阅读说明：本技术 一种柔性磁兼容的植入式脑电电极阵列及其制备方法 (Flexible magnetic compatible implanted electroencephalogram electrode array and preparation method thereof ) 是由 董树荣 潘梦萍 郭维 潘嘉栋 张弓远 于 2020-12-18 设计创作，主要内容包括：本发明公开一种柔性磁兼容的植入式脑电电极阵列,该电极为双面电极,以垂直于大脑皮层的方向被植入皮层内部；该电极包括六层,从下到上,依次为第一柔性封装层、第一金属电极层、第一柔性衬底层、第二柔性衬底层、第二金属电极层、第二柔性封装层；所有的柔性封装层和柔性衬底层选自生物相容性材料；所述第一金属电极层和第二金属电极层头部部分裸露,作为电极触点,尾部部分裸露,作为电极接口；位于所述头部和尾部的中间部分作为电极通道；整个电极的头部设置引导孔,辅助电极的植入。该脑电极阵列采用柔性微纳加工特殊方法制备。该脑电电极阵列采用双面电极阵列排布、易植入、柔性、记录信号质量高。(The invention discloses a flexible magnetic compatible implanted electroencephalogram electrode array, which is a double-sided electrode and is implanted into a cerebral cortex in a direction vertical to the cerebral cortex; the electrode comprises six layers, namely a first flexible packaging layer, a first metal electrode layer, a first flexible substrate layer, a second metal electrode layer and a second flexible packaging layer from bottom to top in sequence; all flexible encapsulation layers and flexible substrate layers are selected from biocompatible materials; the head parts of the first metal electrode layer and the second metal electrode layer are exposed to serve as electrode contacts, and the tail parts of the first metal electrode layer and the second metal electrode layer are exposed to serve as electrode interfaces; the middle parts of the head part and the tail part are used as electrode channels; the head of the whole electrode is provided with a guide hole to assist the implantation of the electrode. The brain electrode array is prepared by adopting a flexible micro-nano processing special method. The brain electrode array adopts double-sided electrode array arrangement, is easy to implant, flexible and high in recorded signal quality.)

1. A flexible magnetic compatible implanted electroencephalogram electrode array is characterized in that the electrode array is a double-sided electrode and is implanted into the cortex in a direction perpendicular to the cerebral cortex; the electrode comprises six layers, namely a first flexible packaging layer, a first metal electrode layer, a first flexible substrate layer, a second metal electrode layer and a second flexible packaging layer from bottom to top in sequence; all flexible encapsulation layers and flexible substrate layers are selected from biocompatible materials; the head parts of the first metal electrode layer and the second metal electrode layer are exposed to serve as electrode contacts, and the tail parts of the first metal electrode layer and the second metal electrode layer are exposed to serve as electrode interfaces; the middle parts of the head part and the tail part are used as electrode channels.

The head of the whole electrode is provided with a guide hole to assist the implantation of the electrode.

2. The flexible magnetic compatible implantable electroencephalogram electrode array according to claim 1, wherein all the flexible encapsulation layers and the flexible substrate layers are selected from any one of the following materials: polyimide, polydimethylsiloxane, polyethylene terephthalate, parylene and photoresist; the thickness of the flexible packaging layer and the flexible substrate layer is 1-100 μm.

3. The flexible magnetic compatible implantable electroencephalogram electrode array according to claim 1 or 2, wherein all the flexible packaging layers and the flexible substrate layers are made of the same material.

4. The flexible magnetic compatibility implanted electroencephalogram electrode array according to claim 1, wherein the first metal electrode layer and the second metal electrode layer are selected from any one of silver, gold, platinum and copper, and the thickness of the metal electrode layers is 0.1-100 μm.

5. The flexible magnetic compatibility implanted electroencephalogram electrode array according to claim 1, wherein electrode contacts of the first metal electrode layer and the second metal electrode layer are rectangles with round corners, and the joints of the electrode contacts and the electrode channels are in circular arc transition; the electrode contact area is 100-3000 μm²The width of each electrode channel of the array is 1-50 μm, and the number of the electrode channels is 2-100. And double-sided electrode array arrangement is adopted.

6. The flexible magnetic compatibility implanted electroencephalogram electrode array according to claim 1, wherein electrode contacts of the first metal electrode layer and the second metal electrode layer are modified with conductive polymers or carbon nanotubes, so that signal quality is improved.

7. The flexible magnetic compatibility implantable electroencephalogram electrode array according to claim 1, wherein an aluminum oxide protective layer is prepared on the first flexible packaging layer and the second flexible packaging layer to improve biocompatibility.

8. A method for preparing a flexible magnetic compatibility implanted electroencephalogram electrode array according to claim 1, which comprises the following steps:

s1: uniformly coating a sacrificial layer on a silicon wafer or a glass sheet, and drying;

s2: uniformly coating a flexible substrate layer solution on the sacrificial layer, and drying;

s3: photoetching a metal electrode layer on the substrate layer to form a shape, wherein the metal electrode layer comprises a rectangular electrode contact with a round angle, an electrode channel and an electrode interface to form a photoresist layer;

s4: sputtering a metal electrode layer on the photoresist layer;

s5: stripping the photoresist;

s6: uniformly coating a flexible packaging layer solution on the metal electrode layer, and drying;

s7: sputtering a layer of protective film on the flexible packaging layer to serve as a barrier layer, wherein the positions of the electrode contact and the electrode interface are exposed;

s8: etching an electrode contact and an electrode interface by dry etching;

s9: washing off the protective layer;

s10: repeating S7-S9 to etch the whole electrode profile;

s11: and washing away the sacrificial layer, and pasting two same electrodes back to form a double-sided six-layer electrode, namely the flexible magnetic compatible implanted electroencephalogram electrode array.

9. The method for preparing a flexible magnetic compatibility implanted electroencephalogram electrode array according to claim 8, wherein when the metal electrode layer is sputtered in S4, a layer of Cr is sputtered first, then the metal used for the metal electrode layer is sputtered, and then a layer of Cr is sputtered, so as to increase the bonding performance of the metal electrode layer, the flexible packaging layer and the flexible substrate layer; meanwhile, after the protective layer is washed away at S9, a gold film needs to be deposited on the exposed Cr layer, and then S10 is performed.

10. The method for preparing the flexible magnetic-compatibility implanted electroencephalogram electrode array according to claim 8, wherein before S4, the photoresist layer formed in S3 is subjected to plasma cleaning.

Technical Field

The invention belongs to the field of biomedicine, and particularly relates to a flexible magnetic compatible implanted electroencephalogram electrode array and a preparation method thereof.

Background

The brain electrical signal is the electric potential synthesis generated by the physiological activity of the brain neuron cell body and has rich brain activity information. The electroencephalogram signals have close relation with brain areas and brain states, and can reflect information which cannot be measured or is inconvenient to obtain by other physical signals, so that the electroencephalogram signals become important basis for human beings to research brain activity mechanisms and diagnose brain diseases.

The electroencephalogram electrodes can be roughly divided into two types, namely an implantable type and a non-implantable type, wherein the non-implantable type electrodes generally refer to electroencephalograms (EEGs), can observe and record brain activities in a non-invasive manner, are generally in the form of electrode caps, collect and record signals from specific positions of scalp, and have the advantages of safety, weak signals and strong noise. The implanted electrodes are multi-finger cortical electroencephalograms (ECoG) and puncture-type Intracortical electrodes IRIs (IRIs). The ECoG belongs to a non-puncture type electroencephalogram signal detection mode, and records the electrophysiological activity of neurons by implanting electrodes into the brain and attaching the electrodes above or below dura mater; while IRIs need to penetrate into brain tissue, it is clear that more powerful and higher quality brain electrical signals can be obtained. Therefore, the implanted electrode has wide application prospect in the detection of electroencephalogram signals and brain science research.

Implantable electrodes also suffer from a number of problems, such as an inflammatory response that may be triggered after the electrode has been implanted into brain tissue for an extended period of time. Factors affecting the inflammatory response of implanted electrodes are many, including: the first is the trauma caused by the implantation of the electrode: the implantation trauma is related to the size of the electrode, the physical properties of the electrode surface and the implantation procedure. In order to reduce the trauma caused by the implantation of the electrode, firstly, the surface of the electrode should be smooth and free of edges and corners, and the electrode is as soft as possible, which is called structural compatibility; the second factor affecting the inflammatory response is: an electrode implantation method; third, movement of the electrodes relative to the brain tissue increases serum access to the brain tissue.

To solve these problems, the first is to reduce the size of the electrode and develop a miniature implantable neural electrode; secondly, the mechanical mismatch between the nerve electrode and the brain tissue, namely the elastic modulus mismatch is reduced; and thirdly, the physical properties of the electrode surface, the implantation method and the operation are optimized, and the structural compatibility is improved. Therefore, the research and development of new electrode implantation modes, electrode structures and electrode materials are significant.

The observation of the brain electrical signals by traditional implanted electrodes, such as ECoG electrodes, remains in the cortex, and signals can be obtained deep into the cortex even though the signal strength is much greater than that of non-implanted EEG electrodes. For the puncture-type electrode, the conventional electrode, such as the kosher array electrode, which has been widely used, has a deeper puncture depth, but cannot match the elastic modulus of the brain tissue in terms of hardness, thereby easily causing inflammation of the surrounding brain tissue.

In view of this concept, an ideal implantable electrode should satisfy the following conditions: (1) the implantation is convenient, and the implantation wound is small; (2) matching the elastic modulus of brain tissue to reduce inflammatory response; (3) the structure compatibility is realized, and the surface of the electrode is smooth and has no edges and corners; (4) the electrode impedance should be as small as possible to record a high quality signal.

Electrodes that fully satisfy all of the above requirements are rare, and therefore, it is necessary to design an implantable electrode that is easy to implant, flexible, and has high recorded signal quality.

Disclosure of Invention

The invention aims to provide a flexible magnetic compatible implanted electroencephalogram electrode array and a preparation process thereof. The electrode is used for assisting implantation of brain tissue through a head circular ring structure, contacts with the brain tissue through a large area of contact to acquire signals, transmits the signals through a metal electrode layer, and is connected to external acquisition equipment through a reserved electrode interface to finish acquisition of brain electrical signals.

In order to achieve the purpose, the invention provides the following technical scheme:

a flexible magnetic compatible implanted electroencephalogram electrode array is a double-sided electrode and is implanted into the cortex in a direction perpendicular to the cerebral cortex; the electrode comprises six layers, namely a first flexible packaging layer, a first metal electrode layer, a first flexible substrate layer, a second metal electrode layer and a second flexible packaging layer from bottom to top in sequence; all flexible encapsulation layers and flexible substrate layers are selected from biocompatible materials; the head parts of the first metal electrode layer and the second metal electrode layer are exposed to serve as electrode contacts, and the tail parts of the first metal electrode layer and the second metal electrode layer are exposed to serve as electrode interfaces; the middle parts of the head part and the tail part are used as electrode channels;

the head of the whole electrode is provided with a guide hole to assist the implantation of the electrode.

Further, all of the flexible encapsulation layer and the flexible substrate layer are selected from any one of the following materials: polyimide, polydimethylsiloxane, polyethylene terephthalate, parylene and photoresist; the thickness of the flexible packaging layer and the flexible substrate layer is 1-100 μm. These materials all possess good chemical stability, easy processability, softness and ductility.

Furthermore, all the substrate layers and the packaging layers are made of the same material, so that the substrate layers and the packaging layers can be effectively prevented from being bonded tightly enough to cause leakage.

Further, the first metal electrode layer and the second metal electrode layer are selected from any one of silver, gold, platinum and copper, and the thickness of the metal electrode layers is 0.1-100 μm. The metals have good biocompatibility, corrosion resistance and electrical conductivity, so that the electrode has a small cross section and a large electrical conductivity, and a signal with higher quality is recorded.

Further, the material of the sacrificial layer is PMMA or photoresist. The sacrificial layer plays a role in connecting the substrate and the flexible substrate layer in process steps, so that the electroencephalogram electrode can be fixed on the substrate for supporting during preparation.

Further, the electrode contacts of the first metal electrode layer and the second metal electrode layer are provided withThe round-cornered rectangle is characterized in that the joint of the electrode contact and the electrode channel is in circular arc transition; the electrode contact area is 100-3000 μm²The width of the electrode channels is 1-50 μm, and the number of the electrode channels is 2-100. Compared with a slender electrode channel, the electrode contact has large area and smooth transition, increases the contact area with tissues, reduces the contact resistance and improves the quality of acquired signals.

Furthermore, electrode contacts of the first metal electrode layer and the second metal electrode layer are modified with conductive polymers or carbon nanotubes, so that the signal quality is improved. Modifying the conductive polymer for good conductivity and biocompatibility will help to form the charge distribution of the electric double layer. When the metal is placed in the electrolyte, a chemical reaction occurs at the interface between the metal and the electrolyte, and a double electric layer of charge distribution is formed at the interface, thereby improving the electrode performance. Meanwhile, the electrode contact is coated by polypyrrole due to modification, a loose porous structure is formed, the contact area of the electrode contact and tissues is effectively increased, and the quality of the obtained electroencephalogram signal is improved.

Compared with the prior art, the invention has the beneficial effects that:

(1) the substrate and the packaging layer of the flexible magnetic compatibility implanted electroencephalogram electrode array are both made of flexible materials, the electrode channel is small in width, the overall shape is slender, and the wound on tissues in the implantation process and after the implantation is small.

(2) The flexible magnetic compatible implanted electroencephalogram electrode array head has the structure of the guide hole, can be used for auxiliary implantation, solves the problem that electrode materials are difficult to implant, can be accurately positioned by external implantation equipment, and achieves the effect of accurate implantation.

(3) The electrode contact area of the flexible magnetic compatible implanted electroencephalogram electrode array is designed to be large, transition is smooth, the contact area between the flexible magnetic compatible implanted electroencephalogram electrode array and tissues is effectively increased, and meanwhile impedance of signal transmission is reduced.

(4) The electrode contact of the flexible magnetic compatible implanted electroencephalogram electrode array can be modified by adopting materials such as conductive polymers or carbon nanotubes, so that the contact area between the contact and tissues is increased, the strength of acquired electroencephalogram signals is effectively increased, and the electrode performance is improved.

(5) An aluminum oxide protective layer can be added outside an electrode contact packaging layer of the flexible magnetic compatibility implanted electroencephalogram electrode array, tissue reaction can be relieved, and biocompatibility can be enhanced.

(6) The flexible magnetic compatible implanted electroencephalogram electrode array is manufactured by adopting a micro-nano processing technology, the process consistency is good, and batch production is easy.

Drawings

FIG. 1 is a schematic structural diagram of an embodiment of an implantable flexible magnetic compatibility electroencephalogram electrode array;

FIG. 2 is a process flow diagram of the flexible magnetic compatibility implanted electroencephalogram electrode array, which is exemplified by the section BB' of FIG. 1;

fig. 3 is a mask of the flexible magnetic compatible implanted electroencephalogram electrode array according to the embodiment, wherein (a) is a metal electrode layer pattern (negative), b) is an electrode contact and electrode interface portion pattern (positive), c) is an electrode contact and electrode interface portion pattern (negative), and d) is an electrode contour pattern (negative);

FIG. 4 is a physical diagram of the flexible magnetic compatibility implanted electroencephalogram electrode array provided by the embodiment;

FIG. 5 is a diagram of a test result of the flexible magnetic compatibility implanted electroencephalogram electrode array provided by the embodiment.

Detailed Description

The present invention will be described in detail below with reference to the accompanying drawings and preferred embodiments, and the objects and effects of the present invention will become more apparent, it being understood that the specific embodiments described herein are merely illustrative of the present invention and are not intended to limit the present invention.

The flexible magnetic compatible implanted electroencephalogram electrode array is implanted into the cerebral cortex in the direction perpendicular to the cerebral cortex. As shown in fig. 1, as one embodiment, the electroencephalogram electrode includes six layers, which are, from bottom to top, a first flexible packaging layer, a first metal electrode layer, a first flexible substrate layer, a second metal electrode layer, and a second flexible packaging layer in sequence; all flexible encapsulation layers and flexible substrate layers are selected from biocompatible materials; the first metal electrode layer and the second metal electrode layer can be divided into an electrode contact area, an electrode channel area and an electrode interface area in function, wherein the head part is exposed and used as an electrode contact, and the tail part is exposed and used as an electrode interface; the middle parts of the head part and the tail part are used as electrode channels.

The head of whole electrode sets up the bullport, combines camera, microscope and other implantation equipment, can implant the electrode to required position accurately. Meanwhile, the width of the head part is slightly smaller than the whole width of the electrode, so that the electrode can be implanted smoothly to cause smaller damage. The guide holes given in FIG. 1 are elliptical holes with dimensions of 54X 32 μm²And the electrode is used for being combined with an implantation device to carry out auxiliary implantation on the electrode. The electrode contact is 30X 60 μm²The round corner rectangle is contacted with brain tissue to obtain signals; the electrode channel is an Ag metal layer with the width of 5 mu m and the length of 3mm, and signals are transmitted to the electrode interface and external acquisition equipment through the electrode channel to be acquired.

As shown in fig. 2, a process flow of the flexible magnetic compatibility implanted electroencephalogram electrode array is shown, and a section BB' in fig. 1 is selected to explain the process flow. In this embodiment, a process flow using PI (polyimide) as a flexible material, Ag as a metal electrode layer, and PMMA as a sacrificial layer is mainly described.

Step (a): preparing a glass substrate: since the electrodes cannot be directly prepared on the soft PI material, a glass substrate or a silicon wafer needs to be prepared as a support. Here, a 4-inch glass substrate may be prepared. (since the lithography machine is suitable for lithography of 4-inch and below wafers and irregular small sheets)

In the experiment, the glass sheets are respectively ultrasonically cleaned in acetone, absolute ethyl alcohol and deionized water, a surface water film is dried by using nitrogen, and the glass sheets are completely dried by using a hot plate to obtain the dry and clean glass substrate.

Step (b): preparing a PMMA sacrificial layer: uniformly coating PMMA solution on a spin coater, and rotating for 500r/min for 5 s; then the substrate is turned to 2000r/min for 30s and baked for 30min at 180 ℃ by a hot plate to be used as a sacrificial layer. The PMMA material can be dissolved in acetone, so that when the sacrificial layer needs to be removed to release the electrode, the substrate with the electrode only needs to be soaked in the acetone.

Step (c): manufacturing a PI flexible substrate layer: uniformly coating a PI solution on a spin coater, and rotating for 500r/min for 5 s; and then the mixture is rotated at 200r/min and heated for 30s until PI is cured (the thickness is about 30 mu m). When the flexible substrate layer is prepared, if the thickness of the substrate layer is too thin, the metal electrode layer is easy to break, so that the thickness is suggested to be more than 10 μm, in the embodiment, the PI flexible substrate layer with the thickness of 30 μm is adopted, and on the basis of ensuring the flexibility of the material, the metal electrode layer can be ensured to be complete and not to break.

Step (d) coating photoresist: uniformly coating photoresist, and baking on a hot plate (5350 positive stripping special photoresist, forward turning 500r/min for 5s, backward turning 3000r/min for 60s, baking on a hot plate at 105 ℃ for 4 min).

Step (e) photoetching an electrode channel and a contact pattern: the mask (as shown in fig. 3 a) and the sample are placed at the corresponding positions in the photo-etching machine, exposed for 3s, and developed for 25 s.

Step (f) oxygen plasma cleaning: 140W, 5 min. Before plating a metal film, in order to ensure the bonding force between the metal layer and the substrate layer, the sample is subjected to oxygen plasma cleaning once, and the number of dangling bonds on the surface of the sample is increased by the operation of one step.

Step (g) sputtering an electrode layer Cr-Ag-Cr: a magnetron sputtering coating system is adopted, a layer of Cr10nm is sputtered, then Ag600nm is sputtered, and then a layer of Cr10nm is sputtered. Wherein Cr is used as a metal material for increasing the adhesion, so that the combination of Ag and PI is firmer.

Step (h) stripping the photoresist: and cleaning and stripping with acetone.

Step (i) manufacturing a packaging layer PI: uniformly coating a PI solution on a spin coater, and rotating for 500r/min for 5 s; and then the mixture is rotated at 800r/min for 60s and heated until PI is cured (10 mu m).

Sputtering an aluminum film and etching; exposing the electrode contact: and photoetching to expose the electrode interface and the electrode contact position, sputtering a layer of aluminum film (400nm) as a barrier layer, then soaking the sample in acetone, and removing the residual photoresist to obtain the sample with the outer surfaces of the electrode interface and the electrode contact position being wrapped by the aluminum film. The reticle is shown in FIG. 3 (b). And (3) putting the sample into an inductive coupling dry etching machine for etching, wherein the part of the sample covered by the aluminum film cannot be etched, and the electrode interface and the electrode contact position which are exposed out of the PI are etched. In etching, if the thickness of the aluminum film is too thin, the aluminum film will be knocked off in the process, and if the thickness of the aluminum film is too thick, the aluminum film is not removed well. Therefore, an aluminum film sputtered at 400nm was selected as the barrier layer. Finally, the Al layer is washed away with a weakly alkaline solution, for example KOH solution.

TABLE 1 ICP parameter set-up

RF Power/W	ICP Power/W	O2/sccm	Ar/sccm	Time/min
					100	600	50	15	40

Step (k) evaporation of the Au layer: a third photolithography is performed, wherein the reticle is as shown in fig. 3 (c). And (4) evaporating a 200nm gold film and removing the photoresist.

After the flexible PI packaging layer is etched, a certain distance is reserved between the electrode interface and the metal at the contact position and the surface of the packaging layer, so that the Au layer can be sputtered to reduce the distance, and the electrode and the cortex tissue are attached more tightly. The Cr layer with biological toxicity is blocked, and oxidation and tissue fluid permeation are prevented.

Etching the electrode array outline, stripping the electrode: and photoetching for the fourth time to form an electrode contour, and etching the electrode contour by using the aluminum film as a barrier layer. Washing the PMMA with acetone, and stripping the electrode to obtain the single-sided electrode. The etching time is about 60min according to the parameters.

There are 18 identical flexible magnetic compatible implanted brain electrodes arrays on a 4 inch glass substrate, and after the previous process is completed, the 18 electrodes need to be stripped off. Therefore, the sample is subjected to a fourth photolithography, and the photolithography mask pattern is the outline of 18 flexible electrodes, including the electrode head ring for auxiliary implantation. The reticle is shown in FIG. 3 (d).

And (m) sticking the two layers of electrodes in the back direction to form a double-sided electrode with a total of six layers. A physical diagram of the flexible magnetic compatibility implantable electroencephalogram electrode array provided by the embodiment is shown in fig. 4.

Because the back of the single-side electrode is not provided with a contact structure, only the single-side contact structure can be contacted with tissues, the number of channels is small, and the quantity of the data which can be acquired is small. Therefore, the two single-side electrodes are pasted in the back direction to form the double-side electrodes, so that the double sides are provided with contact structures and can be in contact with tissues, the number of channels is doubled, and the data acquisition quantity is large.

The flexible magnetic compatibility implanted electroencephalogram electrode array structure provided by the embodiment has the capability of collecting and recording signals, and is tested by simulating electroencephalogram signals by using an SKX-8000 weak electrophysiological signal simulator. And then, the output end of the electrode passes through an FPC (flexible printed circuit) interface, signals are acquired through self-made acquisition equipment based on an ADC (analog to digital converter) chip ADS1299 for electroencephalogram acquisition, and data are received and processed by an upper computer. A probe station is used to apply signals for testing to the electrodes. The probe is used for slightly poking the electrode contact point so as to avoid scratching the electrode, and the input and output signal waveforms are observed after the physiological signal generator and the upper computer software are started.

And (e) in order to facilitate the test, the single-sided electrode obtained in the step (l) is tested without releasing the electrode, and the test is completed under the support of the substrate.

The frequency of the test signal is 10Hz, the amplitude is 300 muV, and the output signal is filtered by direct current and 1-50 Hz. Fig. 5 is a signal waveform diagram after dc filtering, a signal waveform diagram after band-pass filtering, and a frequency spectrum diagram obtained after fourier transform. Although there is interference from noise components, the acquired signal waveform can be distinguished to be close to the frequency of the original signal and slightly attenuated in amplitude.

It will be understood by those skilled in the art that the foregoing is only a preferred embodiment of the present invention, and is not intended to limit the invention, and although the invention has been described in detail with reference to the foregoing examples, it will be apparent to those skilled in the art that various changes in the form and details of the embodiments may be made and equivalents may be substituted for elements thereof. All modifications, equivalents and the like which come within the spirit and principle of the invention are intended to be included within the scope of the invention.