JP5540252B2 - Electrochemical measuring device - Google Patents

Description

  The present invention relates to an electrochemical measurement apparatus that performs electrochemical measurement at high density on-chip (on an integrated circuit).

  Conventionally, it has been known to use an electrochemical measurement technique for observing a chemical change in the vicinity of an interface or for studying DNA or a cell membrane. Recently, it has been proposed to perform this electrochemical measurement on-chip (on an integrated circuit).

  For example, Patent Document 1 proposes a nucleic acid concentration quantitative analysis chip that quantitatively analyzes the concentration of a target nucleic acid contained in a specimen and a nucleic acid concentration quantitative analysis technique using the nucleic acid concentration quantitative analysis chip. Measurement is performed using a three-electrode electrochemical cell having a working electrode, a counter electrode, and a reference electrode. FIG. 1 schematically shows an integrated circuit for electrochemical analysis in Patent Document 1. In the figure, CE is a counter electrode, WE is a working electrode, and RE is a reference electrode. In Patent Document 1, three operational amplifiers are used, and the working electrode WE is connected to the gate of a field effect transistor (FET) (not shown). Measurement is performed using a potential detection method.

  Non-Patent Document 1 proposes a microchannel type DNA sensor. The main part of the signal processing part of this DNA sensor is schematically shown in FIG. In the figure, CE is a counter electrode, WE is a working electrode, and RE is a reference electrode. In Non-Patent Document 1, two operational amplifiers are used, and the working electrode WE is connected to the gate of a field effect transistor (FET) (not shown). Measurement is performed using a potential detection method.

  However, the operational amplifier used in Patent Document 1 and Non-Patent Document 1 occupies a large area of about 1 mm × 1 mm, consumes a large amount of power, and uses an on-chip FET as it is. There is a problem that high measurement is difficult and measurement at each point cannot be performed in parallel.

  On the other hand, Non-Patent Document 2 proposes an 8 × 8 pixel electrochemical sensor using CMOS in order to detect and identify DNA and proteins. Again, a three-pole chemical electric cell having a counter electrode, a working electrode, and a reference electrode is used. FIG. 3 shows a column composed of detection electrodes arranged in an array of the electrochemical sensor of Non-Patent Document 2. Here, ON / OFF of the detection electrode corresponding to each part along the column is sequentially switched, and a current is detected by an operational amplifier provided in the upper part of the figure.

  However, in the technique of Non-Patent Document 2, switching the switch affects the system to be measured, and it is difficult to perform accurate measurement.

JP 2004-309462 A

“Smart Microfluidic Electrochemical DNA sensors with Signal Processing circuits” Japanese Journal of Applied Physics, Vol. 46, No.5A, 2007, pp.3135-3138 “Optical and electrochemical dual-image CMOS sensor for on-chip biomolecular sensing applications”, Sensors and Actuators A 135 (2007) 315-322

  The present invention has been made in view of the above circumstances, and can perform measurement with high accuracy without using an operational amplifier using an on-chip FET, and can perform measurement without affecting the solution system by turning on and off the switch. It is an object to provide a simple electrochemical measurement device.

In order to solve the above-mentioned problems, the present invention firstly has a working electrode, a counter electrode, and a reference electrode disposed in a solution as a sample to perform electrochemical measurement of the sample, and the gate electrode of the FET is used as the working electrode. Is a three-pole electrochemical measuring apparatus that applies a low-frequency voltage between the counter electrode and the FET source electrode, and applies a voltage between the FET gate electrode and the counter electrode. And a displacement current measuring means for measuring a displacement current flowing between the gate electrode and the counter electrode of the FET, and performing an electrochemical measurement based on a measurement result by the displacement current measuring means Providing equipment.

  Second, in the first invention, the area of the gate electrode of the FET is controlled in order to apply a voltage by voltage division and distribution to the solution through the gate insulation resistance, so that the solution is compared with the gate insulation resistance. There is provided an electrochemical measurement device characterized by increasing the impedance.

  Thirdly, in the first or second invention, there is provided an electrochemical measurement apparatus characterized in that an element having an impedance close to the impedance between the counter electrode and the working electrode is provided between the working electrode and the ground electrode. provide.

  Fourth, the electrochemical measurement apparatus according to the third invention is characterized in that the impedance of the element is variable by a control signal.

  According to the present invention, the above configuration is adopted, so that an on-chip FET can be used to perform highly accurate measurement without an operational amplifier, and electrochemical measurement that can be measured without affecting the solution system by turning on and off the switch. A device can be provided.

It is a figure which shows typically the integrated circuit for the electrochemical analysis of patent document 1. FIG. It is a figure which shows typically the integrated circuit for the electrochemical analysis of a nonpatent literature 1. FIG. It is a figure which shows the column which consists of a detection electrode arrange | positioned at the array form of the electrochemical sensor of a nonpatent literature 2. It is a figure which shows the equivalent circuit in the case of connecting the gate electrode of FET to a working electrode, and measuring the impedance Z of a solution. It is a graph showing the relationship between V _g / _{V r} and Z / _{Z g.} It is a figure which shows the equivalent circuit of a capacitive system. It is the figure which arranged the high resistance R in parallel with the gate of FET. It is the figure which arranged the variable high resistance R in parallel with the gate of FET. It is an arrangement view of voltage application means and displacement current measurement means. It is a figure which shows the example which formed high resistance R by FET. It is explanatory drawing of a weak inversion area | region. It is a figure which shows the example which incorporated multiple reference current sources and made high resistance R variable. It is a figure which shows the example which comprised the sensor which detects a displacement current with paired FET. It is a figure which shows the example which formed high resistance R with the switched capacitor. It is a figure which shows the example of a measurement of the distribution voltage at the time of changing the electrode area of a working electrode.

  Hereinafter, the electrochemical measurement apparatus of the present invention will be described in detail based on the embodiments.

  The electrochemical measurement apparatus of the present invention uses a three-pole system including a counter electrode CE, a working electrode WE, and a reference electrode RE. The gate of the FET is connected to the working electrode WE.

FIG. 4 shows an equivalent circuit when the gate of the FET is connected to the working electrode WE and the impedance Z of the solution is measured. When the gate voltage is Vg and the impedance is Zg, the relationship is as shown in Equation 1.

Here, V _g / V _r and Z / Z _g have a relationship as shown in FIG.

Therefore, the measure impedance Z of the solution it is necessary that Z is comparable with Z _g.

The gate of the FET has an infinite impedance in direct current, but is expressed by Z _g = 1 / jωC _g in alternating current. The impedance of the solution is expressed as Z = 1 / jωC. Therefore, the following relationship holds.

Here, the equivalent circuit of the capacitive system is represented as shown on the left side of FIG. 6, and the solution capacity C and the gate capacity _Cg are illustrated as shown on the right side of FIG. Since C of the solution is larger than the planar capacitance due to the three-dimensional effect, Zg >> Z, and it can be seen that the input impedance is too large when the on-chip FET is used as it is.

  Therefore, in the present invention, a high resistance R is provided at the gate of the FET as shown in FIG. That is, an element having an impedance close to the impedance between the counter electrode CE and the working electrode WE is provided between the working electrode WE and the ground electrode. Further, in the present invention, as shown in FIG. 8, the high resistance R can be controlled by a control signal (not shown) so as to be variable so that Vg becomes substantially zero. Thereby, the open-circuit potential is measured using the high resistance R. The impedance of the above element is suitably about 2 to 10 times the impedance between the counter electrode CE and the working electrode WE.

  Further, in the present invention, as shown in FIG. 9, a voltage application means for applying a low frequency voltage is provided between the counter electrode CE and the source electrode of the FET, and the displacement flowing between the gate electrode of the FET and the counter electrode CE. Displacement current measuring means for measuring current is provided.

  In the present invention, by adjusting (decreasing) the electrode area of the working electrode WE, or by increasing the distance between the counter electrode CE and the working electrode WE, or by combining the two, Impedance can be increased.

  Next, examples will be described.

FIG. 10 shows an example in which a high resistance is formed by an FET. The counter electrode CE is applied a voltage _{V r} of -1～1V, the voltage of approximately ± 30 mV to the gate of the FET being connected to the working electrode WE is to be applied. In addition, a high resistance is formed by another FET so as to operate in a linear region (weak inversion region in FIG. 11). Adjust the current _{I s} is a control signal as shown in FIG. 11, so that the high-resistance R can be varied to 1Emuomega～10jiomega.

  FIG. 12 shows an example in which a plurality of reference current sources are incorporated and the high resistance R is variable. The current is connected by a current mirror so as to eliminate the influence of variations in wiring impedance and threshold. It is better to perform termination processing, but it may not be necessary.

  FIG. 13 shows an example in which a sensor for detecting a displacement current is composed of a pair of FETs. In this way, there is an advantage that the influence of the variation in threshold value is reduced and the current mode can be realized with a low current.

  FIG. 14 shows an example in which the high resistance R is composed of a switched capacitor. In this case, the high resistance R can be made variable according to the clock frequency. In this way, restrictions on the transistor operating point can be relaxed, and there is an advantage that the high resistance R is stably formed.

  FIG. 15 uses a 3 mmφ gold electrode as a counter electrode, 10 μmφ, 25 μmφ, 100 μmφ, and 3 mmφ respectively as working electrodes, a 1 GΩ resistor connected in series to a NaCl solution cell as a high resistance, and a voltage of 1 V / 1 mHz. It is the example which measured the voltage of the voltage (solution 1Gohm) applied and distributed.

  The present invention can be expected to be applied to measurement of chemical reaction (liquid-liquid interface state, etc.), quantitative analysis of living organisms / cells, measurement / analysis of membrane characteristics, and the like.

CE Counter electrode WE Working electrode RE Reference electrode V _g Gate voltage R High resistance

Claims (4)

In order to perform electrochemical measurement of a specimen, a working electrode, a counter electrode, and a reference electrode are arranged in a solution that is a specimen, and is a three-pole electrochemical measuring device having a gate electrode of a FET as a working electrode , A voltage applying means for applying a low-frequency voltage between the FET gate electrode and the FET source electrode to apply a voltage between the FET gate electrode and the counter electrode, and a displacement current flowing between the FET gate electrode and the counter electrode An electrochemical measurement apparatus comprising: a displacement current measurement unit that measures the current, and performing an electrochemical measurement based on a measurement result obtained by the displacement current measurement unit.   3. The impedance of the solution is increased compared to the gate insulation resistance by controlling the area of the gate electrode of the FET in order to apply voltage by dividing the voltage into the solution through the gate insulation resistance. 2. The electrochemical measurement apparatus according to 1.   The electrochemical measurement apparatus according to claim 1 or 2, wherein an element having an impedance close to an impedance between the counter electrode and the working electrode is provided between the working electrode and the ground electrode.   The electrochemical measurement apparatus according to claim 3, wherein the impedance of the element is variable by a control signal.

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