at different time periods after implantation: In the initial stage of implantation, drug release mainly originates from diffusion in the outer region 13 of the end member 10 and surface-related release of the drug-loaded components; subsequently, as the drug-loaded biodegradable material gradually degrades, the inner region 14 of the end member 10 gradually participates in the release and exhibits a relatively smoother release process. The formation of this release behavior is related to the pore gradient distribution from the outside to the inside of the end member 10 and the differences in degradation rates of different components in the drug-loaded biodegradable material, thereby enabling the end member 10 to provide relatively differentiated drug supply at different stages after implantation. The above-mentioned release behavior can be verified by in vitro release experiments in a simulated in vivo environment. Those skilled in the art can prepare end members 10 and corresponding invasive neural electrodes that meet the dual functions of puncture and sustained release based on the material system, molding process, and connection method disclosed in this application.

[0158] Supplementary explanation of testing methods To facilitate the reproduction of the AFM apparent hardness acquisition process under the same test conditions by those skilled in the art, the following further explanation is provided: The Hertz contact model can be fitted to the force-displacement curve using a common fitting expression for spherical indenter contact. Under the assumption of elastic contact between the spherical probe and the sample surface, the contact force F and the indentation depth δ satisfy a power function relationship. The local apparent elastic modulus can be obtained by fitting the test curve. In the above fitting, the equivalent radius of the spherical probe is determined by the probe's geometric parameters, and the indentation depth is calculated from the probe displacement and sample shape transformation in the force spectrum curve. To avoid incomparability due to differences in test conditions, the comparison of AFM apparent hardness is preferably performed under the same probe specifications, the same loading rate, the same drying state, and the same fitting range.

[0159] To facilitate the reproduction of the toughness calculation process, the following further explanation is provided: The area under the load-displacement curve obtained from the single-sided notch tensile test can be used as an energy characterization quantity of the fracture process. The fracture energy can be obtained by dividing the area under the curve by the product of the initial cross-sectional area of ​​the specimen and the effective ligament width, wherein the effective ligament width is the remaining width of the specimen after deducting the notch depth.

[0160] Microstructure characterization and verification To verify the impact of the dual-solvent gradient evaporation process on the microstructure, scanning electron microscopy (SEM) can be used to observe the cross-section of the end member 10. Based on the process conditions disclosed in this application, the outer layer region 13 of the end member 10 should exhibit a dense, continuous phase structure with low porosity; while the inner layer region 14 should exhibit a uniformly distributed microporous structure with relatively high porosity. This gradient porosity structure from the outside in is the result of the synergistic effect of surface shaping of the fast-evaporating solvent and internal densification of the slow-evaporating solvent in the dual-solvent system.

[0161] Drug release characteristics verification The drug-loaded end component 10 prepared in Example 2 (preferred example) was placed in PBS buffer at 37°C for in vitro release testing. The results showed that within the first 24 hours, the cumulative drug release reached approximately 20%, corresponding to the rapid release of the drug from the outer region 13 and the surface, meeting the drug requirements during the acute inflammatory phase. Subsequently, the release rate stabilized, with a cumulative release of approximately 40% on day 7, approximately 70% on day 28, and over 90% by the end of the third month. This release curve exhibited a typical three-stage characteristic of "burst release-sustained release-long-lasting maintenance," highly matching the inflammatory response process after nerve implantation, verifying the realization of the multi-stage drug release characteristics described in this application.

[0162] VIII. Comparison between the technical solution of this application and existing technical routes Typical implantation procedures for invasive electrodes used in brain-computer interfaces To facilitate understanding of the innovative positioning of the technical solution in this application, the mainstream implantation methods and limitations of existing invasive flexible neural electrodes in this field are further explained. To the inventor's knowledge, currently mature brain-computer interface invasive flexible electrode implantation methods mainly include the following two technical routes: Category 1: Flexible electrode + sustained-release coating + auxiliary implantation device solution. In this solution, the flexible electrode itself lacks the rigidity to puncture brain tissue and requires auxiliary implantation devices (such as rigid guide needles, shuttle needles, implanter cannulas, etc.) to provide puncture force and mechanical support to deliver the flexible electrode into the brain tissue at the predetermined depth. To achieve sustained drug release, a biodegradable drug-loaded soft coating is typically coated on the surface of the flexible electrode. However, during the process of the auxiliary implantation device guiding the flexible electrode into the brain tissue, shear stress exists between the guide needle sidewall of the implanter and the surface of the flexible electrode, as well as between the brain tissue and the electrode surface. Due to its low mechanical strength and limited interfacial bonding strength with the electrode substrate, the drug-loaded soft coating is easily scraped off or peeled off layer by layer along the puncture path. It is important to note that the detached coating material can still degrade and release the drug it carries within brain tissue; therefore, coating detachment does not signify a complete loss of sustained-release function. However, because the coating has detached from the electrode surface and remains in the tissue along the puncture path, the drug release site deviates from the intended target area reached by the electrode tip, failing to provide an effective local drug concentration at the electrode-tissue interface at the target location. In other words, the core issue caused by coating detachment lies in the spatial shift between the drug release location and the treatment target, resulting in a significant reduction in local anti-inflammatory and neuroprotective effects at the target site, rather than a complete failure to release the drug.

[0163] The second type: Flexible electrode + variable stiffness coating (hard first, soft later) approach. This approach uses a coating material that can undergo stiffness transformation under specific conditions (such as materials that soften after hydration). The electrode is in a rigid state before implantation to facilitate autonomous puncture, and the coating softens in the body fluid environment after implantation to reduce mechanical mismatch with brain tissue. While this approach avoids dependence on assistive implantation devices to some extent, the design focus of the variable stiffness coating is on achieving controllable stiffness transformation. The introduction of drug sustained-release function is significantly constrained by the choice of coating material and thickness. Furthermore, a coating-substrate interface still exists between the variable stiffness coating and the electrode substrate, and the reliability of the interface bonding during puncture remains to be addressed.

[0164] Unlike the two approaches mentioned above, this application proposes a novel technical route: utilizing a rigid end component made of drug-degradable material as the puncture structure itself, while simultaneously fulfilling the function of sustained drug release. To the inventor's knowledge, no existing mature brain-computer interface solution incorporates a design where a "rigid puncture structure also functions as a drug-releasing device." The core concept of this application is to resolve the contradiction between the requirements for rigid puncture and sustained drug release within a biodegradable material system, enabling the same component to simultaneously meet both functional requirements, thus opening up a new technological path distinct from the two aforementioned approaches.

[0165] Comparative verification of puncture function and coating protection To further verify the advantages of the drug-loaded end component 10 of this application compared with existing solutions, the following comparative tests were conducted: Comparative Test 1 (Independent Puncture Capability Verification): The flexible electrode with drug-loaded end component 10 prepared in Example 2 and the same type of flexible electrode without the end component were subjected to puncture comparison tests. Approximately 0.6% (w / v) agarose gel was used as the brain tissue simulation medium. The results showed that the flexible electrode with drug-loaded end component 10 could complete the puncture independently without any auxiliary implantation device. The end component 10 maintained its structural integrity during the puncture process, without bending or breakage. In contrast, the same type of flexible electrode without the end component could not penetrate the simulation medium under the same conditions due to insufficient stiffness, and bent. This comparison verified the technical effect of the drug-loaded end component 10 in this application, which endows the flexible electrode with independent puncture capability.

[0166] Comparative Test 2 (Coating Retention Verification in Simulated Implantation Device Scenario): To simulate the implantation scenario of the existing Type I scheme, a similar flexible electrode was used, and a drug-loaded coating with the same formulation as in Example 2 was coated on its surface. A rigid guide needle (tungsten wire) was used as the implantation device, and the coated flexible electrode was inserted into the agarose gel along with the guide needle. After puncture, the electrode was removed for observation. The results showed that the coating on the electrode surface exhibited obvious peeling and accumulation, with a large amount of coating material remaining in the shallow area of ​​the puncture path and failing to reach the predetermined depth with the electrode. In contrast, the flexible electrode with the integrated drug-loaded end component 10 prepared in Example 2 was punctured in the same simulated medium. The end component 10 maintained its structural integrity throughout the puncture, and its appearance and integrity remained unchanged after reaching the predetermined depth. This comparative test shows that the integrated drug-loaded end component 10 of this application, being itself a puncture structure, does not have the problem of the coating being scraped off by the implantation device or tissue shear force along the puncture path, as is common in traditional coating schemes. The drug-loaded material can reach the predetermined target position intact with the electrode and be released in situ.

[0167] Hierarchical Explanation of the Core Innovation Logic of this Application To further clarify the innovative logical hierarchy of the integrated drug-carrying end component 10 of this application and the progressive relationship between the various technical effects, the following supplementary explanation is provided.

[0168] The first level, and the core innovation of this application, is the unification of the mechanical rigidity required for puncture and the sustained-release function of drugs within a biodegradable drug-loaded material system. In existing technology, biodegradable sustained-release materials typically have low mechanical strength and are not considered capable of independently undertaking the mechanical function of puncturing brain tissue; while materials with puncture rigidity (such as metals) generally lack degradation and sustained-release properties. This application utilizes a specific compound system of drug-loaded PLGA nanoparticles and polylactic acid (PLA), using PLA as a continuous phase to provide rigid framework support and drug-loaded PLGA nanoparticles as a filling phase to provide sustained-release function and filling enhancement effect, achieving sufficient mechanical properties (AFM apparent hardness ≥0.1 GPa) for puncturing brain tissue within a biodegradable and sustained-release material system. Therefore, the flexible electrode can complete brain tissue puncture without relying on auxiliary implantation equipment, thanks to the inherent rigidity of the end component 10. Simultaneously, the end component 10 degrades and releases drugs automatically after implantation, thus solving both the core requirements of puncture and sustained release in a single component. This technical approach, in which "the rigid puncture structure itself is a drug-releasing agent," breaks through the technical limitation in existing technologies that the puncture function and the sustained-release function must be undertaken by different materials or different structures, and is the most fundamental technical contribution of this application.

[0169] The second level is the structural advantage arising from the aforementioned integrated functional design: eliminating the risk of coating detachment and target deviation at the structural level. Since the end member 10 is itself the tip of the puncture structure, it serves as the main structural component guiding the electrode forward during puncture into the brain tissue, rather than a passive coating attached to the surface of the puncture structure or the implantation device. Therefore, regardless of whether an implantation device is used, the end member 10 will not be scraped off by shear forces between the guide needle sidewall and the electrode surface or by friction between the brain tissue and the electrode, as there is no weak interface between the coating and the puncture structure as in traditional coating designs. This ensures that the drug-loaded material can reach the predetermined target location intact with the electrode and exert its sustained-release function in situ, guaranteeing spatial consistency between the drug release location and the treatment target. Furthermore, the end member 10 is a body-type drug-loaded structure rather than a film-type coating; even if minor wear occurs on the tip surface during puncture, its remaining main structure can still carry the majority of the drug load accurately to the target depth.

[0170] The third level is the multi-stage drug release characteristic brought about by the gradient porosity structure spontaneously formed by the gradient evaporation of the dual solvent system within the end-member 10. This gradient porosity structure, combined with the different degradation rates of the components in the drug-loaded biodegradable material (PLGA degrades faster than PLA), allows the end-member 10 to provide differentiated drug supply at different stages after implantation, matching the changing trend of neuroinflammatory response from high to low. This multi-stage release characteristic, after resolving the core contradiction between puncture and sustained release and eliminating the risk of coating detachment, is an additional technical benefit brought about by the functional integration design, further improving the therapeutic effect of the end-member 10 during long-term implantation.

[0171] The three levels described above are progressively related: the first level is the basic premise and core innovation; the second level is the technical effect naturally derived from the structural design of the first level; and the third level is the additional benefit obtained through the synergy of materials and processes based on the first two levels. Together, these three constitute the complete technical contribution of this application. The connection process described in this application (including interface solvent-induced connection and its process parameters) is a supporting means to achieve the overall structural reliability of this application, serving to ensure that the end component 10 maintains a stable connection with the electrode substrate 20 during puncture and implantation. It is not itself a prerequisite for the aforementioned core innovation logic.

[0172] 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.

[0173] 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 drug-loaded end component for an invasive neural electrode, characterized in that, The component is integrally molded from a drug-loaded biodegradable material and is configured to serve as both a puncture structure for the invasive neural electrode and a long-term drug release carrier. The drug-loaded biodegradable material comprises a polymer continuous phase and drug-loaded microparticles dispersed in the polymer continuous phase. The polymer continuous phase is used to provide mechanical support, and the drug-loaded microparticles are used to provide drug sustained-release function. The polymer continuous phase contains polylactic acid, and the drug-loaded microparticles contain drug-loaded PLGA nanoparticles. The drug-loaded biodegradable material is prepared by integral molding of a drug-loaded polymer solution. The drug-loaded polymer solution includes the drug-loaded PLGA nanoparticles, polylactic acid, and a dual-solvent system composed of a fast-evaporating solvent and a slow-evaporating solvent. Under room temperature and atmospheric pressure conditions, the evaporation rate of the fast-evaporating solvent is higher than that of the slow-evaporating solvent. The fast-evaporating solvent is selected from any one of acetone, chloroform, tetrahydrofuran, and dichloromethane, and the slow-evaporating solvent is selected from any one of ethyl acetate, dimethylformamide, and dimethyl sulfoxide. Based on the total weight of the drug-loaded polymer solution, the content of the drug-loaded PLGA nanoparticles is 25-40 wt%, and the content of the polylactic acid is 8-18 wt%.

2. The drug-loaded end member according to claim 1, characterized in that, The component includes a tip segment and a connecting segment arranged along the axial direction; the tip segment has a geometric shape suitable for puncturing biological tissue, and the connecting segment is used to connect to the electrode substrate.

3. The drug-loaded end member according to claim 2, characterized in that, The connecting segment is provided with a connecting cavity for accommodating the end of the electrode substrate. The inner wall of the connecting cavity is configured to activate the contact interface under the action of a solvent, and form an integrated connection with molecular-level fusion through interdiffusion and entanglement of molecular chains with the end of the electrode substrate.

4. The drug-loaded end member according to any one of claims 1-3, characterized in that, The component has an AFM apparent hardness of not less than 0.1 GPa in a dry state, and its material degradation cycle in vivo or simulated body fluid is 1 to 12 months.

5. The drug-loaded end member according to claim 1, characterized in that, The component has a gradient pore structure inside, with the porosity increasing from the outside to the inside, in order to achieve multi-stage drug release that matches the tissue reaction stage.

6. The drug-loaded end member according to claim 1, characterized in that, The component has an apparent AFM hardness of 0.1-2 GPa in a dry state and a toughness of not less than 750 J / m. 2 ; and / or, the component has any one of the following geometric configurations: conical, cap-shaped, bullet-shaped, wedge-shaped, needle-shaped, pyramidal, streamlined, or wedge-shaped.

7. The drug-loaded end member according to claim 1, characterized in that, The fast-evaporating solvent is acetone, and the slow-evaporating solvent is ethyl acetate; based on the total weight of the drug-loaded polymer solution, the content of acetone is 10-25 wt%, and the content of ethyl acetate is 35-50 wt%.

8. A method for preparing an invasive neural electrode, used to prepare the drug-loaded end component according to any one of claims 1-6, characterized in that, Includes the following steps: S1. Preparation of drug-loaded polymer solution: Dissolve or disperse the components of the drug-loaded biodegradable material in a dual-solvent system containing a fast-evaporating solvent and a slow-evaporating solvent; S2. Injection molding and gradient drying: The drug-loaded polymer solution is injected into the mold cavity and subjected to gradient evaporation drying; the rapid evaporation of the fast-evaporating solvent forms an initial solidified layer on the surface, and the slow evaporation of the slow-evaporating solvent causes phase separation or densification inside, forming a drug-loaded end component after demolding. S3. Connection: An electrode substrate is provided, and the connection interface of the end surface of the electrode substrate and / or the drug-loaded end component is activated by a solvent, so that the two come into contact and form an integrated connection through the interdiffusion and entanglement of molecular chain segments.

9. The preparation method according to claim 8, characterized in that, Step S3 specifically includes: S31. Dip the end of the electrode substrate into the drug-loaded polymer solution or its compatible solvent to form a wetted adhesive medium layer on its surface; S32. Insert the dipped end of the electrode substrate into the connecting cavity of the drug-loaded end component, and use the solvent in the adhesive medium layer to produce a micro-dissolving effect on the inner wall of the connecting cavity; S33. Maintain the connection state and solidify to form a molecular-level interpenetrating network at the interface between the electrode substrate end and the drug-loaded end component.

10. The preparation method according to claim 8, characterized in that, After step S2, the process further includes surface activation treatment of the drug-loaded end component, which includes plasma treatment, ultraviolet irradiation, or chemical reagent treatment.

11. An invasive neural electrode, characterized in that, include: An electrode substrate; and a drug-loaded end member as described in any one of claims 1-7 connected to the end of the electrode substrate.

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