CN108918635B - Integrated biosensor chip - Google Patents
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- CN108918635B CN108918635B CN201810428593.XA CN201810428593A CN108918635B CN 108918635 B CN108918635 B CN 108918635B CN 201810428593 A CN201810428593 A CN 201810428593A CN 108918635 B CN108918635 B CN 108918635B
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- G—PHYSICS
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- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N27/00—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means
- G01N27/26—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means by investigating electrochemical variables; by using electrolysis or electrophoresis
- G01N27/416—Systems
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N27/00—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means
- G01N27/26—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means by investigating electrochemical variables; by using electrolysis or electrophoresis
- G01N27/28—Electrolytic cell components
- G01N27/30—Electrodes, e.g. test electrodes; Half-cells
- G01N27/327—Biochemical electrodes, e.g. electrical or mechanical details for in vitro measurements
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Abstract
An integrated biosensor chip comprising: a substrate comprising an array of vias thereon; a plurality of electrode pins inserted into the through holes of the substrate; the electrode plating layers are plated on the upper end surfaces of the electrode pins to form electrode units; the enzyme coating layers are used for promoting the generation of the electrochemical reaction related to the object to be detected and generating an electric signal; the culture isolation bracket is attached to the substrate, and separated chambers are formed under the condition that the electrode plating layer is not covered, wherein each separated chamber contains a sensor unit consisting of more than two electrode units; the bionic tissue unit is used for providing bionic tissues and culture solution environments. The chip of the invention can simultaneously realize the real-time measurement of various biological signals under different parameter conditions, can be applied to high-flux drug screening, pathological research and therapy research, and has the advantages of short time consumption, quick response, high flux and the like.
Description
Technical Field
The present invention relates to an integrated biosensor chip.
Background
In the process of drug development, pathological research and therapeutic research, a large amount of metabolites need to be measured, and complicated external stimuli need to be given; compared with the traditional methods such as immunofluorescence staining, the real-time electrochemical measurement and detection method has the advantages of accurate measurement, rapidness and convenience.
The existing biosensor has a sheet structure containing pins, is large in area and few in unit, and is difficult to realize simultaneous measurement of multiple parameters, so that the requirement of high flux cannot be met, and the efficiency of drug development, pathological research and therapy research is limited.
Disclosure of Invention
The invention mainly aims to overcome the defects of the prior art and provide an integrated biosensor chip, which can simultaneously realize real-time measurement of various biological signals under different parameter conditions on a small-area integrated chip and has the advantages of short time consumption, quick response, high flux, low cost and the like.
In order to achieve the purpose, the invention adopts the following technical scheme:
an integrated biosensor chip comprising:
a substrate comprising an array of through holes thereon, preferably a PCB electrode substrate;
the plurality of electrode pins are inserted into the through holes of the substrate and fixed in the substrate;
the electrode plating layers are plated on the upper end surfaces of the electrode pins to form electrode units;
the enzyme coating layers are coated on the upper surfaces of the electrode coating layers and are different according to different substances to be detected, and the enzyme coating layers are used for promoting the generation of the electrochemical reaction related to the substances to be detected and generating electric signals, preferably the electric signals comprise electric signals responding to the concentration of the substances to be detected;
a culture isolation support attached to the substrate, wherein separate chambers are formed without covering the electrode plating layer, and each separate chamber contains a sensor unit composed of more than two electrode units;
the bionic tissue units with the same number as the sensor units are positioned in the separation chamber and used for providing bionic tissue and culture solution environments and metabolizing to generate products to be detected, preferably, the physical and chemical stimulation is added to realize the environmental control of the bionic tissue units and simulate drug reaction, therapy reaction and pathological reaction.
Further:
the through-hole is the countersunk head through-hole, the electrode stitch with countersunk head through-hole looks adaptation, the lower part of electrode stitch passes the pore end of countersunk head through-hole, the upper portion of electrode stitch is fixed the coarse hole end of countersunk head through-hole, preferably, the size in hole is that coarse end length 0.05 ~ 0.2mm, diameter phi 0.6 ~ 1mm, fine end length 1 ~ 2mm, diameter phi 0.1 ~ 0.5 mm.
The sensor unit comprises three electrode units, namely a working electrode, a counter electrode and a reference electrode, or two electrode units, namely a working electrode and a counter electrode.
The electrode plating layer on the working electrode is made of Au, and the electrode plating layers on the reference electrode and the counter electrode are made of Ag and AgCl.
The countersunk head through hole array is arranged at equal intervals in the transverse and longitudinal directions, and preferably, the hole pitch is 0.6-1 mm.
The electrode pins and the through holes are in clearance fit, adhesion is achieved through brazing/hot melt adhesives, and preferably, the length of the thin ends of the pins exceeds the length of the thin end holes by 1-2 mm.
The electrode plating layer is formed by evaporation, and preferably, the electrode pins are made of gold-plated copper.
The culture isolation scaffold is printed on the substrate by an additive manufacturing method.
The bionic tissue unit comprises a biological scaffold containing cells, cell microspheres, a living body slice and/or cell gel, and the working electrode can realize the measurement of oxygen, glucose, lactic acid, albumin, pH and urea.
The electrochemical reaction enzyme coating layer is coated on the electrode coating layer in a droplet jet printing/hydrogel film application mode, and after the electrochemical reaction enzyme coating layer on the electrode coating layer is worn out, a new electrochemical reaction enzyme coating layer can be coated again after cleaning, so that the electrode unit can be reused.
Compared with the prior art, the invention has the following advantages:
the integrated biosensor chip can integrate a large number of same/different biosensor units on a small area, realizes real-time and simultaneous measurement of the metabolic conditions of the same/different substances related to bionic tissue metabolism under diversified physicochemical stimulation, can be applied to high-throughput and mass drug screening, pathological research and therapy research, has the advantages of high throughput, short time consumption and quick response compared with the traditional biosensor, and can meet the high-throughput requirement in the drug development, pathological research and therapy research processes.
In addition, the chip unit can realize the repeated use of the noble metal by promoting the use, the dissolution and the recoating of the electrochemical reaction enzyme coating layer, thereby reducing the use cost.
Drawings
FIG. 1 is an exploded view of an integrated biosensor chip according to an embodiment of the present invention;
FIG. 2 is a diagram illustrating an assembled state of an integrated biosensor chip according to an embodiment of the present invention.
Fig. 3 is a schematic diagram of an application system of an embodiment of the present invention.
Detailed Description
The embodiments of the present invention will be described in detail below. It should be emphasized that the following description is merely exemplary in nature and is not intended to limit the scope of the invention or its application.
Referring to fig. 1 and 2, in one embodiment, an integrated biosensor chip includes a substrate 6, a plurality of electrode pins 5, a plurality of electrode plating layers 4, a plurality of electrochemical reaction promoting enzyme coating layers 3, a culture isolation support 2, and bionic tissue units 1 in the same number as the sensor units 8, wherein the substrate 6 includes a through hole array, preferably a PCB electrode substrate 6; a plurality of electrode pins 5 are inserted into the through holes of the substrate 6 and fixed in the substrate 6; a plurality of electrode plating layers 4 are plated on the upper end surfaces of the electrode pins 5 to form electrode units; a plurality of enzyme coating layers 3 for promoting electrochemical reaction are coated on the upper surface of the electrode coating layer 4, the enzyme coating layers 3 are different according to different substances to be detected, and are used for promoting the electrochemical reaction related to the substances to be detected to generate electric signals, preferably the electric signals comprise electric signals responding to the concentration of the substances to be detected; the culture isolation bracket 2 is attached to the substrate 6, and separate chambers are formed under the condition that the electrode plating layer 4 is not covered, and each separate chamber contains a sensor unit 8 consisting of more than two electrode units; the bionic tissue unit 1 is positioned in the separation chamber and used for providing bionic tissue and culture solution environment, and can metabolize to generate a product to be detected, preferably, the bionic tissue unit 1 is added with physical and chemical stimulation to realize environmental control of the bionic tissue unit 1 and simulate drug reaction, therapy reaction and pathological reaction.
In the preferred embodiment, the through-hole is the countersunk head through-hole, electrode stitch 5 with countersunk head through-hole looks adaptation, the lower part of electrode stitch 5 passes the pore end of countersunk head through-hole, the upper portion of electrode stitch 5 is fixed the coarse pore end of countersunk head through-hole, preferably, the size of hole is that the length of butt length is 0.05 ~ 0.2mm, diameter phi 0.6 ~ 1mm, the length of thin end is 1 ~ 2mm, diameter phi 0.1 ~ 0.5 mm.
In a preferred embodiment, the sensor unit 8 comprises three electrode units, one working electrode, one counter electrode and one reference electrode, or two electrode units, one working electrode and one counter electrode, respectively.
In a preferred embodiment, the material of the electrode plating layer 4 on the working electrode is Au, and the material of the electrode plating layer 4 on the reference electrode and the counter electrode is Ag and AgCl.
In a preferred embodiment, the countersunk head through hole arrays are arranged at equal intervals in the transverse and longitudinal directions. In a preferred embodiment, the pitch is 0.6 to 1mm, preferably 0.8 mm.
In a preferred embodiment, the electrode pins 5 and the through holes are matched in a clearance fit mode, and bonding is achieved through soldering/hot melt adhesive.
In a preferred embodiment, the length of the pin thin end exceeds the length of the thin end hole by 1-2 mm.
In a preferred embodiment, the electrode plating layer 4 is formed by vapor deposition.
In a preferred embodiment, the material of the electrode pins 5 may be gold-plated copper.
In a preferred embodiment, the culture isolation support 2 is printed on the substrate 6 by means of additive manufacturing.
According to various embodiments, the biomimetic tissue unit 1 may comprise a cell-containing biological scaffold 2, cell microspheres, biopsy and/or cell gel, and the working electrode may enable measurement of oxygen, glucose, lactate, albumin, pH, urea.
In a preferred embodiment, the electrochemical reaction enzyme coating layer 3 can be coated on the electrode coating layer 4 by droplet jet printing/hydrogel film application, and after the electrochemical reaction enzyme coating layer 3 on the electrode coating layer 4 is worn, a new electrochemical reaction enzyme coating layer 3 can be coated again after cleaning, so that the electrode unit can be reused.
FIG. 1 is an exploded schematic view of one embodiment. The embodiment comprises a PCB substrate 6, a plurality of electrode pins 5, a plurality of electrode coating layers 4, a plurality of electrochemical reaction promoting enzyme coating layers 3, a culture isolation bracket 2 and a plurality of bionic tissue units 1. The assembling process comprises the following steps: inserting the electrode pins 5 into the array holes on the PCB substrate 6, aligning the thin end faces and fixing by hot melt adhesive/soldering, then plating an electrode coating 4 on the upper end face of an electrode pin 5 by an evaporation method, printing a culture isolation support 2 on a PCB substrate by using materials with good biocompatibility, including PLGA, SE1700, PDMS, PMMA and the like, by an additive manufacturing method, forming a separation chamber by the culture isolation support 2 under the condition of not covering the electrode coating, then attaching an electrochemical reaction promotion enzyme coating layer 3 on the electrode coating 4 of the working electrode by a micro-droplet spraying/hydrogel film attaching method, putting a biological support, cell microspheres, living body slices, cell gels and other bionic tissue units 1 into each separation chamber, and pouring culture solution to submerge the bionic tissue units, thereby completing the assembly of the integrated biosensor.
FIG. 2 is a simplified assembly diagram of an exemplary embodiment. After the assembly is completed, the number of the sensor units 8 is the same as that of the chambers, and the chambers comprise 2/3 electrode units 7, a working electrode, a counter electrode and one/zero reference electrode; each electrode unit 7 consists of an electrode pin 5 and an electrode coating 4, and the working electrode is additionally provided with an electrochemical reaction promoting enzyme coating 3. After assembly, a stimulus such as drug/virus/cancer cells/growth factors is added to the chamber and incubated in an incubator.
FIG. 3 is a diagram of an exemplary embodiment of an application system. After the integrated biosensor chip is cultured in the incubator for a period of time, when the concentration of the object to be measured needs to be observed, the sensor chip is taken out from the incubator and is installed on the bread board 9 connected with the electrochemical workstation 10, and then the reading of data can be realized. After the observation is finished, the bread plate is taken down and put back into the incubator. The process of observation and culture was repeated. And pouring the bionic tissue 1 and the culture solution in the separation chamber until the whole measurement process is finished, performing ultrasonic cleaning by using an organic solvent, removing the electrochemical reaction promoting enzyme coating layer, and then sticking a new enzyme coating layer again to be reused.
The foregoing is a more detailed description of the invention in connection with specific/preferred embodiments and is not intended to limit the practice of the invention to those descriptions. It will be apparent to those skilled in the art that various substitutions and modifications can be made to the described embodiments without departing from the spirit of the invention, and these substitutions and modifications should be considered to fall within the scope of the invention.
Claims (15)
1. An integrated biosensor chip, comprising:
a substrate comprising an array of vias thereon;
the plurality of electrode pins are inserted into the through holes of the substrate and fixed in the substrate;
the electrode plating layers are plated on the upper end surfaces of the electrode pins to form electrode units;
the enzyme coating layers are coated on the upper surfaces of the electrode coating layers and are different according to different substances to be detected, and the enzyme coating layers are used for promoting the generation of electrochemical reactions related to substances to be detected and generating electric signals;
a culture isolation support attached to the substrate, wherein separate chambers are formed without covering the electrode plating layer, and each separate chamber contains a sensor unit composed of more than two electrode units;
the bionic tissue units with the same number as the sensor units are positioned in the separation chamber and used for providing bionic tissue and culture solution environments, metabolizing to generate products to be detected, and realizing environmental control of the bionic tissue units and simulating drug reactions, therapy reactions and pathological reactions by adding physical and chemical stimulation.
2. The integrated biosensor chip of claim 1, wherein said substrate is a PCB electrode substrate.
3. The integrated biosensor chip of claim 1, wherein said electrical signal comprises an electrical signal responsive to a concentration of an analyte.
4. The integrated biosensor chip of claim 1, wherein the through hole is a countersunk through hole, the electrode pins are fitted into the countersunk through hole, the lower portions of the electrode pins pass through the fine hole ends of the countersunk through hole, and the upper portions of the electrode pins are fixed to the coarse hole ends of the countersunk through hole.
5. The integrated biosensor chip of claim 4, wherein the countersunk through holes have a diameter of 0.05 to 0.2mm at the thick end and a diameter of 0.6 to 1mm at the thin end, and a length of 1 to 2mm at the thin end and a diameter of 0.1 to 0.5mm at the thin end.
6. The integrated biosensor chip of claim 1, wherein the sensor unit comprises three electrode units, one working electrode, one counter electrode and one reference electrode, or two electrode units, one working electrode and one counter electrode, respectively.
7. The integrated biosensor chip of claim 6, wherein the material of the electrode plating on the working electrode is Au, and the material of the electrode plating on the reference electrode and the counter electrode is selected from Ag and AgCl.
8. The integrated biosensor chip of any one of claims 1 to 7, wherein the array of through holes are disposed equidistantly in the lateral and longitudinal directions.
9. The integrated biosensor chip of claim 8, wherein the pitch of the array of through holes is 0.6-1 mm.
10. The integrated biosensor chip according to any one of claims 1 to 7, wherein the electrode pins and the through holes are fitted with a clearance fit, and the adhesion is achieved by soldering or hot melt adhesive.
11. The integrated biosensor chip of claim 10, wherein the length of the thin end of the electrode pin exceeds the length of the thin end hole by 1-2 mm.
12. The integrated biosensor chip of any one of claims 1 to 7, wherein the electrode plating layer is formed by evaporation, and the material of the electrode pins is gold-plated copper.
13. The integrated biosensor chip of any of claims 1 to 7, wherein the culture spacer scaffold is printed on the substrate by an additive manufacturing method.
14. The integrated biosensor chip of any one of claims 6 to 7, wherein the biomimetic tissue unit comprises a cell-containing bioscaffold, cell microspheres, biopsy and/or cell gel, and the working electrode is capable of enabling measurement of oxygen, glucose, lactate, albumin, pH, urea.
15. The integrated biosensor chip of any one of claims 1 to 7, wherein the electrochemical reaction promoting enzyme coating layer is coated on the electrode coating layer by droplet jet printing or hydrogel film application, and the electrochemical reaction promoting enzyme coating layer on the electrode coating layer can be coated with a new electrochemical reaction promoting enzyme coating layer again after being washed after being worn, so that the electrode unit can be reused.
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| CN109870491B (en) * | 2019-03-11 | 2020-12-22 | 太原理工大学 | High-flux microporous plate drug screening chip and preparation method thereof |
| CN115015343B (en) * | 2022-06-07 | 2024-04-26 | 中国科学院天津工业生物技术研究所 | Manufacturing method of all-solid-state miniature dissolved oxygen electrode |
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| JP3801617B2 (en) * | 2003-06-27 | 2006-07-26 | 松下電器産業株式会社 | Pharmacological measurement apparatus and system and well container used therefor |
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