Fine particle measurement device

Abstract

To provide a fine particle measurement device which can solve problems of clogging.SOLUTION: A fine particle measurement device 1 is used with a pore device 100. The pore device 100 has a first liquid room 122 and a second liquid room 124 divided from each other by a barrier wall with fine holes. A measurement device 200 measures a current signal flowing between a first electrode E1 provided in the first liquid room 122 and a second electrode E2 provided in the second liquid room 124. A pressure controller 400 generates a pressure difference between the first liquid room 122 and the second liquid room 124 when clogging in the pore device 100 is detected during measurement.SELECTED DRAWING: Figure 3

Description

[Technical field]

[0001] The present disclosure relates to measurements using pore devices. [Background technology]

[0002] A particle size distribution measurement method called the electrical sensing zone method (Coulter principle) is known. In this measurement method, an electrolyte containing particles is passed through a fine hole called a nanopore. When a particle passes through the pore, the electrolyte in the pore decreases by an amount equivalent to the volume of the particle, increasing the electrical resistance of the pore. Therefore, the volume of the particle (i.e., the particle size) can be measured by measuring the electrical resistance of the pore.

[0003] 1 is a block diagram of a particle measuring apparatus 1R using an electrical sensing zone method. The particle measuring apparatus 1R includes a pore device 100R, a measuring unit 200R, and a processing unit 300.

[0004] The inside of the pore device 100R is filled with an electrolyte 2 containing particles 4 to be detected. The inside of the pore device 100R is divided into two spaces by a pore chip 102, and an electrode 106 and an electrode 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 space via the pores 104 by electrophoresis.

[0005] The measuring device 200R generates a potential difference between the electrode pair 106, 108, and acquires information correlated with the resistance value Rp between the electrode pair. 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 pair 106, 108. This potential difference Vb serves as a driving source for electrophoresis and also as a bias signal for measuring the resistance value Rp.

[0006] A minute current Is that is inversely proportional to the resistance of the pore 104 flows between the electrode pair 106 and 108 . Is = Vb / Rp … (1)

[0007] 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 equation (1) into equation (2), we obtain equation (3). Vs = -Vb × r / Rp … (3) The digitizer 230 converts the voltage signal Vs into digital data Ds. In this manner, the measuring device 200R can obtain a voltage signal Vs that is inversely proportional to the resistance value Rp of the pore 104. The processing device 300 processes the digital data Ds and analyzes the number and particle size distribution of the particles 4 contained in the electrolyte 2.

[0008] 2 is a waveform diagram of an exemplary minute current Is measured by measuring device 200R. Note that the vertical and horizontal axes of the waveform diagrams and time charts referred to in this specification are appropriately enlarged or reduced for ease of understanding, and each waveform shown is simplified, exaggerated, or emphasized for ease of understanding.

[0009] During the short period when a particle passes through, the resistance Rp of the pore 104 increases. Therefore, the current Is decreases in a pulse shape every time a particle passes through. The amplitude of each pulse current is correlated with the particle size. [Prior art documents] [Patent documents]

[0010] [Patent Document 1] JP 2017-016881 A [Patent Document 2] JP 2014-219235 A [Patent Document 3] JP 2018-054594 A [Patent Document 4] International Publication No. 2002 / 084306 Summary of the Invention [Problem to be solved by the invention]

[0011] During measurement, the particles to be detected or other contained substances may block the pores (pore clogging). When pore clogging occurs, measurement becomes impossible. In order to resolve pore clogging, a method of reversing the direction of electrophoresis has been proposed. In the configuration of FIG. 1, when clogging is detected, the voltage source 220 reverses the polarity of the bias voltage applied to the electrodes 106 and 108. This pushes the substances clogging the pores back to the opposite side, and the clogging is resolved.

[0012] Although polarity reversal of the bias voltage can be used easily, it has low removal capability due to the following constraints.

[0013] First, there is an upper limit to the current that can be applied in current measurement, so a strong electrophoretic force cannot be applied. In general electrophoresis, an electrophoretic force is generated by a current of several mA to several hundred mA, but specifically, in current measurement using pores with diameters on the order of μm to nm, only tens of nA to tens of μA can be applied.

[0014] Second, passing a large current causes electrolysis at the electrodes, which changes the concentration of the electrolyte and alters the prerequisites for the measurement.

[0015] Third, the polarity reversal changes the chemical state around the electrode. The voltage-current curve of the electrode-solution measured by cyclic voltammetry generally has hysteresis, and the same current state may not be obtained even if the same voltage is applied.

[0016] For this reason, there are cases where reversing the polarity of the bias voltage does not clear the clogging. In such cases, the measurement is stopped and an attempt is made to clear the clogging by reinjecting the electrolyte and test solution into the pore device. If this does not clear the clogging, the pore device itself is discarded and a new pore device is used.

[0017] The present disclosure has been made in this situation, and one exemplary purpose of an embodiment thereof is to provide a particle measurement device capable of solving the clogging problem. [Means for solving the problem]

[0018] A particle measuring device according to an embodiment of the present disclosure is used together with a pore device. The pore device has a first liquid chamber and a second liquid chamber separated by a partition having a fine hole. The particle measuring device includes a measuring device that measures a current signal flowing between a first electrode provided in the first liquid chamber and a second electrode provided in the second liquid chamber, a pressure control device that generates a pressure difference between the first liquid chamber and the second liquid chamber in an operating state, and a controller that can detect clogging of the pore device based on the current signal and switches the pressure control device to an operating state when clogging is detected.

[0019] Any combination of the above components, or mutual substitution of components or expressions between methods, devices, systems, etc., are also effective as aspects of the present invention or the present disclosure. Furthermore, the description in this section (Means for Solving the Problems) does not explain all essential features of the present invention, and therefore, subcombinations of the described features may also constitute the present invention. Effect of the Invention

[0020] According to certain aspects of the present disclosure, the clogging problem can be solved. [Brief description of the drawings]

[0021] [Figure 1] FIG. 1 is a block diagram of a particle measuring device using an electrical sensing zone method. [Diagram 2] FIG. 1 is a waveform diagram of an exemplary minute current Is measured by a measuring device. [Diagram 3] FIG. 1 is a diagram showing a particle measuring device according to an embodiment. [Figure 4] 4 is a diagram illustrating the operation of the particle measuring device of FIG. 3. [Diagram 5]FIG. 13 is a diagram showing the relationship between pressure and the number of passing particles. [Figure 6] 4 is a flow chart relating to the control of the clogging detection and particle measurement device. [Figure 7] FIG. 2 is a block diagram of a measuring device according to an embodiment. [Figure 8] FIG. 1 is a diagram illustrating an example of the configuration of a pressure control device according to an embodiment. [Figure 9] FIG. 1 is a diagram illustrating an example of the configuration of a pressure control device according to an embodiment. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0022] (Overview of the embodiment) A summary of some exemplary embodiments of the present disclosure will be described. This summary is intended to provide a simplified overview of some concepts of one or more embodiments for a basic understanding of the embodiments as a prelude to the detailed description that follows, and is not intended to limit the scope of the invention or disclosure. This summary is not intended to be an exhaustive overview of all possible embodiments, nor is it intended to identify key elements of all embodiments or to delineate the scope of some or all aspects. For convenience, the term "one embodiment" may be used to refer to one embodiment (example or variant) or multiple embodiments (examples or variants) disclosed in this specification.

[0023] A particle measuring device according to one embodiment is used together with a pore device. The pore device has a first liquid chamber and a second liquid chamber separated by a partition having a fine hole. The particle measuring device includes a measuring device that measures a current signal flowing between a first electrode provided in the first liquid chamber and a second electrode provided in the second liquid chamber, a pressure control device that generates a pressure difference between the first liquid chamber and the second liquid chamber in an operating state, and a controller that can detect clogging of the pore device based on the current signal and switches the pressure control device to an operating state when clogging is detected.

[0024] In this configuration, pressure is used to remove clogging, so clogging can be removed with a strong force. In addition, since there is no need to pass a large current to remove clogging, electrolysis of the electrode and the chemical state around the electrode due to polarity reversal are suppressed, making it possible to perform accurate measurements. Note that "clogging" does not only refer to a state in which the pore is completely blocked, but can also include a state in which the pore is partially blocked, or a state in which a sign of clogging is detected.

[0025] The current signal may contain a DC component (base current) and an AC component (pulse current) superimposed on it. When clogging occurs, the current signal shows a characteristic change. By detecting this change, clogging can be detected.

[0026] In one embodiment, the controller acquires an instantaneous value Iac of an AC component of the current signal and an instantaneous value Idc of a DC component of the current signal, calculates a moving average value Iac_rms of the AC component over a predetermined interval, and a moving average value Idc_rms of the DC component over a predetermined interval, and calculates the following with A as a parameter smaller than 1: |Iac_rms-Iac|>Iac_rms×A …(1) The pressure control device may be placed in an operational state when the relation (1) is satisfied.

[0027] In one embodiment, the controller may be configured to: |Idc_rms-Idc|>Idc_rms×B …(2) and when either the relation (1) or the relation (2) holds, the pressure control device may be put into an operational state.

[0028] In one embodiment, the controller may count the number of times the pressure control device is continuously activated and may execute a predetermined error action if the number exceeds a predetermined threshold.

[0029] In one embodiment, the controller may assert a flag while the pressure control device is operational, such that current signals obtained while the flag is asserted are invalid data and excluded from particle analysis.

[0030] In one embodiment, the controller may store pressure information (pressure value or pressure control device state) in a file in association with waveform data of the current signal. During analysis after measurement, the section in which clogging was removed can be determined based on the pressure information recorded in this file, and the current signal obtained in this section can be treated as invalid data and excluded from the particle analysis.

[0031] In one embodiment, the meter may include a transimpedance amplifier that converts the current signal to a voltage signal, and a digitizer that converts the output of the transimpedance amplifier to a digital signal.

[0032] In one embodiment, the controller may detect clogging based on the AC component of the current signal. When clogging begins to occur, the frequency of pulses increases. Thus, the controller may detect clogging based on the frequency of pulses.

[0033] In one embodiment, the controller may detect clogging based on a DC component of the current signal. The DC component (base current) of the current signal decreases with clogging. Therefore, the controller may detect clogging based on the decrease in the DC component.

[0034] In one embodiment, the measuring device may be capable of reversing the polarity of the voltage applied to the first electrode and the second electrode, and the pressure control device may generate a pressure difference in a direction corresponding to the polarity of the voltage applied until then when clogging is detected.

[0035] In one embodiment, the pressure control device may generate a pressure difference by increasing or decreasing the pressure on the first liquid chamber side relative to the atmosphere while leaving the second liquid chamber open to the atmosphere.

[0036] In one embodiment, the meter may include a transimpedance amplifier that converts the current signal to a voltage signal, and a digitizer that converts the output of the transimpedance amplifier to a digital signal.

[0037] (Embodiment) Preferred embodiments will be described below with reference to the drawings. The same or equivalent components, parts, and processes shown in each drawing are given the same reference numerals, and duplicated descriptions will be omitted as appropriate. In addition, the embodiments are illustrative and do not limit the invention, and all features and combinations thereof described in the embodiments are not necessarily essential to the invention.

[0038] In this specification, "a state in which component A is connected to component B" includes not only a case in which component A and component B are directly physically connected to each other, but also a case in which component A and component B are indirectly connected to each other via other components that do not substantially affect the electrical connection state between them or that do not impair the function or effect achieved by their combination.

[0039] Similarly, "a state in which component C is provided between components A and B" includes not only the case in which components A and C, or components B and C, are directly connected to each other, but also the case in which they are indirectly connected to each other via other components that do not substantially affect the electrical connection between them or that do not impair the functions or effects achieved by their combination.

[0040] In addition, the dimensions (thickness, length, width, etc.) of each component shown in the drawings may be enlarged or reduced as appropriate for ease of understanding. Furthermore, the dimensions of multiple components do not necessarily represent their relative sizes, and even if a component A is drawn thicker than another component B on the drawings, component A may actually be thinner than component B.

[0041] 3 is a diagram showing the particle measuring apparatus 1 according to the embodiment. The particle measuring apparatus 1 includes a pore device 100, a measuring instrument 200, a processing apparatus 300, and a pressure control apparatus 400.

[0042] The pore device 100 includes a pore chip 110 and a chip case 120. The pore chip 110 has pores (fine holes) 112 formed therein. The pore chip 110 is housed inside the chip case 120, and divides the internal space of the chip case 120 into a first liquid chamber 122 and a second liquid chamber 124. The first liquid chamber 122 and the second liquid chamber 124 communicate with each other via the pores 112. A first electrode E1 is provided in the first liquid chamber 122, and a second electrode E2 is provided in the second liquid chamber 124.

[0043] During measurement, the internal space of the chip case 120 is filled with the electrolyte 2 containing the particles 4 to be measured.

[0044] The measuring device 200 applies a voltage V between the first electrode E1 and the second electrode E2, and measures an ion current I flowing between the first electrode E1 and the second electrode E2. The measuring device 200 includes a voltage source 202, a current detection circuit 204, and a waveform capture module 206. The voltage source 202 generates a potential difference V between the first electrode E1 and the second electrode E2. This potential difference V causes particles 4 contained in the electrolyte 2 to move by electrophoresis.

[0045] The current detection circuit 204 generates a current detection signal Vcs indicating an ion current I flowing from the first electrode E1 to the second electrode E2. The waveform capture module 206 captures the waveform of the current detection signal Vcs. The waveform data WAVE generated by the waveform capture module 206 is transmitted to the processing device 300.

[0046] The processing device 300 has a function of a controller 302 that controls the whole particle measuring device 1, and a function of a data processing unit 304 that processes the waveform data WAVE and estimates the particle size of the particles 4. The processing device 300 may be a combination of hardware such as a general-purpose laptop computer, desktop computer, workstation, tablet terminal, etc., and a dedicated software program. Alternatively, the processing device 300 may be hardware dedicated to the particle measuring device 1.

[0047] The controller 302 can set the measurement conditions of the measuring device 200 based on the control signal S1. The controller 302 generates a control signal S2 that instructs control of the activation and deactivation of the pressure control device 400, which will be described later. The controller 302 can also control the state of the data processing unit 304 based on a control signal S3.

[0048] The data processing unit 304 performs processing such as estimating particle diameter based on the waveform data WAVE.

[0049] The processing device 300 is configured to be able to detect clogging of the pores 112 of the pore device 100. The pressure control device 400 is stopped during normal measurement by the measuring device 200. When clogging of the pore device 100 is detected during measurement, the pressure control device 400 generates a pressure difference between the first liquid chamber 122 and the second liquid chamber 124. It is preferable that the pressure is generated in the opposite direction to the movement direction of the particles due to electrophoresis during measurement. The movement direction of the particles in the electrolyte 2 is determined by the direction of the electric field and the charge of the molecules (positive charge or negative charge). In many cases, the particles to be measured are negatively charged in the solution and therefore move from the negative electrode to the positive electrode.

[0050] In this embodiment, the controller 302 has a clogging detection function. Specifically, the controller 302 detects clogging based on the waveform data WAVE of the current signal I from the measuring device 200.

[0051] FIG. 4 is a waveform diagram of the current signal I. The current signal I shown in the middle includes a DC component (base current) that flows due to electrophoresis regardless of the presence of particles, and an AC component (pulse current) that is caused by the particles passing through the pores 112. The upper part of FIG. 4 shows the pulse current corresponding to one particle, and the lower part of FIG. 4 shows the base current. FIG. 4 shows a normal state φ1 in which no clogging occurs, a state in which clogging is progressing, in other words, a state in which a sign of clogging occurs (a sign state) φ2a, and a state in which complete clogging occurs (a complete clogging state) φ2b. The sign state φ2a or the complete clogging state φ2b is collectively referred to as a clogging state φ2.

[0052] In one embodiment, the controller 302 may detect the clogged state φ2 based on the AC component (pulse current) of the current signal I. As shown in FIG. 4, in the normal state φ1, a pulse current is observed every time a particle passes through. In contrast, in the precursor state φ2a, the occurrence of the pulse current is more frequent than in the normal state φ1. In the completely clogged state φ2b, the occurrence frequency of the pulse current approaches zero. Therefore, the controller 302 can detect the precursor state φ2a or the completely clogged state φ2b based on the occurrence frequency of the pulse current.

[0053] In one embodiment, the controller 302 may detect the clogged state φ2 based on the DC component (base current) of the current signal I. As shown in FIG. 4, in the normal state φ1, a relatively large base current is observed. In contrast, in the precursor state φ2a, the base current decreases over time. In the completely clogged state φ2b, the base current remains very small. Therefore, the controller 302 can detect the precursor state φ2a or the completely clogged state φ2b based on the base current.

[0054] The controller 302 may detect the clogging state φ2 using characteristic changes in both the pulse current and the base current, which can further improve the detection accuracy.

[0055] The current measurement by the measuring device 200 continues even during operation of the pressure control device 400. The controller 302 is configured to monitor the current signal I during operation of the pressure control device 400, and detect that the clogging state φ2 has been resolved, that is, that the state has returned to the normal state φ1, based on the current signal I. The return to the normal state φ1 can also be detected based on at least one of the base current and the pulse current of the current signal I.

[0056] The controller 302 generates a control signal S2 for controlling the state of the pressure control device 400 and a control signal S3 for controlling the state of the data processing unit 304 according to the presence or absence of clogging. When the controller 302 detects a clogging state, it activates the pressure control device 400. During the operation of the pressure control device 400, the accuracy of the current signal measured by the measuring device 200 decreases, so the process related to particle measurement by the data processing unit 304 is stopped.

[0057] When the controller 302 detects that the clogging state has been eliminated, it stops the pressure control device 400. It also restarts the processing related to particle measurement by the data processing unit 304.

[0058] Fig. 5 is a diagram for explaining the operation of the particle measuring apparatus 1 of the pore device 100 of Fig. 3. Here, it is assumed that the controller 302 detects the precursor state φ2a.

[0059] time t 0 Before time t, the particle measurement device 1 operates normally. 0 At time t, clogging begins, and short pulses begin to appear in the current signal I. 1 Then, the controller 302 switches the pressure control device 400 to an operating state. When the pressure control device 400 operates, the particles clogging the pores 112 are pushed back toward the original liquid chamber by the pressure of the liquid. This removes the clogging. While the pressure control device 400 is operating, the particle measurement process by the data processing unit 304 is suspended.

[0060] The controller 302 detects a time t 2When it is determined that the clogging has been eliminated at time t 3 Then, the data processing unit 304 resumes particle measurement processing.

[0061] The above is the operation of the particle measuring device 1. According to this particle measuring device 1, electrophoresis is used to move the particles 4 during measurement, while pressure is used to remove clogging, making it possible to remove clogging with a strong force. In addition, since there is no need to pass a large current to remove clogging, electrolysis of the electrodes and chemical conditions around the electrodes due to polarity reversal are suppressed, enabling accurate measurement.

[0062] Next, the detection of clogging by the controller 302 will be described.

[0063] The controller 302 detects the AC component (pulse current) Iac and the DC component (base current) Idc of the current signal. For example, the controller 320 separates the AC component (pulse current) Iac and the DC component (base current) Idc of the current signal by filtering the waveform data WAVE.

[0064] The controller 302 acquires an instantaneous value Iac of the AC component of the current signal and an instantaneous value Idc of the DC component, and then calculates a moving average value Iac_rms of the AC component Iac over a recent predetermined interval, and a moving average value Idc_rms of the DC component Idc over a recent predetermined interval.

[0065] The controller 302 evaluates two relationships. |Iac_rms-Iac|>Iac_rms×A …(1) |Idc_rms-Idc|>Idc_rms×B …(2) A and B are parameters having predetermined values, A<1 and B<1.

[0066] The controller 302 determines that clogging has occurred when at least one of the two relational expressions (1) and (2) holds (is true).

[0067] 6 is a flowchart relating to the detection of clogging and the control of the particle measurement device 1. First, an initialization process S100 is performed. Specifically, a count value Exec_Count is initialized. The count value Exec_Count indicates the number of times that the pressure control device 400 has been continuously operated to remove clogging.

[0068] When the condition for ending the measurement is met (Y in S102), the process ends (S104).

[0069] When the condition for ending the measurement is not met (N in S102), a current signal is detected (S106). Then, the current signal is separated into a DC component Idc and an AC component Iac (S108). Next, average values ​​Idc_rms and Iac_rms of the DC component Idc and the AC component Iac are calculated (S110).

[0070] Next, the relational expressions (1) and (2) are evaluated (S112, S114). If neither of the relational expressions (1) nor (2) holds, it is determined that no clogging has occurred and the process proceeds to step S116. In step S116, the execution flag Exec_flag is set to 0, and the process returns to step S102. The execution flag Exec_flag is a flag indicating that processing to eliminate clogging is currently being performed.

[0071] When at least one of the relational expressions (1) and (2) is satisfied, it is determined that clogging has occurred, and the process proceeds to step S118. In step S118, the execution flag Exec_flag is set to 0, and the pump of the pressure control device 400 is operated (S120). Then, the count value Exec_Count is incremented (S122). Then, the count value Exec_Count is compared with a predetermined threshold value Z. When the number of times Exec_Count that the process for removing clogging has continued is smaller than the threshold value Z (N in S124), the process returns to step S102. When the number of times Exec_Count exceeds the threshold value Z (Y in S124), it is considered that the removal of clogging has failed, so the flag Exec_Flag is set to 0 (S126) and the measurement is terminated (S128). While S104 is a normal end, S128 is an abnormal end.

[0072] While the flag Exec_flag is asserted (=1), the measurement data does not show a correct result. Therefore, for the section where Exec_flag=1, the waveform data WAVE may not be saved. Alternatively, data indicating the section where Exec_flag=1 may be added to the waveform data WAVE and saved. This allows the current signal obtained in the section where clogging occurred to be treated as invalid data and excluded from particle analysis.

[0073] The controller 302 may record the pressure information (pressure value or state of the pressure control device) in a file in association with the waveform data WAVE. During analysis after measurement, the section in which the clogging was removed can be determined based on the pressure information recorded in this file. The current signal obtained in this section may then be treated as invalid data.

[0074] 7 is a block diagram of a measuring device 200A according to an embodiment. The measuring device 200A includes a transimpedance amplifier 210, a voltage source 220, and a digitizer 230. The voltage source 220 corresponds to the above-mentioned voltage source 202. The transimpedance amplifier 210 corresponds to the above-mentioned current detection circuit 204. The digitizer 230 corresponds to the above-mentioned waveform capture module 206.

[0075] The transimpedance amplifier 210 includes an operational amplifier OA1 and a resistor R1. The inverting input terminal of the operational amplifier OA1 is connected to the first electrode E1, and the non-inverting input terminal is grounded. The resistor R1 is connected between the inverting input terminal and the output terminal of the operational amplifier OA1.

[0076] The voltage source 220 applies a voltage V to the first electrode E1. Due to the virtual grounding of the operational amplifier OA1, the potential of the inverting input terminal, i.e., the first electrode E1, becomes the ground (0 V). Therefore, the voltage V is applied between the first electrode E1 and the second electrode E2.

[0077] The ionic current I flowing from the first electrode E1 to the second electrode E2 flows into the transimpedance amplifier 210. The voltage Vcs of the transimpedance amplifier 210 is expressed as follows: Vcs = -I × R1 This results in a voltage proportional to the ion current I. Therefore, the ion current I is I = Vcs / R1 It can be calculated as:

[0078] The digitizer 230 includes an A / D converter 232, a memory 234, and an interface circuit 236. The A / D converter 232 converts the current detection signal Vcs into a digital signal at a predetermined sampling period. The memory 234 stores waveform data. The interface circuit 236 transmits the waveform data stored in the memory 234 to the processing device 300.

[0079] 8 is a diagram showing a pressure control device 400A according to one embodiment. The pressure control device 400A includes a pressure source 410A and a control valve 420A. The pressure source 410A includes an air pressure pump 412.

[0080] The control valve 420A includes valves V1 and V2. It is preferable to provide a buffer air vent because abrupt pressure switching may damage the pore tip 110. The state of the control valve 420A is controlled according to a control signal S2 generated by the controller 302.

[0081] When the pressure control device 400A is stopped, the valve V1 is in a closed state and the valve V2 is in a conducting state. Note that the air pressure pump 412 may be stopped while the pressure control device 400A is stopped.

[0082] When the valve V1 is in a conducting state and the valve V2 is in a blocking state, the pressure control device 400A is in an operating state. This allows a pressure difference to be generated between the first liquid chamber 122 and the second liquid chamber 124. Since the first liquid chamber 122 is open to atmospheric pressure, when a positive pressure air pressure pump 412 is used, a pressure can be generated from the second liquid chamber 124 toward the first liquid chamber 122. Conversely, when a negative pressure air pressure pump 412 is used, a pressure can be generated from the first liquid chamber 122 toward the second liquid chamber 124.

[0083] The measuring device 200 can reverse the polarity of the voltage V applied to the first electrode E1 and the second electrode E2, i.e., the direction of electrophoresis. When clogging is detected, the pressure control device 400 switches the direction of pressure according to the polarity of the voltage V generated by the measuring device 200, i.e., the direction of electrophoresis. Specifically, a pressure difference is generated so as to push back the particles in the opposite direction to the movement of the particles due to electrophoresis.

[0084] 9 is a diagram showing a pressure control device 400B according to an embodiment. The pressure control device 400B mainly includes clog removal pumps 412A and 412B, valves V1 to V5, an internal power supply 402, a main pump 442, a buffer tank 444, and pressure sensors 446 and 448.

[0085] The internal power supply 402 receives a DC power supply voltage from an AC adapter, which is an external power supply, and generates an internal power supply voltage stabilized at a predetermined voltage level by stepping up or stepping down the voltage.

[0086] The buffer tank 444 is connected to the main pump 442 and accumulates pressure. Pressure sensors 446 and 448 detect the pressure inside the buffer tank 444 or on the output side.

[0087] The unclog pump 412A draws in or expels air through port A. The unclog pump 412B draws in or expels air through port B.

[0088] A control signal is input to the controller 430 from an external DSP (Digital Signal Processor) 4. The DSP 4 can be a part of the processing device 300. In response to the control signal from the DSP 4, the controller 430 controls the states of the valves V1 to V5, the clog removal pumps 412A and 412B, and the main pump 442, and switches the operation mode of the pressure control device 400B. When operating the main pump 442, the controller 430 controls the main pump 442 based on the outputs of the pressure sensors 446 and 448 so that the pressure in the buffer tank 444 is constant.

[0089] The operation of the pressure control device 400B of Fig. 9 will be described. This pressure control device 400B is capable of switching between six operation modes.

[0090] The first and second modes are modes related to the above-mentioned clogging removal.

[0091] First mode Valves V1, V3, and V4 are closed (off), V5 is open (on), and V2 is redundant (DC: Don't care). The pneumatic pump 412 and the unclog pump 412B are stopped, and the unclog pump 412A is operational. In the first mode, pressure can be controlled through port A to unclog the pore device 100.

[0092] Second mode Valves V1, V2, and V5 are closed (OFF), V3 is open (ON), and V4 is DC. The main pump 442 and the unclog pump 412A are stopped, and the unclog pump 412B is operational. In the second mode, pressure can be controlled through port B to unclog the pore device 100.

[0093] Third mode The valve V1 is closed (off), V3 and V5 are open (on), and V2 and V4 are redundant (DC: Don't care) and do not care if they are open or closed. The main pump 442 and the clog removal pumps 412A and 412B are stopped. The third mode can be selected in the standby state when replacing the pore device 100.

[0094] -Fourth mode The valve V1 is closed (off), and V2 to V5 are redundant (DC: Don't care). The main pump 442 is in an operating state, and the clogging removal pumps 412A and 412B are in a stopped state. In the fourth mode, pressure can be accumulated in the buffer tank 444.

[0095] 5th mode Valves V1, V2, and V5 are open (ON), and V3 and V4 are closed (OFF). The main pump 442 and the clog removal pumps 412A and 412B are stopped. The fifth mode can be selected after pressure is accumulated in the buffer tank 444 in the fourth mode, and pressure can be applied to the pore device 100 via port A using the pressure of the buffer tank 444. Note that the air pressure pump 412 may be operated in the fifth mode.

[0096] -6th mode Valves V1, V3, and V4 are open (ON), and V2 and V5 are closed (OFF). The main pump 442 and the clog removal pumps 412A and 412B are stopped. The sixth mode can be selected after pressure is accumulated in the buffer tank 444 in the fourth mode, and pressure can be applied to the pore device 100 via port B using the pressure in the buffer tank 444.

[0097] In the pressure control device 400B in Fig. 9, it is possible to omit one of the clog removal pumps 412A and 412B. Also, since the main pump 442, the buffer tank 444, and the pressure sensors 446 and 448 do not contribute to clog removal, some or all of them may be omitted when only the clog removal function is required.

[0098] The embodiment has been described above. This embodiment is merely an example, and it will be understood by those skilled in the art that various modifications are possible in the combination of each component and each processing step, and that such modifications are also within the scope of the present invention. Such modifications will be described below.

[0099] Although the present specification describes a particle measuring instrument, the application of the present invention is not limited thereto, and the present invention can be widely used in measuring instruments that involve measuring minute currents and are used in conjunction with pore devices, including DNA sequencers.

[0100] In the embodiment, the particles are driven by electrophoresis, but the application of the present disclosure is not limited to this, and the present disclosure can also be applied to a driving method that uses a concentration gradient to diffuse into a liquid, or a driving method that uses a pressure difference.

[0101] In particular, for the driving method utilizing pressure difference, the pressure control device 400B in FIG. 8 can be used. Specifically, when the fifth and sixth modes are used, the pump can be stopped while the liquid is being driven, making it possible to perform highly accurate particle measurement without being affected by pump pulsation.

[0102] The present invention has been described based on the embodiments, but the embodiments merely illustrate the principles and applications of the present invention, and many modifications and changes in arrangement are permitted to the embodiments without departing from the spirit of the present invention as defined in the claims. [Explanation of symbols]

[0103] 1 Particulate measurement device 2 Electrolyte 4 particles 100 pore device 110 Pore Tip 112 Poa 120 Chip Case 122 1st liquid chamber 124 2nd liquid chamber E1 1st electrode E2 2nd electrode 200 measuring instruments 202 Voltage Source 204 Current detection circuit 206 Waveform Capture Module 210 Transimpedance Amplifier 220 Voltage Source 230 Digitizer 232 A / D converter 234 Memory 236 Interface Circuit 300 Processing Equipment 302 Controller 304 Data Processing Unit V1, V2, V3, V4, V5 valves 400 Pressure Control Device 410 Pressure Source 412 Pneumatic Pump 412A, 412B Clog removal pump 420 Control valve 430 Controller 442 Main Pump 444 Buffer Tank 446,448 Pressure Sensors

Claims

1. 1. A particle measuring apparatus for use with a pore device, comprising: the pore device has a first liquid chamber and a second liquid chamber separated by a partition having a fine hole; The particle measuring device is a measuring device that measures a current signal flowing between a first electrode provided in the first liquid chamber and a second electrode provided in the second liquid chamber; a pressure control device that generates a pressure difference between the first fluid chamber and the second fluid chamber in an operating state; a controller capable of detecting clogging of the pore device based on the current signal, and causing the pressure control device to enter the operating state when the clogging is detected; A particle measuring device comprising:

2. The controller: acquiring an instantaneous value Iac of an AC component of the current signal and an instantaneous value Idc of a DC component of the current signal; A moving average value Iac_rms of the AC component over a predetermined interval and a moving average value Idc_rms of the DC component over the predetermined interval are calculated, and A is a parameter smaller than 1, |Iac_rms−Iac|>Iac_rms×A…(1) 2. The particle measuring device according to claim 1, further comprising: evaluating a relational expression (1) below: and, when the relational expression (1) holds, bringing the pressure control device into the operating state.

3. The controller may include: |Idc_rms−Idc|>Idc_rms×B…(2) 3. The particle measuring apparatus according to claim 2, further comprising: evaluating a relational expression (2) below: and placing the pressure control device in the operating state when the relational expression (1) or (2) holds.

4. 4. The particle measuring device according to claim 2, wherein the controller counts the number of times that the pressure control device is continuously in the operating state, and executes a predetermined error processing when the number of times exceeds a predetermined threshold value.

5. 4. The particle measuring device according to claim 1, wherein the controller asserts a flag while the pressure control device is in the operating state.

6. 4. The particle measuring device according to claim 1, wherein the controller stores the pressure information in a file in association with the waveform data of the current signal.

7. The measuring instrument is a transimpedance amplifier for converting the current signal into a voltage signal; a digitizer for converting an output of the transimpedance amplifier into a digital signal; 4. The particle measuring device according to claim 1, further comprising:

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