Implantable nerve probe integrated with biological protection layer, preparation method and system

Abstract

The invention provides an implantable nerve probe integrated with a biological protection layer, a preparation method and a system. The nerve probe sequentially comprises a bottom biological protection layer, a bottom flexible substrate layer, a conductive layer, a top flexible substrate layer and a top biological protection layer from bottom to top, the bottom biological protection layer and the top biological protection layer form a biological protection layer located on the outermost periphery of the nerve probe and are used for avoiding erosion of a damp and hot cerebrospinal fluid environment in brain tissue. The integrated biological protection layer located on the outermost periphery of the flexible nerve probe is adopted, corrosion of cerebrospinal fluid to the nerve probe can be inhibited in in-vivo application, the long-term biocompatibility of the flexible nerve probe is effectively improved, the in-vivo long-term service life of the flexible nerve probe is effectively prolonged, and the nerve probe has the advantages of being high in integration level, high in stability and the like; and the requirement of in-vivo long-term effective service of the device can be met.

Description

Technical Field

[0001] This application relates to the field of brain-computer interface neural microelectrodes in the field of biomedical engineering technology, specifically to implantable neural probes with integrated biological protective layers, preparation methods and systems. Background Technology

[0002] Brain-computer interface (BCI) technology is an advanced technology that enables direct information interaction between the brain and the external physical environment, with significant application prospects in neuroscience, brain diseases, and brain-computer interaction. After more than 50 years of research, BCI has evolved from the theoretical proposal and verification stages to its current stage of technological explosion, with countries such as the United States, the European Union, and Japan accelerating their BCI development. Implantable BCI devices possess the ability to acquire rich information from neurons in the brain with high spatiotemporal resolution, offering unique advantages in the fundamental analysis of neural circuits, observation and analysis of brain activity, diagnosis and treatment of neurological diseases, and the establishment of brain functional network models. It is one of the key foundational tools supporting the development of my country's Brain Project.

[0003] However, implantable brain-computer interface devices require invasive insertion into the brain to acquire signals, and low long-term biocompatibility remains a key challenge limiting their clinical application. Firstly, the brain's warm, moist cerebrospinal fluid has a high water content and contains complex biomolecules such as proteins, inorganic salts, enzymes, and reactive oxygen species. Traditional metal microwire electrodes are first implanted into the brain to collect neural discharge signals, but due to limitations in integration methods, spatial resolution is low, and the polymer insulation layer is susceptible to corrosion and cracking within the body; implantable silicon-based electrodes face similar issues. Secondly, silicon-based and metal microwire materials are hard and brittle, with Young's modulus of 150-200 GPa, seven orders of magnitude higher than the brain tissue's modulus of only 10-100 KPa. This results in significant bending stiffness, making it unable to adapt to brain tissue movement, potentially causing tissue damage, and leading to astrocytes encapsulating the microelectrode points, causing device malfunction. Finally, during implantation, due to the dense and highly vascularized nature of neural tissue, rigid implantable brain-computer interface devices with large cross-sections inevitably damage cerebral blood vessels and tissues. Therefore, current implantable brain-computer interface devices have limitations in terms of long-term biocompatibility, such as the failure of the insulating layer due to erosion by cerebrospinal fluid, the failure of microelectrode points encapsulated by glial cells, and damage to cerebral blood vessels and tissues.

[0004] In recent years, implantable brain-computer interface (BCI) devices based on flexible polymer substrates have attracted widespread attention from research teams both domestically and internationally. Among these, BCI devices based on SU8 and PI substrates have been extensively reported. Professor Chong Xie of the University of Texas used the polymer photoresist SU8 as a substrate to fabricate a flexible implantable BCI device with a thickness of only 0.8-1 μm. Immunohistochemical staining analysis of the tissue-probe interface after implantation showed that the thinner flexible BCI device did not generate significant neuroinflammation around it. However, the biocompatibility of SU8 as an implant material remains controversial, and obtaining FDA certification for the fabricated device is challenging. Elon Musk, founder of Neuralink, achieved a flexible electrode with a thickness of 6 μm using a photolithographic polyimide (PI) substrate and implanted it using an implantation robot. To further improve the conformability of PI flexible electrodes to brain tissue, Researcher Fang Ying of the Center for Nanoscience and Technology, Chinese Academy of Sciences, achieved a flexible PI neural tassel with a thickness of 1.5 μm. Reducing the thickness of the flexible BCI device reduces the bending stiffness of the implant while significantly reducing glial cell encapsulation and brain tissue vascular damage. Therefore, there is an urgent need to develop flexible brain-computer interface devices with submicron-thick PI substrates to achieve in vivo applications with low implantation damage and conformity to brain tissue.

[0005] Polyimide (PI) film is one of the earliest used flexible substrate encapsulation materials, possessing excellent chemical inertness, electrical insulation, and temperature stability. Furthermore, PI, as a precursor to polyamic acid esters, is photolithographically compatible, allowing for compatibility with integrated circuit and MEMS processes, and it has not exhibited cytotoxicity after long-term implantation in biological organisms. Therefore, it is widely used in the fabrication of implantable flexible brain-computer interface devices. However, PI polymer films contain hydrophilic imine rings, resulting in a high moisture absorption rate (the ratio of moisture absorbed to its own weight) of 0.7%-1.4%, and the films are prone to delamination and cracking. It is evident that prolonged exposure of the PI polymer film insulation layer to the humid and warm cerebrospinal fluid environment will accelerate its aging, gradually reducing its insulation performance. Professor Sanchez of the University of Miami implanted tungsten wire electrodes with PI film insulation layers into mice, and after 2-3 weeks, the impedance at the electrode points significantly decreased, and damage to the PI film insulation layer was observed upon removal. Walter Lang et al., through immersion aging experiments, observed significant delamination of the insulation layer of PI-based flexible brain-computer interface devices, and short circuits between different channels caused by moisture penetration into the insulation layer. Furthermore, studies have shown that the water resistance of polymer films decreases significantly with decreasing thickness, leading to an accelerated failure cycle of the polymer insulation layer. This indicates that ultrathin polymer films exposed to a humid and hot cerebrospinal fluid environment for extended periods exhibit more pronounced insulation layer erosion failure due to cerebrospinal fluid.

[0006] The patents with publication numbers CN111053535A and CN112244839A both involve implantable flexible neural probes. Although improvements have been made in terms of biocompatibility, inhibition of intraoperative infection and postoperative inflammatory response, there is still a risk of long-term implantation failure due to cerebrospinal fluid erosion. Summary of the Invention

[0007] In view of the deficiencies in the prior art, the purpose of this application is to provide an implantable neural probe with an integrated biological protective layer, a preparation method and a system.

[0008] In a first aspect, this application provides an implantable neural probe with an integrated biological protective layer, comprising, from bottom to top: a bottom biological protective layer, a bottom flexible substrate layer, a conductive layer, a top flexible substrate layer, and a top biological protective layer;

[0009] The bottom and top bioprotective layers form the outermost bioprotective layer of the neural probe, which is used to prevent erosion from the warm and moist cerebrospinal fluid environment within the brain tissue.

[0010] Optionally, the bottom bioprotective layer and the top bioprotective layer are made of any one of silicon carbide, polytetrafluoroethylene, hafnium dioxide, alumina and peptides.

[0011] Optionally, the thickness of the bottom bioprotective layer and the top bioprotective layer is 20-500 μm.

[0012] Optionally, the materials of the bottom flexible substrate layer and the top flexible substrate layer are any one of non-photosensitive polyimide, photosensitive polyimide, parylene, polymer photoresist SU-8, sildimethylsiloxane, and hydrogel.

[0013] Optionally, the thickness of the bottom flexible substrate layer and the top flexible substrate layer is 500nm-2mm.

[0014] Optionally, the conductive layer is made of any one of copper, gold, platinum, silver, and chromium.

[0015] Optionally, the thickness of the conductive layer is 100-10 μm.

[0016] Optionally, the thickness of the neural probe is less than 5 mm.

[0017] A second aspect of this application provides a method for preparing an implantable neural probe with an integrated biological protective layer, comprising:

[0018] A sacrificial layer is deposited on the substrate;

[0019] A bottom bioprotective layer is deposited on the sacrificial layer and then patterned.

[0020] A flexible substrate material was spin-coated onto a patterned bottom bioprotective layer and patterned to obtain a bottom flexible substrate layer and a neural probe base.

[0021] A conductive metal layer is formed and patterned on the bottom flexible substrate layer;

[0022] A flexible substrate material is spin-coated onto a patterned metal conductive layer and patterned to obtain a top flexible substrate layer. Small holes are made at each metal electrode point to expose the metal electrode point.

[0023] A top bioprotective layer is deposited on the top flexible substrate and the base of the neural probe, and then patterned.

[0024] The sacrificial layer is removed, and the device is released to obtain an implantable neural probe with an integrated biological protective layer.

[0025] A third aspect of this application provides a brain-computer interface system comprising an implantable neural probe with an integrated biological protective layer, or an implantable neural probe with an integrated biological protective layer prepared using the method described above.

[0026] The implantable neural probe with an integrated biological protective layer provided in this application adopts an integrated biological protective layer located on the outermost part of the flexible neural probe. In in vivo application, it can inhibit the corrosion of the neural probe by cerebrospinal fluid, effectively improve the long-term biocompatibility and long-term in vivo service life of the flexible neural probe. The neural probe has advantages such as high integration and high stability, which can meet the requirements of long-term effective in vivo service of the device.

[0027] Other technical effects resulting from the additional features will be further illustrated in the corresponding embodiments. Attached Figure Description

[0028] Other features, objects, and advantages of this application will become more apparent from the following detailed description of non-limiting embodiments with reference to the accompanying drawings:

[0029] Figure 1 This is a schematic diagram of the structure of an implantable neural probe with an integrated biological protective layer according to an exemplary embodiment;

[0030] Figure 2 The probe beam region shown according to an exemplary embodiment ( Figure 1 A cross-sectional schematic diagram of the rectangular frame region;

[0031] Figure 3 This is a schematic diagram illustrating the long-term service of an implantable neural probe with an integrated biological protective layer in a warm and moist cerebrospinal fluid environment according to an exemplary embodiment.

[0032] Figure 4This is a flowchart illustrating a method for preparing an implantable neural probe with an integrated biological protective layer according to an exemplary embodiment;

[0033] Figure 5 This is a flowchart illustrating a method for preparing an implantable neural probe with an integrated biological protective layer according to an exemplary embodiment;

[0034] In the figure: 1 is the dura mater, 2 is the skull, 3 is the neural probe, 4 is the packaging interface of the neural probe, 5 is the scalp, 6 is the probe bundle, 7 is the base of the neural probe, 8 is the base packaging pad, 10 is the electrode point, 11 is the bottom flexible substrate layer, and 12 is the bottom biological protective layer. Detailed Implementation

[0035] The present application will now be described in detail with reference to specific embodiments. These embodiments will help those skilled in the art to further understand the present application, but do not limit the present application in any way. It should be noted that those skilled in the art can make several modifications and improvements without departing from the concept of the present application, and these all fall within the protection scope of the present application. Parts not described in detail in the following embodiments can be implemented using existing technology.

[0036] Current flexible brain-computer interface devices are susceptible to failure due to erosion by humid and hot cerebrospinal fluid, failing to meet the application requirements for long-term effective service in vivo. To address these issues, this application provides an implantable neural probe with an integrated biological protective layer.

[0037] Reference Figure 1 and Figure 2 As shown in one embodiment of this application, an implantable neural probe with an integrated biological protective layer includes, from bottom to top: a bottom biological protective layer, a bottom flexible substrate layer, a conductive layer, a top flexible substrate layer, and a top biological protective layer; the bottom biological protective layer and the top biological protective layer form a biological protective layer located at the outermost periphery of the neural probe, which is used to prevent erosion by the warm and moist cerebrospinal fluid environment in the brain tissue.

[0038] Specifically, the implantable neural probe includes a base 7, a probe bundle 6, and a base encapsulation pad 8. Electrode points 10 are provided on the probe bundle 6. The conductive layer includes the electrode points, wires, and the base encapsulation pad. The electrode points (neural signal acquisition microelectrode points) are used to acquire neural signals, and the wires are used to connect the electrode points and the base encapsulation pad. The base encapsulation pad is the area where signals are led out to the acquisition system. A bottom flexible substrate layer 11 and a bottom bioprotective layer 12 are provided below the electrode points 10, and a top flexible substrate layer and a top bioprotective layer are provided above them. Both the base 7 and the probe bundle 6 of the neural probe are covered by the bioprotective layer.

[0039] The aforementioned neural probe integrates two biological protective layers, two substrate layers, and one conductive metal layer within a relatively thin thickness (e.g., 5 mm), exhibiting high integration. Under the protection of the biological protective layers, the substrate layer of the neural probe can shield against the erosion of biological tissue fluid, preventing delamination and cracking, and demonstrating high stability in in vivo applications.

[0040] It should be noted that the structure of each layer of the five-layer neural probe cannot be adjusted arbitrarily. The middle sandwich structure of substrate layer-conductive layer-substrate layer is fixed, and the outer biological protective layer helps to protect the functional integrity of the substrate layer and conductive layer.

[0041] The embodiments described above employ an integrated biological protective layer located on the outermost periphery of the flexible neural probe. In in vivo applications, this layer can inhibit the corrosion of the neural probe by cerebrospinal fluid, effectively improving the long-term biocompatibility and long-term in vivo service life of the flexible neural probe. Compared with existing sandwich structure flexible neural probes, this neural probe has advantages such as high integration and high stability, and can meet the requirements for long-term effective in vivo service of devices.

[0042] In order to inhibit the corrosive effect of cerebrospinal fluid on the neural probe, in some specific embodiments of this application, the bottom biological protective layer and the top biological protective layer are made of any one of silicon carbide, polytetrafluoroethylene, hafnium dioxide, alumina and polypeptide.

[0043] Specifically, the forming methods of the bottom and top bioprotective layers include, but are not limited to, chemical vapor deposition, atomic layer deposition, magnetron sputtering, and physical vapor deposition.

[0044] In the above embodiments of this application, the material used in the biological protective layer has a diffusion coefficient that meets the requirements of low dielectric constant and stable chemical properties, and has excellent antioxidant, acid resistance and low moisture absorption characteristics, so as to effectively resist the erosion of water vapor, various ions, proteins and biological enzymes in the hot and humid cerebrospinal fluid.

[0045] In order to achieve a thinner and lighter overall device, in some specific embodiments of this application, the thickness of the bottom bioprotective layer and the top bioprotective layer is 20-500 μm.

[0046] Specifically, the thickness of the bioprotective layer is determined based on the relationship between the material's diffusion coefficient and moisture absorption rate and thickness. While ensuring the device's water vapor leakage rate, the thickness of the device will not be significantly increased, ensuring that the overall thickness of the implanted device is less than 5mm, which can meet the requirements for low-damage implantation.

[0047] In the above embodiments of this application, the biological protective layer structure located on the outermost edge of the flexible neural probe can effectively prevent the erosion of the warm and moist cerebrospinal fluid environment in the brain tissue, while not affecting the conductivity of the flexible neural probe.

[0048] To improve the flexibility of the neural probe, in some specific embodiments of this application, the bottom flexible substrate layer and the top flexible substrate layer are made of any one of non-photosensitive polyimide, photosensitive polyimide, parylene, polymer photoresist SU-8, sildimethylsiloxane, and hydrogel.

[0049] Specifically, the flexible substrate is patterned using methods such as plasma etching and exposure.

[0050] In some specific embodiments of this application, the thickness of the bottom flexible substrate layer and the top flexible substrate layer is 500nm-2mm.

[0051] In order to enable signals to be drawn from inside the brain region to outside the brain region, in some specific embodiments of this application, the material of the conductive layer is any one of copper, gold, platinum, silver and chromium.

[0052] Specifically, methods for growing conductive layers (metal seed layers) include, but are not limited to, multi-target magnetron sputtering, electrochemical electroplating, electron beam evaporation, ion beam sputtering, and other metal thin film growth methods.

[0053] In some specific embodiments of this application, the thickness of the conductive layer is 100-10 μm.

[0054] In the embodiments described above, the materials of each layer of the flexible neural probe are not biotoxic to living organisms, which can reduce tissue inflammation and chronic damage, and improve the safety of long-term implantation of the device.

[0055] It should be noted that in some other embodiments, the layers of the flexible neural probe can be made of other materials, as long as they can achieve the same function as described above.

[0056] In order to minimize the bending stiffness of the flexible probe and improve its ability to adapt to the floating of brain tissue, in some specific embodiments of this application, the thickness of the neural probe is less than 5 mm.

[0057] In the above embodiments of this application, the ultrathin structure of the neural probe results in a flexible probe with low bending stiffness, which has a high ability to conform to the floating of brain tissue, thereby reducing tissue damage, improving biocompatibility, and enhancing signal quality and stability.

[0058] Reference Figure 3 As shown, the neural probe 3 is implanted into the dura mater 1 through the scalp 5 and skull 2. The encapsulation interface 4 of the neural probe is located outside the scalp 5. Its outer biological protective layer can effectively prevent the neural probe from being eroded by the cerebrospinal fluid in the dura mater 1, effectively improving the long-term biocompatibility and long-term in vivo service life of the flexible neural probe.

[0059] Another embodiment of this application provides a method for preparing an implantable neural probe with an integrated biological protective layer as described above, the method comprising the following steps:

[0060] S1. Deposit a sacrificial layer on the substrate to form a release structure for an ultrathin flexible neural probe;

[0061] S2. A bottom bioprotective layer (such as silicon carbide) is deposited on the sacrificial layer by physical vapor deposition and patterned based on an ion beam etching process;

[0062] S3. Spin-coat a flexible substrate material such as polyimide onto the patterned bottom bioprotective layer and pattern it based on reactive ion etching to obtain the bottom flexible substrate layer and the base of the neural probe.

[0063] S4. A metal conductive layer is formed on the bottom flexible substrate and patterned using photolithography and lift-off processes;

[0064] S5. Spin-coat a flexible substrate material such as polyimide onto the patterned metal conductive layer and pattern it to obtain a top flexible substrate layer. Open small holes on each metal electrode point to expose the metal electrode point.

[0065] S6. Deposit a top bioprotective layer on the top flexible substrate and the base of the neural probe using physical vapor deposition, and pattern it based on ion beam etching.

[0066] S7. Remove the sacrificial layer and release the device to obtain an ultrathin implantable neural probe with an integrated biological protective layer.

[0067] Specifically, in step S4, a metal adhesion layer and a metal layer are sputtered or evaporated onto the bottom flexible substrate and the base of the neural probe. A positive photoresist is spin-coated as a mask. After pre-baking, exposure, development, and post-baking, ion beam etching or wet etching is used to obtain the conductive metal layer with curved traces and pad structures. The conductive layer in S4 includes electrode points, wires, and base packaging pads; all three belong to the same layer and are implemented in the same process step. In step S7, a reagent is used to etch or dissolve the sacrificial layer to release the flexible neural probe.

[0068] It should be noted that in order to prepare the implantable neural probe with the above-mentioned integrated biological protective layer, the following technical obstacles need to be overcome: (1) How to achieve the patterning and exposure of the biological protective layer within the implantable neural probe with a width of hundreds of micrometers, so that the electrode points and pad areas can still form electrical contact with the outside world; (2) How to achieve reliable connection of the multilayer structure without cracking; (3) How to achieve the deposition and patterning of the ultrathin substrate layer, the thickness factor is an important factor affecting implantation damage.

[0069] The embodiments described above utilize organic solvent-diluted photoresist technology to achieve the fabrication of thinner substrate films. Specifically, the photoresist used in the above preparation method is diluted, resulting in lower viscosity and easier spin-coating to obtain thinner films. Based on the bioprotective layer structure, the substrate of the neural probe is protected from erosion by biological tissue fluid. Aging experiments have verified that the stability of the neural probe with the bioprotective layer structure is significantly improved.

[0070] The neural probe preparation method described in the above embodiments of this application is highly compatible with traditional microelectromechanical and semiconductor processing methods. The process is mature, highly reliable, and can achieve high-precision manufacturing, ensuring the performance of the neural probe.

[0071] Another embodiment of this application provides a brain-computer interface system, which includes an implantable neural probe with an integrated biological protective layer as described above, or an implantable neural probe with an integrated biological protective layer prepared using the method described above.

[0072] In the embodiments described above, under the protection of the biological protective layer, the flexible neural probe can effectively resist the erosion of water vapor, various ions, proteins and biological enzymes in the hot and humid cerebrospinal fluid, and effectively prolong its long-term biocompatibility in vivo.

[0073] The preferred features in the above embodiments can be used individually in any embodiment, or in any combination thereof, provided they do not conflict with each other. Furthermore, parts not described in detail in the embodiments can be implemented using existing technologies.

[0074] The following examples and comparative examples will be used to further illustrate this application in order to better understand the above-mentioned technical solutions. It should be understood that the following are only some examples and are not intended to limit this application.

[0075] Application Example 1:

[0076] Using ordinary single-sided polished silicon wafers as the substrate material, the silicon wafers were ultrasonically cleaned in acetone, ethanol and deionized water for 10 minutes respectively, then dried with nitrogen and baked in an oven at 180°C for 1 hour.

[0077] Reference Figure 4 As shown in (1), a 400nm thick layer of aluminum is evaporated on the cleaned silicon wafer as a sacrificial metal layer.

[0078] Reference Figure 4 As shown in (2), a 100 nm thick silicon carbide film is patterned on the sacrificial metal by plasma-enhanced chemical vapor deposition, and the patterning is completed by reactive ion etching of silicon carbide using photoresist as a mask to form the bottom biological protective layer.

[0079] Reference Figure 4As shown in (3), photosensitive polyimide Durimide 7505 was spin-coated on the bottom bioprotective layer at a speed of 3000 rpm. After 6 seconds of exposure, 35 seconds of development, and then baking in a nitrogen environment at 350°C for one hour, a 2μm thick electrode bottom polymer layer (i.e., bottom flexible substrate layer) and nerve probe base were obtained.

[0080] Reference Figure 4 As shown in Figure (4), 30 nm chromium (adhesion layer) and 300 nm gold (conductive layer) are sequentially sputtered onto the bottom polyimide layer, and a 5 μm thick positive photoresist AZ4620 is spin-coated onto the conductive layer. After pre-baking, photolithography, development, and post-baking, a patterned photoresist mask is obtained. The patterned photoresist mask is then used to pattern the metal layer using ion beam etching or wet etching, and the positive photoresist mask is removed with acetone.

[0081] Reference Figure 4 As shown in (5), photosensitive polyimide Durimide 7505 was spin-coated on the metal conductive layer at a speed of 3000 rpm. After 6 seconds of exposure, 35 seconds of development, and then baking in a nitrogen environment at 350°C for one hour, a 2μm thick top polymer layer (i.e., top flexible substrate layer) was obtained after curing.

[0082] Reference Figure 4 As shown in Figure (6), a 100 nm thick silicon carbide film is patterned on the top polymer layer of the electrode by plasma-enhanced chemical vapor deposition, and the patterning is completed by reactive ion etching of silicon carbide using photoresist as a mask to form the top biological protective layer.

[0083] Reference Figure 4 As shown in (7), a dicing machine is used to precisely separate individual flexible neural probe devices.

[0084] Reference Figure 4 As shown in Figure (8), the flexible neural probe and the flexible packaging cable are aligned under a microscope and a micromanipulation platform. The two are then thermo-bonded using anisotropic conductive adhesive with bonding parameters of 0.18 MPa, 240°C, and 18 s, thus completing the packaging of the flexible neural probe.

[0085] Reference Figure 4 As shown in (9), the aluminum sacrificial layer is etched by electrochemistry or dilute hydrochloric acid to release the electrode, so that the flexible probe bundle reaches a free floating state in the water.

[0086] Application Example 2:

[0087] Reference Figure 5As shown in (1), a common single-sided silicon wafer with a 200nm oxide layer was used as the substrate material. The silicon wafer was ultrasonically cleaned in acetone, ethanol and deionized water for 10 minutes, then dried with nitrogen and baked in an oven at 180°C for 1 hour.

[0088] Reference Figure 5 As shown in (2), the silicon wafer with the silicon oxide sacrificial layer is placed on the HMDS oven for processing. A 500-800 nm PTFE protective film is obtained by spin-coating PTFE emulsion on the sacrificial metal. After the biological protective layer is patterned, the film is etched by introducing SF4 / O2 gas through a reactive ion device, or the PTFE film is etched by femtosecond laser to complete the patterning and form the bottom biological protective layer.

[0089] Reference Figure 5 As shown in (3), photosensitive polyimide Durimide 7505 was spin-coated on the bottom bioprotective layer at a speed of 3000 rpm. After 6 seconds of exposure, 35 seconds of development, and then baking in a nitrogen environment at 350°C for one hour, a 2μm thick electrode bottom polymer layer (i.e., bottom flexible substrate layer) and nerve probe base were obtained.

[0090] Reference Figure 5 As shown in (4), 30 nm titanium (adhesion layer) and 300 nm gold (conductive layer) are sequentially sputtered onto the bottom polyimide layer, and a 5 μm thick positive photoresist AZ5214 is spin-coated onto the conductive layer. After pre-baking, photolithography, development, and post-baking, a patterned photoresist mask is obtained. The patterned photoresist mask is then used to pattern the metal layer using ion beam etching or wet etching, and the positive photoresist mask is removed with acetone.

[0091] Reference Figure 5 As shown in (5), photosensitive polyimide Durimide 7505 was spin-coated on the metal conductive layer at a speed of 3000 rpm. After 6 seconds of exposure, 35 seconds of development, and then baking in a nitrogen environment at 350°C for one hour, a 2μm thick top polymer layer (i.e., top flexible substrate layer) was obtained after curing.

[0092] Reference Figure 5 As shown in (6), the silicon wafer after the above process is placed on an HMDS oven for processing. A 500-800nm ​​PTFE protective film is obtained by spin-coating PTFE emulsion on the top polymer layer of the electrode. After patterning the biological protective layer, the film is etched by introducing SF4 / O2 gas through a reactive ion device, or the PTFE film is etched by femtosecond laser to complete the patterning and form the top biological protective layer.

[0093] Reference Figure 5As shown in (7), a dicing machine is used to precisely separate individual flexible neural probe devices.

[0094] Reference Figure 5 As shown in Figure (8), the flexible neural probe and the flexible packaging cable are aligned under a microscope and a micromanipulation platform. The two are then thermo-bonded using anisotropic conductive adhesive with bonding parameters of 0.18 MPa, 240°C, and 18 s, thus completing the packaging of the flexible neural probe.

[0095] Reference Figure 5 As shown in (9), the electrode is released by electrochemical or hydrofluoric acid corrosion of the aluminum sacrificial layer, so that the flexible probe bundle reaches a free floating state in the water.

[0096] The foregoing has described some specific embodiments of this application. It should be understood that this application is not limited to the specific embodiments described above, and those skilled in the art can make various modifications or variations within the scope of the claims, which do not affect the substantive content of this application. The above-described preferred features can be used in any combination without conflict.

Claims

1. An implantable neural probe with an integrated biological protective layer, characterized in that, From bottom to top, it includes: a bottom bioprotective layer, a bottom flexible substrate layer, a conductive layer, a top flexible substrate layer, and a top bioprotective layer; The bottom and top bioprotective layers form the outermost bioprotective layer of the neural probe, which is used to prevent erosion from the warm and moist cerebrospinal fluid environment within the brain tissue.

2. The implantable neural probe with an integrated biological protective layer according to claim 1, characterized in that, The bottom and top bioprotective layers are made of any one of silicon carbide, polytetrafluoroethylene, hafnium dioxide, alumina, and polypeptides.

3. The implantable neural probe with an integrated biological protective layer according to claim 1, characterized in that, The thickness of the bottom biological protective layer and the top biological protective layer is 20-500 μm.

4. The implantable neural probe with an integrated biological protective layer according to claim 1, characterized in that, The materials of the bottom flexible substrate and the top flexible substrate are any one of non-photosensitive polyimide, photosensitive polyimide, parylene, polymer photoresist SU-8, sildimethylsiloxane, and hydrogel.

5. The implantable neural probe with an integrated biological protective layer according to claim 1, characterized in that, The thickness of the bottom flexible substrate layer and the top flexible substrate layer is 500nm-2mm.

6. The implantable neural probe with an integrated biological protective layer according to claim 1, characterized in that, The conductive layer is made of any one of copper, gold, platinum, silver, and chromium.

7. The implantable neural probe with an integrated biological protective layer according to claim 1, characterized in that, The thickness of the conductive layer is 100-10 μm.

8. The implantable neural probe with an integrated biological protective layer according to claim 1, characterized in that, The thickness of the neural probe is less than 5 mm.

9. A method for preparing an implantable neural probe with an integrated biological protective layer as described in any one of claims 1-8, characterized in that, include: A sacrificial layer is deposited on the substrate; A bottom bioprotective layer is deposited on the sacrificial layer and then patterned. A flexible substrate material was spin-coated onto a patterned bottom bioprotective layer and patterned to obtain a bottom flexible substrate layer and a neural probe base. A conductive metal layer is formed and patterned on the bottom flexible substrate layer; A flexible substrate material is spin-coated onto a patterned metal conductive layer and patterned to obtain a top flexible substrate layer. Small holes are made at each metal electrode point to expose the metal electrode point. A top bioprotective layer is deposited on the top flexible substrate and the base of the neural probe, and then patterned. The sacrificial layer is removed, and the device is released to obtain an implantable neural probe with an integrated biological protective layer.

10. A brain-computer interface system, characterized in that, The implantable neural probe with an integrated biological protective layer as described in any one of claims 1-8, or the implantable neural probe with an integrated biological protective layer prepared by the method of claim 9.

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