CN107647865A - A kind of flexible biological electrode and its preparation method and application - Google Patents

A kind of flexible biological electrode and its preparation method and application Download PDF

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Publication number
CN107647865A
CN107647865A CN201710855052.0A CN201710855052A CN107647865A CN 107647865 A CN107647865 A CN 107647865A CN 201710855052 A CN201710855052 A CN 201710855052A CN 107647865 A CN107647865 A CN 107647865A
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flexible
flexible biological
biological electrode
nanometer paper
water resistance
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CN107647865B (en
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方英
郭川
郭一川
李红变
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National Center for Nanosccience and Technology China
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National Center for Nanosccience and Technology China
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/24—Detecting, measuring or recording bioelectric or biomagnetic signals of the body or parts thereof
    • A61B5/25—Bioelectric electrodes therefor
    • A61B5/279—Bioelectric electrodes therefor specially adapted for particular uses
    • A61B5/291—Bioelectric electrodes therefor specially adapted for particular uses for electroencephalography [EEG]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/04—Macromolecular materials
    • A61L31/042—Polysaccharides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials

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  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
  • Heart & Thoracic Surgery (AREA)
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  • Medical Informatics (AREA)
  • Molecular Biology (AREA)
  • Measurement And Recording Of Electrical Phenomena And Electrical Characteristics Of The Living Body (AREA)
  • Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)

Abstract

The invention discloses a kind of flexible biological electrode and its preparation method and application, the flexible biological electrode includes flexible substrates, microelectrode array and insulating barrier, and the flexible substrates are water resistance nanometer paper.The invention provides application of the flexible biological electrode in bio-electro-physiologic signal detection.The flexible biological electrode has good bio-compatibility and conformability, highly sensitive can detect cellular electrophysiologicalsensor signal or the cortex electricity physiological signal of animal etc..

Description

A kind of flexible biological electrode and its preparation method and application
Technical field
The invention belongs to bioelectrode field, is related to a kind of flexible biological electrode and its preparation method and application.
Background technology
The electroneurographic signal such as electrocorticogram spectrogram is for human behavior research and the timely diagnosis of neurogenic disease and controls Treatment has great significance.The collection of cerebral nerve signal is realized, it is to close to build stable electronic device-brain contact interface Key.Brain is in complicated random tortuous structure, therefore, builds super flexible electronic device, realizes the general character of electronic device and brain Contact has very big challenge.In addition, non-volatile recording electroneurographic signal is to research human behavior and the release of electroneurographic signal Between association it is significant.Therefore, super flexible nerve electrode of the exploitation with good biological compatibility, it is to realize nerve The key of electric signal record.
The substrate of current soft type electronic device predominantly synthesizes high polymer material, such as polyethylene terephthalate (PET), polyimides (PI), dimethyl silicone polymer (PDMS) etc., however, these high polymer materials and brain mechanical performance are not Matching, it is difficult to form bringing into conformal contact with brain to build stable electronic device-brain interface.Flexible substrates are processed into finely Structure can greatly improve substrate and the contact interface stability of brain, as CN106667475A discloses a kind of implanted flexibility Nerve microelectrode comb and preparation method thereof and method for implantation, the flexible nervus comb is mainly by flexible substrate layer, flexibility Insulating barrier and the metal contact wires layer composition being arranged between flexible substrate layer and flexible insulating layer；Flexible nervus comb bag Include comb teeth-shaped structure, network, solid construction and the pad being sequentially connected；Comb teeth-shaped structure is provided with electrode site；Pad It is provided with solder joint；Metal contact wires layer is made up of metal contact wires, metal contact wires connection electrode site and solder joint；Electrode site There is no flexible insulating layer with pad surface.But this method step is more, moreover, high molecular bio-compatibility is poor, limitation The long-time stable record of electrode pair electroneurographic signal.
Nanometer paper is a kind of membrane structure for being assembled and being formed by nano-cellulose, has good flexibility and transparency, can be with Foldable electronic, flexible field-effect transistor and flexible solar battery etc. are prepared as substrate.In addition, nanometer paper is green The renewable structure of color, there is good bio-compatibility, had a good application prospect in field of biological detection.However, nanometer The report that paper electronic device is used for biological detection is also seldom.Main cause is that cellulose is hydrophilic-structure, a nanometer paper substrates is existed Meeting hygroscopic swelling even collapses in biotic environment, destroys device electrode structure.Therefore, the water resistance of nanometer paper is improved, is to realize Nanometer paper base electron device is used for the key issue of biological detection.
The content of the invention
In order to solve the above problems, the invention provides a kind of nanometer paper substrate flexible biological electrode and preparation method thereof and answer With the flexible biological electrode has good bio-compatibility and conformability, can have with the detection of efficient stable irregular The electricity physiological signal of shape interface biological tissue.
To reach this goal of the invention, the present invention uses following technical scheme：
On the one hand, the invention provides a kind of flexible biological electrode, the flexible biological electrode to include flexible substrates, micro- electricity Pole array and insulating barrier, the flexible substrates are water resistance nanometer paper.
Flexible biological electrode provided by the invention has selected nanometer paper, and as flexible substrates, nanometer paper used is by natural material It is made after expecting cellulose processing, there is good transparency and flexibility, compared with PET etc. synthesizes polymer-based end, is had more preferable Bio-compatibility, it is possible to reduce immune response of the biological tissue to it；Also, nanometer paper has good in biotic environment Flexibility, flexible biological electrode so of the present invention can organize the formation of conformal structure with target detection, so as to avoid Because be bonded it is bad and caused by distorted signals the problems such as.
Conventional nano paper conformality in water is very poor, it is easy to which moisture expantion makes the electrode structure on its surface up to collapsing Rupture failure.And the nanometer paper in the present invention has good water resistance, soaked for a long time in water and do not occur substantially to expand, its The electrode on surface has good stability in water.
Preferably, the water resistance nanometer paper soaked in water 24 hours size changing rates be less than 2% (such as 1.8%, 1.5%th, 1.3% or 1% etc.)；The size changing rate refers to change of the water resistance nanometer paper in length and width.
In the present invention, the water resistance nanometer paper soaks 24 hours in water, although its thickness can produce change slightly Change, but its change is far smaller than the thickness change of non-water resistance nanometer paper, and the water resistance nanometer paper of the present invention is in thickness On change do not interfere with the performance of final bioelectrode.
In the present invention, the water resistance nanometer paper is prepared by the following procedure method and is prepared：
(1) it is oxidation-treated using cellulose as raw material, obtain oxycellulose；
(2) the oxycellulose dispersion liquid that is obtained through step (1) carries out homogenization, and after through nitrocellulose filter mistake Filter, obtains gluey nano-cellulose, gained glue nano-cellulose is tipped upside down on smooth surface together with filter membrane；
(3) nano-cellulose obtained to step (2)/nitrocellulose filter composite carry out pressure process drying with Nano-cellulose is subjected to keratinization, obtains the water resistance nanometer paper.
Preferably, step (1) described oxidation processes are handled using NaBr/TEMPO/NaClO oxidation systems.
Preferably, the mass concentration of step (1) the nanofiber dispersion liquid is 1-2%, for example, 1%, 1.3%, 1.5%th, 1.8% or 2%.
In the present invention, step (1) described oxidation processes can reduce the interphase interaction of cellulose, to be more favorable for walking Suddenly the progress of (2) homogenization, if not to cellulose carry out oxidation processes, can increase homogenization energy expenditure and Extend the time of homogenization.
Preferably, step (2) described homogenization be using high pressure homogenizer 1300-1800bar (such as 1300bar, 1400bar, 1500bar, 1600bar, 1700bar or 1800bar) pressure under carry out homogenization 5-15min (such as 5min, 7min, 9min, 10min, 12min, 14min or 15min).
Preferably, before step (2) described filtering, it is dilute that the nano-cellulose dispersion liquid after homogenization is added into deionized water It is 0.1-0.5% to release to mass concentration, such as 0.1%, 0.2%, 0.3%, 0.4% or 0.5%, preferably 0.2%.
Preferably, pressure when step (3) pressure process is dried is 10-20kPa, such as 10kPa, 13kPa, 15kPa, 17kPa, 19kPa or 20kPa etc..
Preferably, temperature when step (3) pressure process is dried is 50-70 DEG C, for example, 50 DEG C, 53 DEG C, 55 DEG C, 58 DEG C, 60 DEG C, 63 DEG C, 65 DEG C, 68 DEG C or 70 DEG C.
Preferably, the time that step (3) pressure process is dried is 5-15min, for example, 5min, 7min, 9min, 10min, 12min, 14min or 15min.
Obtained after the water resistance nanometer paper that the method for the invention is prepared is that cellulose has been carried out into keratinization So that hydrophily declines, and the stability increase to water, has good water resistance.
Preferably, the thickness of the nanometer paper is 30-300 microns, for example, 30 microns, 60 microns, 80 microns, 100 microns, 140 microns, 180 microns, 210 microns, 270 microns, 300 microns etc..
In the present invention, the microelectrode array is that metal electrode is arranged in array-like.
Preferably, the metal electrode is inert metal, preferably any one in gold, platinum, iridium or palladium or at least two Combination.
Preferably, the thickness of the metal electrode is 50-200 nanometers, for example, 50 nanometers, 80 nanometers, 110 nanometers, 150 receive Rice, 200 nanometers etc..
In the present invention, the metal electrode is made up of detection site, connecting line and solder joint, connecting line connecting detection site And solder joint.
Preferably, the potentiometric detection site is circle, a diameter of 10-150 microns, for example, 10 microns, 30 microns, it is 60 micro- Rice, 100 microns, 130 microns, 150 microns.
Preferably, for the connecting line by dielectric protection layer, the connecting line and insulating barrier are in core shell structure.
In the present invention, microelectrode array is made up of multiple metal electrodes, the connecting line of metal electrode in microelectrode array Connecting line layer is formed, connecting line layer is wrapped up by insulating barrier, forms insulating barrier-connecting line layer core shell structure；Insulating barrier is only connecting Exist at line, there is no insulating barrier at detection site and solder joint.
Preferably, the insulating barrier be SU-8, polyimides, makrolon or Parylene in any one or extremely Few two kinds combination.
Preferably, the thickness of insulating layer is 0.5-5 microns, for example, 0.5 micron, 1 micron, 2.5 microns, 4 microns, 4.5 Micron, 5 microns etc..
Flexible substrates used in flexible biological electrode provided by the invention are nanometer paper, and the nanometer paper of moistening has well soft It is soft, can preferably be bonded ditch in some animal brains and return structure, so as to avoid because be bonded it is bad and caused by signal lose True problem.It is made after nanometer paper is handled by cellulose simultaneously, the immune response triggered with biological tissue Long Term Contact is smaller, can grow The use of phase stabilization.
Second aspect, the invention provides the preparation method of flexible biological electrode as described above, the preparation method bag Include following steps：
(1) water resistance nanometer paper is prepared；
(2) have on surface and process underlying insulating layer, microelectrode array and upper strata successively on the silicon chip of silica oxide layer Insulating barrier；
(3) sample is placed in silica etching liquid and removed after spin coating organic gel on the silicon chip that step (2) obtains Silica, obtain the composite construction of organic gel and microelectrode array；
(4) organic gel and the composite construction of microelectrode array obtained step (3) is transferred in nanometer paper substrates, is removed Organic gel, obtain the flexible biological electrode.
Preferably, the silicon chip described in step (2) is highly doped silicon wafer.
Preferably, step (2) the silica oxide layer is obtained by thermal oxide.
Preferably, step (3) described organic gel is that mass percent is 1-8% (such as 1%, 4%, 5%, 8% etc.) Polymethyl methacrylate or makrolon.
Preferably, step (3) the silica etching liquid is any in hydrofluoric acid, sodium hydroxide or BOE etching liquids It is a kind of.
The preparation method technique of the flexible biological electrode provided by the invention is simple, easy.Prepare the process of nanometer paper In, the deionized water that cleaning and dispersion process for cellulose use is as solvent, using deionized water as solvent So that the nanometer paper being prepared does not include the harmful compositions such as organic reagent, shadow of the nanometer paper to biological tissue is reduced Ring, and can equally reduce pollution of the reagent to environment.The flexible biological electrode electricity being prepared using the preparation method Learn stable performance.
The third aspect, the invention provides the application of flexible biological electrode as described above, the flexible biological electrode should For bio-electro-physiologic signal detection.
Preferably, the flexible biological application of electrode is in detection cortex electricity physiological signal.
Preferably, the flexible biological application of electrode is in detection rat cerebral cortex electricity physiological signal.
The flexible biological electrode provided by the invention has stable electric property, can apply to bio-electro-physiologic letter Number detection, in specific experiment, applied to the detection of the electricity physiological signal of rat brain, can be steadily in the long term remember Record.
Relative to prior art, the invention has the advantages that：
Flexible biological electrode of the present invention has more preferable conformability, and the nanometer paper of wetting has good softness Property, biological tissue's irregular surface can be preferably bonded, and nanometer paper used is water resistance nanometer paper, the life of nanometer paper substrate Thing electrode has good electrical stability, can be steadily in the long term carry out record measurement；Nanometer paper is handled by cellulose simultaneously After be made, with the immune response that biological tissue Long Term Contact triggers much smaller than the immune response that the plastic-substrates such as PET trigger, reduce Injury to biological tissue's organ.
Brief description of the drawings
Fig. 1 is the preparation technology flow chart of water resistance nanometer paper in embodiment 1.
Fig. 2 is the apparent form figure of front and rear dispersion liquid high-pressure homogeneous to cellulose in embodiment 1.
Fig. 3 is the optical photograph of obtained nanometer paper in embodiment 1.
Fig. 4 is the process chart that flexible biological electrode step (2), (3) and (4) are prepared in embodiment 1.
Fig. 5 is the optical photograph for the flexible biological electrode being prepared in embodiment 1；Wherein, 1 is detection site, and 2 be to receive Rice paper substrate, 3 be connecting line, and 4 be solder joint.
Fig. 6 A are the bringing into conformal contact situations for the flexible biological electrode and monkey brain concave plane being prepared in embodiment 1 Figure.
Fig. 6 B are the bringing into conformal contact situation map of bioelectrode and monkey brain concave plane that PET is flexible substrates.
Fig. 7 is that the rat brain cortex electrograph optics that the flexible biological electrode that experimental example 1 is provided using embodiment 1 obtains shines Piece.
Fig. 8 is that experimental example 1 injects rat brain cortex local field potentials variation diagram before and after novocillin solution.
Fig. 9 is the immunofluorescence dyeing image of the flexible biological electrode provided in experimental example 2 using embodiment 1.
Figure 10 is the PET base flexible biological electrode immunofluorescence dyeing image provided in comparative example 1.
Embodiment
Technical scheme is further illustrated below by embodiment.Those skilled in the art should be bright , the embodiment be only to aid in understand the present invention, be not construed as to the present invention concrete restriction.
Embodiment 1
In the present embodiment, the flexible biological electrode includes flexible substrates, microelectrode array and insulating barrier, the flexibility Substrate is water resistance nanometer paper, and the preparation method of the flexible biological electrode comprises the following steps：
(1) preparation of water resistance nanometer paper：
The preparation method of the water resistance nanometer paper, technological process (receiving in embodiment 2-6 afterwards as shown in Figure 1 The method provided by the present embodiment for preparing of rice paper is carried out, unique the difference is that the thin and thick of nanometer paper).
The nanometer paper that thickness is 30 microns is prepared, is specifically comprised the following steps：
(a) cellulose oxidation
5g is bleached into dry pine pulp and is scattered in 250mL Na2CO3/NaHCO3In cushioning liquid (pH=10), 2 are added, 2,6,6- tetramethyl piperidines-nitrogen-oxide (TEMPO) 78.1mg and NaBr 514.4mg, are slowly added to 12%NaClO solution 3.1mL and mechanical agitation 4h, with pH meter pH value determination and with 1mol/L NaOH regulation and control pH value holding 10 in course of reaction.
(b) cellulose cleans
Cellulose dispersion liquid obtained by (a) is removed into reaction reagent with suction method, cellulose is transferred in beaker and added Enter 500mL deionized waters, the magnetic agitation 0.5h under 500rpm repeats said process 3 times, removes reaction reagent.
(c) nano-cellulose is prepared
Homogenization 10min is carried out using high pressure homogenizer under 1500bar pressure to cellulose dispersion liquid to be received Rice cellulose.Fig. 2 shows the mode of appearance of dispersion liquid before and after homogeneous operation (A is before homogeneous, B is after homogeneous), it is seen that homogeneous After operation, nano-cellulose reduces to light scattering, and dispersion liquid is changed into transparent from white.
(d) cellulose filter
Nano-cellulose dispersion liquid addition deionized water is diluted to 0.2% (mass fraction), takes 15mL dispersion liquids to use A diameter of 47mm nitrocellulose filter carries out filtering the most of water of operation removing, obtains the gluey nanofiber on filter membrane Element.Gained glue nano-cellulose is tipped upside down on smooth surface together with filter membrane.
(e) prepared by cellulose keratinization and nanometer paper
It is 30 micron/nano paper to apply 15kPa pressure vacuums at 60 DEG C to dry 10min to obtain thickness.Fig. 3 is nanometer paper Optical photograph, it is seen that nanometer paper have well the transparency.Obtained water resistance nanometer paper soaks 24 hours sizes in water Rate of change is less than 2%.
(2) insulating barrier-microelectrode array-insulation layer structure is prepared
(a) lower floor's SU-8 insulating barriers are prepared
Silicon chip is sequentially placed into acetone, isopropanol, ultrasonic (100W) cleaning 10min, high pressure nitrogen drying.By drying Silicon chip is placed in plasma surface treatment system (PJ-2), power 100W processing 3min.The spin coating photoresist SU-8 on silicon chip 2000.5, initial speed 500rpm, maintain 8s；Stabilized (steady-state) speed 2000rpm, maintain 60s；95 DEG C of heating 1min of thermal station；Thickness 0.5 Micron.Uv-exposure (time for exposure 240s), 95 DEG C of heating 1min of thermal station；Develop (SU-8Developer, 60s), be fixing (different Propyl alcohol, 30s), high pressure nitrogen drying；180 DEG C of heating 30min of thermal station, obtain lower floor's SU-8 insulating barriers, and thickness is 0.5 micron.
(b) microelectrode array is prepared on underlying insulating layer
The silicon chip handled well in (a) is placed in plasma surface treatment system (PJ-2), power 100W processing 1min. The spin coating photoresist S1813 on silicon chip, initial speed 500rpm, maintain 8s；Stabilized (steady-state) speed 2000rpm, maintain 60s；Thermal station 115 DEG C heating 3min；Thickness 1800nm.Uv-exposure (time for exposure 55s)；Develop (MF319,60s), it is fixing (deionized water, 30s), high pressure nitrogen dries up.Using plated film instrument to evaporation Cr/Au (5 nanometers/50 nanometers) on silicon chip, silicon chip is placed in acetone 80 DEG C of heating water baths are with the Cr/Au beyond figure needed for removing, a diameter of 150 microns of potentiometric detection site.
(c) upper strata SU-8 insulating barriers are prepared
Upper strata SU-8 insulating barriers are processed with the same method of lower floor's SU-8 insulating barriers is prepared, finally obtain insulating barrier-micro- electricity Pole array-insulation layer structure.
(3) spin coating photoresist PMMA (2%, solvent is chlorobenzene), initial speed are continued in the silicon chip obtained by step (2) 500rpm, maintain 8s；Stabilized (steady-state) speed 4000rpm, maintain 60s；115 DEG C of heating 1min of thermal station；It is subsequently placed in hf etching liquid In, 6h is stood, is transferred in deionized water and cleans 3 times, obtain the composite construction of organic gel and microelectrode array.
(4) organic gel and the composite construction of microelectrode array obtained step (3) is transferred in nanometer paper substrates, is placed in 30min is soaked in acetone, isopropanol immersion 3min, high pressure nitrogen drying, obtains flexible biological electrode.
The bioelectrode of PET base is prepared by step (2) described in the embodiment-step (4) methods described, it is different It is that flexible substrates replace with PET base, control material is used as using the bioelectrode of the PET base.
Fig. 4 shows the process chart for preparing step (2), (3) and (4) in flexible biological electrode, and Fig. 5 shows preparation The optical photograph of obtained flexible biological electrode, wherein, 1 is detection site, and 2 be nanometer paper substrates, and 3 be connecting line, and 4 be weldering Point.
Fig. 6 A show the conformal structure that flexible biological electrode prepared by the present invention is formed with monkey brain, illustrate flexible biological The good flexibility of electrode, structure can be returned with the complicated ditch of brain and be preferably bonded, there is good conformability.Fig. 6 B are shown PET is bringing into conformal contact situation of the bioelectrode with monkey brain concave plane of flexible substrates, compared with Fig. 6 A, it can be clearly seen that It is poor as the bioelectrode of flexible substrates and being bonded for monkey brain concave plane using PET.
Embodiment 2
In the present embodiment, the flexible biological electrode includes flexible substrates, microelectrode array and insulating barrier, the flexibility Substrate is water resistance nanometer paper；The preparation method of the flexible biological electrode comprises the following steps：
(1) preparation of water resistance nanometer paper
The method of (1) with reference to the step of embodiment 1, except that take 70mL nano-cellulose solution to be filtered, its He operates identical with the method for step (1) in embodiment 1, and it is 150 microns of water resistance nanometer paper to obtain thickness, and what is obtained is resistance to Water nano paper soaks 24 hours size changing rates in water and is less than 2%.
(2) insulating barrier-microelectrode array-insulation layer structure is prepared
In step (2), it is that metal electrode material is used in the present embodiment step (b) with the difference of embodiment 1 Cr/Pt (5 nanometers/100 nanometers), a diameter of 10 microns of potentiometric detection site.
(3) spin coating photoresist PMMA (4%, solvent is chlorobenzene), initial speed on the silicon chip obtained by step (2) 500rpm, maintain 8s；Stabilized (steady-state) speed 5000rpm, maintain 60s；115 DEG C of heating 1min of thermal station；It is subsequently placed in 2mol/L NaOH quarters Lose in liquid, stand 6h, be transferred in deionized water and clean 3 times, obtain the composite construction of organic gel and microelectrode array.
(4) organic gel and the composite construction of microelectrode array obtained step (3) is transferred in nanometer paper substrates, is placed in 30min is soaked in acetone, isopropanol immersion 3min, high pressure nitrogen drying, obtains flexible biological electrode.
Embodiment 3
In the present embodiment, the flexible biological electrode includes flexible substrates, microelectrode array and insulating barrier, the flexibility Substrate is water resistance nanometer paper；The preparation method of the flexible biological electrode comprises the following steps：
(1) preparation of water resistance nanometer paper
The method of (1) with reference to the step of embodiment 1, except that take 140mL nano-cellulose solution to be filtered, its He operates identical with the method for step (1) in embodiment 1, and it is 300 microns of nanometer paper to obtain thickness, and obtained water resistance is received Rice paper soaks 24 hours size changing rates in water and is less than 2%.
(2) insulating barrier-microelectrode array-insulation layer structure is prepared
In step (2), it is with the difference of embodiment 1, the insulating materials in the present embodiment step (a) and (c) For SU-8 2005, thickness of insulating layer is 5 microns；Metal electrode material used in step (b) is Cr/Pd (5 nanometers/195 nanometers), A diameter of 30 microns of potentiometric detection site.
(3) spin coating photoresist PMMA (8%, solvent is chlorobenzene), initial speed on the silicon chip obtained by step (2) 500rpm, maintain 8s；Stabilized (steady-state) speed 6000rpm, maintain 60s；115 DEG C of heating 1min of thermal station；It is subsequently placed in BOE etching liquids, 6h is stood, is transferred in deionized water and cleans 3 times, obtain the composite construction of organic gel and microelectrode array.
(4) organic gel and the composite construction of microelectrode array obtained step (3) is transferred in nanometer paper substrates, is placed in 30min is soaked in acetone, isopropanol immersion 3min, high pressure nitrogen drying, obtains flexible biological electrode.
Embodiment 4
In the present embodiment, the flexible biological electrode includes flexible substrates, microelectrode array and insulating barrier, the flexibility Substrate is water resistance nanometer paper；The preparation method of the flexible biological electrode comprises the following steps：
(1) method of the step of preparation reference embodiment 1 of water resistance nanometer paper (1), except that taking 70mL nanometers Cellulose solution is filtered, and other operations are identical with the method for step (1) in embodiment 1, and it is 150 microns to obtain thickness Nanometer paper, obtained water resistance nanometer paper soak 24 hours size changing rates in water and are less than 2%.
(2) insulating barrier-microelectrode array-insulation layer structure is prepared
In step (2), it is with the difference of embodiment 1, the insulating materials in the present embodiment step (a) and (c) For polyimides, thickness of insulating layer is 2.5 microns；Metal electrode material used in step (b) is Ir (50 nanometers), potentiometric detection position Spot diameter is 80 microns.
(3) spin coating photoresist PC (1%, solvent is chloroform) on the silicon chip obtained by step (2), initial speed 500rpm, Maintain 8s；Stabilized (steady-state) speed 6000rpm, maintain 60s；115 DEG C of heating 1min of thermal station；It is subsequently placed in BOE etching liquids, stands 6h, It is transferred in deionized water and cleans 3 times, obtains the composite construction of organic gel and microelectrode array.
(4) organic gel and the composite construction of microelectrode array obtained step (3) is transferred in nanometer paper substrates, is placed in 30min is soaked in acetone, isopropanol immersion 3min, high pressure nitrogen drying, obtains flexible biological electrode.
Embodiment 5
In the present embodiment, the flexible biological electrode includes flexible substrates, microelectrode array and insulating barrier, the flexibility Substrate is water resistance nanometer paper；The preparation method of the flexible biological electrode comprises the following steps：
(1) preparation of water resistance nanometer paper
The nanometer paper that thickness is 30 microns is prepared in (1) with reference to the step of embodiment 1, and obtained water resistance nanometer paper exists 24 hours size changing rates are soaked in water and are less than 2%.
(2) insulating barrier-microelectrode array-insulation layer structure is prepared
In step (2), it is with the difference of embodiment 1, the insulating materials in the present embodiment step (a) and (c) For Parylene, thickness of insulating layer is 3 microns；Metal electrode material used in step (b) is Cr/Ir (5 nanometers/120 nanometers), A diameter of 70 microns of potentiometric detection site.
(3) spin coating photoresist PC (5%, solvent is chlorobenzene) on the silicon chip obtained by step (2), initial speed 500rpm, Maintain 8s；Stabilized (steady-state) speed 6000rpm, maintain 60s；115 DEG C of heating 1min of thermal station；It is subsequently placed in BOE etching liquids, stands 6h, It is transferred in deionized water and cleans 3 times, obtains the composite construction of organic gel and microelectrode array.
(4) organic gel and the composite construction of microelectrode array obtained step (3) is transferred in nanometer paper substrates, is placed in 30min is soaked in acetone, isopropanol immersion 3min, high pressure nitrogen drying, obtains flexible biological electrode.
Embodiment 6
In the present embodiment, the flexible biological electrode includes flexible substrates, microelectrode array and insulating barrier, the flexibility Substrate is water resistance nanometer paper；The preparation method of the flexible biological electrode comprises the following steps：
(1) preparation of water resistance nanometer paper
The method of (1) with reference to the step of embodiment 1, except that take 140mL nano-cellulose solution to be filtered, its He operates identical with the method for step (1) in embodiment 1, and it is 300 microns of nanometer paper to obtain thickness, and obtained water resistance is received Rice paper soaks 24 hours size changing rates in water and is less than 2%.
(2) insulating barrier-microelectrode array-insulation layer structure is prepared
In step (2), it is with the difference of embodiment 1, the insulating materials in the present embodiment step (a) and (c) For polyimides/Parylene, thickness of insulating layer is 4 microns；(b) metal electrode material used in is Au (80 nanometers), current potential A diameter of 100 microns of detection site.
(3) spin coating photoresist PMMA (1%, solvent is methyl phenyl ethers anisole), initial speed on the silicon chip obtained by step (2) 500rpm, maintain 8s；Stabilized (steady-state) speed 5000rpm, maintain 60s；115 DEG C of heating 1min of thermal station；It is subsequently placed in BOE etching liquids, 6h is stood, is transferred in deionized water and cleans 3 times, obtain the composite construction of organic gel and microelectrode array.
(4) organic gel and the composite construction of microelectrode array obtained step (3) is transferred in nanometer paper substrates, is placed in 30min is soaked in acetone, isopropanol immersion 3min, high pressure nitrogen drying, obtains flexible biological electrode.
Experimental example 1 obtains rat cerebral cortex electrograph
Flexible biological electrode used in this experimental example is the flexible biological electrode being prepared in embodiment 1.
To about 300g rat injection 0.42g/mL urethanes (urethane) solution 1mL, treat that it is in During narcosis, its head is fixed on brain position indicator, removes the scalp of appropriate location, expose skull Bregma and Lambda points, between being drilled in skull Bregma and Lambda point with cranium, the position mill on the right side of middle seam opens 4 × 4mm window, exposes Brain tissue, the detection site of flexible biological electrode is attached on brain tissue, 128 passage Electrophysiologies record system is accessed in rear end System.Exclusive PCR, after system correctly can stably work, into rat cerebral tissue, injection concentration is 200IU/ μ L mould The plain μ L of G sodium solutions 2.5, the local field potentials of electrocorticogram before and after record injection.
Fig. 7 shows the rat brain cortex electrograph optical photograph that the flexible biological electrode provided using embodiment 1 is obtained, figure 8 show rat brain cortex local field potentials change before and after injection novocillin solution, it can be seen that in injection novocillin There is significant change in about 100s after solution, the electrocorticogram of rat, and this is epileptic signal, it was confirmed that flexible biological used Electrode can apply to the detection of bio-electro-physiologic signal really.
The bio-compatibility of the flexible biological electrode of experimental example 2
The flexible biological electrode detected in this experimental example is the flexible biological electrode that embodiment 1 provides.
(1) the potentiometric detection Post section of flexible biological electrode is fabricated to a diameter of 2mm disk, is put into 75% alcohol Middle immersion 1h, is then placed in sterile artificial cerebrospinal fluid and soaks 1h.
(2) mouse to an about 25g injects 1% Nembutal sodium solution 0.25mL, when it is in narcosis, Its head is fixed on brain position indicator；Scalp is cut off in two ear line midpoints, exposes Bregma the and Lambda points of skull, Between being drilled in skull Bregma and Lambda point with cranium, the position mill on the right side of middle seam opens a diameter about 2.5mm window, exposes brain Tissue.The disk obtained in step (1) is attached on brain tissue, then carefully suture scalp and use tissue glue bond, general Even application is at wound after the pulvis and aqua of artificial tooth base resin mix.
(3) mouse is normally fed 4 weeks
(4) with after 1% Nembutal sodium solution anesthetized mice, successively with physiological saline and 4%PFA tissue fixative solutions to small Mouse is irrigated, and then carefully takes out Mice brain tissues.Brain tissue is cut to the thin of 100 μ m-thicks along coronal-plane with vibrations slicer Piece, take out the brain piece for including experimental site.
(5) the brain piece comprising experimental site for obtaining step (4) is put into containing GFAP (GFAP) primary antibody Concentration is 1:In 1000 3% bovine serum albumin(BSA) (BSA) solution, and it is incubated overnight under 4 DEG C of environment；Cleaned with PBS solution Brain piece 3 times, each 10min；Brain piece is put into secondary antibody concentration as 1:In 1000 3%BSA solution, 2h is incubated at room temperature；It is molten with PBS Liquid cleaning brain piece 3 times, each 10min；Paster, dry in the air piece, and uses mountant mounting.
(6) sample is shot using single photon confocal imaging system, obtains the immunofluorescence dyeing image of sample.
Fig. 9 is the immunofluorescence dyeing image of the flexible biological electrode provided in experimental example 2 using embodiment 1.From figure As can be seen that because of immune response and astroglia that hyperplasia goes out is less, illustrate flexible biological electrode tool provided by the invention There is good bio-compatibility.
Comparative example 1
(1) the potentiometric detection Post section of PET base bioelectrode is fabricated to a diameter of 2mm disk, is put into 75% 1h is soaked in alcohol, is then placed in sterile artificial cerebrospinal fluid and soaks 1h.
(2) mouse to an about 25g injects 1% Nembutal sodium solution 0.25mL, when it is in narcosis, Its head is fixed on brain position indicator；Scalp is cut off in two ear line midpoints, exposes Bregma the and Lambda points of skull, Between being drilled in skull Bregma and Lambda point with cranium, the position mill on the right side of middle seam opens a diameter about 2.5mm window, exposes brain Tissue.The disk obtained in step (1) is attached on brain tissue, then carefully suture scalp and use tissue glue bond, general Even application is at wound after the pulvis and aqua of artificial tooth base resin mix.
(3) mouse is normally fed 4 weeks
(4) with after 1% Nembutal sodium solution anesthetized mice, successively with physiological saline and 4%PFA tissue fixative solutions to small Mouse is irrigated, and then carefully takes out Mice brain tissues.Brain tissue is cut to the thin of 100 μ m-thicks along coronal-plane with vibrations slicer Piece, take out the brain piece for including experimental site.
(5) the brain piece comprising experimental site for obtaining step (4) is put into containing GFAP (GFAP) primary antibody Concentration is 1:In 1000 3% bovine serum albumin(BSA) (BSA) solution, and it is incubated overnight under 4 DEG C of environment；Cleaned with PBS solution Brain piece 3 times, each 10min；Brain piece is put into secondary antibody concentration as 1:In 1000 3%BSA solution, 2h is incubated at room temperature；It is molten with PBS Liquid cleaning brain piece 3 times, each 10min；Paster, dry in the air piece, and uses mountant mounting.
(6) sample is shot using single photon confocal imaging system, obtains the immunofluorescence dyeing image of sample.
Figure 10 is the PET base flexible biological electrode immunofluorescence dyeing image provided in comparative example 1.Can with Fig. 9 contrasts To find out, relative to conventional synthesis polymer-based end (PET), the flexible biological electrode pair brain tissue that embodiment 1 is provided is immunized Reaction is smaller, illustrates that flexible biological electrode provided by the invention has more preferable bio-compatibility.
Applicant states that the present invention illustrates flexible biological electrode of the present invention and preparation method thereof by above-described embodiment And application, but the invention is not limited in above-described embodiment, that is, it is real not mean that the present invention has to rely on above-described embodiment ability Apply.Those skilled in the art is it will be clearly understood that any improvement in the present invention, to the equivalence replacement of raw material selected by the present invention And the addition of auxiliary element, selection of concrete mode etc., all fall within protection scope of the present invention and it is open within the scope of.

Claims (10)

  1. A kind of 1. flexible biological electrode, it is characterised in that the flexible biological electrode include flexible substrates, microelectrode array and absolutely Edge layer, the flexible substrates are water resistance nanometer paper.
  2. 2. flexible biological electrode according to claim 1, it is characterised in that the water resistance nanometer paper soaks 24 in water Hour size changing rate is less than 2%.
  3. 3. flexible biological electrode according to claim 1 or 2, it is characterised in that the water resistance nanometer paper passes through as follows Preparation method is prepared：
    (1) it is oxidation-treated using cellulose as raw material, obtain oxycellulose；
    (2) the oxycellulose dispersion liquid that is obtained through step (1) carries out homogenization, and after filtered through nitrocellulose filter, Gluey nano-cellulose is obtained, gained glue nano-cellulose is tipped upside down on smooth surface together with filter membrane；
    (3) nano-cellulose obtained to step (2)/nitrocellulose filter composite carries out pressure process drying that will receive Rice cellulose carries out keratinization, obtains the water resistance nanometer paper；
    Preferably, step (1) described oxidation processes are handled using NaBr/TEMPO/NaClO oxidation systems；
    Preferably, step (2) described homogenization is that homogeneous is carried out under 1300-1800bar pressure using high pressure homogenizer Handle 5-15min；
    Preferably, before step (2) described filtering, the nano-cellulose dispersion liquid after homogenization is added into deionized water and is diluted to Mass concentration is 0.1-0.5%, preferably 0.2%；
    Preferably, pressure when step (3) pressure process is dried is 10-20kPa；
    Preferably, temperature when step (3) pressure process is dried is 50-70 DEG C；
    Preferably, the time that step (3) pressure process is dried is 5-15min.
  4. 4. the flexible biological electrode according to any one of claim 1-3, it is characterised in that the water resistance nanometer paper Thickness is 30-300 microns；
    Preferably, the microelectrode array is that metal electrode is arranged in array-like.
  5. 5. the flexible biological electrode according to any one of claim 1-4, it is characterised in that the metal electrode is inertia In metal, preferably gold, platinum, iridium or palladium any one or at least two combination；
    Preferably, the thickness of the metal electrode is 50-200 nanometers.
  6. 6. the flexible biological electrode according to any one of claim 1-5, it is characterised in that the metal electrode is by detecting Site, connecting line and solder joint composition, connecting line connecting detection site and solder joint；
    Preferably, the detection site is circular, a diameter of 10-150 microns；
    Preferably, for the connecting line by dielectric protection layer, the connecting line and insulating barrier are in core shell structure.
  7. 7. the flexible biological electrode according to any one of claim 1-6, it is characterised in that the insulating barrier be SU-8, In polyimides, makrolon or Parylene any one or at least two combination；
    Preferably, the thickness of insulating layer is 0.5-5 microns.
  8. 8. the preparation method of the flexible biological electrode according to any one of claim 1-7, it is characterised in that the preparation Method comprises the following steps：
    (1) water resistance nanometer paper is prepared；
    (2) have on surface and process underlying insulating layer, microelectrode array and upper strata insulation on the silicon chip of silica oxide layer successively Layer；
    (3) sample is placed in silica etching liquid and removes dioxy after spin coating organic gel on the silicon chip that step (2) obtains SiClx, obtain the composite construction of organic gel and microelectrode array；
    (4) organic gel and the composite construction of microelectrode array obtained step (3) is transferred in water resistance nanometer paper substrates, is gone Except organic gel, the flexible biological electrode is obtained.
  9. 9. preparation method according to claim 8, it is characterised in that the silicon chip described in step (2) is highly doped silicon wafer；
    Preferably, step (2) the silica oxide layer is obtained by thermal oxide；
    Preferably, step (3) described organic gel is the polymethyl methacrylate or makrolon that mass percent is 1-8%；
    Preferably, step (3) the silica etching liquid is any one in hydrofluoric acid, sodium hydroxide or BOE etching liquids.
  10. 10. the application of the flexible biological electrode according to any one of claim 1-7, it is characterised in that described flexible raw Thing application of electrode is in bio-electro-physiologic signal detection；
    Preferably, the flexible biological application of electrode is in detection cortex electricity physiological signal；
    Preferably, the flexible biological application of electrode is in detection rat cerebral cortex electricity physiological signal.
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CN113123158A (en) * 2021-03-26 2021-07-16 南京大学 Water-resistant transparent paper and preparation method and application thereof
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