JP7082015B2 - Measuring device - Google Patents

Description

The present invention relates to measurement using a nanopore device.

A particle size distribution measurement method called the electrical detection band method (Coulter principle) is known. In this measurement method, an electric field liquid containing particles is passed through pores called nanopores. As the particles pass through the pores, the electrolyte in the pores is reduced by an amount corresponding to the volume of the particles, increasing the electrical resistance of the pores. Therefore, by measuring the electrical resistance of the pores, the volume of the passing particles can be measured when the thickness of the pores is larger than that of the particles, and when the thickness of the pores is sufficiently smaller than that of the particles. , The cross-sectional area (ie, diameter) of the passing particles can be measured.

FIG. 1 is a block diagram of a fine particle measurement system 1R using an electrical detection band method. The fine particle measurement system 1R includes a nanopore device 100, a measurement device 200R, and a data processing device 300.

The inside of the nanopore device 100 is filled with the electrolytic solution 2 containing the particles 4 to be detected. The inside of the nanopore device 100 is separated into two spaces by a nanopore chip 102, and electrodes 106 and 108 are provided in the two spaces. When a potential difference is generated between the electrodes 106 and 108, an ionic current flows between the electrodes, and the particles 4 move from one space to the other via the pores 104 by electrophoresis.

The measuring device 200R generates a potential difference between the electrode pairs 106 and 108, and acquires information having a correlation with the resistance value Rp between the electrode pairs. The measuring device 200R includes a transimpedance amplifier 210, a voltage source 220, and a digitizer 230. The voltage source 220 generates a potential difference Vb between the electrode pairs 106 and 108. This potential difference Vb is a driving source for electrophoresis and a bias signal for measuring the resistance value Rp.

A minute current Is, which is inversely proportional to the resistance of the pore 104, flows between the electrode pairs 106 and 108.
Is = Vb / Rp ... (1)

The transimpedance amplifier 210 converts the minute current Is into a voltage signal Vs. When the conversion gain is r, the following equation holds.
Vs = r × Is ... (2)
Substituting Eq. (1) into Eq. (2) gives Eq. (3).
Vs = Vb × r / Rp ... (3)
The digitizer 230 converts the voltage signal Vs into digital data Ds. In this way, the measuring device 200R can obtain a voltage signal Vs that is inversely proportional to the resistance value Rp of the pore 104.

FIG. 2 is a waveform diagram of an exemplary minute current Is measured by the measuring device 200R. The vertical and horizontal axes of the waveform charts and time charts referred to in the present specification are appropriately enlarged or reduced for easy understanding, and each waveform shown is also simplified for easy understanding. It is made, or exaggerated or emphasized.

The resistance value Rp of the pores 104 increases for a short period of time through which the particles pass. Therefore, the current Is decreases in a pulse shape as the particles pass through. The amplitude of the individual pulse currents correlates with the particle size. The data processing apparatus 300 processes the digital data Ds and analyzes the number of particles 4 and the particle size distribution contained in the electrolytic solution 2.

Japanese Unexamined Patent Publication No. 2011-513739 Japanese Unexamined Patent Publication No. 4-040373 Special Table No. 7-504989 Japanese Unexamined Patent Publication No. 2004-510980

In the conventional fine particle measurement system 1R, measurement (hereinafter referred to as calibration measurement) is performed using international standard particles having a known particle size (referred to as standard particle size), and the signal strength (pulse current) obtained as a result is obtained. The correspondence between the amplitude) and the standard particle size is obtained. Then, when measuring an arbitrary particle, the diameter of the particle is estimated based on the obtained signal strength and the relative relationship obtained by the calibration measurement.

The conventional estimation of particle size will be described in detail. FIG. 3 is an example of a histogram of signal intensity obtained when measuring international standard particles. The signal strength on the horizontal axis indicates the amount of change in the digital data Ds for each pulse, in other words, the amplitude of the pulse current, and the vertical axis indicates the number of pulses.

The center of the histogram in FIG. 3 is the reference intensity I _REF corresponding to the standard particle size _φ0 . Therefore, when the signal intensity obtained when measuring an arbitrary particle is I _x , the particle size φ _x is estimated from the relationship between I _REF and R ₀ .

As described above, in the fine particle measurement system 1R using the conventional electric detection band method, the electrical calibration of the signal accuracy is not carried out. Therefore, what the digital data Ds shows is only a relative value of the amount of current, and cannot give a physical meaning to the digital data Ds. Therefore, even if the measuring instrument performs unexpected processing on the input signal, the output signal may be treated as correct.

From this concern, it can be said that conventionally, only a part of the raw data generated by the fine particle measurement system 1R can be used for particle size measurement and particle number measurement, and the remaining data is wasted. On the flip side, since only part of the data can be used, it is difficult to apply it to advanced applications such as analysis of particle shape and analysis of transit transients when particles pass through nanopores. It should be noted that this problem should not be regarded as a general recognition of those skilled in the art.

The present invention has been made in such a situation, and one of the exemplary purposes of the embodiment is to provide a measuring device capable of measuring absolute values of current and voltage.

One aspect of the invention relates to a measuring device that measures a signal that correlates with the impedance of a nanopore device having pores and electrode pairs. The measuring device has an output terminal pair that can be connected to the electrode pair of the nanopore device, a front-end circuit that generates an analog detection signal that correlates with the impedance between the output terminal pairs, and a front-end circuit that converts the analog detection signal into a digital detection signal. It is equipped with an A / D converter. A calibration device having a known resistance value can be connected between the output terminal pairs in place of the nanopore device, and calibration can be performed with the calibration device connected.

Another aspect of the invention relates to a method of calibrating a measuring device that measures a signal that correlates with the impedance of a nanopore device having pores and electrode pairs. The measuring device uses an output terminal pair that can be connected to the electrode pair of the nanopore device, a bias voltage source that can apply a DC bias voltage between the output terminal pairs, and a current signal that flows between the output terminal pairs as a voltage signal. It includes a transimpedance amplifier for conversion and an A / D converter for converting the output of the transimpedance amplifier into a digital value. The calibration method is a step of connecting a known resistor instead of a nanopore device between the output terminal pairs, and an A / D converter obtained by applying a known DC bias voltage between the known resistors. It is provided with a step of acquiring the output of the above and a step of acquiring the calibration parameter based on the output of the A / D converter.

It should be noted that any combination of the above components and the components and expressions of the present invention that are mutually replaced between methods, devices and the like are also effective as aspects of the present invention.

According to an aspect of the present invention, it is possible to provide a measuring device in which the signal accuracy of a current signal or a voltage signal is guaranteed.

It is a block diagram of the fine particle measurement system using the electric detection band method. It is a waveform diagram of an exemplary microcurrent Is measured by a measuring device. This is an example of a histogram of the signal strength obtained when measuring international standard particles. It is a block diagram of the fine particle measurement system which concerns on embodiment. It is a block diagram of the fine particle measurement system in a current calibration mode. 6 (a) and 6 (b) are diagrams illustrating calibration of the current measurement system. It is a block diagram of the fine particle measurement system in a voltage calibration mode. It is a figure explaining the calibration of a voltage application system. It is a block diagram of a measuring device. It is a flowchart of calibration in the fine particle measurement system which concerns on embodiment. It is a block diagram of the current measurement system of the measuring apparatus which concerns on modification 3. FIG. It is a block diagram of the measuring apparatus which concerns on modification 4. It is a block diagram of the measuring apparatus which concerns on modification 5.

Hereinafter, the present invention will be described with reference to the drawings based on the preferred embodiments. The same or equivalent components, members, and processes shown in the drawings shall be designated by the same reference numerals, and duplicate description thereof will be omitted as appropriate. Further, the embodiment is not limited to the invention, but is an example, and all the features and combinations thereof described in the embodiment are not necessarily essential to the invention.

In the present specification, the "state in which the member A is connected to the member B" means that the member A and the member B are physically directly connected, and the member A and the member B are electrically connected to each other. It also includes cases of being indirectly connected via other members that do not substantially affect the connection state or impair the functions and effects performed by the combination thereof.

Similarly, "a state in which the member C is provided between the member A and the member B" means that the member A and the member C, or the member B and the member C are directly connected, and their electricity. It also includes cases of being indirectly connected via other members that do not substantially affect the connection state or impair the functions and effects performed by the combination thereof.

(Basic configuration)
FIG. 4 is a block diagram of the fine particle measurement system 1 according to the embodiment. The fine particle measurement system 1 includes a nanopore device 100, a measurement device 200, and a data processing device 300.

The nanopore device 100 is as described with reference to FIG. 1, and includes a nanopore chip 102 provided with pores 104 and electrode pairs 106 and 108. The inside of the nanopore chip 102 is filled with an electrolytic solution such as KCl (potassium chloride) or PBS (phosphate buffered saline).

The measuring device 200 includes output terminal pairs OUT1, OUT2, a front-end circuit 202, a digitizer 230, an interface 240, and a calibration controller 250. The nanopore device 100 is detachably connected to the output terminal pairs OUT1 and OUT2. In the state where the nanopore device 100 is connected, the output terminal pairs OUT1 and OUT are electrically connected to the electrode pairs 106 and 108 via the pins P1 and P2 of the nanopore device 100. The front-end circuit 202 can generate an analog detection signal Vs having a correlation with the impedance between the output terminal pair OUT1 and OUT2 in a state where the nanopore device 100 is mounted.

The digitizer 230 includes an A / D converter and converts the analog detection signal Vs into the digital detection signal Ds.

In the present embodiment, the front-end circuit 202 can apply a bias voltage Vb between the output terminal pairs OUT1 and OUT2 and measure the current Is flowing at that time. The front-end circuit 202 includes a transimpedance amplifier 210 and a voltage source 220.

The data processing device 300 is an interface with the user, and also has a function of integrally controlling the fine particle measurement system 1 and acquiring, storing, and displaying the measurement result. The data processing device 300 may be a general-purpose computer or workstation, or may be hardware designed exclusively for the fine particle measurement system 1.

The measuring device 200 can switch between a normal measurement mode and a calibration mode. The data processing device 300 switches the operation mode of the measuring device 200 according to the operation of the user (operator).

The operation in the normal measurement mode is the same as that of the measuring device 200R of FIG. The nanopore device 100 is connected between the output terminals of the measuring device 200 and OUT1 and OUT2. The voltage source 220 applies a DC bias voltage Vb between the electrode pairs 106 and 108 in the normal measurement mode. For example, the voltage source 220 includes a D / A converter and generates a bias voltage Vb according to the input digital data. The transimpedance amplifier 210 converts the current Is flowing through the nanopore device 100 into a voltage signal Vs. The digitizer 230 converts the voltage signal Vs into digital data Ds. The interface 240 transmits the digital data Ds to the data processing device 300. The time series data of the digital data Ds represents a current waveform. The data processing device 300 processes the digital data Ds obtained in the normal measurement mode, and acquires the number and particle size of the particles 4 contained in the electrolytic solution 2. Furthermore, since the signal accuracy of the current signal and the voltage signal is guaranteed by the calibration mode described below, it is possible to acquire detailed feature quantities such as the shape of particles based on the current waveform.

Next, the calibration mode will be described. When the interface 240 receives predetermined control data from the data processing device 300, the measuring device 200 is set to the current calibration mode. The calibration controller 250 controls the operation of the measuring device 200 in the current calibration mode.

FIG. 5 is a block diagram of the fine particle measurement system 1C in the current calibration mode. In the current calibration mode, the calibration device 400 is connected between the output terminals of the measuring device 200 and OUT1 and OUT2. The calibration device 400 includes a standard resistor R with a known resistance value. The measuring device 200 can calibrate at least a part of the inside of the measuring device 200 in a state where the calibration device 400 is connected.

The measuring device 200 can include a device holder. The nanopore device 100 can be attached to this device holder. As shown in FIG. 4, the nanopore device 100 has pins P1 and P2 connected to electrode pairs 106 and 108. From the device holder, the output terminal pairs OUT1 and OUT2 are exposed in such a manner that they can contact the pins P1 and P2 of the nanopore device 100. In this case, the calibration device 400 includes pins P1 and P2 that can be attached to the device holder of the measuring device 200 and can be contacted with the output terminal pairs OUT1 and OUT2 in a state of being attached to the device holder. That is, it is desirable that the calibration device 400 and the nanopore device 100 have compatibility in shape and size. As a result, the impedance of the signal path can be made uniform between the particle measurement using the nanopore device 100 and the calibration using the calibration device 400, and the calibration accuracy can be improved.

The above is the configuration of the fine particle measurement system 1. Next, the operation will be described.
1. 1. Calibration of the current measurement system First, calibration of the current measurement system, that is, the transimpedance amplifier 210 and the digitizer 230 will be described. In this calibration, the voltage application system and the voltage source 220 have been calibrated, and the accuracy of the bias voltage Vb is guaranteed. The calibration of the voltage source 220 will be described later.

As described above, in the current calibration mode, the calibration device 400 is connected to the measuring device 200. At the time of calibration of the current measurement system, the calibration program is executed in the data processing device 300. The data processing device 300 transmits control data to the measuring device 200 and sets the measuring device 200 in the current calibration mode. Subsequently, the data processing device 300 transmits the set value Db of the bias voltage Vb to the measuring device 200 while switching between a plurality of N values x ₁ , x ₂ , ..., X _N. The calibration controller 250 inputs the set value x _i received from the data processing device 300 to the voltage source 220, and generates a bias voltage _Vbi .

The front-end circuit 202 and the digitizer 230 generate a digital detection signal Ds _i corresponding to the bias voltage Vbi ( _i = 1, 2, ..., N). The digital detection signal Ds _i (i = 1, 2, ..., N) is transmitted to the data processing device 300.

It is preferable to measure the digital detection signal Ds _i a plurality of times for each bias voltage Vb. In this case, the average value _mi of the digital detection signals Ds _i obtained by a plurality of measurements is calculated.

6 (a) and 6 (b) are diagrams illustrating calibration of the current measurement system. The horizontal axis of FIG. 6A represents the applied bias voltage _Vbi , and the vertical axis represents the measured digital detection signal value _mi . Here, N = 2. The data processing device 300 calculates an average value m ₁ of a plurality of digital detection signals Ds ₁ obtained when Vb = Vb ₁ . Further, the data processing device 300 calculates the average value m ₂ of the plurality of digital detection signals Ds ₂ obtained when Vb = Vb ₂ .

The current I _i that flows when _Vbi is applied to the standard resistance R is I _i = Vb _i / R. FIG. 6B shows a case in which the horizontal axis is rewritten to the current I using this relationship.

Calibration of the current measurement system is equivalent to determining the function relating the measured value m and the current I in FIG. 6 (b). When m ₁ , m ₂ , I ₁ , and I ₂ are known, the current I corresponding to any m can be expressed by the following equation (4).
I = (I ₂ -I ₁ ) / (m ₂ -m ₁ ) x (m-m ₁ ) + I ₁ ... (4)

When m is obtained as the value of the digital detection signal Ds as a result of measuring the nanopore device 100 in the normal measurement mode, the true value of the corresponding current amount can be calculated from the equation (1).

This preferably, when Vb ₁ = 0 [V], the calibration process can be simplified.
When Vb ₁ = 0 [V], I ₁ = 0 [A]. Therefore, the equation (4) can be rewritten into the equation (5).
I = I ₂ / (m ₂ -m ₁ ) x (m-m ₁ ) ... (5)
Substituting I ₂ = Vb ₂ / R gives Eq. (6).
I = Vb ₂ / {R × (m ₂ -m ₁ )} × (m-m ₁ )… (6)

After acquiring the measured values m ₁ and m ₂ , the data processing apparatus 300 calculates the gain GAIN_CUR based on the following equation. Further, the measured value m ₁ is held as an offset OFS_CUR.
GAIN_CUR = Vb ₂ / {R × ( _{m2 -} m1)}
OFS_CUR = m ₁

Then, at the time of normal measurement, the true value of the current can be calculated based on the equation (7) based on the GAIN_CUR and OFS_CUR acquired in the current calibration mode.
I = GAIN_CUR × (m-OFS_CUR)… (7)

(Calibration of voltage application system)
FIG. 7 is a block diagram of the fine particle measurement system 1D in the voltage calibration mode. When configuring the voltage application system (voltage source 220), a voltage measuring instrument such as a digital multimeter 500 is connected between the output terminals of the measuring device 200 and OUT1 and OUT2 in place of the nanopore device 100.

At the time of calibration of the voltage application system, the calibration program is executed in the data processing device 300. The data processing device 300 transmits control data to the measuring device 200 and sets the measuring device 200 in the voltage calibration mode. Subsequently, the data processing device 300 transmits the set value Db of the bias voltage Vb to the measuring device 200 while switching between a plurality of N values x ₁ , x ₂ , ..., X _N. The calibration controller 250 inputs the set value x _i ( _i = 1, 2, ..., N) received from the data processing device 300 to the voltage source 220 to generate a bias voltage Vbi.

The bias voltage Vbi ( _i = 1, 2, ..., N) is measured by the digital multimeter 500. The measured value _bi of the bias voltage _Vbi is input to the data processing device 300.

For each bias voltage Vb, the digital multimeter 500 preferably makes a plurality of measurements. The data processing device 300 calculates the average value _bi of a plurality of measurements for each bias voltage _Vbi .

FIG. 8 is a diagram illustrating calibration of the voltage application system. The horizontal axis of FIG. 8 represents the set value _Db given to the voltage source 220, and the vertical axis represents the value bi of the bias voltage Vb measured by the digital multimeter 500. Here, N = 2.

The data processing device 300 acquires the measured value b ₁ of the bias voltage Vb ₁ obtained when the set value x ₁ . Further, the data processing device 300 acquires the measured value b ₂ of the bias voltage Vb ₂ obtained when the set value x ₂ .

The function g (x) passing through the two points in FIG. 8 is represented by the equation (8).
y = g (x) = (b ₂ -b ₁ ) / (x ₂ -x ₁ ) · (x-x ₁ ) + b ₁ ... (8)

In the measuring device 200, the value x'of the setting data Db required to obtain the value y of the arbitrary bias voltage Vb is expressed by the equation (9).
x'= g ^-1 (y) = (x ₂ -x ₁ ) / (b ₂ -b ₁ ) · (y-b ₁ ) + x ₁ ... (9)

The data processing device 300 is
GAIN_V = (x ₂ -x ₁ ) / (b ₂ -b ₁ )
OFS_y = b ₁
OFS_x = x ₁
And keep their values. After the calibration is completed, in the normal operation mode, when generating an arbitrary bias voltage y, the value of Ds is set.
x'= GAIN_V ・ (y-OFS_y) + OFS_x ... (10)
To generate. This makes it possible to generate an accurate bias voltage Vb.

Preferably, when Vb ₁ = 0 [V], the calibration process can be simplified. At this time, since x ₁ = 0, the gain and offset to be calculated are corrected by the following equations.
GAIN_V = x ₂ / (b ₂ -b ₁ )
OFS_y = b ₁
OFS_x = 0
Will be. When generating an arbitrary bias voltage y, as the value of Ds,
x'= GAIN_V ・ (y-OFS_y) ... (11)
Should be generated.

The calculation corresponding to the formula (7) of the current measurement system and the formula (11) of the voltage application system may be performed inside the measuring device 200. FIG. 9 is a block diagram of the measuring device 200D.

Two parameters GAIN_CUR and OFS_CUR are generated by the voltage calibration mode described above. These parameters are written non-volatilely to the memory 256 of the measuring device 200.

The calibration controller 250D has a first calculation unit 252. The first calculation unit 252 converts the value m of the digital data Ds into the current value I of the equation (7) according to the equation (7) in the normal operation mode. The interface 240 transmits digital data Ds'indicating the correct current I after conversion to the data processing device 300.

Further, two parameters GAIN_V and OFS_y are generated by the above-mentioned current calibration mode. These parameters are also written non-volatilely to the memory 256 of the measuring device 200. The calibration controller 250D has a second calculation unit 254. In the normal operation mode, the second calculation unit 254 converts the value x of the setting data Ds received from the data processing device 300 into the value x'of the equation (11) according to the equation (11), and converts the value x into the voltage source 220. Supply.

FIG. 10 is a flowchart of calibration in the fine particle measurement system 1 according to the embodiment. First, the voltage calibration mode (S100) is performed to calibrate the voltage application system. This guarantees the accuracy of the bias voltage Vb generated by the voltage source 220.

Subsequently, the current calibration mode (S102) is executed to calibrate the current measurement system. This guarantees the accuracy of the current signal measured by the transimpedance amplifier 210 and the digitizer 230. After the completion of these calibrations, normal measurement is possible and the impedance of the nanopore device 100 is measured.

Then, the same calibration parameter is used at the time of normal measurement until a predetermined period elapses from the previous calibration execution (N in S104). When the predetermined period elapses (Y in S104), calibration is performed again (S100, S102).

According to this embodiment, the value of the input signal (current signal Is) obtained from the output signal (digital data Ds) can be guaranteed within a certain accuracy, and the absolute value can be used for particle shape analysis or transient phenomenon. It can be used for advanced applications such as analysis.

Further, since the output signal value is guaranteed to be based on the input signal, the reliability as a measuring device can be guaranteed.

The present invention has been described above based on the embodiments. It is understood by those skilled in the art that this embodiment is an example, and that various modifications are possible for each of these components and combinations of each processing process, and that such modifications are also within the scope of the present invention. be. Hereinafter, such a modification will be described.

(Modification 1)
The parameters obtained by the calibration may be stored non-volatilely in the built-in memory of the data processing device 300, and the parameters may be loaded into the measuring device 200 each time the measuring device 200 is started.

(Modification 2)
In the embodiment, calibration is realized by the program control of the data processing device 300, but this is not the case. For example, a processor such as an FPGA (Field Programmable Gate Array), a microcomputer, or an ASIC (Application Specific Integrated Circuit) may be built in the measuring device 200, and the measuring device 200 may execute a calibration program.

(Modification 3)
FIG. 11 is a block diagram of the current measuring system of the measuring device 200E according to the modified example 3. In FIG. 9, the measuring device 200D corrects the digital data by digital signal processing. In FIG. 11, the measuring device 200E corrects digital data by analog signal processing. The calibration hardware 270 includes an adder 272, a D / A converter 274 for offset correction, and a D / A converter 276 for gain correction. The offset correction D / A converter 274 converts the offset correction value OFS_CUR obtained in the above-mentioned current calibration mode into an analog offset voltage V _OFS . The adder 272 adds the offset voltage V _OFS to the output voltage Vs of the transimpedance amplifier 210. The gain correction D / A converter 276 converts the gain correction value GAIN_CUR obtained in the current calibration mode into an analog reference voltage V _REF and supplies it to the reference terminal of the digitizer 230 (A / D converter).

(Modification example 4)
FIG. 12 is a block diagram of the measuring device 200F according to the modified example 4. An external voltage source 510 that has already been calibrated can be connected to the measuring device 200F. Then, the output voltage V _EXT of the external voltage source 510 can be applied to the calibration device 400 by changing from the output terminal OUT 2 to the output voltage V _INT of the internal voltage source 220. For example, the measuring device 200F may include an external power supply connection pin (EXT) and a multiplexer (selector) 260. In the current calibration mode, the multiplexer 260 can calibrate the current measurement system before the calibration of the voltage application system is completed by selecting the external voltage _VEXT .

(Modification 5)
FIG. 13 is a block diagram of the measuring device 200G according to the modified example 5. In this modification, the front-end circuit 202G can pass a current Ib between the output terminal pairs OUT1 and OUT2, and can measure the voltage Vs generated between the output terminal pairs OUT1 and OUT2 at that time. The front-end circuit 202G includes a bias current source 280 and an amplifier 282. The bias current source 280 supplies a DC bias current Ib between the output terminal pairs OUT1 and OUT2. The amplifier 282 amplifies the voltage signal Vs generated between the output terminal pair OUT1 and OUT2, and supplies the voltage signal Vs to the digitizer 230.

Calibration of the measuring device 200G can be performed separately for a voltage measuring system including an amplifier 282 and a digitizer 230 and a current application system including a bias current source 280. When calibrating the voltage measurement system, a calibration device 400 having a standard resistance may be connected to the output terminal pairs OUT1 and OUT2. Further, when calibrating the current application system, an external current measuring device may be connected to the output terminal pairs OUT1 and OUT2. The calibration process itself is as described above.

The measuring device 200G may further include a connection terminal (EXT pin) to which the external current source 520 can be connected. At the time of calibration, instead of the bias current Ib generated by the bias current source 280, the current _IEXT generated by the external current source 520 can be supplied to the device connected to the output terminal pair. The measuring device 200G may include a selector 262 for switching the current source.

(Modification 6)
Although the fine particle measuring device has been described in the present specification, the application of the present invention is not limited to this, and it can be widely used for a measuring instrument accompanied by minute current measurement using a nanopore device such as a DNA sequencer.

Although the present invention has been described based on the embodiments, the embodiments merely show the principles and applications of the present invention, and the embodiments deviate from the ideas of the present invention defined in the claims. Many modifications and arrangement changes are allowed to the extent that they are not.

1 Fine particle measurement system 2 Electrolyte 4 Particle 100 Nanopore device 102 Nanopore chip 104 Pore 106, 108 Electrode 110 Shield case 200 Measuring device 202 Front end circuit 210 Transimpedance amplifier 220 Voltage source 230 Digitizer 240 Interface 250 Calibration controller 260 multiplexer 270 Bias current source 272 amplifier 300 data processing device 400 calibration device 500 digital multimeter 510 external voltage source 520 external current source

Claims (9)

A measuring device that measures a signal that correlates with the impedance of a nanopore device that has pores and a pair of electrodes.
A device holder that includes an output terminal pair that can be connected to an electrode pair of a nanopore device and to which the nanopore device is mounted at the time of measurement.
A front-end circuit that generates an analog detection signal that correlates with the impedance between the output terminal pairs.
An A / D converter that converts the analog detection signal into a digital detection signal,
With a calibration device that has a known resistance value and is compatible with the nanopore device in terms of pin connection and is mounted on the device holder during calibration.
Equipped with
The front-end circuit
A bias voltage source to which a DC bias voltage can be applied between the output terminal pairs,
A transimpedance amplifier that converts the current signal flowing between the output terminal pairs into a voltage signal,
The voltage signal is the analog detection signal.
A measuring device characterized in that calibration is performed with the calibration device mounted on the device holder at the time of calibration. The measuring device according to claim 1 , wherein the bias voltage is set to a plurality of values at the time of calibration, and the bias voltage is calibrated based on a plurality of digital detection signals obtained corresponding to the plurality of values. .. The measuring device according to claim 1 or 2 , wherein an external voltage measuring device can be connected to the output terminal pair in place of the nanopore device and the calibration device at the time of calibration. It also has a connection terminal to which an external voltage source can be connected.
The invention according to any one of claims 1 to 3 , wherein a voltage generated by the external voltage source can be applied to the output terminal pair in place of the bias voltage generated by the bias voltage source at the time of calibration. Measuring device. The measuring device according to claim 1, wherein the front-end circuit is capable of passing a current between the output terminal pairs and measuring a voltage generated between the output terminal pairs at that time. The front-end circuit includes a bias current source capable of supplying a DC bias current between the output terminal pairs, and the analog detection signal is characterized by responding to a voltage generated between the output terminal pairs. The measuring device according to claim 5 . The measuring device according to claim 6 , wherein the bias current is set to a plurality of values at the time of calibration, and the bias current is calibrated based on a plurality of digital detection signals obtained corresponding to the plurality of values. .. The measuring device according to claim 6 or 7 , wherein an external current measuring device can be connected to the output terminal pair in place of the nanopore device and the calibration device at the time of calibration. It also has a connection terminal to which an external current source can be connected.
6 . Measuring device.

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