JP2009216516A - Biosensor chip and its manufacturing method - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To reduce a user's load by providing a biosensor chip capable of high-sensitivity, high-speed and high-precision measurement, and its manufacturing method. <P>SOLUTION: This biosensor chip 10 includes: a spacer layer 26 sandwiched between a lower substrate 21 and an upper substrate 22 facing mutually; detection electrodes 12a, 12b provided on the surface of the spacer layer 26 side of the lower substrate 21; a hollow reaction part 11 formed of the lower substrate 21, the upper substrate 22 and the spacer layer 26; a reagent 13 provided near the detection electrodes 12a, 12b in the hollow reaction part 11; and a sample collection port 11a for introducing a sample into the hollow reaction part 11. Gold nanoparticles 15 are arranged at least on the detection electrodes 12a, 12b in the hollow reaction part 11 and between each detection electrode. <P>COPYRIGHT: (C)2009,JPO&INPIT

Description

  The present invention relates to a biosensor chip that measures and analyzes a chemical substance using a reagent contained in a hollow reaction part of the chip, and a manufacturing method thereof.

Conventionally, a biosensor chip that collects a sample and measures and analyzes a chemical substance is known (see, for example, Patent Document 1).
In this biosensor chip, first and second substrates are stacked, and a pair of conductive tracks are provided between them. The conductive track is exposed through the opening at one end of the biosensor chip, and is pressed against the punctured finger or the like to guide the sample to the reagent in the opening to perform measurement. This biosensor chip is used for daily blood glucose level monitoring of many people such as diabetic patients.

Further, for example, in a system using a biosensor chip (test strip) for detecting blood glucose disclosed in Patent Document 2, the biosensor chip has a sample chamber for storing reagents such as glucose oxidase and mediator and electrodes. .
When the user applies a blood sample to the sample chamber, the reagent reacts with glucose, and a redox reaction occurs when the measuring instrument applies a voltage to the electrodes. The meter measures the resulting current and calculates a blood glucose level based on this current.
In such a system, since it is necessary to monitor the blood glucose level on a daily basis, it is desirable to use a biosensor chip that requires a very small amount of blood sample for measurement in order to reduce the burden on the patient.

JP 2004-279433 A JP-T 2006-511788

  In the above system for detecting blood sugar, when a reagent is dissolved by blood, an enzyme reaction is started, and as a result, a reduced electron carrier is accumulated, and its amount is a substrate concentration, that is, a glucose concentration in blood. Is proportional to The reduced electron carrier accumulated for a certain time is oxidized by an electrochemical reaction, and the measuring device calculates the glucose concentration (blood glucose level) from the anode current measured at this time.

By the way, from the viewpoint of self-management, in recent years, further downsizing and miniaturization of biosensor chips are desired. This is in order to reduce the burden of sampling of the subject to be inspected, and it is required to derive the inspection result accurately and quickly with a small amount of sample. In the blood glucose level measurement by self-management, the user himself / herself collects blood, so that the blood collection time is short and the blood collection amount is small, the burden on the user is reduced. Under such circumstances, there is a demand for a biosensor chip to realize measurement more easily and reliably. That is, high sensitivity, high speed, and high accuracy of the enzyme reaction are desired.
The present invention has been made in view of the above circumstances, and aims to reduce the burden on the user by providing a biosensor chip capable of high-sensitivity, high-speed, and high-accuracy measurement and a manufacturing method thereof. To do.

The above object of the present invention is achieved by the following configuration.
(1) Two substrates facing each other, a spacer layer sandwiched between the two substrates, and a plurality of detections provided on the surface of at least one of the two substrates on the spacer layer side Electrode, a hollow reaction portion formed by the two substrates and the spacer layer, a reagent provided in the hollow reaction portion in the vicinity of the detection electrode, and sample collection for introducing a sample into the hollow reaction portion Mouth,
A biosensor chip having
A biosensor chip comprising gold nanoparticles arranged on at least the detection electrode and between the detection electrodes in the hollow reaction part.

  According to the biosensor chip of the above configuration, utilizing the characteristics such as a high specific surface area and high conductivity of the gold nanoparticles, a catalytic function that a region for activating oxygen is newly generated at the oxide interface, The current signal generated by the enzyme reaction can be amplified, and a high current value can be obtained in the electrochemical reaction.

  (2) The biosensor chip according to (1), wherein the gold nanoparticles have a particle size of 2 to 30 nm.

  According to the biosensor chip having such a configuration, the gold nanoparticle having a particle diameter of 2 nm is substantially maximized, the catalytic function is remarkably activated in the particle diameter range of 2 to 30 nm, and the current signal generated by the enzyme reaction Amplification becomes possible more effectively.

  (3) The biosensor chip according to (1) or (2), wherein the reagent contains glucose oxidase as an oxidase and potassium ferricyanide as a mediator.

  According to the biosensor chip having such a configuration, when blood is measured as a sample, when the blood reaches the detection electrode, glucose oxidase and potassium ferricyanide on the detection electrode are dissolved, and glucose in the blood is dissolved. The reacting enzyme reaction is started. The current signal can be amplified by the catalytic function of the gold nanoparticles by the enzyme reaction generated at this time.

(4) The biosensor chip manufacturing method according to any one of (1) to (3),
Including a step of disposing a gold nanoparticle solution on at least the detection electrode in the hollow reaction part and between the detection electrodes,
The method for producing a biosensor chip, wherein the gold nanoparticle solution contains 0.17 to 0.3 μg / μL of the gold nanoparticles having a particle size of 2 to 30 nm.

  According to such a method for manufacturing a biosensor chip, the catalytic function is remarkably activated when the particle size of the gold nanoparticles in the arranged gold nanoparticle solution is 2 to 30 nm. Moreover, the gold | metal nanoparticle solution to arrange | position contains 0.17-0.3 microgram / microliter of gold nanoparticles with a particle size of 2-30 nm, and a biosensor chip can obtain a fixed stable electric current value.

According to the biosensor chip and the method for manufacturing the same according to the present invention, the gold nanoparticle is disposed on the detection electrode and between the detection electrodes in at least the hollow reaction part. The current signal generated by the enzyme reaction can be amplified by using the characteristic, and a high current value can be obtained in the electrochemical reaction.
As a result, high-sensitivity, high-speed and high-precision measurement is possible, and the burden on the user can be reduced.

Hereinafter, preferred embodiments of a biosensor chip and a manufacturing method thereof according to the present invention will be described with reference to the drawings.
1A is a plan view showing a biosensor chip according to an embodiment of the present invention, FIG. 1B is a side view of FIG. 1A, and FIG. 1C is a front view of FIG. 2 is an enlarged plan view of a main part of the biosensor chip shown in FIG.

  As shown in FIG. 1, the biosensor chip 10 according to the present embodiment has a sample collection port 11a opened at the tip. Since the sample collection port 11a is provided at the tip of the biosensor chip 10, it is easy to collect a sample. In addition, the biosensor chip 10 has a hollow reaction portion 11 that communicates with the sample collection port 11a and has detection electrodes 12a and 12b and a reagent 13, and further, an air guide that communicates the hollow reaction portion 11 with the outside. A passage 14 is provided. The sample collected from the sample collection port 11 a flows into the hollow reaction part 11 and reacts with the reagent 13.

The biosensor chip 10 has a laminated structure in which a spacer layer 26 is sandwiched between a lower substrate 21 and an upper substrate 22.
As the material of the upper and lower substrates 21 and 22 and the spacer layer 26, an insulating material film is selected. As the insulating material, ceramics, glass, paper, biodegradable material (for example, polylactic acid microbial production polyester, etc.), Examples thereof include thermoplastic materials such as polyvinyl chloride, polypropylene, polystyrene, polycarbonate, acrylic resin, polybutylene terephthalate and polyethylene terephthalate (PET), thermosetting resins such as epoxy resins, and plastic materials such as UV curable resins. A plastic material such as polyethylene terephthalate is preferable because of its mechanical strength, flexibility, and ease of chip fabrication and processing. Representative PET resins include Melinex and Tetron (trade names, manufactured by Teijin DuPont Films, Inc.), Lumirror (trade names, manufactured by Toray Industries, Inc.), and the like.

The tip of the biosensor chip 10 is formed in a narrow shape, and the hollow reaction part 11 is formed in the interior by cutting out the spacer layer 26. The tip of the hollow reaction part 11 is a sample collection port 11a.
A pair of detection electrodes 12 a and 12 b are provided on the upper surface of the lower substrate 21. These detection electrodes 12a and 12b are bent toward the sides approaching each other at the tip of the biosensor chip 10 and face each other at a predetermined interval in the hollow reaction portion 11. A reagent 13 that reacts with the sample is provided between or in the vicinity of the detection electrodes 12a and 12b facing each other in the hollow reaction portion 11.

  Examples of the reagent 13 include enzymes such as glucose oxidase (GOD), glycolose dehydrogenase (GDH), cholesterol oxidase and urigase, and electron acceptors such as potassium ferricyanide, ferrocene and benzoquinone. In consideration of the blood sampling burden of the specimen, the volume of the hollow reaction part 25 is preferably 1 μL (microliter) or less, and particularly preferably 300 nL (nanoliter) or less. With such a minute hollow reaction part 25, a sufficient blood volume of the specimen can be collected even if the diameter of the chip body 21 is small.

  At the rear end portion of the biosensor chip 10, the lower substrate 21 protrudes from the upper substrate 22 and the spacer layer 26, and the rear end portions of the detection electrodes 12 a and 12 b are exposed on the upper surface of the lower substrate 21. Yes. In the present invention, the spacer layer 26 includes an insulating layer and an adhesive layer which will be described later.

Further, an air conduction path 14 is provided at the rear end of the hollow reaction part 11, and the air conduction path 14 communicates the hollow reaction part 11 with the outside.
The air conduction path 14 is provided so that the combined shape of the air conduction path 14 and the hollow reaction portion 11 is a T-shape so as to penetrate the biosensor chip 10 from side to side. The air hole openings 18 of the air conduction path 14 are provided on both side surfaces of the biosensor chip.
Since the hollow reaction part 11 is opened at the air hole opening 18 through the air conduction path 14, the introduction of the sample is performed by the discharge action of the internal air when the sample flows into the hollow reaction part 11 from the sample collection port 11a. Becomes better. Further, if a negative pressure is applied to the air hole opening 18 by a suction means such as a vacuum pump, the negative pressure acts on the hollow reaction portion 11 via the air conduction path 14, so that a sample suction effect is obtained. This further improves sample introduction.

Next, a more specific structure of the hollow reaction part 11 and the detection electrodes 12a and 12b in the present embodiment will be described with reference to FIG.
The tip of the lower substrate 21, which is one substrate, is curved in a convex shape, and the sample collection port 11a is opened at the protruding tip. The sampling port 11a communicates with the hollow reaction part 11 behind the sampling port 11a. Each of the detection electrodes 12a and 12b is formed in parallel, is bent at a substantially right angle in a direction close to each other in the hollow reaction portion 11, and is disposed to face each other with a predetermined interval.

  Gold nanoparticles 15 are arranged on the detection electrodes 12a and 12b and between the detection electrodes 12a and 12b in the hollow reaction part 11. The gold nanoparticles 15 have characteristics such as strength, conductivity, and heat conduction ability that are greatly improved by the nanoscale particle size. In addition, the catalytic function for activating oxygen is greatly improved. This serves to amplify the output signal of the biosensor chip 10 in the electrochemical reaction process, which leads to improvement in detection speed, accuracy and sensitivity of the biosensor chip 10.

  The material of the detection electrodes 12a and 12b on which the gold nanoparticles 15 are arranged can be selected from gold, platinum, palladium, graphite, carbon black, and the like. The structures of the detection electrodes 12a and 12b may be flat plate electrodes or needle electrodes (solid or hollow). In order to obtain a clean surface, the surfaces of the detection electrodes 12a and 12b may be treated with acid, alkali, physical polishing, or ultrasonic waves.

  The reagent 13 contains glucose oxidase as an oxidase and potassium ferricyanide as a mediator. When blood as a sample reaches the detection electrodes 12a and 12b, glucose oxidase and potassium ferricyanide on the detection electrodes 12a and 12b are dissolved, and an enzyme reaction that reacts with glucose in the blood is started.

  That is, when blood is sucked into the hollow reaction part 11 through the sample collection port 11a by capillary action and reaches the detection electrodes 12a and 12b, glucose oxidase and potassium ferricyanide on the detection electrodes 12a and 12b are dissolved. It reacts with glucose in the blood. That is, the enzyme reaction is started. Glucose is converted into gluconic acid by glucose oxidase on the detection electrodes 12a and 12b, but at the same time, electrons are given to ferricyan ions, which are electron carriers (mediators), and converted into ferrocyan ions. The amount is proportional to the substrate concentration, ie the glucose concentration in the blood.

Here, when a constant voltage is applied to the detection electrodes 12a and 12b, the generated ferrocyan ions give electrons (e −) to the working electrode and return to ferricyan ions. On the other hand, at the counter electrode, hydrogen ions (H ⁺ ) receive electrons and generate water (H ₂ O) together with oxygen (O ₂ ). At this time, the blood glucose level can be obtained by measuring the amount of anode current generated according to the glucose concentration. The current signal due to the enzyme reaction generated at this time is amplified by the catalytic function of the gold nanoparticles 15.

  As described above, in the biosensor chip 10 according to the present embodiment, the catalytic function that a high specific surface area and high conductivity of the gold nanoparticle 15 and a region for activating oxygen are newly generated at the oxide bonding interface, etc. Using this characteristic, the current signal generated by the enzyme reaction can be amplified, and a high current value can be obtained in the electrochemical reaction.

  Therefore, according to the biosensor chip 10, since the gold nanoparticles 15 are disposed on the detection electrodes 12a and 12b and between the detection electrodes 12a and 12b in the hollow reaction part 11, the high specific surface area of the gold nanoparticles 15 and A high current value can be obtained in an electrochemical reaction by amplifying a current signal generated by an enzyme reaction using the property of high conductivity. As a result, high-sensitivity, high-speed and high-precision measurement is possible, and the burden on the user can be reduced.

Next, a method for manufacturing the biosensor chip 10 will be described.
FIG. 3 is a schematic diagram showing steps (a) to (d) for arranging gold nanoparticles in the method of manufacturing a biosensor chip.

  In the manufacturing method of the biosensor chip 10 according to the present embodiment, as shown in FIG. 3, the portions on the detection electrodes 12 a and 12 b in the hollow reaction portion 11 and the portions except only between the detection electrodes 12 a and 12 b are mask M. Process. The gold nanoparticle solution AuL is dropped only on the detection electrodes 12a and 12b that are not masked and between the detection electrodes 12a and 12b. After the gold nanoparticle solution AuL is dropped, the gold nanoparticle solution AuL is solidified through a drying process for a predetermined time, and the gold nanoparticles 15 are arranged on the detection electrodes 12a and 12b and between the detection electrodes 12a and 12b.

  After the gold nanoparticles 15 are fixed, the reagent 13 is fixed. The fixed gold nanoparticles 15 may be washed with water. Thereby, the reagent (enzyme) 13 can be stabilized on the gold | metal nanoparticle 15 which carried out the washing process, and storage stability can be improved.

In the above embodiment, the gold nanoparticles 15 are disposed on the detection electrodes 12a and 12b and between the detection electrodes 12a and 12b, and then the reagent 13 is disposed thereon. A mixed solution with the gold nanoparticles 15 may be disposed on the detection electrodes 12a and 12b and between the detection electrodes 12a and 12b.
In the above embodiment, since the gold nanoparticles 15 are arranged on the detection electrodes 12a and 12b and between the detection electrodes 12a and 12b, a mixed solution of the reagent 13 and the gold nanoparticles 15 or gold nanoparticles Although the solution AuL or the like is dropped and then dried and solidified, the mixed solution or the gold nanoparticle solution AuL or the like may be applied and then dried and solidified.

Example 1
Glucose concentration and current were measured using carbon nanoparticles on the carbon detection electrodes 12a and 12b and between the detection electrodes 12a and 12b in the hollow reaction part 11 and gold nanoparticles not disposed. The correlation with the value was examined. The results are shown in FIG.

Note that the predetermined distance d = 0.41 mm between the detection electrodes 12a, 12b shown in FIG. 2, the length 12L = 1.4 mm, the width 12aw = 0.58mm, and the width 12bw = 0.45mm of the detection electrodes 12a, 12b. The reaction part was formed. As the gold nanoparticles, gold nanoparticles having a particle diameter of 2 nm were prepared using a protective material K ₂ CO ₃ and a reducing material NaBH ₄ . In addition, glucose oxidase and potassium ferricyanide were used as reagents, and the current value for each glucose concentration of the glucose solution dropped on the reaction part was measured in the case where gold nanoparticles were placed and the case where gold nanoparticles were not placed.

  As is clear from the graph showing the correlation between the glucose concentration and the current value shown in FIG. 4, good linearity is maintained even when 2 nm gold nanoparticles are arranged, and about 3 times as compared with those not arranged. Current value.

(Example 2)
A reaction part was formed in the same manner as in Example 1, and the amount of gold nanoparticle solution AuL was changed (entirely) on the carbon detection electrodes 12a and 12b and between the electrodes without changing the amount of gold nanoparticle of 30 nm. Particles were placed. After dropping a glucose solution having a glucose concentration of 5 mM into the reaction part, the current value after 60 seconds was plotted, and the correlation between the amount of gold nanoparticles and the current value was examined. The results are shown in FIG.

As apparent from the graph showing the correlation between the amount of gold nanoparticles and the current value in FIG. 5, the current value increased depending on the amount of gold nanoparticles arranged in the reaction part. That is, the catalytic function was remarkably activated by the gold nanoparticles having a particle size of 2 to 30 nm in the dropped gold nanoparticle solution.
In addition, when the amount of gold nanoparticles was 0.8652 μg or more, the current value was substantially constant. Therefore, the current value increases depending on the amount of gold nanoparticles in the dropped gold nanoparticle solution, and then becomes substantially constant, so that the minimum necessary amount to obtain the constant stable current value is obtained. The gold nanoparticle concentration was found.

That is, when the dropped gold nanoparticle solution AuL contains 0.17 μg / μL or more of gold nanoparticles having a particle size of 2 to 30 nm, the biosensor chip can obtain a constant and stable current value. However, if the gold nanoparticle solution AuL contains more than 0.3 μg / μL of gold nanoparticles having a particle size of 2 to 30 nm, aggregation is likely to occur, and problems such as solution deterioration and clogging of the coating apparatus are likely to occur. Become.
Therefore, in order to obtain a stable current value in consideration of the solution stability, it is preferable to contain 0.17 to 0.3 μg / μL of gold nanoparticles having a particle size of 2 to 30 nm.

Further, as is apparent from the graph of FIG. 5, the amount of gold nanoparticles disposed on and between the detection electrodes 12a and 12b by dropping or coating has an effect of increasing the current value in the range of 0.8 to 2 μg. It has become the maximum.
Therefore, in the sensor structure (electrode size and reaction part size) of the biosensor chip 10 of the present example, the optimal amount of the gold nanoparticle solution AuL is 0.8 to 2 μg.

(Example 3)
A reaction part was formed in the same manner as in Example 1, and a glucose solution with a glucose concentration of 10 mM was dropped into each reaction part in which 0.8625 μg of gold nanoparticles having particle sizes of 2 nm, 12 nm, and 30 nm were arranged, and then the current value The correlation between the particle size of gold nanoparticles and the current value was examined.
As is clear from the graph showing the correlation between the particle size of the gold nanoparticles and the current value in FIG. 6, it is possible to obtain a higher current value when the gold nanoparticles are arranged than when the gold nanoparticles are not provided. It was. In particular, the gold nanoparticle having a particle diameter of 2 nm has a current value of 3.5 times that of the gold nanoparticle without the gold nanoparticle.

From this, the gold nanoparticles with a particle size of 2 nm are substantially maximized, the catalytic function is remarkably activated in the particle size range of 2 to 30 nm, and the current signal generated by the enzyme reaction can be amplified more effectively. It was found that
That is, when the particle size of the gold nanoparticle is 2 to 30 nm, the biosensor chip can obtain a high current value.

Example 4
In the same manner as in Example 1, a reaction part was formed, and a gold nanoparticle solution AuL containing 0.173 μg of gold nanoparticles having a particle diameter of 2 nm was applied on the carbon detection electrodes 12a and 12b and between the electrodes. After drying, each reaction was performed using Sample 1 coated with 0.3 μL of reagents (glucose oxidase and potassium ferricyanide) and vacuum-dried, and Sample 2 in which only the reagent was placed and gold nanoparticles were not placed. The response current value was measured when a glucose solution having a glucose concentration of 100 mg / dL was dropped on the part. The results are shown in FIG.
In addition, a sample 3 in which a mixed solution of 3.9 μL of the gold nanoparticle solution AuL and 0.3 μL of the reagent is applied on and between the detection electrodes 12a and 12b and vacuum-dried, and only the reagent are arranged. Then, using the sample 4 on which no gold nanoparticles were arranged, the response current value when a glucose solution having a glucose concentration of 100 mg / dL was dropped into each reaction part was measured. The results are shown in FIG.

As is clear from the graph of the response curve of the current value shown in FIG. 7, in the sample 1 in which the gold nanoparticle solution AuL was first applied and vacuum-dried and then the reagent was applied and vacuum-dried, The peak current value was about 2.19 times that of Sample 2 without particles.
Further, as is apparent from the graph of the response curve of the current value shown in FIG. 8, in the sample 3 in which the mixed solution of the gold nanoparticle solution AuL and the reagent prepared in advance was applied and vacuum dried, The peak current value was about 1.67 times that of Sample 4 without.

(Example 5)
In the same manner as in Example 1, a reaction part was formed, and a gold nanoparticle solution AuL containing 0.69 μg of gold nanoparticles having a particle size of 2 nm was applied on and between the carbon detection electrodes 12a and 12b and between the electrodes. After drying, 0.3 μL of reagents (glucose oxidase and potassium ferricyanide) were further applied and vacuum-dried, and those without gold nanoparticles were used, and the ambient temperature was 25 ° C., 30 ° C., 35 While changing the temperature to ° C., a glucose solution having a glucose concentration of 10 mM was dropped into each reaction part, and the current value at each environmental temperature was measured. The results are shown in Table 1.

  As is clear from Table 1, it is found that the arrangement of gold nanoparticles has a smaller current ratio between 35 ° C. and 25 ° C., and the temperature dependency when the environmental temperature fluctuates is reduced. did it.

  Furthermore, since the linearity of the current value in the high concentration region is better at a high temperature, the linearity in the high concentration region is improved when the gold nanoparticles are arranged when measured at a high temperature.

(A) is a top view which shows the biosensor chip based on embodiment of this invention, (B) is a side view of (A), (C) is a front view of (A). It is a principal part enlarged plan view of the biosensor chip shown in FIG. It is a schematic diagram which shows the process of arrange | positioning a gold nanoparticle in the manufacturing method of a biosensor chip by (a)-(d). It is a graph showing the correlation between glucose concentration and current value with respect to the presence or absence of gold nanoparticles. It is a graph showing the correlation between the amount of gold nanoparticles and the current value. It is a graph showing the correlation between the particle size of gold nanoparticles and the current value. It is a graph of the response curve of the electric current value by the presence or absence of a gold nanoparticle. It is a graph of the response curve of the electric current value by the presence or absence of a gold nanoparticle.

Explanation of symbols

DESCRIPTION OF SYMBOLS 10 ... Biosensor chip 11 ... Hollow reaction part 11a ... Sample collection port 12a, 12b ... Electrode for detection 13 ... Reagent 14 ... Air conduction path 15 ... Gold nanoparticle 18 ... Air-hole opening part 21 ... Lower board | substrate (board | substrate)
22 ... Upper substrate (substrate)
23 ... Insulating layer 25 ... Adhesive layer 26 ... Spacer layer AuL ... Gold nanoparticle solution

Claims (4)

Two substrates facing each other, a spacer layer sandwiched between the two substrates, and a plurality of detection electrodes provided on the surface of the spacer layer side of at least one of the two substrates A hollow reaction part formed by the two substrates and the spacer layer; a reagent provided in the vicinity of the detection electrode in the hollow reaction part; a sample collection port for introducing a sample into the hollow reaction part;
A biosensor chip having
A biosensor chip comprising gold nanoparticles arranged on at least the detection electrode and between the detection electrodes in the hollow reaction part.   The biosensor chip according to claim 1, wherein the gold nanoparticles have a particle size of 2 to 30 nm.   The biosensor chip according to claim 1 or 2, wherein the reagent contains glucose oxidase as an oxidase and potassium ferricyanide as a mediator. It is a manufacturing method of the biosensor chip according to any one of claims 1 to 3,
Including a step of disposing a gold nanoparticle solution on at least the detection electrode in the hollow reaction part and between the detection electrodes,
The method for producing a biosensor chip, wherein the gold nanoparticle solution contains 0.17 to 0.3 μg / μL of the gold nanoparticles having a particle size of 2 to 30 nm.

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