CN103031246A - Microelectrode array chip for multi-parameter detection of nerve cells and preparation method thereof - Google Patents
Microelectrode array chip for multi-parameter detection of nerve cells and preparation method thereofDownload PDFInfo
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- CN103031246A CN103031246ACN2011103045867ACN201110304586ACN103031246ACN 103031246 ACN103031246 ACN 103031246ACN 2011103045867 ACN2011103045867 ACN 2011103045867ACN 201110304586 ACN201110304586 ACN 201110304586ACN 103031246 ACN103031246 ACN 103031246A
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Abstract
Translated fromChinese
Description
Technical field
The present invention relates to micro-processing technology and the nano-modified field of biosensor, is a kind of microelectrode array chip and preparation method for the detection of neurocyte multiparameter.
Background technology
The method of traditional detection neurocyte electricity physiological signal is patch clamp, voltage clamp etc. substantially, usually only can obtain the data of a small amount of several passages, and positioning of electrode is difficult, complex operation, can cause in various degree damage to cell simultaneously, and cause cell dead within very short time, limited to a great extent the detection to cellular electrophysiologicalsensor and electrochemistry aspect; The extracellular signal detection method is owing to can realize can't harm, measure for a long time, development along with MEMS (micro electro mechanical system) (MEMS) processing technology, outer microelectrode array (the microelectrode of born of the same parents, MEA) provide the method for a kind of long-term non-destructive monitoring cellular electrophysiologicalsensor activity, by the high-throughput passage, with the electroactive data transmission of dozens or even hundreds of cell out, and can navigate to individual cells, realize detecting in real time the change of the membrane potential under extraneous electricity irritation and the drug effect.Some microelectrode array chips that adopt various materials and technique to be prepared from have appearred both at home and abroad, can realize the synchronous detection of colony's neurocyte bioelectrical activity, yet the microelectrode array that before uses does not have integrated electrochemical to detect the function of neurotransmitter, its reason mainly is the concentration that bare electrode can't detect neurotransmitter in the biological tissue, moreover the present reliable method that does not also have at microelectrode finishing enzyme, the method for certain neurotransmitter of detection that therefore more can't be single-minded.Detect at present neurotransmitter and adopt large electrode or the method for external microdialysis more, detect real-time poor, and sensitivity is not high.
Summary of the invention
The purpose of this invention is to provide a kind of microelectrode array chip and preparation method for the detection of neurocyte multiparameter, to overcome the deficiencies in the prior art, use MEMS fabrication techniques micro-electrode chip, and on electrode pointed decoration film sensitive material, nano material has good biocompatibility, can cultivate neurocyte at electrode.This array chip function is integrated, the electrochemical signals of the electricity physiological signal of detection neurocyte that can be simultaneously real-time and Dopamine HCL, vagusstoff, L-glutamic acid neurotransmitter, and have the function that cell is applied electricity irritation concurrently.Carry out neuronal cell cultures on the microelectrode array surface, can carry out the correlative study that the neurocyte multiparameter is detected.
For achieving the above object, the present invention has adopted following technical solution:
A kind of microelectrode array chip that detects for the neurocyte multiparameter, it comprises dielectric base 1,microelectrode array 2, toelectrode 3,reference electrode 4, lead-inwire 5,contact 6 andsensitive membrane material 7; Dielectric base 1 is the carrier of whole chip, andmicroelectrode array 2 is in the central position on dielectric base 1 surface, and a plurality of circular microelectrodes that arrange with matrix form, that made by conductive film material have distributed in themicroelectrode array 2;Microelectrode array 2 finishinges have thesensitive membrane material 7 that is respectively applied to detect electricity physiological signal and electrochemical signals;Microelectrode array 2 periphery circles are provided withelectrode 3, andreference electrode 4, andelectrode 3,reference electrode 4 all are Polygons, and are symmetrical; Circular microelectrode,electrode 3 andreference electrode 4 are all extended to substrate 1 edge by a plurality of conductive films lead-inwires 5, there are a plurality ofsquare contacts 6 inboard, substrate 1 edge, be inside and outside two-layer setting, each 5 outer end that go between is electrically connected with asquare contact 6, is connected with external circuit with convenient; Leaded 5 surface coverage have insulation layer.
Described microelectrode array chip for the detection of neurocyte multiparameter, its described dielectric base 1 is made substrate 1 length of side 25mm～80mm, thickness 1mm～2mm with the hard transparent insulating material.
The described microelectrode array chip that detects for the neurocyte multiparameter, its described hard transparent insulating material, be silica glass, polyvinyl chloride or polycarbonate one of them.
Described microelectrode array chip for the detection of neurocyte multiparameter, its describedmicroelectrode array 2, used conductive film material are metal or the metallic compound of good biocompatibility;Microelectrode array 2 comprises 9～64 microelectrodes, wherein be used for the microelectrode diameter 10 μ m of Electrophysiology signal detection～30 μ m, be used for the microelectrode diameter 30 μ m that the neurotransmitter electrochemical signals detected and applied electricity irritation～50 μ m, microelectrode spacing 50 μ m～400 μ m;
Lead-inwire 5 and the conductive film material ofcontact 6 are identical with microelectrode, and thickness is 200～300nm, guarantee that its physical strength can bear the pressure that standard electronic components and parts Elastic metal probe causes.
The described microelectrode array chip that detects for the neurocyte multiparameter, its described toelectrode 3 be the Pt film to electrode,reference electrode 4 is Ag/AgCl laminated film reference electrode; Quantity toelectrode 3,reference electrode 4 is 1～8, is used for providing reference potential and keeps current potential stable;
When the quantity toelectrode 3,reference electrode 4 was 4 or 8,1 or 2 pair ofelectrode reference electrodes 4 formed one group, and totally four groups, be positioned on the diagonal lines, symmetrical.
Described microelectrode array chip for the detection of neurocyte multiparameter, its describedsensitive membrane material 7 is can improve Dopamine HCL is detected optionally nano composite material, or the enzyme matrix material of specific detection vagusstoff or L-glutamic acid neurotransmitter.
Described microelectrode array chip for the detection of neurocyte multiparameter, its describedsensitive membrane material 7 is nanometer platinum black, iridium oxide, carbon nanotube/nafion laminated film, graphene nanometer sheet/nafion laminated film, electron mediator and enzyme matrix material one of them, or their organic assembling.
The described microelectrode array chip that detects for the neurocyte multiparameter, the enzyme in its described enzyme matrix material is L-GLOD, acetylcholinesterase, E.C. 1.1.99.1 one of them.
The described microelectrode array chip that detects for the neurocyte multiparameter, the conductive film material that its describedmicroelectrode array 2 is selected, be gold, platinum, titanium nitride or indium tin oxide one of them.
Described microelectrode array chip for the detection of neurocyte multiparameter, the insulating layer material of its described lead-inwire 5 surface coverage is the organic or inorganic insulating material.
The described microelectrode array chip that detects for the neurocyte multiparameter, its described organic or inorganic insulating material, be silicon-dioxide, silicon nitride, nitrogen-oxygen-silicon, SU8, polyimide or polyphenylene ethyl one of them.
A kind of preparation method of the described microelectrode array chip that detects for the neurocyte multiparameter, it comprises the steps:
A) through spin coating one deck photoresist material on the dielectric base 1 of surface cleaning, thickness is greater than three times that intend the sputter conductive membrane layer, formsmicroelectrode array 2 behind the photoetching development, to the pattern ofelectrode 3,reference electrode 4, lead-inwire 5 andcontact 6;
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, stay required electrode, lead-inwire 5 andcontact 6;
D) by plasma enhanced chemical vapor deposition (PECVD) silicon-dioxide, silicon nitride, nitrogen-oxygen-silicon, or the method for spin coating SU8, polyimide, polyphenylene ethyl, the substrate 1 surface coverage insulation layer that is preparing conductive membrane layer, method by photoetching and plasma etching, exposemicroelectrode array 2, toelectrode 3,reference electrode 4 andcontact 6, keep the insulation layer that all wire surfaces cover;
E) on the surface toelectrode 3, the technique of adopt photoetching, sputter, peeling off, the Pt metal film layer of preparation thickness 250nm～500nm;
F) on the surface ofreference electrode 4, the technique of adopt photoetching, sputter, peeling off, the Ag metal film layer of preparation thickness 500nm～800nm, and carry out chlorination by chemistry or electrochemical method, or apply Ag/AgCl slurry and oven dry at the surperficial silk-screen ofreference electrode 4, finally form Ag/AgCl laminated film reference electrode.
Described preparation method, its described step b) before, the in advance Cr of sputter 10nm～50nm or Ti Seed Layer are to increase the adhesivity of conductive membrane layer and substrate 1.
Described preparation method, its described step b) in, during the microelectrode conductive membrane layer of sputter a layer thickness 250nm～500nm, if the microelectrode conductive film is selected the Pt material, then can omit step e).
Described preparation method, the method that it also comprisesmicroelectrode array 2 surperficial pointed decoration carbon nanomaterials/nafion/ nanometer platinum black laminated film comprises the steps:
A) nafion is joined in the dehydrated alcohol, the quality percent by volume that makes nafion is 0.05%～5%, carbon nanomaterial is joined in nafion and the dehydrated alcohol mixture, the quality percent by volume that makes carbon nanomaterial is 0.05%～10%, then ultrasonic 30～60min forms the carbon nanomaterial of black homogeneous/nafion mixed solution, and wherein carbon nanomaterial can be carbon nanotube or graphene nanometer sheet;
B) microelectrode is used respectively acetone, ethanol and washed with de-ionized water, then plasma etching is two minutes;
C) will contain that the alcohol mixed solution of carbon nanomaterial and nafion is manual to drip on electrod-array 2 seasoning;
D) photoresist material is spin-coated on chip surface, 100 ℃ of bakings of hot plate 5min, photoetching development protects the carbon nanomaterial of electrode part and the mixture film of nafion, and other parts develop to fall;
E) plasma etching 1min～3min removes the carbon nanomaterial outside the electrode and nafion mixture, then photoresist material is removed with acetone;
F) electrode is placed the Platinic chloride (H of 20mmol/L2PtCl6) and hydrochloric acid (HCl) mixed solution of 2mol/L in, the electroplating nano platinum black.
The microelectrode array chip that neurocyte multiparameter of the present invention detects, the function that multichannel nerve electric physiological detection, nerve electric stimulation, neurotransmitter detect is integrated, realize the high-throughput synchronous detection, 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 the relation of studying the two phase inter-modulation provides more convenient effective instrument, be the inherent mechanism of further investigation nerve information coding, transmission, and the pathogeny of some neuropsychiatric diseases provides new visual angle.
Description of drawings
Fig. 1 is that the present invention is used for the microelectrode array chip structure iron that the neurocyte multiparameter detects;
Fig. 2 is the local enlarged diagram that microelectrode array distributes;
Fig. 3 a-Fig. 3 e is the process drawing that the present invention is used for the microelectrode array chip preparation method of neurocyte multiparameter detection; Wherein:
Fig. 3 a is the pattern of contact conductor and contact;
Fig. 3 b is for following the Pt thin film layer of sputter 250nm;
Fig. 3 c stays required electrode, lead-in wire and contact for adopting stripping technology to remove unnecessary Ti/Pt thin film layer;
Fig. 3 d is at the substrate surface for preparing the Pt thin film layer, PECVD silicon nitride (Si3N4) insulation layer, thickness 800nm.By photoetching and SF6The method of plasma etching exposes microelectrode, to electrode, reference electrode and contact, keeps the silicon nitride dielectric layer that all wire surfaces cover;
Fig. 3 e is the surface at reference 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 reference electrode;
Fig. 4 a-Fig. 4 e is the procedure chart of the present invention's microelectrode array chip pointed decoration carbon nanomaterial of being used for the neurocyte multiparameter and detecting/nafion/ nanometer platinum black laminated film; Wherein:
Fig. 4 a is carbon coating nano material/nafion composite layer;
Fig. 4 b is that spin coating AZ4620 photoresist material is as protective layer;
Fig. 4 c stays the shielded matrix material of electrode surface and protective layer for etching away unnecessary matrix material;
Fig. 4 d is after removing protective layer, the matrix material that stays;
Fig. 4 e continues the decorated nanometer platinum black at matrix material;
Fig. 5 is the schema of pointed decoration carbon nanomaterial/nafion/ nanometer platinum black laminated film.
The drawing reference numeral explanation:
1 is thatdielectric base 2 is microelectrode array
3 is thatelectrode 4 is reference electrode
5 is that lead-inwire 6 is the contact
But 7 is the microelectrode of multiplexing functions, can be used for electric physiological detection and also can be used for the neurotransmitter detection or apply electricity irritation.
Embodiment
The present invention is used for the microelectrode array chip that the neurocyte multiparameter detects, by dielectric base, microelectrode array, electrode, reference electrode, contact conductor and contact are consisted of.Described dielectric base is the carrier of whole chip, the central position on the dielectric base surface, distributed that several are arranged with matrix form, by the circular microelectrode that conductive film material is made, consist of microelectrode array.Wherein, the part microelectrode is for detection of the Electrophysiology signal, and the part microelectrode applies electricity irritation for detection of the concentration of different neurotransmitters or to neurocyte.The microelectrode array periphery is furnished with four larger-size Pt films to electrode, and four Ag/AgCl laminated film reference electrodes.All circular microelectrodes all extend to basal edge by 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 layer.
Dielectric base is selected the hard transparent insulating material, can be silica glass, polyvinyl chloride, polycarbonate, and these materials have the characteristics of chemistry, stable mechanical performance, can tolerate the impact of temperature, pressure, chemical reagent in little course of processing.Select transparent material to be conducive at microscopically 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 and to improve the selectivity that different neurotransmitters are detected, the microelectrode surface is pointed decoration nano material or sensitive membrane material as required.
Microelectrode array comprises 9～64 microelectrodes, wherein be used for the microelectrode diameter 10 μ m of Electrophysiology signal detection～30 μ m, be used for the microelectrode diameter 30 μ m that the neurotransmitter electrochemical signals detected and applied electricity irritation～50 μ m, microelectrode spacing 50 μ m～200 μ m.
Than the large at least order of magnitude of microelectrode, in electrophysiologicalsignal signal detection or apply in the process of electricity irritation, reference electrode is used for providing reference potential to the size of electrode and reference electrode; In the testing process of neurotransmitter electrochemical signals, electrode is used for providing a current circuit, and with reference electrode, consists of 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 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.
The insulating layer material that circular microelectrode wire surface covers is the organic or inorganic insulating material of good biocompatibility, can be silicon-dioxide, silicon nitride, nitrogen-oxygen-silicon, SU8, polyimide, polyphenylene ethyl.
Microelectrode array chip for the detection of neurocyte multiparameter of the present invention, its preparation method comprises the steps:
1. through spin coating one deck photoresist material on the dielectric base of surface cleaning, 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, reference electrode, contact conductor and contact;
2. at the microelectrode conductive membrane layer of photoetching agent pattern surface sputtering a layer thickness 250nm～500nm, the in case of necessity in advance Cr of sputter 10nm～50nm or Ti Seed Layer are to increase the adhesivity 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. by PECVD silicon-dioxide, silicon nitride, nitrogen-oxygen-silicon, or the method for spin coating SU8, polyimide, polyphenylene ethyl, cover insulation layer at the substrate surface for preparing conductive membrane layer, method by photoetching and plasma etching, expose microelectrode, to electrode, reference electrode and contact, keep the insulation layer that all wire surfaces cover;
5. on described surface to electrode, the technique of adopt photoetching, sputter, peeling off, the Pt metal film layer of preparation thickness 250nm～500nm if the microelectrode conductive film in thestep 2 has been selected Pt, then can omit this step;
6. on the surface of described reference electrode, the technique of adopt photoetching, sputter, peeling off, the Ag metal film layer of preparation thickness 500nm～800nm, and carry out chlorination by chemistry or electrochemical method, or apply Ag/AgCl slurry and oven dry at the surperficial silk-screen of reference electrode, finally form Ag/AgCl laminated film reference electrode.
Microelectrode array chip for the detection of neurocyte multiparameter of the present invention, the method for pointed decoration carbon nanomaterial/nafion/ nanometer platinum black laminated film comprises the steps:
1 joins nafion in the dehydrated alcohol, the quality percent by volume that makes nafion is 0.05%～5%, carbon nanomaterial is joined in nafion and the dehydrated alcohol mixture, the quality percent by volume that makes carbon nanomaterial is 0.05%～10%, then ultrasonic 30～60min forms the nano material of black homogeneous/nafion mixed solution, and wherein carbon nanomaterial can be carbon nanotube or graphene nanometer sheet;
2 use respectively acetone, ethanol and washed with de-ionized water with microelectrode, and then plasma etching is two minutes;
3 alcohol mixed solutions that will contain carbon nanomaterial and nafion drip on electrod-array 2 seasoning by hand;
4 are spin-coated on chip surface with photoresist material, 100 ℃ of bakings of hot plate 5min, and photoetching development protects the nano material of electrode part and the mixture film of nafion, and other parts develop to fall;
5 plasma etching 1min～3min remove the carbon nanomaterial outside the electrode and nafion mixture, then photoresist material are removed with acetone;
6 place the Platinic chloride (H of 20mmol/L with electrode2PtCl6) and hydrochloric acid (HCl) mixed solution of 2mol/L in, the electroplating nano platinum black.
Below in conjunction with accompanying drawing the embodiment that the present invention is used for the microelectrode array chip of neurocyte multiparameter detection is elaborated.
The microelectrode array chip structure that detects for the neurocyte multiparameter provided by the invention as shown in Figure 1.Whole chip is by dielectric base 1,microelectrode array 2, toelectrode 3,reference electrode 4,contact conductor 5, andcontact 6 anddecorative layer 7 consist of.
Dielectric base 1 is selected biology laboratory slide glass commonly used, as the carrier of whole chip.The long 76.2mm of slide glass, wide 25.4mm, thick 1mm.In the central position of slide surface, 64 the circular microelectrodes of being made by the Pt thin-film material that distributed consist ofmicroelectrode array 2.
Microelectrode is arranged with 8 * 8 box formation substantially, and interelectrode distance 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 3 among Fig. 2 or 4 diameters are 30 μ m, and the microelectrode diameter in the microelectrode array 2 among Fig. 2 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 more is beneficial to of electrode diameter, electrode diameter are during greater than 30 μ m, and the signal that electrode is recorded to is too much, will be unfavorable for the separation of individual cells electrical signal.But large electrode diameter is conducive to increase the strength of signal that neurotransmitter detects, and can bear larger stimulating current.Therefore, in the present embodiment, diameter less than the microelectrode of 30 μ m only for detection of the electricity physiological signal of neurocyte; Diameter only for detection of the neurotransmitter electrochemical signals, or carries out electricity irritation to neurocyte greater than the microelectrode of 30 μ m; Diameter is that the microelectrode of 30 μ m then can carry out the switching of three kinds of functions as required.
Be furnished with four larger-size Pt films toelectrode 3 in a side of slide glass, and four Ag/AgCl laminated film reference electrodes 4.Two electrodes all are Polygons, and are symmetrical, and tail end is bar shaped and extends to respectively the slide glass edge, and minimum edge is about about 3mm.In electrophysiologicalsignal signal detection or apply in the process of electricity irritation, reference electrode is used for providing reference potential; In the testing process of neurotransmitter electrochemical signals,electrode 3 is used for providing a current circuit, and with reference electrode, consists of the three-electrode system of Electrochemical Detection.
All circular microelectrodes all extend to the slide glass edges at two ends by Pt film lead-inwire 5, thesquare contact 6 of terminal formation, and contact length of side 1.27mm arranges spacing 2.54mm equally with array format.The size of this size and standard electronic components and parts Elastic metal probe is complementary.When the metal probe on being welded on circuit card 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 layer, can make the isolation that reaches between neurocyte and ionogen nutrient solution and the lead-in wire on the electricity.Carry out neuronal cell cultures on the chip, in conjunction with supporting detection system, can carry out detection and the correlative study of neurocyte many kinds of parameters.
The present invention is used for the concrete preparation process of the microelectrode array chip that the neurocyte multiparameter detects, and details are as follows with reference to figure 3:
1. at the upper spin coating one deck positive photoresist AZ1500 of the slide glass (Glass) of process surface cleaning, thickness 1 μ m forms allmicroelectrode arrays 2 on the mask plate, (Fig. 3 a) to the pattern ofelectrode 3,reference electrode 4, contact conductor andcontact 6 behind the photoetching development;
2. in the Ti Seed Layer of photoetching agent pattern surface sputtering a layer thickness 30nm, to increase the adhesivity of Pt conductive membrane layer and substrate of glass, follow the Pt thin film layer (Fig. 3 b) of sputter 250nm;
3. adopt stripping technology to remove unnecessary Ti/Pt thin film layer, stay requiredelectrode 2～4, lead-inwire 5 andcontact 6, (Fig. 3 c);
4. at the substrate surface for preparing the Pt thin film layer, PECVD silicon nitride (Si3N4) insulation layer, thickness 800nm.By photoetching and SF6The method of plasma etching exposesmicroelectrode 7,8, toelectrode 3,reference electrode 4 andcontact 6, keeps the silicon nitride dielectric layer (Fig. 3 d) that all wire surfaces cover;
5. on the surface ofreference 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 reference electrode 4 (Fig. 3 e).
The present invention is used for the pointed decoration procedure of the microelectrode array chip that the neurocyte multiparameter detects, and details are as follows with reference to figure 4:
1 will contain manual the dropping on electrod-array of alcohol mixed solution of carbon nanomaterial and nafion, and (Fig. 4 a) in seasoning;
2 are spin-coated on chip surface with photoresist material, 100 ℃ of bakings of hot plate 5min, and photoetching development protects the carbon nanomaterial of electrode part and the mixture film of nafion, other parts develop to fall (Fig. 4 b);
3 plasma etching 1min～3min remove (Fig. 4 c) with the carbon nanomaterial outside the electrode and nafion mixture;
Then 4 remove (Fig. 4 d) with photoresist material with acetone;
5 place the Platinic chloride (H of 20mmol/L with electrode2PtCl6) and hydrochloric acid (HCl) mixed solution of 2mol/L in, the electroplating nano platinum black.Specifically adopt the method for electrochemical deposition, at microelectrode 8 surface finish nano platinum black (Pt Black) particles (Fig. 4 e) that are used for the Electrophysiology detection.Detailed process is, with the Platinic chloride (H of deionized water preparation 20mmol/L2PtCl6) and hydrochloric acid (HCl) mixed solution of 2mol/L, add in the perfusion groove as electroplate liquid.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 (Fig. 4 e).
Above embodiment is just in order to play the purpose 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 method such as other functional materials all should be within claim protection domain of the present invention.
Claims (15)
1. one kind is used for the microelectrode array chip that the neurocyte multiparameter detects, and it is characterized in that: comprise dielectric base (1), microelectrode array (2), to electrode (3), reference electrode (4), lead-in wire (5), contact (6) and sensitive membrane material (7); Dielectric base (1) is the carrier of whole chip, microelectrode array (2) is in the central position on dielectric base (1) surface, and a plurality of circular microelectrodes that arrange with matrix form, that made by conductive film material have distributed in the microelectrode array (2); Microelectrode array (2) finishing has the sensitive membrane material (7) that is respectively applied to detect electricity physiological signal and electrochemical signals; Microelectrode array (2) periphery circle is provided with electrode (3), and reference electrode (4), and electrode (3), reference electrode (4) all are Polygons, and is symmetrical; Circular microelectrode, to electrode (3) and reference electrode (4) all by a plurality of conductive films go between (5) extend to substrate (1) edge, there are a plurality of square contacts (6) substrate (1) inboard, edge, be inside and outside two-layer setting, each lead-in wire (5) outer end is electrically connected with a square contact (6), is connected with external circuit with convenient; Leaded (5) surface coverage has insulation layer.
2. the microelectrode array chip that detects for the neurocyte multiparameter according to claim 1 is characterized in that: described dielectric base (1), make substrate (1) length of side 25mm～80mm, thickness 1mm～2mm with the hard transparent insulating material.
3. the microelectrode array chip that detects for the neurocyte multiparameter according to claim 2 is characterized in that: described hard transparent insulating material, be silica glass, polyvinyl chloride or polycarbonate one of them.
4. the microelectrode array chip that detects for the neurocyte multiparameter according to claim 1, it is characterized in that: described microelectrode array (2), used conductive film material are metal or the metallic compound of good biocompatibility; Microelectrode array (2) comprises 9～64 microelectrodes, wherein be used for the microelectrode diameter 10 μ m of Electrophysiology signal detection～30 μ m, be used for the microelectrode diameter 30 μ m that the neurotransmitter electrochemical signals detected and applied electricity irritation～50 μ m, microelectrode spacing 50 μ m～400 μ m;
The conductive film material of lead-in wire (5) and contact (6) is identical with microelectrode, and thickness is 200～300nm, guarantees that its physical strength can bear the pressure that standard electronic components and parts Elastic metal probe causes.
5. the microelectrode array chip that detects for the neurocyte multiparameter according to claim 1 is characterized in that: described to electrode (3) for the Pt film to electrode, reference electrode (4) is Ag/AgCl laminated film reference electrode; Quantity to electrode (3), reference electrode (4) is 1～8, is used for providing reference potential and keeps current potential stable;
When the quantity to electrode (3), reference electrode (4) was 4 or 8,1 or 2 pair of electrode (3), 1 or 2 reference electrodes (4) formed one group, and totally four groups, be positioned on the diagonal lines, symmetrical.
6. the microelectrode array chip that detects for the neurocyte multiparameter according to claim 1, it is characterized in that: described sensitive membrane material (7) is can improve Dopamine HCL is detected optionally nano composite material, or the enzyme matrix material of specific detection vagusstoff or L-glutamic acid neurotransmitter.
7. the microelectrode array chip that detects for the neurocyte multiparameter according to claim 6, it is characterized in that: described sensitive membrane material (7) is the nanometer platinum black, iridium oxide, carbon nanotube/nafion laminated film, graphene nanometer sheet/nafion laminated film, electron mediator and enzyme matrix material one of them, or their organic assembling.
8. according to claim 6 or the 7 described microelectrode array chips that detect for the neurocyte multiparameter, it is characterized in that: the enzyme in the described enzyme matrix material is L-GLOD, acetylcholinesterase, E.C. 1.1.99.1 one of them.
9. according to claim 1 or the 4 described microelectrode array chips that detect for the neurocyte multiparameter, 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.
10. the microelectrode array chip that detects for the neurocyte multiparameter according to claim 1, it is characterized in that: the insulating layer material of described lead-in wire (5) surface coverage is the organic or inorganic insulating material.
11. the microelectrode array chip for the detection of neurocyte multiparameter according to claim 10, it is characterized in that: described organic or inorganic insulating material, be silicon-dioxide, silicon nitride, nitrogen-oxygen-silicon, SU8, polyimide or polyphenylene ethyl one of them.
12. the preparation method of a microelectrode array chip that detects for the neurocyte multiparameter as claimed in claim 1 is characterized in that: comprise the steps:
1) at the upper spin coating one deck photoresist material of the dielectric base (1) of process surface cleaning, 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), reference electrode (4), lead-in wire (5) and contact (6);
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, stay required electrode, lead-in wire (5) and contact (6);
4) by plasma enhanced chemical vapor deposition silicon-dioxide, silicon nitride, nitrogen-oxygen-silicon, or the method for spin coating SU8, polyimide, polyphenylene ethyl, preparing the substrate of conductive membrane layer (1) surface coverage insulation layer, method by photoetching and plasma etching, expose microelectrode array (2), to electrode (3), reference electrode (4) and contact (6), keep the insulation layer that all wire surfaces cover;
5) on the surface to electrode (3), the technique of adopt photoetching, sputter, peeling off, the Pt metal film layer of preparation thickness 250nm～500nm;
6) on the surface of reference electrode (4), the technique of adopt photoetching, sputter, peeling off, the Ag metal film layer of preparation thickness 500nm～800nm, and carry out chlorination by chemistry or electrochemical method, or apply Ag/AgCl slurry and oven dry at the surperficial silk-screen of reference electrode (4), finally form Ag/AgCl laminated film reference electrode.
13. preparation method according to claim 12 is characterized in that: described step 2) before, the in advance Cr of sputter 10nm～50nm or Ti Seed Layer are to increase the adhesivity of conductive membrane layer and substrate (1).
14. preparation method according to claim 12 is characterized in that: described step 2), during the microelectrode conductive membrane layer of sputter a layer thickness 250nm～500nm, if the microelectrode conductive film is selected the Pt material, then can omit step 5).
15. preparation method according to claim 12 is characterized in that: also comprise the method for the surperficial pointed decoration carbon nanomaterial of microelectrode array (2)/nafion/ nanometer platinum black laminated film, comprise the steps:
A) nafion is joined in the dehydrated alcohol, the quality percent by volume that makes nafion is 0.05%～5%, carbon nanomaterial is joined in nafion and the dehydrated alcohol mixture, the quality percent by volume that makes carbon nanomaterial is 0.05%～10%, then ultrasonic 30～60min forms the carbon nanomaterial of black homogeneous/nafion mixed solution, and wherein carbon nanomaterial can be carbon nanotube or graphene nanometer sheet;
B) microelectrode is used respectively acetone, ethanol and washed with de-ionized water, then plasma etching is two minutes;
C) will contain that the alcohol mixed solution of carbon nanomaterial and nafion is manual to drip on electrod-array (2) seasoning;
D) photoresist material is spin-coated on chip surface, 100 ℃ of bakings of hot plate 5min, photoetching development protects the carbon nanomaterial of electrode part and the mixture film of nafion, and other parts develop to fall;
E) plasma etching 1min～3min removes the carbon nanomaterial outside the electrode and nafion mixture, then photoresist material is removed with acetone;
F) electrode is placed the Platinic chloride of 20mmol/L and the hydrochloric acid mixed solution of 2mol/L, electroplating nano platinum black.
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