CN110327544B

CN110327544B - Implanted high-density electrode point flexible probe electrode and preparation method thereof

Info

Publication number: CN110327544B
Application number: CN201910537043.6A
Authority: CN
Inventors: 刘景全; 郭哲俊; 吉博文; 王隆春; 洪雯; 奚野
Original assignee: Shanghai Jiaotong University
Current assignee: Shanghai Jiaotong University
Priority date: 2019-06-20
Filing date: 2019-06-20
Publication date: 2020-10-02
Anticipated expiration: 2039-06-20
Also published as: CN110327544A

Abstract

The invention provides an implanted high-density electrode point flexible probe electrode and a preparation method thereof, wherein the electrode comprises a polymer insulating layer and a metal layer, the polymer insulating layer and the metal layer are sequentially overlapped from bottom to top to form an electrode structure consisting of a plurality of polymer insulating layers and a plurality of metal layers, and each metal layer is coated between the polymer insulating layers to ensure that the metal layers arranged at intervals are electrically insulated; electrode points are arranged on the upper surface, the lower surface and one side or two side surfaces of the electrode, and surface electrode points and side electrode points are formed on the electrode. The invention provides a design scheme of laterally distributed electrode points, wherein the electrode points are distributed on the upper surface, the lower surface and the lateral surface of an electrode, and compared with common surface electrode points, the distribution mode of the lateral electrode points has higher electrode point density.

Description

Implanted high-density electrode point flexible probe electrode and preparation method thereof

Technical Field

The invention relates to a flexible probe implanted bioelectrode used in the technical field of biomedical engineering, in particular to an implanted high-density electrode point flexible probe electrode and a preparation method thereof.

Background

The brain-computer interface technology provides a brain-external communication mode, which bypasses peripheral nerves and muscle tissues, directly transmits signals of the brain to the outside through manual means or transmits external information to the brain in a stimulation mode.

In the seventies of the last century, Benabid, a neurosurgery family of the university of Gelernobuer, France, used nerve electrodes to stimulate the ventral intermedius thalamus for the first time to treat tremor of Parkinson's disease, and obtained more satisfactory results. Today, Deep Brain Stimulation (DBS) has been approved by the U.S. food and drug administration as a therapeutic approach for essential tremor, parkinson's disease, dystonia and obsessive-compulsive disorder in 1997, 2003 and 2009, respectively. Compared with common operation damage and drug treatment, DBS has the characteristics of high effective rate, small side effect, minimally invasive electrode implantation operation, controllable and reversible treatment effect, few complications and the like. In addition, the compound also has a certain application prospect for depression, Alzheimer's disease, chronic pain and post-traumatic stress syndrome.

In The past decades, there have been many kinds of neural microelectrodes applied to neural circuit research, such as a metal wire electrode mentioned in robinson d.a. The article "The electrical properties of metal microelectrodes", which is simple and convenient to manufacture, low in cost, and has minimal damage to The organism after implantation, and is The most mature neural microelectrode used for The first time, but this kind of electrode has only a single probe and only one electrode point on The front end, and The small number of electrode points has not been able to satisfy The requirements of high resolution stimulation and recording. With the development of MEMS technology, high-density electrodes based on silicon substrates are emerging in large numbers, wherein most typical are kosher electrodes and michigan electrodes, such as the kosher electrodes mentioned in the paper "neural intense controlled sexual devices by a human with a tepplegia" by researchers at Leigh r. hochberg and John p.donoghue at the university of braun university, which have a three-dimensional array structure that makes them well suited for recording the activity of neurons at different depths in the cortex, and the michigan electrodes mentioned in the paper "a high-efficient IC-compatible recording radar" at the university of michigan, which integrate multiple electrode points on a single probe, with higher integration and electrode point density. Compatible with MEMS technology, the processing of the silicon-based electrode has higher controllability and repeatability, but the higher Young modulus of silicon relative to the biological tissue can cause the decline of peripheral nerve signals and tissue necrosis in the long-term embedding process, and in addition, the silicon-based nerve probe is easy to break after being subjected to tangential stress.

In recent years, electrodes based on flexible thin films have been realized by the development of biocompatible polymers and processing techniques thereof, such as the polyimide-based flexible thin film probe mentioned in the article "Polymer Neural Interface with Dual-sized electrodes for Neural stimulation and Recording" by Angela tokker et al, and such electrodes use polyimide as the substrate of the electrode, and the modulus is two orders of magnitude less than that of the silicon substrate, so that the biocompatibility is better, and the electrode is more advantageous in long-term implantation.

Disclosure of Invention

Aiming at the defects in the prior art, the invention aims to provide an implanted high-density electrode point flexible probe electrode and a preparation method thereof.

According to the first aspect of the invention, an implantable high-density electrode point flexible probe electrode is provided, the electrode comprises a polymer insulating layer and a metal layer, the polymer insulating layer and the metal layer are sequentially overlapped from bottom to top to form an electrode structure consisting of a plurality of polymer insulating layers and a plurality of metal layers, and each metal layer is coated between the polymer insulating layers to electrically insulate the metal layers arranged at intervals;

the electrode points are arranged on the upper surface, the lower surface and one side or two side surfaces, namely the surface electrode points and the side surface electrode points are formed on the electrode.

The high-density electrode points are arranged on the upper surface, the lower surface and one side or two side surfaces of a single probe. The mode of setting the electrode points can improve the integrated number of the electrode points on a single probe, and the aim of high-density electrode points is fulfilled.

Further, the surface electrode points are formed by wrapping the graphical metal layers with the polymer insulating layers covering the uppermost layer and the bottommost layer of the electrode and forming holes at the corresponding electrode points.

Further, the side electrode points are formed by exposing the tail ends of the metal layers outside the polymer insulating layers, and high-density electrode point arrays are stacked on the side surfaces of the electrodes.

Preferably, the polymeric insulating layer is a biocompatible flexible polymeric material.

More preferably, the biocompatible flexible polymer material is selected from any one of polyimide and parylene.

Preferably, each of the polymer insulating layers has a thickness of 1 μm to 10 μm.

Preferably, the overall thickness of the electrode is 10 to 50 μm.

Preferably, the metal layer is a patterned metal conductor or a patterned conductive polymer, wherein the metal conductor is any one of gold, platinum, chromium and titanium; the conductive polymer is one or more than two mixed polymers of carbon nano tubes, graphene and silver nanowires.

According to a second aspect of the present invention, there is provided a method for preparing an implantable high-density flexible probe electrode, comprising:

spin coating or depositing a polymer insulating layer at the bottommost layer on a substrate and patterning by adopting a photoetching process method;

sequentially sputtering or evaporating a metal adhesion layer and a metal layer on the patterned polymer insulation layer at the bottom layer, spin-coating a positive photoresist on the metal layer to be used as a mask, and performing prebaking, exposure, development and postbaking, and performing ion beam etching or wet etching to obtain a patterned metal layer;

spin-coating and patterning the next polymer insulating layer on the patterned metal layer;

spin-coating and patterning a next metal layer on the patterned next polymer insulating layer, and overlapping the polymer insulating layer and the metal layer from bottom to top until the polymer insulating layer at the topmost layer is stacked; and the tail end of the wire of each metal layer is exposed at the outer end of the polymer insulating layer to form a side electrode point, and holes are formed on the polymer insulating layer at the topmost layer and the polymer insulating layer at the bottommost layer in a photoetching mode to form an upper surface electrode point, a lower surface electrode point and a pad interface.

According to a third aspect of the invention, a bioelectrical recording or electrical stimulation electrode is provided, comprising the implanted high-density electrode point flexible probe electrode.

Compared with the prior art, the invention has at least one of the following beneficial effects:

1. the invention provides a design scheme of electrode points distributed on the side surface, wherein the electrode points are distributed on the upper surface, the lower surface and the side surface of the electrode, compared with the common surface electrode points, the distribution mode of the side electrode points has higher electrode point density, the electrode points expose the polymer insulating layer by utilizing the side surface of the metal layer, and the design has higher integration level compared with the microelectrode formed by common photoetching due to the very thin thickness of the polymer film and the metal layer, so that the integral spatial resolution of the electrode is further increased.

2. According to the preparation method, the MEMS processing technology is used according to the method according to actual needs, and high-controllability and high-repeatability processing can be realized.

3. The electrode and the preparation method are compatible with high controllability and repeatability of the silicon-based probe electrode, and the polymer with lower modulus relative to silicon is used as the substrate material of the electrode, so that the whole electrode is softer and can move along with the movement of human tissues, and the probability of tissue damage and electrode self damage is reduced.

4. The implanted high-density electrode point flexible probe electrode can be applied to the clinical treatment of nerve diseases such as Parkinson's syndrome, Alzheimer's disease, depression and the like or the research of neuroscience.

Drawings

Other features, objects and advantages of the invention will become more apparent upon reading of the detailed description of non-limiting embodiments with reference to the following drawings:

FIG. 1a is a schematic diagram of an implantable high-density electrode point flexible probe electrode according to a preferred embodiment of the present invention;

FIG. 1b is a schematic side view of FIG. 1 a;

in fig. 1a and 1b, the reference numbers are respectively as follows: the electrode comprises a surface electrode point 1, a side electrode point 2 and a polymer insulating layer 3;

FIG. 2 is a flow chart of the preparation of an implantable high density electrode point flexible probe electrode according to a preferred embodiment of the present invention;

FIG. 3a is a graph showing current-voltage characteristics of the lateral electrode points in a preferred embodiment of the present invention;

FIG. 3b is a graph showing the impedance characteristics of the side electrode points in a preferred embodiment of the present invention;

FIG. 4 is a structural view of 4 probe electrodes in a preferred embodiment of the present invention;

the scores in FIG. 4 are respectively expressed as: 4 is a probe electrode, and 5 is an electrode pad interface;

FIG. 5 is a schematic illustration of the implantation of the implantable bioelectrical recording or electrical stimulation flexible high density electrode of the present invention into an organism (brain);

the scores in FIG. 5 are respectively expressed as: a is scalp, b is skull, c is dura mater, d is arachnoid, e is cortex, f cortex, g is white matter.

Detailed Description

The present invention will be described in detail with reference to specific examples. The following examples will assist those skilled in the art in further understanding the invention, but are not intended to limit the invention in any way. It should be noted that variations and modifications can be made by persons skilled in the art without departing from the spirit of the invention. All falling within the scope of the present invention.

Referring to fig. 1a and 1b, which are schematic structural views of a preferred embodiment of an implantable high-density electrode point flexible probe electrode, the electrode includes a polymer insulating layer 3 and a metal layer, the polymer insulating layer 3 and the metal layer are sequentially overlapped from bottom to top to form an electrode structure composed of multiple polymer insulating layers 3 and multiple metal layers, and each metal layer is wrapped between the polymer insulating layers 3 to electrically insulate the metal layers arranged at intervals; electrode points are arranged on the upper surface, the lower surface and one side or two side surfaces of the electrode, and a surface electrode point 1 and a side surface electrode point 2 are formed on the electrode.

In the above-mentioned electrode structure, every electrode point all walks the line independently, and not the intercommunicating, is insulating each other between every wire promptly, is separated by polymer insulation layer 3. The rear end of the electrode can adopt wired connection modes such as welding, hot pressing and the like or wireless connection of an integrated NFC chip, a wifi Bluetooth module and an acquisition system to realize signal input and reading.

The embodiment is further provided that the surface electrode points 1 are formed by wrapping the patterned metal layer by the polymer insulating layers 3 covering the uppermost layer and the bottommost layer of the electrode and forming holes at the corresponding electrode points; the side electrode points 2 are formed by exposing the ends of the metal layers outside the polymer insulating layer 3, and a high-density electrode point array is stacked on the side of the electrode. The distribution mode of the electrode points can stack a high-density electrode array on a small area to realize high-density electrodes, and the spatial resolution of the recorded signals is improved.

In other preferred embodiments, the surface electrode dots 1 are formed of circular holes having a diameter of 10 μm to 50 μm.

In other preferred embodiments, each polymeric insulator layer 3 has a thickness of 1 μm to 10 μm; the overall thickness of the electrode is 10 to 50 μm.

In other preferred embodiments, the polymer insulating layer 3 is a biocompatible flexible polymer material, and the biocompatible flexible polymer material may be selected from any one of polyimide and parylene. The polymer with the lower modulus relative to silicon is used as the substrate material of the electrode, so that the whole electrode is softer and moves along with the movement of human tissues, and the probability of damage to the tissues and the electrode is reduced.

In other preferred embodiments, the metal layer is a patterned metal conductor or a patterned conductive polymer, wherein the metal conductor may be any one of gold, platinum, chromium, and titanium. The multilayer metal conductors in the electrode structure can be any one of the above metals respectively, and a plurality of superposed layers of different metals are formed in the electrode structure. The conductive polymer can be one or more than two mixed polymers of carbon nano-tube, graphene and silver nano-wire.

Referring to fig. 2, a flow chart of a method for manufacturing an implantable high-density electrode point flexible probe electrode, an embodiment of the method can be performed by referring to the following steps:

preparing a sacrificial layer on the substrate as shown by S1 in FIG. 2; the substrate may be a polished silicon wafer or other substrate. The sacrificial layer may be metallic aluminum, typically greater than 200nm thick. The preparation here may be a deposition, evaporation process.

Spin coating and patterning the sacrificial layer to obtain the polymer insulation layer 3 of the lowest layer, as shown by S2 in fig. 2; the method comprises the steps of cleaning the sacrificial layer, spin-coating the sacrificial layer on the sacrificial layer, and patterning to obtain the polymer insulating layer 3 at the bottommost layer.

As shown in S3 in fig. 2, a metal adhesion layer and a metal layer, which may be Cr and Au respectively, are sequentially sputtered or evaporated on the polymer insulation layer 3 at the bottom layer, and the thicknesses of the metal adhesion layer and the metal layer are 10 to 100nm and 200 to 500nm, respectively. And (3) spin-coating a positive photoresist on the metal layer to be used as a mask, and obtaining the patterned metal layer by adopting ion beam etching or wet etching after prebaking, exposing, developing and postbaking.

As shown at S4 in fig. 2: the next polymer insulating layer 3 is spin coated and patterned on the patterned metal layer.

As shown in S5 in fig. 2, the metal layer is spin-coated and patterned on the patterned polymer insulating layer 3, and steps S3 and S4 are repeated to overlap the polymer insulating layer 3 and the metal layer from bottom to top until the topmost polymer insulating layer 3 is stacked. The tail end of the metal layer lead is exposed at the outer end of the polymer insulating layer 3 to form a side electrode point 2, and holes are formed on the top polymer insulating layer 3 and the bottommost polymer insulating layer 3 in a photoetching mode to form an upper surface electrode point 1, a lower surface electrode point 1 and a pad interface.

As shown at S6 in fig. 2: and corroding or dissolving the sacrificial layer to complete the release of the electrode.

The polymer insulating layers 3 are made of non-photosensitive or photosensitive polyimide or colorless transparent parylene, the thickness range can be 1-50 micrometers, and generally, the thinner polymer film is better in flexibility but more difficult in the implantation process, and the thinner film is more easily damaged, and the specific thickness can be adjusted and controlled according to needs.

In another embodiment, a detailed description of the preparation of an implantable high-density electrode point flexible probe electrode is provided with reference to the steps of the preparation method, which comprises the following steps:

s1: a common 3-inch round glass sheet is used as a substrate material of an electrode, the glass sheet is respectively placed into acetone, ethanol and deionized water for ultrasonic cleaning for 5 minutes, and after cleaning is finished, the glass sheet is dried by blowing with nitrogen and then is placed into an oven at 180 ℃ for baking for 3 hours.

S2: a chemical vapor deposition system (CVD) was used to deposit 5 μm Parylene C (Parylene C) on the glass sheet as the lowest polymer insulating layer 3 in the electrode structure.

S3: and spin-coating a 5-micron-thick positive photoresist AZ4620 on the 5-micron Parylene C, and carrying out pre-baking, photoetching, developing and post-baking to obtain a patterned photoresist mask. And etching the lowermost Parylene C film covered by the patterned positive photoresist mask by using an oxygen plasma etching device to expose electrode point holes with the diameter of 10 microns on the bottom layer. The positive photoresist mask was removed with acetone after patterning the bottom parylene c. And sequentially sputtering a layer of Cr and a layer of Au as metal layers on the patterned bottom layer Parylene C, wherein the thickness of the Cr is 30nm, and the thickness of the Au is 300 nm. And throwing positive photoresist (AZ4620)5 microns on the Au layer, developing after exposure, baking, and then forming electrode points and wires by wet etching, wherein the diameter of the electrode points is 12 microns, so that the patterned metal layer is obtained.

S4: the positive resist mask was removed with acetone, and as in the previous process, 5 μm Parylene C was deposited again using Chemical Vapor Deposition (CVD) on the patterned metal layer as the next polymer insulating layer 3, and the positive resist was patterned and the Parylene C film was patterned with an oxygen plasma etching apparatus.

S5: and sequentially sputtering a Cr layer and an Au layer on the patterned Parylene C film and patterning the Cr layer and the Au layer, overlapping the polymer insulating layer 3 and the metal layer from bottom to top until the polymer insulating layer 3 on the topmost layer is stacked, and preparing a plurality of layers of Parylene C films and metal layers until the design requirements are met. The tail end of the metal layer lead is exposed at the outer end of the polymer insulating layer 3 to form a side electrode point 2, and holes are formed on the top polymer insulating layer 3 and the bottommost polymer insulating layer 3 in a photoetching mode to form an upper surface electrode point 1, a lower surface electrode point 1 and a pad interface.

S6: finally, the formed electrode was slowly peeled off from the glass substrate with tweezers.

Referring to fig. 3a and 3b, the voltammetry characteristics and impedance characteristics of the single side electrode point 2 of the flexible probe electrode of the above embodiment are tested, as shown in fig. 3a and 3b, respectively, and the impedance of 1KHz is 12K Ω, which has the capability of recording nerve electrical signals.

In a specific embodiment, a method for preparing a high-density electrode point flexible probe electrode based on photosensitive polyimide is provided, and the method comprises the following steps:

s1: a common single-side polished silicon wafer is used as a substrate material of an electrode, the silicon wafer is respectively put into acetone, ethanol and deionized water for ultrasonic cleaning for 5 minutes, and then the silicon wafer is dried by nitrogen and then is put into an oven at 180 ℃ for baking for 3 hours. And depositing a layer of aluminum with the thickness of 400nm on the cleaned silicon wafer as sacrificial layer metal.

S2: photosensitive polyimide Durimide 7505(1000 r 7 s, 1500 r 30 s) is coated on the sacrificial layer metal in a spin mode, a polyimide layer of an electrode with the thickness of 5 mu m is obtained after 6 s exposure, 35 s development and 350 ℃ solidification, a graphical polyimide layer is obtained and is used as a polymer insulating layer 3 of the bottom layer, an electrode point with the opening diameter of 10 mu m is arranged on the polymer insulating layer 3 of the bottom layer, the overall shape of the electrode is determined by the shape of a photoetching mask plate, and the electrode can be adjusted according to actual conditions.

S3: and sputtering 30nm chromium and 300nm gold on the polymer insulating layer 3 at the bottommost layer in sequence to form a metal layer. And spin-coating a positive photoresist AZ4620 with the thickness of 5 mu m on the metal layer, and obtaining a patterned photoresist mask through prebaking, photoetching, developing and postbaking. Patterning the metal layer by using ion beam etching or wet etching after patterning, removing the positive photoresist mask by using acetone to obtain a patterned metal layer, and forming lower surface electrode points and corresponding leads in the step, wherein the size of each metal electrode point is 12 mu m, and each metal electrode point is covered with a patterned opening on polyimide with the diameter of 10 mu m.

S4: and spin-coating photosensitive polyimide on the patterned metal layer, exposing, developing and curing to obtain a polyimide layer with the thickness of 5 μm, and using the polyimide layer as a next polymer insulating layer 3 to isolate the patterned metal layer from a next prepared metal layer.

S5: according to the preparation process of the polymer insulating layer 3 and the metal layers, the polymer insulating layer 3 and the metal layers are overlapped from bottom to top until the polymer insulating layer 3 at the topmost layer is stacked, and the multilayer polymer insulating layer 3 and the multilayer metal layers are prepared until the design requirements are met. The tail end of each metal layer lead is exposed at the outer end of the polymer insulating layer 3 to form a side electrode point 2, and holes are formed on the top polymer insulating layer 3 and the bottommost polymer insulating layer 3 in a photoetching mode to form an upper surface electrode point 1, a lower surface electrode point 1 and a bonding pad interface.

S6: and corroding the sacrificial layer of aluminum by adopting electrochemistry or dilute hydrochloric acid to release the electrode.

In a third aspect, the present embodiment further provides a bioelectrical recording or electrical stimulation electrode, which includes an implantable high-density electrode point flexible probe electrode.

The implanted high-density flexible electrode for bioelectrical recording or electrical stimulation may be a single-probe type electrode or a multi-probe array type electrode, and is shown in fig. 4 as 4 probe array type electrodes. In practical application, the number of the electrode points and the probes and the corresponding sizes and positions can be designed according to practical requirements. In the application of the implanted high-density flexible electrode for bioelectricity recording or electrical stimulation, the probe electrode integrally adopts flexible polymer as a substrate material, and a pad interface at the rear end of the electrode can be connected with other hard switching interfaces such as a PCB (printed circuit board), a silicon-based connector and the like. Referring to fig. 5, a bioelectrical recording or stimulating electrode, including an implanted high-density electrode point flexible probe electrode, is implanted in a living body (brain).

The foregoing description of specific embodiments of the present invention has been presented. It is to be understood that the present invention is not limited to the specific embodiments described above, and that various changes and modifications may be made by one skilled in the art within the scope of the appended claims without departing from the spirit of the invention.

Claims

1. The utility model provides an implanted high density electrode point flexible probe electrode which characterized in that: the electrode comprises polymer insulating layers and metal layers, wherein the polymer insulating layers and the metal layers are sequentially overlapped from bottom to top to form an electrode structure consisting of a plurality of polymer insulating layers and a plurality of metal layers, and each metal layer is coated between the polymer insulating layers to electrically insulate the metal layers which are arranged at intervals;

and electrode points are arranged on the upper surface, the lower surface and one side or two side surfaces of the electrode, and surface electrode points and side electrode points are formed on the electrode.

2. The implantable high-density electrode point flexible probe electrode of claim 1, wherein said surface electrode points are formed by wrapping said patterned metal layer with said polymer insulating layer covering the uppermost and lowermost layers of said electrode and forming openings at the respective electrode points.

3. The implantable high-density electrode spot flexible probe electrode according to claim 1, wherein said side electrode spots are formed by exposing the ends of said metal layer outside said polymer insulating layer, and an array of electrode spots are stacked on the side of said electrode.

4. An implantable high-density electrode site flexible probe electrode according to any one of claims 1 to 3, wherein said polymer insulating layer is a biocompatible flexible polymer material.

5. The implantable high-density electrode site flexible probe electrode of claim 4, wherein the biocompatible flexible polymer material is selected from any one of polyimide and parylene.

6. An implantable high-density electrode site flexible probe electrode according to any one of claims 1 to 3, wherein: the thickness of each polymer insulating layer is 1-10 mu m.

7. An implantable high-density electrode site flexible probe electrode according to any one of claims 1 to 3, wherein: the overall thickness of the electrode is 10 to 50 μm.

8. The implantable high-density electrode point flexible probe electrode according to claim 1, wherein the metal layer is a patterned metal conductor or a patterned conductive polymer, wherein the metal conductor is any one of gold, platinum, chromium and titanium; the conductive polymer is one or more than two mixed polymers of carbon nano tubes, graphene and silver nanowires.

9. A method for preparing an implantable high-density electrode point flexible probe electrode according to any one of claims 1 to 8, which is characterized in that: the method comprises the following steps:

10. A bioelectrical recording or stimulating electrode, characterized by: comprising an implantable high-density electrode site flexible probe electrode according to any one of claims 1 to 5.