Four-mode integrated nerve probe and preparation method thereof

Abstract

The invention relates to the technical field of nerve probes, and provides a four-mode integrated nerve probe and a preparation method thereof. The four-mode integrated nerve probe provided by the invention comprises a flexible substrate, an electric signal recording module, an ultrasonic stimulation module, a light stimulation module and a microfluidic channel. The electric signal recording module is used for recording electroneurographic signals, the ultrasonic stimulation module is used for ultrasonic stimulation, the optical stimulation module is used for optical stimulation and signal recording, and the microfluidic channel is filled with drugs through a microfluidic channel control port in the probe body and releases the drugs through a microfluidic channel outlet in the needle tip. According to the four-mode integrated nerve probe provided by the invention, multiple functions are integrated into one probe, so that comprehensive detection and regulation of a nervous system are realized, and the technical problems that a traditional nerve probe is single in function, inflammation is caused by a rigid material and multi-mode integration is insufficient are solved.

Description

Technical Field

[0001] The present invention relates to the technical field of neural probes, and in particular to a four-mode integrated neural probe and a preparation method thereof. Background Art

[0002] Over the past decade or so, research in neuroscience has made tremendous progress. Brain-computer interfaces (BCIs), key devices that connect the human or animal brain to external devices for real-time communication, represent the technological frontier for enabling brain-controlled control of external devices. As demand for BCIs continues to grow, various neural electrodes have been developed to address various challenges encountered in neuroscience research and clinical applications.

[0003] Existing neural probes offer limited functionality, supporting only electrical signal recording or optical stimulation, failing to meet diverse needs. Ultrasound stimulation and drug release, in particular, have yet to be effectively integrated with optoelectronic modules. Furthermore, the rigid materials used in conventional neural probes (such as silicon) can easily trigger chronic tissue inflammation.

[0004] Based on the multifunctional neural probe, the present invention realizes the integration of four modes (electricity, ultrasound, light, and microfluidic channels), enabling the probe to meet more diverse research and treatment needs. The probe adopts PI flexible material, which solves the technical problems of single function of neural probe, inflammation caused by rigid materials, and insufficient multimodal integration. Summary of the Invention

[0005] The present invention provides a four-mode integrated neural probe and a preparation method thereof, which are used to solve the technical problems in the prior art of single function of neural probes, inflammation caused by rigid materials, and insufficient multi-modal integration.

[0006] In one aspect, the present invention provides a four-mode integrated neural probe comprising: a flexible substrate, an electrical signal recording module, an ultrasound stimulation module, a light stimulation module, and a microfluidic channel; The flexible substrate is made of polyimide; The electrical signal recording module consists of a Cr / Au electrode array distributed on the needle tip, which is connected to a welding board via a flexible flat cable for recording neural electrical signals; The ultrasonic stimulation module is a piezoelectric micro-machined ultrasonic transducer embedded in the needle tip. The piezoelectric micro-machined ultrasonic transducer is made of lead zirconate titanate piezoelectric material. The expansion and contraction of the piezoelectric layer drives the deformation of the structural layer to generate ultrasonic waves for ultrasonic stimulation. The optical stimulation module consists of a SU-8 optical waveguide in the middle of the needle body and an optical fiber placed in a groove at the top of the probe. The SU-8 optical waveguide and the optical fiber are coupled for optical stimulation and signal recording. The microfluidic channel is arranged inside the needle body, and the medicine is filled through the microfluidic channel control port on the probe body, and the medicine is released through the microfluidic channel outlet at the needle tip.

[0007] According to a four-mode integrated neural probe provided by the present invention, the surface of the four-mode integrated neural probe is coated with a polylactic acid layer, and the thickness of the polylactic acid layer is 10-50 μm.

[0008] According to a four-mode integrated neural probe provided by the present invention, the Cr / Au electrode array consists of 8 electrodes, and the electrode spacing is 50-200 μm.

[0009] According to a four-mode integrated neural probe provided by the present invention, the method for preparing the piezoelectric micromechanical ultrasonic transducer comprises the following steps: Double-sided silicon dioxide is grown on the surface of the bottom silicon material by a thermal oxygen epitaxial growth method; Vacuum silicon-silicon bonding is performed on another silicon wafer and the silicon dioxide layer on the front side of the bottom silicon material, and a top silicon material is formed by high-temperature annealing to obtain insulating substrate silicon; A titanium seed layer, a lead electrode layer, and a strontium ruthenate buffer layer are sequentially deposited on the surface of the top silicon material to form a bottom electrode; A lead zirconate titanate film is formed on the surface of the bottom electrode by sputtering technology; A strontium ruthenate layer and a lead layer are sequentially deposited on the surface of the lead zirconate titanate film and patterned to form a top electrode; The lead zirconate titanate film is etched by a wet etching process to form a vibration structure; The insulating substrate silicon is etched from the back by using a deep reactive ion etching process to obtain a piezoelectric micromechanical ultrasonic transducer; The resonant frequency range of the piezoelectric micromechanical ultrasonic transducer is 1-10 MHz.

[0010] According to a four-mode integrated neural probe provided by the present invention, the thickness of the titanium seed layer is 1~10nm, the thickness of the lead electrode layer is 50~150nm, the thickness of the strontium ruthenate buffer layer is 10~30nm, and the lead zirconate titanate film is further adjusted to a thickness of 30~50μm by chemical mechanical polishing.

[0011] According to a four-mode integrated neural probe provided by the present invention, the refractive index of the SU-8 optical waveguide is 1.6-1.8, the width of the optical waveguide is 20-100 μm, and the coupling efficiency with the optical fiber is ≥80%.

[0012] According to a four-mode integrated neural probe provided by the present invention, the cross-sectional diameter of the microfluidic channel is 10-50 μm, and the inner wall of the microfluidic channel is coated with a hydrophilic coating.

[0013] In another aspect, the present invention further provides a method for preparing a four-mode integrated neural probe, comprising the following steps: Spin-coat a sacrificial layer of polyethylene glycol onto a silicon substrate; Spin-coating polyimide on the polyethylene glycol sacrificial layer and curing to form a flexible substrate; Sputtering a Cr / Au layer and patterning it with photolithography to form a Cr / Au electrode array and a welding plate; Spin coating SU-8 optical waveguide material, applying photoresist on the surface of SU-8 optical waveguide material and curing the photoresist in specific areas through mask and ultraviolet light irradiation, using developer and removing excess photoresist to form SU-8 optical waveguide; A microfluidic channel, a microfluidic channel control port, and a hole for placing a piezoelectric micromechanical ultrasonic transducer are formed on the needle body by interval drilling and ion etching; removing the silicon substrate by wet etching; The Cr / Au electrode array and the welding board are connected by flexible cables, the optical fiber is coupled to the SU-8 optical waveguide, and the piezoelectric micromachined ultrasonic transducer is bonded to the hole in the needle body for placing the piezoelectric micromachined ultrasonic transducer using epoxy resin; A polylactic acid layer is coated on the surface of the needle body and dried to obtain a four-mode integrated neural probe.

[0014] According to the preparation method of a four-mode integrated neural probe provided by the present invention, the thickness of the polyethylene glycol sacrificial layer is 5-20 μm, the thickness of the Cr layer is 5-20 nm, and the thickness of the Au layer is 100-300 nm.

[0015] According to the method for preparing a four-mode integrated neural probe provided by the present invention, the drying temperature of the polylactic acid coating is 60-80° C., and the drying time is 1-3 hours.

[0016] The four-mode integrated neural probe and its preparation method provided by the present invention solve the technical problem of single function of neural probes in the prior art by integrating electrical, ultrasonic, optical and microfluidic channels into a single probe, and achieve the beneficial effect of all-round neural detection and regulation.

[0017] The four-mode integrated neural probe and its preparation method provided by the present invention adopt flexible materials, use polyimide as the substrate, and coat the needle surface with a polylactic acid coating that balances implantation stiffness and biocompatibility. These solve the technical problems in the prior art of poor biocompatibility of neural probes and the susceptibility of rigid materials to chronic tissue inflammatory reactions. The four-mode integrated neural probe and its preparation method are suitable for long-term implantation and reduce the risk of tissue damage.

[0018] The four-mode integrated neural probe and its preparation method provided by the present invention solve the technical problem of insufficient multi-modal integration of neural probes in the prior art by effectively integrating ultrasonic stimulation and drug release functions with optoelectronic modules, and meet the demand for ultrasonic stimulation while integrating optoelectronic integration and microfluidic channels. BRIEF DESCRIPTION OF THE DRAWINGS

[0019] In order to more clearly illustrate the technical solutions in the present invention or the prior art, a brief introduction is given below to the drawings required for use in the embodiments or the description of the prior art. Obviously, the drawings described below are some embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying any creative work.

[0020] Figure 1 Schematic diagram of the structure of a four-mode integrated neural probe provided by an embodiment of the present invention; Figure 2 Schematic diagram of the needle tip structure of the four-mode integrated neural probe provided by an embodiment of the present invention; Figure 3 Schematic diagram of a method for preparing a piezoelectric micromachined ultrasonic transducer provided by an embodiment of the present invention; Figure 4 It is a schematic diagram of the preparation method of the four-mode integrated neural probe provided in an embodiment of the present invention.

[0021] Reference numerals: 1. Cr / Au electrode array; 2. Piezoelectric micromachined ultrasonic transducer; 3. Electrical pad; 4. SU-8 optical waveguide; 5. Groove on top of probe; 6. Microfluidic channel control port; 7. Flexible flat cable; 8. Microfluidic channel outlet. DETAILED DESCRIPTION

[0022] To make the objectives, technical solutions, and advantages of the present invention more clear, the technical solutions of the present invention will be clearly and completely described below in conjunction with the accompanying drawings. Obviously, the embodiments described are only some of the embodiments of the present invention, not all of them. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making creative efforts shall fall within the scope of protection of the present invention.

[0023] The following combination Figures 1 to 4 The present invention describes a four-mode integrated neural probe and a method for preparing the same.

[0024] Figure 1 Schematic diagram of the structure of the four-mode integrated neural probe provided by an embodiment of the present invention.

[0025] Figure 2 Schematic diagram of the needle tip structure of the four-mode integrated neural probe provided in an embodiment of the present invention.

[0026] like Figure 1 and Figure 2 As shown, the embodiment of the present invention provides The four-mode integrated neural probe includes: a flexible substrate, an electrical signal recording module, an ultrasonic stimulation module, a light stimulation module and a microfluidic channel; the flexible substrate is made of polyimide; the electrical signal recording module is composed of a Cr / Au electrode array distributed on the needle tip, which is connected to the welding board through a flexible cable for recording neural electrical signals; the ultrasonic stimulation module is a piezoelectric micromechanical ultrasonic transducer embedded in the needle tip, which is made of lead zirconate titanate piezoelectric material. The expansion and contraction of the piezoelectric layer drives the deformation of the structural layer to generate ultrasonic waves for ultrasonic stimulation; the light stimulation module is composed of an SU-8 optical waveguide in the middle of the needle body and an optical fiber placed in the groove at the top of the probe. The SU-8 optical waveguide is coupled to the optical fiber for optical stimulation and signal recording; the microfluidic channel is arranged inside the needle body, and the drug is filled through the microfluidic channel control port on the probe body and released through the microfluidic channel outlet at the needle tip.

[0027] In the present invention, the surface of the four-mode integrated neural probe is coated with a polylactic acid layer, and the thickness of the polylactic acid layer is 10-50 μm, preferably 15-45 μm, and more preferably 20-40 μm.

[0028] In the present invention, the Cr / Au electrode array consists of 8 electrodes, and the electrode spacing is 50-200 μm, preferably 70-180 μm, and more preferably 90-160 μm.

[0029] Figure 3 Schematic diagram of a method for preparing a piezoelectric micromechanical ultrasonic transducer provided in an embodiment of the present invention.

[0030] like Figure 3 As shown, the preparation method of the piezoelectric micromechanical ultrasonic transducer provided by the embodiment of the present invention includes the following steps: growing double-sided silicon dioxide on the surface of the bottom silicon material by a thermal oxygen epitaxial growth method; vacuum silicon-silicon bonding is performed on another silicon wafer and the silicon dioxide layer on the front of the bottom silicon material, and a top silicon material is formed by high-temperature annealing to obtain an insulating substrate silicon; a titanium seed layer, a lead electrode layer and a strontium ruthenium buffer layer are sequentially deposited on the surface of the top silicon material to form a bottom electrode; a lead zirconate titanate film is generated on the surface of the bottom electrode by sputtering technology; a strontium ruthenium layer and a lead layer are sequentially deposited on the surface of the lead zirconate titanate film, and a top electrode is formed by patterning; the lead zirconate titanate film is etched by a wet etching process to form a vibration structure; and the insulating substrate silicon is etched from the back by a deep reactive ion etching process to obtain a piezoelectric micromechanical ultrasonic transducer.

[0031] In the present invention, the resonant frequency range of the piezoelectric micromechanical ultrasonic transducer is 1-10 MHz, preferably 2-8 MHz, and more preferably 4-6 MHz.

[0032] In the present invention, the thickness of the titanium seed layer is 1-10 nm, preferably 3-8 nm, and more preferably 5-7 nm.

[0033] In the present invention, the thickness of the lead electrode layer is 50-150 nm, preferably 70-130 nm, and more preferably 90-110 nm.

[0034] In the present invention, the thickness of the strontium ruthenate buffer layer is 10-30 nm, preferably 15-25 nm, and more preferably 18-22 nm.

[0035] In the present invention, the lead zirconate titanate film is further adjusted to a thickness of 30-50 μm, preferably 35-45 μm, and more preferably 38-42 μm by chemical mechanical polishing.

[0036] In the present invention, the refractive index of the SU-8 optical waveguide is 1.6-1.8, the optical waveguide width is 20-100 μm, preferably 40-80 μm, more preferably 50-70 μm, and the coupling efficiency with the optical fiber is ≥80%.

[0037] In the present invention, the cross-sectional diameter of the microfluidic channel is 10-50 μm, preferably 20-40 μm, and more preferably 25-35 μm, and the inner wall of the microfluidic channel is coated with a hydrophilic coating.

[0038] Figure 4 It is a schematic diagram of the preparation method of the four-mode integrated neural probe provided in an embodiment of the present invention.

[0039] like Figure 4 As shown, Figure 4 (A~G) are side sectional views. Figure 4(a-g) are front cross-sectional views. The method for preparing a four-mode integrated neural probe provided by an embodiment of the present invention includes the following steps: spin-coating a polyethylene glycol sacrificial layer on a silicon substrate; spin-coating polyimide on the polyethylene glycol sacrificial layer and curing it to form a flexible substrate; sputtering a Cr / Au layer and patterning it with photolithography to form a Cr / Au electrode array and a welding plate; spin-coating SU-8 optical waveguide material, applying photoresist on the surface of the SU-8 optical waveguide material, and curing the photoresist in specific areas through a mask and ultraviolet light irradiation, using a developer and removing excess photoresist to form S U-8 optical waveguide; microfluidic channels, microfluidic channel control ports and holes for placing piezoelectric micromechanical ultrasonic transducers are formed in the needle body through interval drilling and ion etching; the silicon base plate is removed by wet etching; the Cr / Au electrode array and the welding board are connected by flexible cables, the optical fiber is coupled with the SU-8 optical waveguide, and the piezoelectric micromechanical ultrasonic transducer is bonded to the needle body through epoxy resin to form the hole for placing the piezoelectric micromechanical ultrasonic transducer; a polylactic acid layer is coated on the surface of the needle body and dried to obtain a four-mode integrated neural probe.

[0040] In the present invention, the thickness of the polyethylene glycol sacrificial layer is 5~20μm, preferably 10~15μm, and more preferably 12~13μm; the thickness of the Cr layer is 5~20nm, preferably 10~15nm, and more preferably 12~13nm; the thickness of the Au layer is 100~300nm, preferably 150~250nm, and more preferably 180~220nm.

[0041] In the present invention, the drying temperature of the polylactic acid coating is 60-80° C., preferably 65-75° C., and more preferably 68-72° C.; the drying time is 1-3 hours, preferably 1.5-2.5 hours.

[0042] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit it. Although the present invention has been described in detail with reference to the aforementioned embodiments, those skilled in the art should understand that they can still modify the technical solutions described in the aforementioned embodiments, or make equivalent replacements for some of the technical features therein. However, these modifications or replacements do not deviate the essence of the corresponding technical solutions from the spirit and scope of the technical solutions of the various embodiments of the present invention.

Claims

1. A four-mode integrated neural probe, characterized in that: include: Flexible substrate, electrical signal recording module, ultrasound stimulation module, light stimulation module and microfluidic channel; The flexible substrate is made of polyimide; The electrical signal recording module consists of a Cr / Au electrode array distributed on the needle tip, which is connected to a welding board via a flexible flat cable for recording neural electrical signals; The ultrasonic stimulation module is a piezoelectric micro-machined ultrasonic transducer embedded in the needle tip. The piezoelectric micro-machined ultrasonic transducer is made of lead zirconate titanate piezoelectric material. The expansion and contraction of the piezoelectric layer drives the deformation of the structural layer to generate ultrasonic waves for ultrasonic stimulation. The optical stimulation module consists of a SU-8 optical waveguide in the middle of the needle body and an optical fiber placed in a groove at the top of the probe. The SU-8 optical waveguide and the optical fiber are coupled for optical stimulation and signal recording. The microfluidic channel is arranged inside the needle body, and the medicine is filled through the microfluidic channel control port on the probe body, and the medicine is released through the microfluidic channel outlet at the needle tip.

2. The four-mode integrated neural probe according to claim 1, characterized in that: The surface of the four-mode integrated neural probe is coated with a polylactic acid layer, and the thickness of the polylactic acid layer is 10-50 μm.

3. The four-mode integrated neural probe according to claim 1, characterized in that: The Cr / Au electrode array consists of 8 electrodes, and the electrode spacing is 50-200 μm.

4. The four-mode integrated neural probe according to claim 1, characterized in that: The method for preparing the piezoelectric micromechanical ultrasonic transducer comprises the following steps: Double-sided silicon dioxide is grown on the surface of the bottom silicon material by a thermal oxygen epitaxial growth method; Vacuum silicon-silicon bonding is performed on another silicon wafer and the silicon dioxide layer on the front side of the bottom silicon material, and a top silicon material is formed by high-temperature annealing to obtain insulating substrate silicon; A titanium seed layer, a lead electrode layer, and a strontium ruthenate buffer layer are sequentially deposited on the surface of the top silicon material to form a bottom electrode; A lead zirconate titanate film is formed on the surface of the bottom electrode by sputtering technology; A strontium ruthenate layer and a lead layer are sequentially deposited on the surface of the lead zirconate titanate film and patterned to form a top electrode; The lead zirconate titanate film is etched by a wet etching process to form a vibration structure; The insulating substrate silicon is etched from the back by using a deep reactive ion etching process to obtain a piezoelectric micromechanical ultrasonic transducer; The resonant frequency range of the piezoelectric micromechanical ultrasonic transducer is 1-10 MHz.

5. The four-mode integrated neural probe according to claim 4, characterized in that: The thickness of the titanium seed layer is 1-10 nm, the thickness of the lead electrode layer is 50-150 nm, the thickness of the strontium ruthenate buffer layer is 10-30 nm, and the lead zirconate titanate film is further adjusted to a thickness of 30-50 μm by chemical mechanical polishing.

6. The four-mode integrated neural probe according to claim 1, characterized in that: The refractive index of the SU-8 optical waveguide is 1.6-1.8, the width of the optical waveguide is 20-100 μm, and the coupling efficiency with the optical fiber is ≥80%.

7. The four-mode integrated neural probe according to claim 1, characterized in that: The cross-sectional diameter of the microfluidic channel is 10-50 μm, and the inner wall of the microfluidic channel is coated with a hydrophilic coating.

8. A method for preparing the four-mode integrated neural probe according to any one of claims 1 to 7, characterized in that: The following steps are involved: Spin-coat a sacrificial layer of polyethylene glycol onto a silicon substrate; Spin-coating polyimide on the polyethylene glycol sacrificial layer and curing to form a flexible substrate; Sputtering a Cr / Au layer and patterning it with photolithography to form a Cr / Au electrode array and a welding plate; Spin coating SU-8 optical waveguide material, applying photoresist on the surface of SU-8 optical waveguide material and curing the photoresist in specific areas through mask and ultraviolet light irradiation, using developer and removing excess photoresist to form SU-8 optical waveguide; A microfluidic channel, a microfluidic channel control port, and a hole for placing a piezoelectric micromechanical ultrasonic transducer are formed on the needle body by interval drilling and ion etching; removing the silicon substrate by wet etching; The Cr / Au electrode array and the welding board are connected by flexible cables, the optical fiber is coupled to the SU-8 optical waveguide, and the piezoelectric micromachined ultrasonic transducer is bonded to the hole in the needle body for placing the piezoelectric micromachined ultrasonic transducer using epoxy resin; A polylactic acid layer is coated on the surface of the needle body and dried to obtain a four-mode integrated neural probe.

9. The method for preparing the four-mode integrated neural probe according to claim 8, characterized in that: The thickness of the polyethylene glycol sacrificial layer is 5-20 μm, the thickness of the Cr layer is 5-20 nm, and the thickness of the Au layer is 100-300 nm.

10. The method for preparing a four-mode integrated neural probe according to claim 8, characterized in that: The polylactic acid coating is dried at a temperature of 60 to 80° C. and for a time of 1 to 3 hours.

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