CN102445477A - 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 stripped nerve information bimodulus detects microelectrode array chip and preparation method.
Background technology
Neurocyte is to form the neural basic structure functional unit of higher mammal, and hundreds of millions of neurocyte is connected to form complicated network through 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 the synchronous detection of neuroelectricity physiological signal and neurotransmitter electrochemical signals; Nationality has important scientific meaning and practical value with the pathogenesis of interaction mechanism, the coding and decoding process of nerve information of research neurocyte, neural psychotic disorder and drug response etc.
For a long time; People utilize traditional patch-clamp, glass microelectrode, tinsel microelectrode etc.; Neurocyte electricity physiological signal under body or isolated condition detects, and only can obtain the data of a small amount of several passages usually, and positioning of electrode is difficult, complex operation; In recent years; Development along with MEMS (MEMS) process technology; Some microelectrode array chips that adopt various materials and prepared to form have appearred both at home and abroad; Can realize the synchronous detection of colony's neurocyte bioelectrical activity, like the MEA chip of German Multichannel company exploitation, the Michigan implantation micro-electrode having array that U.S. NeuroNexus company produces etc.; But these electrodes are the function of not integrated detection neurotransmitter as yet, can't further investigate the internal relation between neuroelectricity physiological signal and the corresponding neurotransmitter change in concentration; And for the detection of neurotransmitter electrochemical signals, at present methods that adopt large electrodes, external microdialysis more, it is poor to detect real-time, and sensitivity is not high, can't realize the synchronous detection with electricity physiological signal.
Summary of the invention
The objective of the invention is to the deficiency to above-mentioned prior art, provide a kind of stripped nerve information bimodulus to detect microelectrode array chip and preparation method, this array chip function is integrated, and circuit interface is simple, and is easy to use.The microelectrode array chip of preparing contains a plurality of passages, can be used in the synchronous detection of neurocyte electricity physiology and two kinds of patterns of neurotransmitter galvanochemistry information that exsomatizes, and has the function that pair cell applies electro photoluminescence concurrently.The animal nerve histotomy that exsomatizes is attached to the microelectrode array surface of chip, or on chip, carries out neuronal cell cultures, the bimodulus that can carry out the stripped nerve information of animal detects and correlative study.
For realizing this purpose, the present invention has adopted following technical scheme:
A kind of stripped nerve information bimodulus detects 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 entire chip, is microelectrode array in the center on dielectric base surface, and a plurality of circular microelectrodes that arrange with matrix form, that processed by conductive film material have distributed in the 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 all are polygon, is symmetrically distributed, and tail end is bar shaped and extends to basal edge respectively; All circular microelectrodes all extend to the substrate edges at two ends through the conductive film lead-in wire, and lead terminal is electrically connected with square contact, are connected with external circuit with convenient, and all wire surfaces are coated with insulation course.
Described stripped nerve information bimodulus detects microelectrode array chip, the material selection hard transparent insulating material of its said dielectric base, be quartz glass, PVC or polycarbonate one of them, substrate length of side 25mm～80mm, thickness 1mm～2mm.
Described stripped nerve information bimodulus detects microelectrode array chip, and the conductive film material that its said microelectrode array is selected for use is the metal or the metallic compound of good biocompatibility, and finishing has nano material or sensitive membrane material; Microelectrode array comprises 9～64 microelectrodes; The microelectrode diameter 10 μ m～30 μ m that wherein are used for neural electrophysiologicalsignal signal detection; Be used for microelectrode diameter 30 μ m～50 μ m that the neurotransmitter electrochemical signals detects and applies electro photoluminescence, microelectrode spacing 50 μ m～200 μ m;
The size of electrode and contrast electrode than the big at least one magnitude of microelectrode, is used to provide reference potential and keeps current potential stable;
The 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 the elasticity metal probe is caused in the standard electronic components and parts.
Described stripped nerve information bimodulus detects microelectrode array chip, the conductive film material that its said microelectrode array is selected for use, be gold, platinum, titanium nitride or indium tin oxide one of them; Wire surface dielectric layer covered material is the organic or inorganic insulating material of good biocompatibility.
Described stripped nerve information bimodulus detects microelectrode array chip, its said wire surface dielectric layer covered material, be silicon dioxide, silicon nitride, nitrogen-oxygen-silicon, SU8, polyimide or Parylene one of them.
A kind of described stripped nerve information bimodulus detects the preparation method of microelectrode array chip, and it comprises the steps:
A) through spin coating one deck photoresist on the dielectric base 1 of surface clean, thickness is greater than three times that intend the sputter conductive membrane layer, forms microelectrode array behind the photoetching development, to the pattern of electrode, contrast electrode, lead-in wire and contact;
B) at the microelectrode conductive membrane layer of photoresist patterned surfaces sputter one layer thickness 250nm～500nm;
C) adopt stripping technology to remove unnecessary conductive membrane layer, stay required electrode, lead-in wire and contact;
D) through plasma enhanced chemical vapor deposition (PECVD) silicon dioxide, silicon nitride, nitrogen-oxygen-silicon; Or the method for spin coating SU8, polyimide, Parylene; Cover insulation course at the substrate surface for preparing conductive membrane layer; Through the method for photoetching and plasma etching, expose microelectrode array, to electrode, contrast electrode and contact, keep all wire surface dielectric layer covered;
E) on said surface to electrode 3, the technology of adopt photoetching, sputter, peeling off, the Pt metal film layer of preparation thickness 250nm～500nm;
F) on the surface of said contrast electrode; The technology of adopt photoetching, sputter, peeling off; The Ag metal film layer of preparation thickness 500nm～800nm; And carry out chlorination through chemistry or electrochemical method, or apply Ag/AgCl slurry and oven dry at the surperficial silk-screen of contrast electrode, finally form Ag/AgCl laminated film contrast electrode;
G) drip through electrochemical deposition or physics be coated with, method such as absorption, at microelectrode surface finish nano material or the sensitive membrane material of setting difference in functionality.
Described preparation method, before its said step b), the Cr of sputter 10nm～50nm or Ti Seed Layer in advance are to increase the adhesiveness of conductive membrane layer and substrate.
Described preparation method in its said step b), during the microelectrode conductive membrane layer of sputter one layer thickness 250nm～500nm, if the microelectrode conductive film is selected the Pt material for use, then can omit step e).
Stripped nerve information bimodulus provided by the invention detects microelectrode array chip, and the function that multichannel nerve electric physiological detection, nerve electric stimulation, neurotransmitter detect is integrated, realizes the high flux synchronous detection, and easy to use, circuit interface is simple and reliable.The technology of having broken through in the past can only be to the limitation of two kinds of nerve information pattern separate detection, real-time difference; For the relation of studying the two phase inter-modulation provides convenient more effective instrument; Be the inherent mechanism of further investigation nerve information coding, transmission, and the pathogenesis of some neural psychotic disorders provides new visual angle.
Description of drawings
Fig. 1 detects the microelectrode array chip structural drawing for the stripped nerve information bimodulus of the present invention;
Fig. 2 is the local enlarged diagram of two kinds of different microelectrode arrays, wherein:
Microelectrode diameter among Fig. 2 a is 30 μ m;
Microelectrode diameter among Fig. 2 b comprises five kinds of 10 μ m, 20 μ m, 30 μ m, 40 μ m, 50 μ m;
Fig. 3 detects microelectrode array chip preparation method's process chart for the stripped nerve information bimodulus of the present invention;
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 removes unnecessary Ti/Pt thin layer for adopting stripping technology, stays required electrode, lead-in wire and contact;
Fig. 3 d is at the substrate surface for preparing the Pt thin layer, PECVD silicon nitride (Si
3N
4) insulation course, thickness 800nm.Through photoetching and SF
6The method of plasma etching exposes microelectrode, to electrode, contrast electrode and contact, keeps 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 100 ℃ baking oven, dried 3 hours, finally form Ag/AgCl laminated film contrast electrode;
Fig. 3 f is being used for microelectrode surface finish nano platinum black (Pt Black) particle of neuroelectricity physiological detection for adopting the method for electrochemical deposition;
To be coated with concentration be 1% Nafion (ion-exchange polymer) ethanolic solution to Fig. 3 g in order to drip on microelectrode array surface, after drying naturally, and formation ion selectivity Nafion film.
The drawing reference numeral explanation: 1 is dielectric base, and 2 is microelectrode array, and 3 is to electrode; 4 is contrast electrode, and 5 are lead-in wire, and 6 is the contact; But 7 is the microelectrode of multiplexing functions, and 8 for only being used for the microelectrode of electric physiological detection, and 9 for only being used for the microelectrode that neurotransmitter detected or applied electro photoluminescence.
Embodiment
The present invention's nerve information bimodulus that exsomatizes detects microelectrode array chip, by dielectric base, microelectrode array, electrode, contrast electrode, contact conductor and contact are constituted.Said dielectric base is the carrier of entire chip, the center on dielectric base surface, distributed that several are arranged with matrix form, by the circular microelectrode that conductive film material is processed, constitute microelectrode array.Wherein, the part microelectrode is used to detect the neuroelectricity physiological signal, and the part microelectrode is used to detect the concentration of different neurotransmitters or neurocyte is applied electro photoluminescence.The microelectrode array periphery is furnished with a larger-size Pt film to electrode, and an Ag/AgCl laminated film contrast electrode.All circular microelectrodes all extend to basal edge through the conductive film lead-in wire, and the square contact of terminal formation conveniently is connected with external circuit, and all wire surfaces all are coated with insulation course.
Dielectric base is selected the hard transparent insulating material for use, can be quartz glass, PVC, polycarbonate, and these materials have the characteristics of chemistry, stable mechanical performance, can tolerate the influence of temperature, pressure, chemical reagent in little process.Select for use transparent material to help tested stripped neurocyte being observed at microscopically.Dielectric base length of side 25mm～80mm, thickness 1mm～2mm.
The conductive film material that microelectrode array is selected for use is the 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, the microelectrode surface is decorated nanometer material or sensitive membrane material as required.
Microelectrode array comprises 9～64 microelectrodes; The microelectrode diameter 10 μ m～30 μ m that wherein are used for neural electrophysiologicalsignal signal detection; Be used for microelectrode diameter 30 μ m～50 μ m that the neurotransmitter electrochemical signals detects and applies electro photoluminescence, microelectrode spacing 50 μ m～200 μ m.
Than the big at least one magnitude of microelectrode, in electrophysiologicalsignal signal detection or apply in the process of electro photoluminescence, contrast electrode is used to provide reference potential to the size of electrode and contrast electrode; In the testing process of neurotransmitter electrochemical signals, be used to provide a current return to electrode, and, constitute the three-electrode system of Electrochemical Detection with contrast electrode.
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 the elasticity metal probe is caused in the standard electronic components and parts.When metal probe gently is pressed on the 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.
Circular microelectrode wire surface dielectric layer covered material is the organic or inorganic insulating material of good biocompatibility, can be silicon dioxide, silicon nitride, nitrogen-oxygen-silicon, SU8, polyimide, Parylene.
Stripped nerve information bimodulus of the present invention detects microelectrode array chip, and its preparation method comprises the steps:
1. through spin coating one deck photoresist on the dielectric base of surface clean, thickness is greater than three times that intend the sputter conductive membrane layer, forms all microelectrode arrays behind the photoetching development, to the pattern of electrode, contrast electrode, contact conductor and contact;
2. at the microelectrode conductive membrane layer of photoresist patterned surfaces sputter one layer thickness 250nm～500nm, the Cr of sputter 10nm～50nm or Ti Seed Layer in advance in case of necessity are to increase the adhesiveness of conductive membrane layer and substrate;
3. adopt stripping technology to remove unnecessary conductive membrane layer, stay required electrode, lead-in wire and contact;
4. through PECVD silicon dioxide, silicon nitride, nitrogen-oxygen-silicon; Or the method for spin coating SU8, polyimide, Parylene; Cover insulation course at the substrate surface for preparing conductive membrane layer; Through the method for photoetching and plasma etching, expose microelectrode, to electrode, contrast electrode and contact, keep all wire surface dielectric layer covered;
5. on said surface to electrode, the technology of adopt photoetching, sputter, peeling off, the Pt metal film layer of preparation thickness 250nm～500nm if the microelectrode conductive film in the step 2 has been selected Pt for use, then can omit this step;
6. on the surface of said contrast electrode; The technology of adopt photoetching, sputter, peeling off; The Ag metal film layer of preparation thickness 500nm～800nm; And carry out chlorination through chemistry or electrochemical method, or apply Ag/AgCl slurry and oven dry at the surperficial silk-screen of contrast electrode, finally form Ag/AgCl laminated film contrast electrode;
7. drip the method that is coated with, adsorbs through electrochemical deposition or physics, at microelectrode surface finish nano material or the sensitive membrane material of setting difference in functionality.
Below in conjunction with accompanying drawing an embodiment of the present invention is elaborated.
It is as shown in Figure 1 that stripped nerve information bimodulus provided by the invention detects the microelectrode array chip structure.Entire chip is by dielectric base 1, microelectrode array 2, constitute electrode 3, contrast electrode 4, contact conductor 5 and contact 6.
Dielectric base 1 is selected biology laboratory microslide commonly used for use, as the carrier of entire chip.The long 76.2mm of microslide, wide 25.4mm, thick 1mm.In the center of slide surface, 64 the circular microelectrodes of being processed by the Pt membraneous material that distributed constitute microelectrode array 2.
Microelectrode is arranged with 8 * 8 box formation basically, and electrode separation 100 μ m also can do the adjustment of a definite form.Fig. 2 is the local enlarged diagram of two kinds of different microelectrode arrays 2, and the microelectrode diameter among Fig. 2 (a) is 30 μ m, and the microelectrode diameter among Fig. 2 (b) comprises 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 about 10 μ m, the more little electrical activity that detects individual cells that is beneficial to more of electrode diameter, electrode diameter are during greater than 30 μ m, and the signal that electrode records is too much, will be unfavorable for the separation of individual cells electric signal.But big electrode diameter helps increasing the signal intensity that neurotransmitter detects, and can bear bigger stimulating current.Therefore, in the present embodiment, diameter only is used to detect the electricity physiological signal of neurocyte less than the microelectrode of 30 μ m, like the electrode 7 among the figure; Diameter only is used to detect the neurotransmitter electrochemical signals greater than the microelectrode of 30 μ m, or neurocyte is carried out electro photoluminescence, like the electrode 9 among the figure; Diameter is that the microelectrode of 30 μ m then can carry out the switching of three kinds of functions as required, like the electrode 8 among the figure.In order to improve signal to noise ratio (S/N ratio), can be at microelectrode surface finish nano platinum black particle.In order to improve the selectivity that detects neurotransmitter dopamine, can be at microelectrode finishing ion selectivity Nafion film.
Be furnished with a larger-size Pt film to electrode 3 in a side of microslide, and an Ag/AgCl laminated film contrast electrode 4.Two electrodes all are polygon, are symmetrically distributed, and tail end is bar shaped and extends to the microslide edge respectively, and minimum edge is about about 3mm.In electrophysiologicalsignal signal detection or apply in the process of electro photoluminescence, contrast electrode is used to provide reference potential; In the testing process of neurotransmitter electrochemical signals, be used to provide a current return to electrode 3, and, constitute the three-electrode system of Electrochemical Detection with contrast electrode.
All circular microelectrodes all extend to the microslide edges at two ends through Pt film lead-in wire 5, the square contact 6 of terminal formation, and contact length of side 1.27mm arranges spacing 2.54mm equally with array format.The size of elasticity metal probe is complementary in this size and the standard electronic components and parts.When the metal probe on being welded on circuit board gently is pressed on the contact, can realize being connected of chip and external circuit.
All wire surfaces all are coated with the silicon nitride film insulation course, can make between neurocyte and electrolyte nutrient solution and the lead-in wire to reach the isolation on the electricity.The animal nerve histotomy that exsomatizes 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 the stripped nerve information of animal detects and correlative study.
Details are as follows with reference to figure 3 for concrete preparation process of the present invention:
1. going up spin coating one deck positive photoresist AZ1500 through the microslide (Glass) of surface clean, thickness 1 μ m forms all microelectrode arrays 2 on the mask plate, (Fig. 3 a) to the pattern of electrode 3, contrast electrode 4, contact conductor and contact 6 behind the photoetching development;
2. in the Ti Seed Layer of photoresist patterned surfaces sputter one layer thickness 30nm,, follow the Pt thin layer (Fig. 3 b) of sputter 250nm to increase the adhesiveness of Pt conductive membrane layer and substrate of glass.
3. adopt stripping technology to remove unnecessary Ti/Pt thin layer, stay required electrode 2～4, lead-in wire 5 and contact 6, (Fig. 3 c);
4. at the substrate surface for preparing the Pt thin layer, PECVD silicon nitride (Si
3N
4) insulation course, thickness 800nm.Through photoetching and SF
6The method of plasma etching exposes microelectrode 7,8, to electrode 3, contrast electrode 4 and contact 6, keeps 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 oven dry 3 hours in 100 ℃ baking oven finally form Ag/AgCl laminated film contrast electrode 4 (Fig. 3 e);
7. adopt the method for electrochemical deposition, at the microelectrode that is used for the neuroelectricity physiological detection 8 surface finish nano platinum black (Pt Black) particles (Fig. 3 f).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, add in the perfusion groove as electroplate liquid.Connecting electrochemical workstation CHI660, is working electrode with microelectrode to be finished, and platinum filament is to electrode, applies set potential, adopts chronoamperometry to electroplate 5 minutes.
8. drip on microelectrode array 2 surface that to be coated with concentration be 1% Nafion (ion-exchange polymer) ethanolic solution, after drying naturally, formation ion selectivity Nafion film (Fig. 3 g).
Above embodiment is just in order to play illustrative purposes; Be not limitation of the present invention, on the basis of above-mentioned explanation, can do many improvement and change the present invention; Do to improve and change, and select for use the method such as other functional material all should be within claim protection domain of the present invention.
Claims (8)
1. a stripped nerve information bimodulus detects 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 entire chip, is microelectrode array (2) in the center on dielectric base (1) surface, and a plurality of circular microelectrodes that arrange with matrix form, that processed by conductive film material have distributed in the microelectrode array (2); Microelectrode array (2) one sides are provided with a Pt film to electrode (3), and an Ag/AgCl laminated film contrast electrode (4), and electrode (3) and contrast electrode (4) all are polygon, are symmetrically distributed, and tail end is bar shaped and extends to substrate (1) edge respectively; All circular microelectrodes all extend to substrate (1) edges at two ends through conductive film lead-in wire (5), and lead-in wire (5) is terminal to be electrically connected with square contact (6), is connected with external circuit with convenient, and leaded (5) surface coverage has insulation course.
2. stripped nerve information bimodulus according to claim 1 detects microelectrode array chip; It is characterized in that: the material selection hard transparent insulating material of said dielectric base (1); Be quartz glass, PVC or polycarbonate one of them; Substrate (1) length of side 25mm～80mm, thickness 1mm～2mm.
3. stripped nerve information bimodulus according to claim 1 detects microelectrode array chip; It is characterized in that: the conductive film material that said microelectrode array (2) is selected for use is the metal or the metallic compound of good biocompatibility, and finishing has nano material or sensitive membrane material; Microelectrode array (2) comprises 9～64 microelectrodes; The microelectrode diameter 10 μ m～30 μ m that wherein are used for neural electrophysiologicalsignal signal detection; Be used for microelectrode diameter 30 μ m～50 μ m that the neurotransmitter electrochemical signals detects and applies electro photoluminescence, microelectrode spacing 50 μ m～200 μ m;
The size of electrode (3) and contrast electrode (4) than the big at least one magnitude of microelectrode, is used to provide reference potential and keeps 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 the elasticity metal probe is caused in the standard electronic components and parts.
4. detect microelectrode array chips according to claim 1 or 3 described stripped nerve information bimodulus, it is characterized in that: the conductive film material that said microelectrode array (2) is selected for use, be gold, platinum, titanium nitride or indium tin oxide one of them; The insulating layer material of lead-in wire (5) surface coverage is the organic or inorganic insulating material of good biocompatibility.
5. stripped nerve information bimodulus according to claim 4 detects microelectrode array chip; It is characterized in that: the insulating layer material of said lead-in wire (5) surface coverage, be silicon dioxide, silicon nitride, nitrogen-oxygen-silicon, SU8, polyimide or Parylene one of them.
6. the preparation method of a stripped nerve information bimodulus detection microelectrode array chip as claimed in claim 1 is characterized in that: comprise the steps:
1) going up spin coating one deck photoresist through the dielectric base (1) of surface clean, thickness is greater than three times that intend the sputter conductive membrane layer, forms microelectrode array (2) behind the photoetching development, to the pattern of electrode (3), contrast electrode (4), lead-in wire (5) and contact (6);
2) at the microelectrode conductive membrane layer of photoresist patterned surfaces sputter～layer thickness 250nm～500nm;
3) adopt stripping technology to remove unnecessary conductive membrane layer, stay required electrode, lead-in wire (5) and contact (6);
4) through 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; Through the method for photoetching and plasma etching, expose microelectrode array (2), to electrode (3), contrast electrode (4) and contact (6), keep all wire surface dielectric layer covered;
5) on said surface to electrode (3), the technology of adopt photoetching, sputter, peeling off, the Pt metal film layer of preparation thickness 250nm～500nm;
6) on the surface of said contrast electrode (4); The technology of adopt photoetching, sputter, peeling off; The Ag metal film layer of preparation thickness 500nm～800nm; And carry out chlorination through chemistry or electrochemical method, or apply Ag/AgCl slurry and oven dry at the surperficial silk-screen of contrast electrode (4), finally form Ag/AgCl laminated film contrast electrode;
7) drip through electrochemical deposition or physics be coated with, method such as absorption, at microelectrode surface finish nano material or the sensitive membrane material of setting difference in functionality.
7. preparation method as claimed in claim 6 is characterized in that: said step 2) before, the Cr of sputter 10nm～50nm or Ti Seed Layer in advance are to increase the adhesiveness of conductive membrane layer and substrate.
8. preparation method as claimed in claim 6 is characterized in that: said step 2), during the microelectrode conductive membrane layer of sputter one layer thickness 250nm～500nm, if the microelectrode conductive film is selected the Pt material for use, then can omit step 5).
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