CN102445477B - Ex-vivo nerve information dual-mode detection microelectrode array chip and preparation method thereof - Google Patents
Ex-vivo nerve information dual-mode detection microelectrode array chip and preparation method thereof Download PDFInfo
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Abstract
The invention discloses an ex-vivo nerve information dual mode detection microelectrode array chip and a preparation method of the ex-vivo nerve information dual mode detection microelectrode array chip, relating to the sensor technology. The chip consists of an insulation substrate, a microelectrode array, a counter electrode, a reference electrode, an electrode lead wire and a contact point and a surface insulation layer and is processed and prepared by adopting the MEMS (micro electro mechanical system) technology, wherein a microelectrode is a sensitive unit which is directly contacted with ex-vivo nerve cells of an animal, can be used for synchronous detection of transmission modes of a neural electrophysiological signal and a nervous transmitter electrochemical signal by combining the counter electrode and the reference electrode and also has the function of applying electrophotoluminescence to cells. The ex-vivo nerve information dual mode detection microelectrode array chip has function integration, is simple in circuit interface, is convenient to use and is suitable for performing dual-mode detection of ex-vivo nerve information of animals and related research in laboratories.
Description
Technical field
The present invention relates to the micro-processing technology field of biology sensor, is that a kind of exsomatizednerve information bimodulus detects microelectrode array chip and preparation method.
Background technology
Neurocyte is to form the neural Basic Structure And Functions unit of higher mammal, and hundreds of millions of neurocyte is connected to form complicated network by cynapse.It is two kinds of patterns that nerve information transmits that neurocyte pulsed discharge and neurotransmitter discharge, the two interdependence, phase inter-modulation.Therefore, colony's neurocyte is implemented to the synchronous detection of Electrophysiology signal and neurotransmitter electrochemical signals, nationality, with the interaction mechanism of Studies On Neuronal, the pathogenesis of the coding and decoding process of nerve information, neuropsychiatric disease and drug response etc., has important scientific meaning and practical value.
For a long time, people utilize traditional patch-clamp, glass microelectrode, tinsel microelectrode etc., neurocyte electricity physiological signal at body or in vitro is detected, conventionally only can obtain the data of a small amount of several passages, and electrode location difficulty, complex operation; In recent years, development along with MEMS (micro electro mechanical system) (MEMS) process technology, there is the microelectrode array chip that some adopt various materials and technique to be prepared from both at home and abroad, can realize the synchronous detection of colony's neurocyte bioelectrical activity, as the MEA chip of German Multichannel company exploitation, the Michigan implantation micro-electrode having array that U.S. NeuroNexus company produces etc., but the function of the not yet integrated detection neurotransmitter of these electrodes, cannot further investigate the internal relation between Electrophysiology signal and corresponding neurotransmitter concentration change; And for the detection of neurotransmitter electrochemical signals, the methods that adopt large electrodes, external microdialysis, detect real-time poor more at present, sensitivity is not high, cannot realize the detection of synchronizeing with electricity physiological signal.
Summary of the invention
The object of the invention is to for above-mentioned the deficiencies in the prior art, provide a kind of exsomatizednerve information bimodulus to detect microelectrode array chip and preparation method, this array chip function is integrated, and circuit interface is simple, easy to use.The microelectrode array chip of preparing contains a plurality of passages, can be used in the synchronous detection of Neurons in Vitro electricity physiology and two kinds of patterns of neurotransmitter Electrochemistry Information, and has the function that cell is applied to electro photoluminescence concurrently.In vitro animal nerve histotomy is attached to the microelectrode array surface of chip, or on chip, carries out neuronal cell cultures, the bimodulus that can carry out animal exsomatizednerve information detects and correlative study.
For realizing this purpose, the present invention has adopted following technical scheme:
Information bimodulus detects a microelectrode array chip, and it comprises dielectric base, microelectrode array, to electrode, contrast electrode, lead-in wire and contact; Dielectric base is the carrier of whole chip, in the center on dielectric base surface, is microelectrode array, and a plurality of arrange with matrix form, circular microelectrodes of being made by conductive film material have distributed in microelectrode array; Microelectrode array one side is provided with a Pt film to electrode, and an Ag/AgCl laminated film contrast electrode, and electrode and contrast electrode are all to polygon, and symmetrical, tail end is bar shaped and extends to respectively basal edge; All circular microelectrodes are all gone between and are extended to substrate edges at two ends by conductive film, and lead terminal is electrically connected to square contact, to facilitate with external circuit, are connected, and all wire surfaces are coated with insulation course.
Described exsomatizednerve information bimodulus detects microelectrode array chip, the material selection hard transparent insulating material of dielectric base described in it, be quartz glass, Polyvinylchloride or polycarbonate one of them, substrate length of side 25mm～80mm, thickness 1mm～2mm.
Described exsomatizednerve information bimodulus detects microelectrode array chip, the metal that the conductive film material that described in it, microelectrode array is selected is good biocompatibility or metallic compound, and finishing has nano material or sensitive membrane material; Microelectrode array comprises 9～64 microelectrodes, wherein for the microelectrode diameter 10 μ m～30 μ m of Electrophysiology input, the microelectrode diameter 30 μ m～50 μ m that detect and apply electro photoluminescence for neurotransmitter electrochemical signals, microelectrode spacing 50 μ m～200 μ m;
To the size of electrode and contrast electrode than at least large order of magnitude of microelectrode, for reference potential being provided and keeping current potential stable;
Lead-in wire and the conductive film material of contact are identical with microelectrode, and thickness is greater than 300nm, guarantee that its physical strength can bear the pressure that standard electronic components and parts Elastic metal probe causes.
Described exsomatizednerve information bimodulus detects microelectrode array chip, the conductive film material that described in it, microelectrode array is selected, be gold, platinum, titanium nitride or indium tin oxide one of them; The organic or inorganic insulating material that the insulating layer material that wire surface covers is good biocompatibility.
Described exsomatizednerve information bimodulus detects microelectrode array chip, the insulating layer material that described in it, wire surface covers, be silicon dioxide, silicon nitride, nitrogen-oxygen-silicon, SU8, polyimide or Parylene one of them.
Exsomatizednerve information bimodulus detect the preparation method of microelectrode array chip, it comprises the steps:
A) spin coating one deck photoresist in the process dielectric base 1 of surface clean, thickness is greater than three times of plan sputter conductive membrane layer, forms microelectrode array, the pattern to electrode, contrast electrode, lead-in wire and contact after photoetching development;
B) at the microelectrode conductive membrane layer of photoetching agent pattern surface sputtering a layer thickness 250nm～500nm;
C) adopt stripping technology to remove unnecessary conductive membrane layer, leave required electrode, lead-in wire and contact;
D) by plasma enhanced chemical vapor deposition (PECVD) silicon dioxide, silicon nitride, nitrogen-oxygen-silicon, or the method for spin coating SU8, polyimide, Parylene, at the substrate surface for preparing conductive membrane layer, cover insulation course, by the method for photoetching and plasma etching, expose microelectrode array, to electrode, contrast electrode and contact, retain the insulation course that all wire surfaces cover;
E), on the described surface to electrode 3, the technique of adopt photoetching, sputter, peeling off, prepares the Pt metal film layer of thickness 250nm～500nm;
F) on the surface of described contrast electrode, the technique of adopt photoetching, sputter, peeling off, the Ag metal film layer of preparing thickness 500nm～800nm, and carry out chlorination by chemistry or electrochemical method, or apply Ag/AgCl slurry and dry at the surperficial silk-screen of contrast electrode, finally form Ag/AgCl laminated film contrast electrode;
G) by electrochemical deposition or physics, drip the methods such as painting, absorption, at microelectrode surface finish nano material or the sensitive membrane material of setting difference in functionality.
Described preparation method, step b described in it) before, the Cr of sputter 10nm～50nm or Ti Seed Layer in advance, to increase the adhesiveness of conductive membrane layer and substrate.
Described preparation method, step b described in it) in, during the microelectrode conductive membrane layer of sputter a layer thickness 250nm～500nm, if microelectrode conductive film is selected Pt material, can omit step e).
Exsomatizednerve information bimodulus provided by the invention detects microelectrode array chip, and the function that multichannel nerve electric physiological detection, nerve electric stimulation, neurotransmitter are detected is integrated, realizes high flux and synchronously detects, and easy to use, circuit interface is simple and reliable.Having broken through conventional art can only be to two kinds of nerve information pattern separate detection, the poor limitation of real-time, for studying the relation of the two phase inter-modulation, provide more convenient effective instrument, for the inherent mechanism of further investigation nerve information coding, transmission, and the pathogenesis of some neuropsychiatric diseases provides new visual angle.
Accompanying drawing explanation
Fig. 1 is that exsomatizednerve information bimodulus of the present invention detects microelectrode array chip structural drawing;
Fig. 2 is the local enlarged diagram of two kinds of different microelectrode arrays, wherein:
Microelectrode diameter in Fig. 2 a is 30 μ m;
Microelectrode diameter package in Fig. 2 b is containing five kinds of 10 μ m, 20 μ m, 30 μ m, 40 μ m, 50 μ m;
Fig. 3 is the process chart that exsomatizednerve information bimodulus of the present invention detects microelectrode array chip preparation method;
Fig. 3 a is the pattern of contact conductor and contact;
Fig. 3 b is for following the Pt thin layer of sputter 250nm;
Fig. 3 c, for adopting stripping technology to remove unnecessary Ti/Pt thin layer, leaves required electrode, lead-in wire and contact;
Fig. 3 d is at the substrate surface for preparing Pt thin layer, PECVD silicon nitride (Si
3n
4) insulation course, thickness 800nm.By photoetching and SF
6the method of plasma etching, exposes microelectrode, to electrode, contrast electrode and contact, retains the silicon nitride dielectric layer that all wire surfaces cover;
Fig. 3 e is the surface at contrast electrode, the Ag/AgCl slurry of silk-screen coating thickness 200 μ m, and in the baking oven of 100 ℃, dry 3 hours, finally form Ag/AgCl laminated film contrast electrode;
Fig. 3 f is for adopting the method for electrochemical deposition, at microelectrode surface finish nano platinum black (Pt Black) particle detecting for Electrophysiology;
Fig. 3 g, for dripping and be coated with Nafion (ion-exchange polymer) ethanolic solution that concentration is 1% on microelectrode array surface, after naturally drying, forms ion selectivity Nafion film.
Drawing reference numeral explanation: 1 is dielectric base, and 2 is microelectrode array, and 3 is to electrode, 4 is contrast electrode, and 5 is lead-in wire, and 6 is contact, 7 be can multiplexing functions microelectrode, 8 is only for the microelectrode of electric physiological detection, 9 for only detecting or apply the microelectrode of electro photoluminescence for neurotransmitter.
Embodiment
Exsomatizednerve information bimodulus of the present invention detects microelectrode array chip, by dielectric base, microelectrode array, electrode, contrast electrode, contact conductor and contact are formed.Described dielectric base is the carrier of whole chip, the center on dielectric base surface, and several circular microelectrodes that arrange with matrix form, that made by conductive film material that distributed, form microelectrode array.Wherein, part microelectrode is for detection of Electrophysiology signal, and part microelectrode is for detection of the concentration of different neurotransmitters or neurocyte is applied to electro photoluminescence.Microelectrode array periphery is furnished with a larger-size Pt film to electrode, and an Ag/AgCl laminated film contrast electrode.All circular microelectrodes are all gone between and are extended to basal edge by conductive film, and end forms square contact, are conveniently connected with external circuit, and all wire surfaces are all coated with insulation course.
Dielectric base is selected hard transparent insulating material, can be quartz glass, Polyvinylchloride, polycarbonate, and these materials have the feature of chemistry, stable mechanical performance, can tolerate the impact of temperature, pressure, chemical reagent in micro-process.Select transparent material to be conducive under the microscope tested Neurons in Vitro be observed.Dielectric base length of side 25mm～80mm, thickness 1mm～2mm.
The conductive film material that microelectrode array is selected is metal or the metallic compound of good biocompatibility, can be gold, platinum, titanium nitride, indium tin oxide, in order to improve signal to noise ratio (S/N ratio) and to improve the selectivity that different neurotransmitters are detected, microelectrode surface is decorated nanometer material or sensitive membrane material as required.
Microelectrode array comprises 9～64 microelectrodes, wherein for the microelectrode diameter 10 μ m～30 μ m of Electrophysiology input, the microelectrode diameter 30 μ m～50 μ m that detect and apply electro photoluminescence for neurotransmitter electrochemical signals, microelectrode spacing 50 μ m～200 μ m.
To the size of electrode and contrast electrode, than at least large order of magnitude of microelectrode, in electrophysiologicalsignal signal detection or apply in the process of electro photoluminescence, contrast electrode is used for providing reference potential; In the testing process of neurotransmitter electrochemical signals, to electrode, be used for providing a current return, and together with contrast electrode, form the three-electrode system of Electrochemical Detection.
The conductive film material of circular microelectrode lead-in wire and contact is identical with microelectrode, and thickness is greater than 300nm, guarantees that its physical strength can bear the pressure that standard electronic components and parts Elastic metal probe causes.When metal probe is gently pressed on contact, can realize being connected of chip and external circuit.The operation of spun gold pressure welding when this circuit interface has been avoided conventional MEMS device package, interface is simple, connects reliable, reusable.
The organic or inorganic insulating material that the insulating layer material that circular microelectrode wire surface covers is good biocompatibility can be silicon dioxide, silicon nitride, nitrogen-oxygen-silicon, SU8, polyimide, Parylene.
Exsomatizednerve information bimodulus of the present invention detects microelectrode array chip, and its preparation method comprises the steps:
1. passing through spin coating one deck photoresist in the dielectric base of surface clean, thickness is greater than three times of plan sputter conductive membrane layer, forms all microelectrode arrays, the pattern to electrode, contrast electrode, contact conductor and contact after photoetching development;
2. at the microelectrode conductive membrane layer of photoetching agent pattern surface sputtering a layer thickness 250nm～500nm, the Cr of sputter 10nm～50nm or Ti Seed Layer in advance if desired, to increase the adhesiveness of conductive membrane layer and substrate;
3. adopt stripping technology to remove unnecessary conductive membrane layer, leave required electrode, lead-in wire and contact;
4. by PECVD silicon dioxide, silicon nitride, nitrogen-oxygen-silicon, or the method for spin coating SU8, polyimide, Parylene, at the substrate surface for preparing conductive membrane layer, cover insulation course, by the method for photoetching and plasma etching, expose microelectrode, to electrode, contrast electrode and contact, retain the insulation course that all wire surfaces cover;
5. on the described surface to electrode, the technique of adopt photoetching, sputter, peeling off, prepares the Pt metal film layer of thickness 250nm～500nm, if the microelectrode conductive film in step 2 has been selected Pt, can omit this step;
6. on the surface of described contrast electrode, the technique of adopt photoetching, sputter, peeling off, the Ag metal film layer of preparing thickness 500nm～800nm, and carry out chlorination by chemistry or electrochemical method, or apply Ag/AgCl slurry and dry at the surperficial silk-screen of contrast electrode, finally form Ag/AgCl laminated film contrast electrode;
7. by electrochemical deposition or physics, drip the method for painting, absorption, at microelectrode surface finish nano material or the sensitive membrane material of setting difference in functionality.
Below in conjunction with accompanying drawing, a specific embodiment of the present invention is elaborated.
Exsomatizednerve information bimodulus provided by the invention detects microelectrode array chip structure as shown in Figure 1.Whole chip is by dielectric base 1, microelectrode array 2, form electrode 3, contrast electrode 4, contact conductor 5 and contact 6.
Dielectric base 1 is selected the microslide that biology laboratory is conventional, as the carrier of whole chip.The long 76.2mm of microslide, wide 25.4mm, thick 1mm.In the center of slide surface, 64 the circular microelectrodes of being made by Pt membraneous material that distributed, form microelectrode array 2.
Microelectrode is arranged with 8 * 8 box formation substantially, and electrode separation 100 μ m, also can do the adjustment of certain forms.Fig. 2 is the local enlarged diagram of two kinds of different microelectrode arrays 2, and the microelectrode diameter in Fig. 2 (a) is 30 μ m, and the microelectrode diameter package in Fig. 2 (b) is containing five kinds of 10 μ m, 20 μ m, 30 μ m, 40 μ m, 50 μ m.Because the cell space diameter of neurocyte to be measured is in 10 μ m left and right, the more little electrical activity that detects individual cells that is more beneficial to of electrode diameter, when electrode diameter is greater than 30 μ m, the signal that electrode is recorded to is too much, will be unfavorable for the separation of individual cells electric signal.But large electrode diameter is conducive to increase the signal intensity that neurotransmitter detects, and can bear larger stimulating current.Therefore,, in the present embodiment, the microelectrode that diameter is less than 30 μ m is only for detection of the electricity physiological signal of neurocyte, as the electrode 7 in figure; Diameter is greater than the microelectrode of 30 μ m only for detection of neurotransmitter electrochemical signals, or neurocyte is carried out to electro photoluminescence, as the electrode 9 in figure; Diameter is that the microelectrode of 30 μ m can carry out the switching of three kinds of functions as required, as the electrode 8 in figure.In order to improve signal to noise ratio (S/N ratio), can be at microelectrode surface finish nano platinum-black.In order to improve the selectivity that detects neurotransmitter dopamine, can be at microelectrode finishing ion selectivity Nafion film.
In a side of microslide, be furnished with a larger-size Pt film to electrode 3, and an Ag/AgCl laminated film contrast electrode 4.Two electrodes are all polygon, symmetrical, and tail end is bar shaped and extends to respectively microslide edge, and minimum edge is about 3mm left and right.In electrophysiologicalsignal signal detection or apply in the process of electro photoluminescence, contrast electrode is used for providing reference potential; In the testing process of neurotransmitter electrochemical signals, electrode 3, for a current return is provided, and together with contrast electrode, is formed to the three-electrode system of Electrochemical Detection.
All circular microelectrodes all extend to microslide edges at two ends by Pt film lead-in wire 5, and end forms square contact 6, and contact length of side 1.27mm, arranges with array format equally, spacing 2.54mm.The size of this size and standard electronic components and parts Elastic metal probe matches.When the metal probe on being welded on circuit board is gently pressed on contact, can realize being connected of chip and external circuit.
All wire surfaces are all coated with silicon nitride film insulation course, can make to reach the isolation in electricity between neurocyte and electrolyte nutrient solution and lead-in wire.In vitro animal nerve histotomy is attached to the microelectrode array surface of chip, or on chip, carries out neuronal cell cultures, in conjunction with supporting detection system, the bimodulus that can carry out animal exsomatizednerve information detects and correlative study.
Details are as follows with reference to figure 3 for concrete preparation process of the present invention:
1. at the upper spin coating one deck positive photoresist AZ1500 of the microslide (Glass) through surface clean, thickness 1 μ m, forms all microelectrode arrays 2 on mask plate, (Fig. 3 a) to the pattern of electrode 3, contrast electrode 4, contact conductor and contact 6 after photoetching development;
2. in the Ti Seed Layer of photoetching agent pattern surface sputtering a layer thickness 30nm, to increase the adhesiveness of Pt conductive membrane layer and substrate of glass, follow the Pt thin layer (Fig. 3 b) of sputter 250nm.
3. adopt stripping technology to remove unnecessary Ti/Pt thin layer, leave required electrode 2～4, go between 5 and contact 6, (Fig. 3 c);
4. at the substrate surface for preparing Pt thin layer, PECVD silicon nitride (Si
3n
4) insulation course, thickness 800nm.By photoetching and SF
6the method of plasma etching, exposes microelectrode 7,8, to electrode 3, contrast electrode 4 and contact 6, retains the silicon nitride dielectric layer (Fig. 3 d) that all wire surfaces cover;
5. on the surface of contrast electrode 4, the Ag/AgCl slurry of silk-screen coating thickness 200 μ m, and in the baking oven of 100 ℃, dry 3 hours, finally form Ag/AgCl laminated film contrast electrode 4 (Fig. 3 e);
7. adopt the method for electrochemical deposition, at microelectrode 8 surface finish nano platinum black (Pt Black) particles (Fig. 3 f) that detect for Electrophysiology.Detailed process is, with the chloroplatinic acid (H of deionized water preparation 20mmol/L
2ptCl
6) and hydrochloric acid (HCl) mixed liquor of 2mol/L, as electroplate liquid, add in perfusion groove.Connect electrochemical workstation CHI660, take microelectrode to be finished as working electrode, platinum filament is to electrode, applies set potential, adopts chronoamperometry to electroplate 5 minutes.
8. on microelectrode array 2 surfaces, drip and be coated with Nafion (ion-exchange polymer) ethanolic solution that concentration is 1%, after naturally drying, form ion selectivity Nafion film (Fig. 3 g).
Above embodiment is just in order to play the object of explanation; be not limitation of the present invention, on the basis of the above description, the present invention can be many modifications and changes; institute makes improvements and changes, and selects the methods such as other functional material all should be within the claims in the present invention protection domain.
Claims (7)
1. exsomatizednerve information bimodulus detects a microelectrode array chip, it is characterized in that: comprise dielectric base (1), microelectrode array (2), to electrode (3), contrast electrode (4), lead-in wire (5) and contact (6); Dielectric base (1) is the carrier of whole chip, center on dielectric base (1) surface is microelectrode array (2), and a plurality of arrange with matrix form, circular microelectrodes of being made by conductive film material have distributed in microelectrode array (2); Microelectrode array (2) one sides are provided with a Pt film to electrode (3), an and Ag/AgCl laminated film contrast electrode (4), electrode (3) and contrast electrode (4) are all to polygon, and symmetrical, tail end is bar shaped and extends to respectively substrate (1) edge; All circular microelectrodes all by conductive film go between (5) extend to substrate (1) edges at two ends, lead-in wire (5) end is electrically connected to square contact (6), to facilitate with external circuit, be connected, leaded (5) surface coverage has insulation course;
Wherein, metal or metallic compound that the conductive film material that described microelectrode array (2) is selected is good biocompatibility, finishing has nano material or sensitive membrane material; Microelectrode array (2) comprises 9～64 microelectrodes, wherein for the microelectrode diameter 10 μ m～30 μ m of Electrophysiology input, the microelectrode diameter 30 μ m～50 μ m that detect and apply electro photoluminescence for neurotransmitter electrochemical signals, microelectrode spacing 50 μ m～200 μ m;
To the size of electrode (3) and contrast electrode (4) than at least large order of magnitude of microelectrode, for reference potential being provided and keeping current potential stable;
The conductive film material of lead-in wire (5) and contact (6) is identical with microelectrode, and thickness is greater than 300nm, guarantees that its physical strength can bear the pressure that standard electronic components and parts Elastic metal probe causes.
2. exsomatizednerve information bimodulus according to claim 1 detects microelectrode array chip, it is characterized in that: the material selection hard transparent insulating material of described dielectric base (1), be quartz glass, Polyvinylchloride or polycarbonate one of them, dielectric base (1) length of side 25mm～80mm, thickness 1mm～2mm.
3. exsomatizednerve information bimodulus according to claim 1 detects microelectrode array chip, it is characterized in that: the conductive film material that described microelectrode array (2) is selected, be gold, platinum, titanium nitride or indium tin oxide one of them; The organic or inorganic insulating material that the insulating layer material of lead-in wire (5) surface coverage is good biocompatibility.
4. exsomatizednerve information bimodulus according to claim 3 detects microelectrode array chip, it is characterized in that: the insulating layer material of described lead-in wire (5) surface coverage, be silicon dioxide, silicon nitride, nitrogen-oxygen-silicon, SU8, polyimide or Parylene one of them.
5. exsomatizednerve information bimodulus as claimed in claim 1 detects a preparation method for microelectrode array chip, it is characterized in that: comprise the steps:
1) at the upper spin coating one deck photoresist of the dielectric base (1) through surface clean, thickness is greater than three times of plan sputter conductive membrane layer, forms microelectrode array (2), the pattern to electrode (3), contrast electrode (4), lead-in wire (5) and contact (6) after photoetching development;
2) at the microelectrode conductive membrane layer of photoetching agent pattern surface sputtering a layer thickness 250nm～500nm;
3) adopt stripping technology to remove unnecessary conductive membrane layer, leave required electrode, lead-in wire (5) and contact (6);
4) by plasma enhanced chemical vapor deposition (PECVD) silicon dioxide, silicon nitride, nitrogen-oxygen-silicon, or the method for spin coating SU8, polyimide, Parylene, preparing the substrate of conductive membrane layer (1) surface coverage insulation course, by the method for photoetching and plasma etching, expose microelectrode array (2), to electrode (3), contrast electrode (4) and contact (6), retain the insulation course that all wire surfaces cover;
5), on the described surface to electrode (3), the technique of adopt photoetching, sputter, peeling off, prepares the Pt metal film layer of thickness 250nm～500nm;
6) on the surface of described contrast electrode (4), the technique of adopt photoetching, sputter, peeling off, the Ag metal film layer of preparing thickness 500nm～800nm, and carry out chlorination by chemistry or electrochemical method, or apply Ag/AgCl slurry and dry at the surperficial silk-screen of contrast electrode (4), finally form Ag/AgCl laminated film contrast electrode;
7) by electrochemical deposition or physics, drip painting, adsorption method, at microelectrode surface finish nano material or the sensitive membrane material of setting difference in functionality.
6. preparation method as claimed in claim 5, is characterized in that: described step 2) before, the Cr of sputter 10nm～50nm or Ti Seed Layer in advance, to increase the adhesiveness of conductive membrane layer and substrate.
7. preparation method as claimed in claim 5, is characterized in that: described step 2), during the microelectrode conductive membrane layer of sputter a layer thickness 250nm～500nm, if microelectrode conductive film is selected Pt material, can omit step 5).
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