Multifunctional optical flexible neural probe and neural modulation system

Abstract

The application discloses a kind of multi-functional optical flexible nerve probe and nerve control system, belong to neural engineering technical field.The probe includes by PDMS made of laminated flexible main part, it is integrated with recording electrode, micro light emitting diode, at least two drug delivery channels and a rigidity control channel;Probe edge has wavy profile, and drug outflow hole is arranged at wave crest to form anti-blocking liquid storage cavity.Rigidity control channel can be filled with phase change material (such as gallium) or magnetic rheological fluid, and the rigidity dynamic switching of hardening when probe implantation and softening after implantation is realized by external temperature or magnetic field control.The application solves the technical problems of flexible probe implantation difficulty, rigid probe long-term damage and single function, realizes implant rigidity controllable, long-term biocompatibility is good, and multi-modal nerve interaction of integrated electric recording, light stimulation and reliable drug delivery.

Description

Technical Field

[0001] This invention relates to the fields of medical devices and neural engineering technology, specifically to a flexible probe that can be implanted into biological tissue and a system containing the probe, and more particularly to a multimodal flexible neural probe and its control system that integrates neural signal recording, optogenetic stimulation, drug delivery and adjustable implantation stiffness. Background Technology

[0002] Neural probes, as key tools for interaction with the nervous system in brain-computer interfaces and neuroscience research, encompass core functions such as neural signal acquisition (e.g., electrophysiological recording), stimulation (e.g., optogenetic regulation), and drug delivery. They are crucial for in-depth exploration of neural circuit mechanisms and the treatment of neurological diseases such as Parkinson's disease and epilepsy. Traditional neural probes are mostly made of rigid materials such as silicon or metals, with Young's modulus as high as approximately 200 GPa, which is several orders of magnitude lower than the extremely low Young's modulus (approximately 0.4-15 kPa) of brain tissue itself. This significant difference in mechanical properties leads to unavoidable friction and shear forces between the rigid probe and surrounding soft tissue during continuous micro-movements caused by physiological activities such as respiration and vascular pulsation. This results in chronic inflammatory responses and glial scar formation, ultimately causing a severe degradation of the quality of recorded neural signals over time.

[0003] To improve biocompatibility, the industry has shifted to using flexible materials such as polydimethylsiloxane (PDMS) to fabricate probes. Their elastic modulus (approximately 1 MPa) is closer to that of brain tissue, aiming to achieve long-term mechanical compatibility. However, purely flexible probes, due to their insufficient stiffness, often struggle to accurately puncture and reach deep brain tissue target sites during implantation, posing a fundamental operational challenge. Furthermore, most existing neural probes tend to have limited functionality, either focusing solely on high-fidelity electrical signal recording or optogenetic stimulation. They lack the ability to integrate multimodal synergistic functions such as electrophysiological recording, photomodulation, and chemical delivery onto a single device, thus limiting their breadth and depth of application in complex neuroscience research.

[0004] Although some studies have attempted to integrate microchannels into probes to achieve drug delivery, the traditional straight-through outlet design is easily blocked by the surrounding moist, soft and deformable brain tissue after implantation, causing the drug delivery channel to fail.

[0005] Therefore, developing a neural probe that can address the immediate rigidity requirements during implantation, ensure long-term flexibility and compatibility after implantation, and effectively integrate and reliably achieve multiple functions of recording, stimulation, and drug delivery has become a key technological bottleneck that urgently needs to be overcome in this field. Summary of the Invention

[0006] The technical problem to be solved by this invention is: how to reconcile the contradiction between the instantaneous high stiffness required for implantation and the tissue compatibility and flexibility required for long-term implantation, while overcoming the limitations of traditional single-function probes and solving the problem of microchannel drug delivery ports being easily blocked by tissue.

[0007] To address the aforementioned problems, this invention provides a multifunctional optical flexible neural probe, comprising:

[0008] The probe consists of a base layer, an intermediate layer, and a cover layer stacked sequentially along its thickness direction. The probe has a probe tip area near the front end and an interface area near the rear end.

[0009] Multiple electrodes and at least one micro-light-emitting diode are disposed in the probe tip region of the substrate layer. The multiple electrodes and the micro-light-emitting diode are electrically connected to the pads in the interface region through metal wires arranged in the intermediate layer.

[0010] A microfluidic structure disposed inside the cover plate layer, the microfluidic structure including at least two drug delivery channels extending along the probe length direction and a stiffness control channel, the rear ends of the at least two drug delivery channels being respectively connected to a first liquid inlet and a second liquid inlet disposed in the interface area, and the rear end of the stiffness control channel being connected to a stiffness control medium inlet disposed in the interface area.

[0011] The probe has a wavy profile that undulates periodically along the length of the probe at at least one side edge of the probe tip region. Multiple peaks and troughs are formed on the wavy profile. Multiple liquid outflow holes are respectively opened at the multiple peaks, and each liquid outflow hole is connected to at least one of at least two drug delivery channels.

[0012] As an optional implementation, the stiffness control channel is filled with a liquid metal magnetic fluid, which includes a liquid metal matrix and magnetic nanoparticles dispersed in the liquid metal matrix.

[0013] As an alternative implementation, the stiffness control channel is filled with liquid gallium before the probe is inserted into the tissue, and the stiffness control channel is cooled before insertion into the tissue to make the liquid gallium solid.

[0014] As an optional implementation, multiple liquid outlet holes are arranged sequentially along the length of the probe, with the diameter of the liquid outlet holes gradually increasing from the end closest to the probe tip area to the end furthest from the probe tip area.

[0015] As an optional implementation, one side of the probe is provided with multiple wavy profiles spaced apart from each other, with a spacing of 170 μm between two adjacent wavy profiles along the length of the probe, and the multiple wavy profiles are arranged at equal intervals.

[0016] As an optional implementation, the probe's geometry satisfies:

[0017] The thickness of the base layer is 19 μm, the thickness of the intermediate layer is 20 μm, and the thickness of the cover layer is 30 μm;

[0018] The probe has a width of 277 μm;

[0019] At least two of the drug delivery channels have a cross-sectional height of 10 μm and a cross-sectional width of 15 μm, and the stiffness control channel has a cross-sectional height of 15 μm and a cross-sectional width of 100 μm.

[0020] On the other hand, the present invention also provides a neural modulation system, comprising:

[0021] The aforementioned multifunctional optical flexible neural probe;

[0022] An external injection pump that is fluidly connected to the first liquid inlet and the second liquid inlet;

[0023] A medium delivery unit that is connected to the stiffness control medium input port and is used to deliver or extract the liquid metal magnetic fluid to the stiffness control channel;

[0024] A magnetic field generator is located outside the area where the stiffness control channel is located and is used to generate a magnetic field.

[0025] A control unit electrically connected to the plurality of electrodes, the micro LEDs, the external injection pump, the medium delivery unit, and the magnetic field generator.

[0026] This invention utilizes an independent stiffness-regulating channel within a flexible probe, filled with a phase change material (such as gallium) or magnetorheological fluid. External temperature or magnetic field controls its state change, allowing the probe to temporarily transform into a high-stiffness state before implantation for precise puncture. After implantation, it regains its inherent flexibility under body temperature or when the magnetic field is removed, achieving mechanical compatibility with brain tissue. This "combination of stiffness and flexibility" fundamentally reconciles the contradiction between implantation operability and long-term biocompatibility. Furthermore, addressing the clogging issue of existing microfluidic probes, this invention places the drug outlet orifice at the crest of the probe's wavy profile. This design naturally forms a tiny fluid reservoir between the orifice and the tissue contact surface, effectively preventing direct physical blockage by soft tissue and providing space for initial drug collection and uniform diffusion, significantly improving the reliability and coverage uniformity of drug delivery. Furthermore, this invention successfully integrates a high-density electrode array, a micro-light-emitting diode, an independent multi-channel drug delivery microfluidic channel, and the aforementioned stiffness regulation channel in an ultra-thin multilayer PDMS substrate through microfabrication technology. This achieves the integration of four functions—electrophysiological signal recording, optogenetic stimulation, chemical substance delivery, and implantation stiffness regulation—on a single device, providing an integrated platform for multimodal neural interaction research.

[0027] In addition to serving drug delivery, the probe's unique wave-shaped structure can also create a good mechanical anchoring effect in brain tissue, helping to reduce probe displacement caused by physiological pulsation. These characteristics work together to ensure that more stable and high-quality neural signals can be obtained during long-term implantation, thus enhancing the practicality and reliability of the entire system. Attached Figure Description

[0028] To more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the accompanying drawings used in the description of the embodiments or the prior art will be briefly introduced below.

[0029] Figure 1 This is a schematic diagram of the overall structure of the flexible neural probe of the present invention;

[0030] Figure 2 This is a top view of the flexible neural probe of the present invention;

[0031] Figure 3 This is a schematic diagram of the internal structure of the intermediate layer of the present invention;

[0032] Figure 4 This is a schematic diagram of the tip region structure of the flexible neural probe of the present invention;

[0033] Figure 5 This is a schematic diagram of the cover plate layer structure of the present invention;

[0034] Figure 6This is a schematic diagram of the interface area end face of the cover plate layer of the present invention;

[0035] In the figure: 1. Substrate layer; 11. Electrode; 12. Micro LED; 2. Intermediate layer; 21. Metal wire; 22. Pad; 3. Cover layer; 31. Drug delivery channel; 311. First liquid inlet; 312. Second liquid inlet; 32. Stiffness control channel; 4. Wavy profile; 41. Liquid outflow hole. Detailed Implementation

[0036] Example 1:

[0037] This embodiment provides a multifunctional optical flexible neural probe, such as Figure 1 and Figure 2 As shown, the probe's basic shape is a slender strip, featuring a probe tip region for implantation into biological tissue and an interface region for connection with external devices. The main structure of the probe can be formed from polydimethylsiloxane (PDMS), a material with excellent biocompatibility and elasticity, using microfabrication technology. The probe employs a three-layer stacked architecture, consisting of a base layer 1, an intermediate layer 2, and a cover layer 3 along its thickness direction. This layered design is the physical basis for achieving multifunctional integration.

[0038] The basal layer 1, serving as the direct carrier of functional elements, has an optimized thickness of 19 μm. This thickness ensures sufficient mechanical strength to support subsequently integrated components while maintaining overall flexibility. In the probe tip region of this layer, multiple electrodes 11 for recording extracellular potentials of nerve cells are embedded using microfabrication techniques. These electrodes 11 are preferably made of chemically stable and highly conductive platinum material and are arranged in an array with a specific spacing. The spacing between the electrodes 11 can be selected within the range of 35 μm to 65 μm to accommodate the needs of recording signals at different resolutions. Simultaneously, at least one micro-light-emitting diode 12 is integrated in or near the electrode array. This micro-diode emits light of a specific wavelength, such as 470 nm blue light or 590 nm yellow light, to activate or inhibit the activity of genetically modified neurons expressing light-sensitive channel proteins.

[0039] The substrate layer 1, which carries the electrode 11 and the micro-LED 12, needs to be electrically connected to an external control system; this task is accomplished by the intermediate layer 2. The thickness of the intermediate layer 2 can be set to 20 μm, slightly thicker than the substrate layer 1 to accommodate the internal structure. Figure 3As shown, a network of metal wires 21 is fabricated within the intermediate layer 2 using photolithography, metal deposition, and patterning processes. One end of these metal wires 21 is reliably connected to the pins of the electrodes 11 and micro-LEDs 12 in the substrate layer 1, while the other end extends to the interface area at the back end of the probe and terminates on a series of exposed pads 22. These pads 22 serve as electrical interfaces, facilitating connection to external signal amplifiers, light source drivers, and other devices via micro-connectors.

[0040] like Figure 5 and Figure 6 As shown, at least two independent drug delivery channels 31 and a stiffness control channel 32 are formed inside the cover layer 3 through micromachining etching. These channels are encapsulated within the PDMS material of the cover layer 3, forming a self-contained embedded flow channel system. The two drug delivery channels 31 extend parallel to each other along the probe length direction. They have small cross-sectional dimensions, with a cross-sectional height of up to 10 μm and a cross-sectional width of up to 15 μm. This dimensional design ensures sufficient fluid throughput while minimizing the impact on the overall flexibility and size of the probe. The rear end of each drug delivery channel 31 is connected to an independent liquid inlet in the interface area, i.e. Figure 6 The first liquid inlet 311 and the second liquid inlet 312 shown can be used to connect to an external microinfusion pump, thereby independently delivering different or the same drugs, neurotransmitters, fluorescent dyes, or rinsing solutions. The stiffness control channel 32 is significantly larger than the drug delivery channel 31, with a cross-sectional height of 15 μm and a cross-sectional width of 100 μm, providing space for accommodating a functional stiffness control medium and generating an effective mechanical effect. The rear end of the stiffness control channel 32 also has a dedicated stiffness control medium inlet in the interface area.

[0041] like Figures 1 to 5 As shown, one edge of the probe is not straight, but designed as a wavy profile 4 that undulates periodically along its length. This wavy profile 4 consists of a series of continuous, smoothly transitioning peaks and troughs. This wavy design is not merely for aesthetic purposes, but rather stems from specific considerations in biomechanics and fluid dynamics.

[0042] First, it integrates mechanical anchoring into the structure. When the probe is implanted into the brain tissue, the soft PDMS material fits tightly into the tissue. The undulation of the wave-shaped contour 4 increases the contact surface area and interfacial friction, just like the barbs on an anchor. This effectively resists the relative sliding between the probe and the tissue caused by physiological activities such as breathing and heartbeat, thereby enhancing the stability of the implantation and laying the foundation for long-term stable signal recording.

[0043] Secondly, and more importantly, this profile offers a solution to the long-standing technical challenge of microchannel clogging. For example... Figure 4 As shown, the liquid outflow orifice 41 for drug release is not randomly located, but precisely drilled into the side of the crest of the wavy contour 4, and ultimately connects to the drug delivery channel 31 encapsulated inside the cover layer 3. The physical significance of this layout is that after the probe is implanted, the troughs will make relatively close contact with the brain tissue surface, while at the crests, due to the bulge of the contour, a tiny gap will naturally separate the liquid outflow orifice 41 from the tissue surface, forming a natural "fluid reservoir." The existence of this reservoir is crucial; it effectively prevents the soft, moist brain tissue from directly collapsing under contact pressure and blocking the liquid outflow orifice 41, which may only be 10 to 20 μm in diameter, thus ensuring unobstructed drug flow. The drug can first initially collect within this small cavity, and then more evenly infiltrate and diffuse into the surrounding target tissue area, avoiding the uneven drug distribution problems caused by direct blockage or single-point high-speed injection in traditional direct-outlet designs. In a specific implementation, multiple liquid outflow holes 41 are distributed at equal intervals along the wavy profile 4, and each hole can be connected to at least one of the two drug delivery channels 31 to achieve controlled fluid distribution.

[0044] Furthermore, to optimize hydrodynamic performance, the diameter of the liquid outlet orifice 41 can be designed to gradually increase from the orifice closest to the tip region towards the interface region along the probe's length. For example, the diameter of the first orifice can be 10 μm, the second 15 μm, and the third 20 μm. This gradient design helps balance the flow resistance at different locations and the pressure difference caused by varying distances from the liquid inlet, resulting in more uniform flow rates at each outlet. Additionally, multiple parallel and spaced wavy profiles 4 can be provided on the other side of the probe. These profiles together form a multi-rib structure on both sides of the probe's tip region, further enhancing anchoring and fluid distribution capabilities. The spacing between these parallel wavy profiles 4 can be 170 μm, and they are arranged regularly in an equidistant manner.

[0045] Regarding the implementation of the stiffness control channel 32, this embodiment provides two optional implementation paths.

[0046] The first implementation is based on the principle of phase change material (PDMS) phase change material. In this scheme, the stiffness control channel 32 is designed as a cavity that can be temporarily filled with PDMS. Specifically, before the probe implantation surgery, the operator injects liquid gallium into the channel through the stiffness control medium inlet using an external micro-injection pump or other media delivery unit. Gallium is a low-melting-point metal with a melting point of approximately 29.8°C. Subsequently, by actively cooling the channel locally or along with the target tissue surface (e.g., by spraying frozen saline), the temperature of the liquid gallium in the channel is lowered below its melting point, thus solidifying into a solid state. In its solid state, gallium has an elastic modulus much higher than that of PDMS. When it fills and solidifies within the channel, it is equivalent to embedding a slender "metal skeleton" within the soft probe, which can greatly improve the overall bending stiffness and axial compressive strength of the probe, transforming it from a soft and difficult-to-manipulate state into a state with sufficient rigidity to smoothly penetrate the meninges and accurately reach the target location in the deep brain region. Once implanted, the approximately 37°C tissue heat within the channel will rapidly melt the solid gallium into a liquid state under the constant body temperature of the organism. At this point, the liquid gallium can be completely removed from the channel using negative pressure aspiration. After removal, the probe's cross-sectional area and overall stiffness will be further reduced, restoring it to its original extreme flexibility and maximizing its mechanical fit with brain tissue. Alternatively, the liquid gallium can be retained within the channel, in which case the probe's stiffness falls between that of a completely filled solid gallium probe and one that is completely empty, allowing for selection based on specific research needs.

[0047] The second implementation is based on the intelligent response characteristics of magnetorheological fluids. In this scheme, the stiffness control channel 32 is pre-filled or injected with a specially formulated liquid metal magnetorheological fluid. This fluid typically uses a low-melting-point gallium indium tin alloy, or Galinstan, as the carrier fluid, with a melting point below -19°C, thus remaining liquid at any physiological temperature. Within this liquid metal matrix, nanoscale superparamagnetic iron oxide particles are uniformly dispersed as magnetic response units through surface modification technology. Without an external magnetic field, the magnetic nanoparticles are randomly distributed in the carrier fluid, exhibiting typical Newtonian fluid characteristics with low viscosity, contributing little to the probe stiffness, thus maintaining the probe's overall flexibility. When probe stiffening is required, such as for precise guidance during implantation or temporary stabilization of the recording site due to brain pulsation interference after implantation, a sufficiently strong static or low-frequency alternating magnetic field is applied from outside the probe. The magnetic field causes the superparamagnetic nanoparticles dispersed in the liquid metal to be polarized in a very short time, aligning into chain-like or columnar structures along the magnetic field lines. These microstructures significantly increase the apparent viscosity of the fluid, even generating yield stress, instantly "locking" the originally free-flowing liquid metal into a rigid, solid-like state. This increases the stiffness of the entire stiffness control channel 32 region and even the entire probe by several orders of magnitude. When the probe needs to regain its flexibility to reduce long-term mechanical stimulation to the tissue, simply removing the external magnetic field causes the chain structure of the magnetic particles to rapidly disintegrate due to thermal motion, the fluid returns to a low-viscosity liquid state, and the probe softens accordingly. If necessary, the magnetic fluid can also be completely removed through the inlet at the rear end of the channel.

[0048] Both of these stiffness adjustment mechanisms enable non-invasive, reversible, and rapid external control of the probe's mechanical properties.

[0049] To enable those skilled in the art to fully understand and reproduce the probe described in this embodiment, a set of optimized probe geometry parameters are provided below:

[0050] The total width of the probe can be designed to be 277 μm, aiming to minimize implantation damage.

[0051] As mentioned earlier, the thickness of the three-layer structure is as follows: the base layer 1 is 19 μm, the middle layer 2 is 20 μm, and the cover layer 3 is designed to be 30 μm thick, slightly thicker than the first two layers, because it needs to be processed with microfluidic channels inside and serves as one of the main load-bearing layers.

[0052] The drug delivery channel 31 encapsulated inside the cover layer 3 has a rectangular cross-section with a height of 10 μm and a width of 15 μm.

[0053] The stiffness control channel 32 also has a rectangular cross-section, with a height of 15μm and a width of 100μm.

[0054] The period of the wavy profile 4, that is, the distance between the center points of adjacent crests or troughs along the probe length, can be set to 170 μm.

[0055] To more intuitively demonstrate the advancements of the porous wavy design in this embodiment compared to the traditional single-channel design, the following explanation is based on quantitative data from in vitro simulation tests.

[0056] Regarding the reliability of anti-clogging, the clogging rate of traditional single-channel designs typically fluctuates between 5% and 15% after long-term implantation. However, the design in this embodiment, through the fluid storage chamber created by the wave-shaped structure and the redundant design of multiple pores, successfully controls the clogging rate to below 1% in long-term testing, significantly improving the reliability of the drug delivery route.

[0057] Regarding drug distribution, the coefficient of variation of drug concentration in traditional designs is between 20% and 40%, and the uniformity is only 60% to 80%. However, this embodiment, with the synergistic effect of multiple outlets and the reservoir, reduces the coefficient of variation of drug concentration to less than 5%, achieving an extremely high distribution uniformity of over 95%, thus avoiding the problem of excessively high or low local concentrations.

[0058] In terms of drug delivery efficiency, traditional designs require 5 to 15 seconds to cover 90% of the target area, while this embodiment can achieve this in just 1 to 3 seconds, significantly improving the diffusion rate and onset speed.

[0059] The above comparative data fully demonstrates that this embodiment has achieved substantial improvements in three core performance aspects: reliability of anti-clogging holes, uniformity of drug distribution, and drug delivery efficiency.

[0060] Furthermore, it should be noted that the optical flexible neural probe provided in this embodiment fully utilizes mature technologies such as soft lithography, molding, and plasma bonding during the fabrication process, and combines them to meet the multi-layer and multi-material integration requirements of this probe.

[0061] The entire fabrication process begins with the formation of the base layer 1 on a silicon wafer. First, a sacrificial layer material is spin-coated onto a standard silicon wafer, followed by a PDMS prepolymer mixture with a target thickness of 19 μm. Using ultraviolet lithography, the PDMS layer is exposed and patterned using a photomask that includes the overall planar outline of the probe, the reserved groove positions for the electrodes 11 and micro-LEDs 12, and the necessary via patterns. Subsequently, the uncured portions and the underlying sacrificial layer are removed using a PDMS lift-off process, resulting in a first PDMS film prototype with precise planar patterning on the silicon wafer. Following this, platinum metal is deposited within the patterned grooves using a metal deposition process to form the contact pads and lead portions of the electrodes 11. The pre-fabricated micro-LED chips 12 are then precisely mounted onto the reserved sites using micro-assembly technology and fixed with conductive adhesive. After integrating these functional elements, the surface of the PDMS layer is briefly treated with oxygen plasma to significantly improve its surface energy and hydrophilicity, creating an active surface for subsequent irreversible bonding.

[0062] Next, the intermediate layer 2 containing the metal wires 21 is prepared. This layer serves as a planar isolation and wiring layer, and its preparation is relatively simple. A PDMS prepolymer with a target thickness of 20 μm can be spin-coated onto a planar substrate, and after curing, a planar PDMS film is obtained. Then, the designed metal wire pattern 21 is fabricated on the surface of this planar film using photolithography and metal deposition processes (such as sputtering titanium / gold layers). Subsequently, the surface with the wire pattern is activated by oxygen plasma treatment.

[0063] Next, the cover layer 3, which integrates a microfluidic structure, is prepared. This step requires the fabrication of a silicon mold. First, grooves defining the drug delivery channel 31 and the stiffness control channel 32 are etched on another silicon wafer using multiple photolithography and deep reactive ion etching processes. The depth of these grooves corresponds to the height of the channels. Subsequently, a layer of PDMS prepolymer is coated onto the grooved mold using a controlled spin-coating process and cured to form a PDMS film of uniform thickness. Crucially, this cured PDMS layer fills all the grooves on the mold, creating a raised channel structure on the lower surface of the PDMS film (the surface in contact with the mold), while the upper surface remains flat. After curing, this PDMS film is peeled off the mold, and another PDMS film is used to seal the surface in contact with the mold, resulting in the cover layer 3. At this point, the drug delivery channel 31 and the stiffness control channel 32 have become cavities completely embedded within the material of the cover layer 3. The corresponding positions of the edge region and interface region of the cover layer 3 still require drilling or cutting processes to form liquid inlets and liquid outlets 41. Finally, the flat upper surface of the cover layer 3 is treated with oxygen plasma.

[0064] The final assembly and bonding are performed in a precision mask aligner. First, the activated intermediate layer 2 (the side with the wire pattern) is aligned and bonded to the surface of the base layer 1, ensuring that the endpoints of the metal wires 21 are precisely connected to the pads 22 of the electrodes 11 and the micro-LEDs 12. Then, the flat upper surface of the capping layer 3 is aligned and bonded to the upper surfaces of the bonded base layer 1 and intermediate layer 2 (i.e., the flat upper surface of the intermediate layer 2). In this bonding step, the microfluidic channels inside the capping layer 3 are physically independent of the intermediate layer 2. The intermediate layer 2 only provides a flat support substrate and does not participate in forming any channel walls, completely eliminating the leakage risk that may be caused by multi-layer alignment forming channels and simplifying the bonding process. After applying uniform pressure, the three-layer PDMS structure is formed into a single unit through plasma activation bonding. After this series of processes, the three-dimensional main structure of the probe is essentially formed. Subsequent process steps include: releasing the complete PDMS probe structure from the carrier; performing edge cutting or contour finishing to form the final wavy profile 4; cleaning or additional metallizing the pads 22 in the interface area to improve connection reliability; and cleaning and disinfection.

[0065] In summary, the multifunctional optical flexible neural probe provided in this embodiment integrates four functions—electrorecording, photostimulation, dual-path drug delivery, and adjustable stiffness—through a three-layer PDMS flexible stacked structure. Its wavy edge contour and porous design, through comparative verification, significantly outperform traditional solutions in terms of anti-clogging reliability, drug distribution uniformity, and drug delivery efficiency. Furthermore, the stiffness control channel 32, based on phase change materials or magnetorheological fluids, endows the probe with the ability to switch between a "rigid implantation state" and a "flexible working state." Simultaneously, the fabrication process demonstrates the feasibility of this complex device. These features work synergistically, enabling precise implantation with minimal tissue damage and maintaining excellent biocompatibility and stable, reliable multimodal neural information interaction performance during long-term implantation, providing an effective tool for neuroscience research and the treatment of neurological diseases.

[0066] Example 2:

[0067] This embodiment provides a neuromodulation system comprising the probe described in Embodiment 1. The core of this system is the aforementioned multifunctional optical flexible neural probe, which is a front-end component that directly interacts with biological tissue. To provide drug stimulation to the probe, the system is equipped with a high-precision external injection pump. This external injection pump is preferably a dual-channel microfluidic injection pump, whose outlet is fluidly connected to the first liquid inlet 311 and the second liquid inlet 312 on the probe interface area via a flexible microcatheter. This allows for independent and precise control of the flow rate, dosage, and timing of different or identical drug solutions infused into the two drug delivery channels 31.

[0068] To achieve dynamic control of probe stiffness, the system also includes a dedicated medium delivery unit and a magnetic field generator.

[0069] When a stiffness adjustment scheme based on phase change materials (such as gallium) is adopted, the medium delivery unit can be a micro-fluid control device with heating and cooling functions and high precision, such as the high-precision injection pump integrated with the Peltier temperature control module mentioned above. It is connected to the stiffness control medium input port through a conduit and is responsible for injecting liquid gallium into the stiffness control channel 32 before implantation and cooling and solidifying it, as well as heating and melting it or suctioning it under negative pressure after implantation.

[0070] When employing a stiffness adjustment scheme based on magnetorheological fluid, the medium delivery unit is primarily used to fill or remove the magnetorheological fluid into the channel, while the magnetic field generator becomes a key component. This magnetic field generator can be an array of permanent magnets (e.g., a customized Heilbeck array constructed from N52-grade neodymium iron boron magnets) capable of generating a high-intensity, uniform static magnetic field. It is positioned outside the probe implantation area to ensure that the magnetic field it generates effectively covers the area where the stiffness adjustment channel 32 is located within the probe, thereby controlling the probe's "hardness" state through the "switching" of the magnetic field. These external devices are all mature products available or customized in the prior art.

[0071] The central control unit coordinates the orderly operation of all the aforementioned components. This control unit typically consists of a computer, a dedicated digital signal processor, and multiple interface circuit boards. In terms of electrical connections, the control unit is connected to the pads 22 of the probe interface area via high-density microcables. These connections serve two purposes: firstly, to provide precise drive current to the micro-LEDs 12, controlling their luminous intensity, frequency, and pulse width to execute complex optogenetic stimulation protocols; secondly, to receive weak neural electrical signals from the electrodes 11. These signals are processed in real-time by preamplifiers, filters, and analog-to-digital converters within the control unit, converting them into digital signals for recording, analysis, and display. Regarding fluid and physical field control, the control unit communicates with the external injection pump, the media delivery unit, and the magnetic field generator via data lines. It can send commands to the external injection pump to start or stop drug infusion and precisely set infusion parameters; it can send commands to the media delivery unit to control the gallium injection, cooling, or aspiration process; and it can control the on / off state or magnetic field strength adjustment of the magnetic field generator. Through preset programs or real-time operation by the experimenter, the control unit can precisely synchronize or execute four operations—light stimulation, electrical recording, drug delivery, and stiffness adjustment—in time or in a complex sequence.

[0072] In summary, this embodiment integrates advanced microelectronics, microfluidics, materials science, and neuroscience experimental methods into a unified interface, greatly simplifying the operation process of complex experiments and improving the reliability, repeatability, and spatiotemporal accuracy of the experiments. It provides an effective technical means for in-depth analysis of brain function and circuit mechanisms.

Claims

1. A multifunctional optical flexible neural probe, characterized in that, include: The base layer (1), intermediate layer (2) and cover layer (3) are stacked sequentially along the thickness direction of the probe. The probe has a probe tip area near the front end and an interface area near the rear end. Multiple electrodes (11) and at least one micro-light-emitting diode (12) are disposed in the probe tip region of the base layer (1). The multiple electrodes (11) and the micro-light-emitting diode (12) are electrically connected to the pads (22) in the interface region through metal wires (21) arranged in the intermediate layer (2). A microfluidic structure is disposed inside the cover plate layer (3). The microfluidic structure includes at least two drug delivery channels (31) extending along the probe length direction and a stiffness control channel (32). The rear ends of the at least two drug delivery channels (31) are respectively connected to a first liquid inlet (311) and a second liquid inlet (312) disposed in the interface area. The rear end of the stiffness control channel (32) is connected to a stiffness control medium inlet disposed in the interface area. The probe has a wavy profile (4) that undulates periodically along the length of the probe at at least one side edge of the probe tip region. Multiple peaks and troughs are formed on the wavy profile (4). Multiple liquid outflow holes (41) are respectively opened at the multiple peaks. Each liquid outflow hole (41) is connected to at least one of at least two drug delivery channels (31).

2. The multifunctional optical flexible neural probe according to claim 1, characterized in that: The stiffness control channel (32) is filled with liquid metal magnetic fluid, which includes a liquid metal matrix and magnetic nanoparticles dispersed in the liquid metal matrix.

3. The multifunctional optical flexible neural probe according to claim 1, characterized in that: The stiffness control channel (32) is filled with liquid gallium before the probe is inserted into the tissue, and the stiffness control channel (32) is cooled before insertion into the tissue to make the liquid gallium solid.

4. The multifunctional optical flexible neural probe according to claim 1, characterized in that: Multiple liquid outlet holes (41) are arranged sequentially along the length of the probe. The diameter of the liquid outlet holes (41) gradually increases from the end closest to the probe tip area to the end furthest from the probe tip area along the length of the probe.

5. The multifunctional optical flexible neural probe according to claim 1, characterized in that: The probe has multiple wavy contours (4) spaced apart on one side. The distance between two adjacent wavy contours (4) along the length of the probe is 170 μm. The multiple wavy contours (4) are arranged at equal intervals.

6. The multifunctional optical flexible neural probe according to claim 1, characterized in that, The probe's geometry satisfies: The thickness of the base layer (1) is 19 μm, the thickness of the intermediate layer (2) is 20 μm, and the thickness of the cover layer (3) is 30 μm; The probe has a width of 277 μm; At least two of the drug delivery channels (31) have a cross-sectional height of 10 μm and a cross-sectional width of 15 μm, and the stiffness control channel (32) has a cross-sectional height of 15 μm and a cross-sectional width of 100 μm.

7. A neural modulation system, characterized in that, include: The multifunctional optical flexible neural probe as described in any one of claims 1-6; An external injection pump that is fluidly connected to the first liquid inlet (311) and the second liquid inlet (312); A medium delivery unit that is connected to the stiffness control medium input port and is used to deliver or extract liquid metal magnetic fluid to the stiffness control channel (32); A magnetic field generator is set outside the area where the stiffness control channel (32) is located and is used to generate a magnetic field; A control unit electrically connected to the plurality of electrodes (11), the micro light-emitting diodes (12), the external injection pump, the medium delivery unit, and the magnetic field generator.

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