CN116250842A

CN116250842A - Dual-mode flexible implantable photoelectric integrated microelectrode, preparation method and application

Info

Publication number: CN116250842A
Application number: CN202211477042.5A
Authority: CN
Inventors: 范鹏辉; 蔡新霞; 宋轶琳; 王怡丁; 戴玉川; 李欣蓉
Original assignee: Aerospace Information Research Institute of CAS
Current assignee: Aerospace Information Research Institute of CAS
Priority date: 2022-11-23
Filing date: 2022-11-23
Publication date: 2023-06-13

Abstract

The invention discloses a dual-mode flexible implantation type photoelectric integrated microelectrode, a preparation method and application thereof. The flexible printed circuit board consists of a flexible material substrate layer, a metal conducting layer, a flexible insulating layer, a flexible circuit board and a miniature optical device. The electrode is released by adopting a laser cutting mode, so that the process efficiency is improved. The photoelectric integration comprises two possible schemes, namely, the optical fiber is adhered to the flexible electrode needle handle through biological glue, and the scheme can integrate the optical fiber and assist in implanting the flexible electrode; the other scheme is that the micro diode is packaged at the front end of the flexible electrode to directly perform optical stimulation, and an optical fiber jumper and an external light source are not needed. The electrode detection site realizes electrophysiology and neurotransmitter dual-mode detection by electrochemical plating of metal nano-particles and conductive polymers and improves the electrode performance. The invention constructs a long-term detection regulation closed loop system, can realize the optical regulation and control of target brain areas of rodents and non-human primates and simultaneously carry out the in-situ synchronous detection of the concentration of nerve electrophysiology and neurotransmitters, and is beneficial to the research of nerve mechanisms.

Description

Dual-mode flexible implantable photoelectric integrated microelectrode, preparation method and application

Technical Field

The invention relates to the field of micro-electromechanical system processing, optical nerve regulation and control and electrophysiological electrochemical nerve information detection, in particular to a dual-mode flexible implantation type photoelectric integrated microelectrode, a preparation method and application. The integrated microelectrode can be used for optical nerve regulation and control and dual-mode nerve information detection.

Background

The brain contains billions of neurons that transmit information via electrical signals and neurotransmitter chemical signals, thereby performing brain functions. Long-term synchronous detection of electrophysiological signals and neurotransmitters is a powerful tool for understanding brain mechanisms. The non-human primate has a gene more similar to that of human, has more important significance in brain science research, and is particularly important to develop nerve electrodes which can be used for various experimental animals such as mice, monkeys and the like. The nerve light regulation can specifically activate or inhibit different types of neurons under the action of light pulses with specific wavelengths by means of optogenetic or optically controlled nano medicines, and plays an important role in the research of closed-loop neuroscience for constituting detection regulation. At present, the detection of the nerve information is mainly focused on electrophysiology, and the commonly used microfilament electrode and silicon-based microelectrode have larger hardness and cause larger brain injury in the long-term detection process. The flexible implantable neural electrode based on the micro-electromechanical processing technology has great advantages in the aspect of long-term detection due to the Young modulus similar to that of the brain. In the research, the nerve light regulation and the nerve information detection are mostly carried out separately, or an in-vivo regulation and separation experience mode is adopted. This approach results in the inability to detect in situ neural information during the regulatory process, increasing the limitations of research.

Based on the above, a flexible dual-mode nerve microelectrode array integrated with a light regulation module is developed for realizing the in-situ nerve electrophysiology and neurotransmitter detection in the nerve light regulation process. The invention provides two optical modulation and control modules, one of which is to realize optical transmission by adopting optical fibers, the integration mode is simple, and the problem of flexible electrode implantation is solved; the other is that the front end is integrated with the mu LED, so that the problems of an external light source and optical fiber winding are avoided. The invention can be used for rodent such as mice and the like, and can also be used for scientific research of non-human primates such as macaques and the like. The invention forms a nerve detection regulation closed loop, and has important significance for long-term nerve regulation detection and neuroscience research of free-moving animals.

Disclosure of Invention

First, the technical problem to be solved

The invention provides a dual-mode flexible implantation type photoelectric integrated microelectrode, a preparation method and application thereof, and aims to solve the technical problems.

(II) technical scheme

To achieve the above object, as an aspect of the present invention, there is provided a dual-mode flexible implantable optoelectronic integrated microelectrode comprising:

the substrate layer is made of flexible materials, is needle-shaped and is used as a support of the whole flexible electrode; a conductive layer disposed on the base layer; comprising the following steps:

circular detection sites which are arranged at the lower end of the microelectrode in a staggered manner; rectangular metal electrodes for connecting the anode and the cathode of the mu LED are arranged on two sides of the lower end of the microelectrode; rectangular bonding pads connected with the detection sites through metal wires are regularly and symmetrically arranged at packaging interfaces at the upper ends of the electrodes; a lead connecting the microelectrode detection site and the bonding pad;

the insulating layer is made of flexible materials and is identical to the base layer in shape, and is positioned on the conducting layer and used for covering the wires and exposing the microelectrode detection sites and the bonding pads;

the flexible printed circuit board is used for electrically conducting the flexible electrodes and the external interfaces, and the metal contacts of the flexible printed circuit board are in one-to-one correspondence with the electrode pads.

Further, the dual-mode flexible implanted photoelectric integrated microelectrode also comprises an optical fiber ceramic ferrule for light transmission; or a mu LED, directly as a light source.

In some embodiments of the invention, the flexible material includes Parylene, polyimide, and epoxy near ultraviolet photoresist SU-8.

In some embodiments of the invention, the material of the conductive layer is chromium/gold or titanium/platinum, with a thickness of 30nm/250nm.

In some embodiments of the invention, the microelectrode detection site diameter is 10-30 μm; the detection site spacing is 30-150 mu m; the length and width of the bonding pad are 200-500 mu m; the pad pitch was 150 μm. The width of the wires is 4-6 μm, and the spacing is 8-12 μm.

In some embodiments of the invention the dual mode detection includes neurophysiologic detection and neurotransmitter detection. The nerve electrophysiology detection sampling rate is 20KHz-40KHz, and the signals can be divided into action potential and field potential through filtering treatment; neurotransmitter assays include assays for the concentration of chemical transmitters such as dopamine, 5 hydroxytryptamine, and glutamate.

In some embodiments of the invention, the microelectrode detection site is modified with electrochemical plating nanoparticles and enzymes; the nano particles comprise platinum nano particles, conductive polymers PEDOT and Nafion; the enzyme is glutamate enzyme.

In some embodiments of the invention, the base layer has a thickness of 3-15 μm; the thickness of the insulating layer is 2-8 mu m.

In some embodiments of the invention, the fiber optic ferrule inner core diameter is 100 and 200 μm; the outer diameter of the ceramic head is 1.25mm; the numerical aperture of the fibers was 0.22 and 0.39. The optical fiber ceramic ferrule comprises an optical fiber and a ceramic head, and the ceramic head is packaged at one end of the optical fiber.

In some embodiments of the invention, the flexible circuit board material is polyimide with a thickness of 0.13mm; the flexible circuit board metal contacts are arranged and the sizes of the flexible circuit board metal contacts and the electrode pads are consistent, and the flexible circuit board metal contacts and the electrode pads correspond to each other one by one.

In some embodiments of the invention, electrical conduction is achieved between the flexible neural electrode and the flexible circuit board through anisotropic conductive adhesive.

In some embodiments of the invention, the flexible neural electrode is affixed to the optical fiber by bio-glue bonding and silicone rubber.

In some embodiments of the invention, the μled is electrically encapsulated at the front end of the electrode by conductive silver paste and reinforced by a shadowless glue.

As another aspect of the present invention, there is provided a method for preparing a dual-mode flexible implantable photoelectrode, comprising:

depositing a flexible base layer on a silicon or glass substrate by vapor deposition;

forming a conductive layer pattern of the photoresist by first photoetching;

evaporating a metal layer;

forming a conductive layer (the conductive layer including a detection site, a metal electrode, a wire, and a pad) by a lift-off process;

forming an insulating layer on the conductive layer by depositing a second layer of flexible material;

forming a photoresist mask by second photoetching;

plasma oxygen etching the insulating layer to expose the microelectrode detection sites and the bonding pads;

releasing the electrode by using a laser cutting mode;

electrically connecting the flexible electrode and the flexible circuit board through anisotropic conductive adhesive;

electroplating nanoparticles on the flexible electrode sites;

one scheme of the optical stimulation is that an optical fiber is adhered to an electrode needle handle through biological glue, the front end of the optical fiber is positioned at a position 200 mu m above a detection site on the front face of an electrode, and finally the optical fiber is fixed on a flexible circuit board through silicon rubber. The other scheme of the optical stimulation is that the front end of the electrode is integrated with the mu LED, conductive silver paste is coated on the left and right sides of the front end of the electrode, which are reserved on the left and right sides of the front end of the electrode, of the metal electrode for connecting the cathode and the anode of the mu LED, then the mu LED is placed at a preset position under a microscope, after preliminary solidification, a proper amount of shadowless glue is coated on the two metal electrodes and the two sides of the mu LED, and the mu LED is fixed after ultraviolet irradiation.

As still another aspect of the present invention, there is provided a neuromodulation detection system based on the dual-mode flexible implantable optoelectronic integrated microelectrode as described above, comprising:

the dual-mode flexible implantable photoelectric integrated microelectrode is used for light regulation and control and dual-mode nerve information detection; a top transparent electromagnetic shielding box for providing an activity area for experimental animals and a shielding environment for detection; the behavior recorder is used for recording the behavior of the experimental animal;

wire harness rotor: is used for shrinking the nerve signal transmission line, preventing the line from winding and increasing the exercise resistance of the experimental animal.

Based on the technical scheme, the dual-mode flexible implantable photoelectric integrated microelectrode has at least one or a part of the following beneficial effects compared with the prior art:

(1) The flexible implantation type photoelectric integrated microelectrode has better biocompatibility and smaller brain damage caused by long-term implantation. The anisotropic conductive adhesive is adopted for encapsulation, the total width of the encapsulation interface of the rear end electrode is 2.5mm, the size is smaller, and the device is lighter for experimental animals such as rodents, non-human primates and the like.

(2) The invention can adopt optical fiber for optical transmission, has simple integration mode and can assist in implantation of the flexible electrode.

(3) The other light stimulation scheme of the invention is to integrate a light source mu LED at the front end of the flexible electrode, and is more suitable for animal experiment research in a free motion state.

(4) The dual-mode flexible implantation type photoelectric integrated microelectrode provided by the invention can realize in-situ dual-mode neural information detection while carrying out optogenetic neural regulation. The optogenetic effectiveness can be verified in situ and the information of the change of nerve signals in the regulation stage can be provided.

Drawings

FIG. 1 is a schematic diagram of a dual-mode flexible implantable microelectrode design of the present invention;

FIG. 2 is a flow chart of a dual-mode flexible implantable microelectrode process of the present invention;

FIG. 3 is a schematic diagram of a dual-mode flexible implantable microelectrode electrical packaging process according to the present invention;

FIG. 4 is a graph showing impedance testing, electrophysiological detection, and dopamine detection calibration of a dual-mode flexible implantable microelectrode of the present invention;

FIG. 5 is a schematic diagram of a dual-mode flexible fiber integrated microelectrode of the present invention;

FIG. 6 is a schematic diagram of a dual-mode flexible μLED integrated microelectrode of the present invention;

fig. 7 is a schematic diagram of a neuromodulation system according to an embodiment of the present invention.

In the above figures, the reference numerals have the following meanings:

1-electrode detection sites; 2-metal electrodes; 3-conducting wires; 4-electrode needle handle; 5-electrode packaging interface; 6-electrode pads; 7-a hot press head of a hot press; 8-a flexible circuit board; 9-flexible circuit board metal contacts; 10-anisotropic conductive adhesive; 11-flexible electrodes; 12-optical fiber; 13-silicone rubber; 14-optical fiber ceramic head; 15-conductive silver paste; 16-mu LED; 17-shadowless glue; 18-an upper computer; 19-a transmission line; 20-wire harness rotor; 21-open field shielding box; 22-behavior recorder.

Detailed Description

The invention discloses a dual-mode flexible implanted photoelectric integrated microelectrode, which can realize optical nerve regulation and control of experimental animals in a free motion state and in-situ electrophysiological electrochemical nerve information detection, and provides a new research strategy for neuroscience research.

The present invention will be further described in detail below with reference to specific embodiments and with reference to the accompanying drawings, in order to make the objects, technical solutions and advantages of the present invention more apparent.

Some embodiments of the present invention will now be described more fully hereinafter with reference to the accompanying drawings, in which some, but not all embodiments are shown. Indeed, various embodiments of the invention may be embodied in many different forms and should not be construed as limited to the embodiments set forth herein; rather, these embodiments are provided so that this disclosure will satisfy applicable legal requirements.

In one exemplary embodiment of the present invention, a dual-mode flexible implantable optoelectronic integrated microelectrode is provided. As shown in fig. 1, a dual-mode flexible implantable electrode design is shown. The electrode is of a three-layer structure, and comprises a bottom flexible material basal layer, a middle conductive layer and a top flexible material insulating layer. The most important structure of the electrode is an intermediate conductive layer, and the conductive layer comprises an electrode detection site 1, a metal electrode 2 for connecting a cathode and an anode of the mu LED, an electrode pad 6 and a wire 3. The electrode detection sites 1 and the metal electrodes 2 used for connecting the anode and the cathode of the mu LED are positioned at the lower ends of the electrodes, the electrode packaging interfaces 5 formed by the electrode pad arrays are partially positioned at the upper ends of the electrodes, and the pads 6 are connected with the electrode detection sites 1 one by one through the leads 3. The length and width of the electrode packaging interface 5 are 3 multiplied by 2.5mm, the part below the electrode packaging interface is called an electrode needle handle 4, the length is 10mm, and the width is 0.4mm. The electrode pads 6 are designed as a 3×6 array, each size being 250×500 μm. The detection sites 1 are classified into two types of diameters of 15 μm and 30 μm. The size of the metal electrode 2 on both sides for connecting the anode and cathode of the LED is 300×50 μm.

FIG. 2 is a flow chart of a dual-mode flexible implantable microelectrode process where the flexible electrode is fabricated using a MEMS process. The method comprises the following steps:

(1) Boiling 4 inch silicon wafer in concentrated sulfuric acid to remove surface impurities. And then, depositing a Parylene film with the thickness of 5 mu m on the surface of the silicon wafer by a vapor deposition method to serve as a flexible electrode substrate layer. As shown in fig. 2 (a);

(2) And spin-coating the reverse photoresist AZ 5214E on the silicon wafer deposited with the substrate layer at the rotating speed of 2000r/s for 60s. Then the substrate is placed on a hot plate at 110 ℃ for pre-baking for 120s and is subjected to first masking exposure. And then placing the photoresist on a hot plate at 120 ℃ for reverse baking for 90s, and then performing flood exposure, development and post baking to form a photoresist pattern. As shown in fig. 2 (b).

(3) A 300nm/2500nm chromium/gold metal conductive layer was deposited on the photoresist image by physical vapor deposition evaporation. As shown in fig. 2 (c).

(4) And removing the metal conductive layer above the photoresist through a stripping process to prepare a conductive layer consisting of a detection site 1, a metal electrode 2 connected with the anode and the cathode of the mu LED, a wire 3 and a bonding pad 6. As shown in fig. 2 (d).

(5) After oxygen plasma cleaning is carried out on the conductive layer, a 3 mu m Parylene film is deposited as an insulating layer. As shown in fig. 2 (e).

(6) And spin-coating AZ 1500 photoresist at a rotating speed of 1000r/s for 60s. After exposure and development, a photoresist mask exposing the bonding pad 6, the metal electrode 2 connecting the anode and cathode of the LED and the detection site 1 is formed. As shown in fig. 2 (f).

(7) The bonding pad 6, the metal electrode 2 connecting the anode and cathode of the LED and the Parylene insulating layer above the detection site 1 are removed by oxygen plasma etching. As shown in fig. 2 (g).

(8) The laser cutting of the release electrode comprises drawing an electrode outline in drawing software and selecting three alignment points; the electrode contour outline drawing is led into an upper computer of a laser processing instrument, and unreleased electrode processing sheets are placed on a laser processing operation table; sequentially selecting alignment points in the layout on the processing piece; setting laser processing parameters, in this example, 20KHz frequency laser, and cutting depth of 15 μm; the electrodes are separated by laser cutting. And then placing the silicon wafer into deionized water to obtain a single release electrode. As shown in fig. 2 (h).

The released flexible electrode needs to be electrically connected with the circuit board to detect signals. The invention designs the flexible circuit board 8 which is matched with the flexible electrode pads 6 in size and corresponds to the flexible electrode pads one by one, wherein the width of the flexible circuit board is 1.5cm, the height of the flexible circuit board is 0.9cm, the thickness of the flexible circuit board is 0.13mm, and the flexible circuit board is light in weight. The metal contacts 9 on the flexible circuit board 8 are 250 x 500 μm in size and 150 μm apart. The present invention discloses an electrical package using a thermo-compression method of an anisotropic conductive paste 10. Fig. 3 is a schematic diagram of electrical packaging of the flexible electrode, which is sequentially from bottom to top, including a flexible electrode 11, an anisotropic conductive adhesive 10, a flexible circuit board 8, and a hot press thermal head 7. The specific implementation method is as follows: the anisotropic conductive paste 10 was first adhered to the flexible circuit board 8 and fixed by preheating at 80 degrees celsius. The flexible electrode 11 is then attached in alignment with the flexible circuit board 8 with the aid of an alignment microscope. Finally, a thermal pressure head 7 at 120 ℃ and 2Mpa pressure acts on the flexible electrode 11 for 10s to complete electrical conduction. As shown in fig. 3. And the electrode detection sites of the packaged flexible electrode 11 are in the same direction with the back surface of the flexible circuit board.

The electrically packaged flexible electrode can carry out nano material modification on the surface of the detection site 1 by an electrochemical plating method so as to improve the electrical property and the electrochemical detection property. The electrophysiological detection site 1 can be modified by layering platinum nanoparticles and a conductive polymer, wherein the platinum nanoparticles are electroplated in a mixed solution of chloroplatinic acid and lead acetate by a chronoamperometry method, and the conductive polymer PEDOT is electroplated in a mixed solution of poly (sodium 4-benzenesulfonate) and PEDOT (20 mM) by a cyclic voltammetry method, as shown in FIG. 2 (i).

The electrochemical detection site can be electroplated with Nafion with the mass fraction of 1% on the basis of the electrophysiological detection site to improve the anti-interference performance of dopamine detection so as to realize stable dopamine detection; or coating a glutamate enzyme mixed solution on the electrophysiological detection site and electroplating a phenylenediamine (mPD) film to realize stable detection of the glutamate. Wherein the glutamate enzyme mixed solution comprises 0.2 unit/. Mu.L glutamate enzyme, 1% bovine serum albumin and 0.125% glutaraldehyde.

Fig. 4 is a graph of the results of the electrode electrophysiological detection and neurotransmitter dopamine detection after nano-modification. Fig. 4 (a) is an impedance test chart of a detection site and a bare electrode site (unmodified nanomaterial) after modification of the nanomaterial, and it can be seen that the electrode impedance is greatly reduced after modification of the nanomaterial, which is more beneficial to improving the detection performance. Fig. 4 (b) shows neural action potentials detected by in vivo experiments using the electrodes of the present invention. Fig. 4 (c) is a graph showing the results of in vitro dopamine calibration using the flexible electrode of the present invention, using electrochemical chronoamperometry, at a voltage of 0.25V. It can be seen that the electrochemical current gradually increased as the concentration of the added dopamine increases. And (3) performing linear fitting on the calibration result, wherein the flexible electrode dopamine detection line is 200nM, the sensitivity is 82 mu M/pA, and the linearity can reach 0.999 as shown in fig. 4 (d).

Optoelectronic integration includes fiber optic integration or mu LED integration. Fig. 5 is a schematic diagram of optical fiber integration, in which the flexible electrode 11, the flexible circuit board 8, the optical fiber 12 and the silicone rubber 13 are sequentially arranged from the back to the front. The fiber optic ferrule 14 and the optical fiber 12 are packaged together to form a fiber optic ferrule that connects the transmission line 19 of the optical fiber for light transmission, the transmitted light being used for optical stimulation. The fiber optic ceramic head 14 is located at the upper end of the optical fiber 12.

Wherein the flexible electrode 11 and the flexible circuit board 8 have completed an electrical package. The length of the optical fiber was 2cm. Firstly, vertically fixing an electrically packaged flexible electrode, and coating 1/3 part of the lower end of an optical fiber 12 with biological glue; then placing the optical fiber in the center of the electrically packaged flexible circuit board, and adjusting the optical fiber 12 until the tip of the optical fiber is positioned at a position about 200 mu m above the electrode detection site; the flexible electrode needle handle is stirred by a thread hooking pen to be contacted with the optical fiber, and the front end of the flexible electrode 11 and the front end of the optical fiber 12 are bonded under the action of biological glue; finally, the silicon rubber 13 is smeared on the metal contact of the flexible circuit board 8 to strengthen the optical fiber.

Fig. 6 is a schematic diagram of the LED assembly, which includes, in order from bottom to top, a flexible microelectrode 11, a conductive silver paste 15, a LED16 and a shadowless glue 17. The LED size in this example is 270×220 μm. The conductive silver paste 15 is used for conducting the metal electrode 2 at the lower end of the flexible microelectrode 11 with the anode and cathode of the mu LED. The specific implementation method is that firstly, according to the size of the mu LED16 and the positions of the anode and the cathode of the mu LED, a conducting wire on an electrode is used as an auxiliary wire, and the application range of the conductive silver paste and the placement position of the mu LED are determined. The conductive silver paste 15 is then applied to the metal electrode 2 and part of the intermediate conductor on both sides of the electrode using a disposable syringe. The LED16 was placed using a tool and pressed gently. Then, a proper amount of shadowless glue 17 is smeared on two sides of the mu LED, the shadowless glue is irradiated by an ultraviolet lamp to be solidified, and the mu LED is fixed on the electrode.

In connection with the present invention, an example of a nerve modulation detection system based on a flexible dual-mode mu LED integrated microelectrode is provided, as shown in fig. 7, the nerve modulation detection system includes an open field shielding box 21 for placing experimental animals, a transmission line 19 for electrode signal acquisition and LED driving, a wire harness rotor 20 for preventing the transmission line from winding, an upper computer 18 and a video recorder 22. The detection system specifically operates as follows: the dual-mode flexible implantation type mu LED photoelectric integrated microelectrode is implanted into the target brain region of the experimental animal through operation. After a one-week recovery period, the laboratory animals may be placed in a custom-made top clear open field shielded box 21. The flexible electrode rear end interface is connected to a transmission line 19. The transmission line 19 passes through a harness rotor 20 to reduce the effect of wire winding on the laboratory animal. At the same time, the upper video recorder 22 achieves behavioral recordings of the laboratory animal from the top view position. The LED drive, neural signal recording and video recorder are time synchronized by the same host computer 18.

The foregoing description of the embodiments has been provided for the purpose of illustrating the general principles of the invention, and is not meant to limit the invention thereto, but to limit the invention thereto, and any modifications, equivalents, improvements and equivalents thereof may be made without departing from the spirit and principles of the invention.

Claims

1. A dual-mode flexible implantable optoelectronic integrated microelectrode comprising:

the substrate layer is made of flexible materials and is in a needle-shaped outline and used as a support of the whole flexible implantable photoelectric integrated microelectrode;

a conductive layer disposed on the base layer; comprising the following steps: the circular detection sites are arranged at the lower end of the microelectrode in a staggered manner; rectangular metal electrodes used for connecting the anode and the cathode of the mu LED, wherein the rectangular metal electrodes are arranged on two sides of the lower end of the microelectrode; rectangular bonding pads connected with the detection sites through metal wires, wherein the rectangular bonding pads are regularly and symmetrically arranged at packaging interfaces at the upper ends of the electrodes; a wire connecting the detection site and the bonding pad;

the insulating layer is made of flexible materials and is the same as the base layer in shape, and is positioned on the conducting layer and used for covering the wires and exposing the detection sites and the bonding pads of the microelectrodes;

and the flexible printed circuit board is used for electrically conducting the flexible implantable photoelectric integrated microelectrode and the external interface, and the metal contacts of the flexible printed circuit board are in one-to-one correspondence with the bonding pads.

2. The dual-mode flexible implantable optoelectronic integrated microelectrode according to claim 1, further comprising a fiber ceramic ferrule or a μled; the optical fiber ceramic ferrule is used for optical transmission;

the mu LED is directly used as a light source for light stimulation.

3. The dual-mode flexible implantable optoelectronic integrated microelectrode according to claim 1, wherein the flexible materials of the base layer and the insulating layer comprise one or more of Parylene (Parylene), polyimide and epoxy near ultraviolet photoresist SU-8.

4. The dual-mode flexible implantable optoelectronic integrated microelectrode according to claim 1, wherein the overall length of the microelectrode is 6 to 60mm, the length and width of the packaging interface at the upper end of the microelectrode are 3 x 2.5mm, and the electrode needle handle width is 300 to 500 μm; the diameter of the detection site at the lower end of the microelectrode is 10-30 mu m; the detection site spacing is 30-150 mu m; the length and width of the metal electrode connected with the anode and the cathode of the mu LED are 300 multiplied by 50 mu m; the length and width of the packaging interface bonding pads at the upper end of the microelectrode are 200-500 mu m, the spacing between the bonding pads is 150 mu m, and the bonding pads are arranged in an array; the width of the wires is 4-6 mu m, and the spacing is 8-12 mu m; the electrode detection sites are connected with the upper packaging bonding pads in a one-to-one correspondence manner through wires.

5. The dual-mode flexible implantable optoelectronic integrated microelectrode according to claim 1, wherein the integrated micro-optical device comprises an optical fiber or a μled, wherein the diameter of the optical fiber is in the range of 100-200 μm, the numerical aperture of the optical fiber is 0.22 and 0.39, and the length of the optical fiber is 10-60mm; the LED has a length-width dimension of 220 x 270 μm and a thickness of 50 μm.

6. The dual mode flexible implantable optoelectronic integrated microelectrode according to claim 1, wherein the base layer has a thickness of 3 to 15 μm; the thickness of the insulating layer is 2-8 mu m.

7. The method for preparing the dual-mode flexible implantable photoelectric integrated microelectrode according to any one of claims 1 to 6, comprising:

forming a flexible material substrate on a silicon or glass substrate by a vapor deposition method or a spin coating method;

patterning the photoresist by first photoetching, evaporating the metal layer and stripping to form an electrode conducting layer; forming an insulating layer on the conductive layer by depositing or spin-coating a second layer of flexible material;

forming a photoresist mask by second photoetching, and etching the insulating layer by plasma oxygen to expose microelectrode sites and bonding pads;

the individual electrodes are separated and released using a laser cutting method.

8. The method of manufacturing according to claim 7, wherein the method of electrical packaging of the dual-mode flexible implantable microelectrode comprises: using anisotropic conductive adhesive to electrically conduct the micro-electrode upper end packaging interface bonding pads with flexible circuit board metal contacts under the action of 120 ℃ and 2Mpa pressure, wherein the flexible circuit board metal contacts are in one-to-one correspondence with the electrode upper end packaging interface bonding pads; the electrically packaged electrode includes a microelectrode and a flexible circuit board in electrical communication with the microelectrode.

9. The dual-mode flexible implantable optoelectronic integrated microelectrode according to any one of claims 1 to 6 or the microelectrode produced by the production method of any one of claims 7 to 8, characterized in that the optical fiber coated with the bio-glue is placed on the back of the electrically packaged electrode flexible circuit board, the optical fiber is bonded with the electrode needle handle and the flexible circuit board through the bio-glue, and finally the optical fiber is reinforced at the joint (namely the upper end packaging interface of the electrode) of the flexible circuit board and the microelectrode through the silicone rubber.

10. The dual-mode flexible implantable optoelectronic integrated microelectrode according to any one of claims 1 to 6 or the microelectrode produced by the production process of any one of claims 7 to 8, characterized in that the μled is electrically encapsulated over the detection site at the lower end of the electrode by means of conductive silver paste and then fixed by means of shadowless glue.

11. The dual-mode flexible implantable optoelectronic integrated microelectrode according to any one of claims 1 to 6 or the microelectrode produced by the production process of any one of claims 7 to 8, wherein a micro-optical device is integrated with the dual-mode flexible implantable optoelectronic integrated microelectrode for in situ neurophysiologic and neurotransmitter detection at the same time as optical stimulation; neurophysiologic information includes nerve action potentials and field potentials, neurotransmitters including dopamine, 5 hydroxytryptamine, and glutamate.

12. The dual-mode flexible implantable optoelectronic integrated microelectrode according to any one of claims 1 to 6 or the microelectrode produced by the production process of any one of claims 7 to 8, wherein electrode detection sites are distributed on the surface of the microelectrode needle handle for both electrophysiological and neurotransmitter electrochemical detection, the two modification processes being different:

when the method is used for electrophysiological detection, detection sites are modified by layering platinum nano-particles and conductive polymers such as poly (3, 4-ethylenedioxythiophene) (PEDOT);

when the method is used for neurotransmitter electrochemical detection, the detection site is electroplated with a perfluorinated sulfonic acid group polymer (Nafion) film (the film thickness is less than 1 μm) on the basis of electrophysiological detection modification to detect the concentration of dopamine or is coated with glutamate enzyme to detect the concentration of glutamate.

13. Use of a bimodal flexible implantable optoelectronic integrated microelectrode according to any one of claims 1 to 6 or a microelectrode produced by the method of production according to any one of claims 7 to 8 for neuromodulation and bimodal neuro information detection in rodents or non-human primates.