DE102019123163A1 - MEASURING DEVICE AND CALIBRATION METHOD - Google Patents

Abstract

One purpose of the present invention is to provide a measuring device which is capable of measuring an absolute value of a current or otherwise a voltage. A measuring device 200 measures a signal which corresponds to a resistance of a nanopore device which has an opening 104 and a pair of electrodes. The nanopore device can be connected between an output connection pair OUT1 and OUT2. A front end circuit 202 generates an analog signal V _S which corresponds to the resistance between the output connection pair OUT1 and OUT2. A digitizer 230 converts the analog detection signal Vs into a digital detection signal D _S. Instead of the nanopore device 100, a calibration device 400, which has a known resistance value R, can be connected between the output connection pair OUT1 and OUT2. The measuring device 200 is designed to be calibrated in a state in which the calibration device 400 is connected.

Description

FIELD OF THE INVENTION

The present invention relates to a measurement using a nanopore device.

STATE OF THE ART

A method for measuring the particle size distribution, which is referred to as the “electrical sensing zone method” (Coulter principle), is known. With this measurement method, an electrolyte solution with particles is applied in such a way that it passes through an opening called “nanopore”. When a particle passes through such an opening, the amount of the electrolyte solution with which the opening is filled is reduced by an amount corresponding to the volume of the particle, which increases the electrical resistance of the opening. Accordingly, in a case where the opening has a thickness larger than the particle size, by measuring the electrical resistance of the opening, this arrangement is able to measure the volume of the particle passing through the opening. Conversely, in a case where the opening has a thickness sufficiently smaller than the particle size, this arrangement is able to measure the cross-sectional area (i.e. the particle diameter) of the particle that passes through the opening.

1 Figure 3 is a block diagram showing a small particle measurement system 1R shows which uses the "electrical sensing zone method". The small particle measurement system 1R has a nanopore device 100 , a measuring device 200R and a data processing device 300 on.

The interior of the nanopore device 100 is with an electrolytic solution 2nd filled which the particles to be detected 4th having. The interior of the nanopore device 100 is by means of a nanopore chip 102 divided so that two interiors are defined. The electrodes 106 and 108 are assigned to the two rooms. If there is an electrical potential difference between the electrodes 106 and 108 generates an ion current flow between the electrodes. In addition, the particles migrate 4th by electrophoresis from a specific room via the opening 104 in the other room.

The measuring device 200R generates the electrical potential difference between the pair of electrodes 106 and 108 and captures information that correlates with the resistance value Rp have between the pair of electrodes. The measuring device 200R has a transimpedance amplifier 210 , a voltage source 220 and a digitizer 230 on. The voltage source 220 generates an electrical potential difference Vb between the pair of electrodes 106 and 108 . The electrical potential difference Vb acts as the driving source of electrophoresis and is used as a bias signal to measure the resistance value Rp.

A small current Is flows through the pair of electrodes 106 and 108 in inverse proportion to the resistance of the opening 104 . $$\text{Is}=\text{Vb / Rp}$$

The transimpedance amplifier 210 converts the small current Is into a voltage signal Vs. With the conversion gain as r, the following expression holds. $$\text{Vs}=\text{r}\times \text{Is}$$

Substituting expression (1) into expression (2) gives the following expression (3). $$\text{Vs}=\text{Vb}\times \text{r / Rp}$$

The digitizer 230 converts the voltage signal Vs into digital data Ds. The measuring device is as described above 200R able the voltage signal Vs in inverse proportion to the resistance value Rp the opening 104 capture.

2nd Fig. 10 is a waveform diagram of an example of the small current Is which of the measuring device 200R is measured. Note that the vertical and horizontal axes shown in the waveform and time charts in the present description are expanded or reduced accordingly for better understanding. In addition, each waveform is simplified or exaggerated in the drawings for emphasis or understanding.

During a short period of time in which a particle is opening 104 passes through, the resistance value Rp the opening 104 large. The current drops accordingly Is in the form of a pulse every time a particle enters the opening 104 goes through. The amplitude of each current pulse correlates with the particle size. The data processing device 300 processes the digital data Ds so the number of in the electrolytic solution 2nd contained particles 4th to analyze their particle distribution or the like.

[State of the art documents]

[Patent documents]

• [Patent Document 1] Japanese Patent Application Laid-Open No. 2011-513739
• [Patent Document 2] Japanese Patent Application Laid-Open No. H04-040373
• [Patent Document 3] Japanese translation PCT patent application publication no. H07-504989
• [Patent Document 4] Japanese Patent Application Laid-Open No. 2004-510980

DISCLOSURE OF THE INVENTION

TECHNICAL PROBLEM

With such a conventional small particle measurement system 1R a measurement is carried out (which is hereinafter referred to as “calibration measurement”), using international standard particles, each of which has a known particle diameter (which is referred to as “standard particle diameter”). As a measurement result, a relation between a signal intensity (pulse-current amplitude) measured during this measurement and the standard particle diameter is recorded. If unknown particles are measured in such an arrangement, the particle diameter is estimated on the basis of the signal intensity measured in this way and the correspondence relation obtained in the calibration measurement.

In the following, the estimation of the particle size according to a conventional technique is described in detail. 3rd shows an example of a signal intensity histogram recorded in the international standard particle measurement. Here the horizontal axis represents a signal intensity, which represents a change in the digital data Ds for each pulse, ie the amplitude of the pulse current. The vertical axis represents the number of pulses.

The middle of the 3rd The histogram shown represents a standard intensity I _REF which is the standard particle diameter φ ₀ corresponds. If the signal intensity I _x when measuring unknown particles, the particle diameter becomes accordingly φ _x of which based on the relation between IREF and φ ₀ estimated.

As described above, electrical calibration of the signal accuracy in the small particle measurement system 1R which uses such a conventional “electrical sensing zone method” is not supported. Accordingly, the digital data represent D _S only a relative current value. That is, the digital data D _S have no physical meaning. In a case where a measuring device has an unintended deviation in its input signal, this arrangement accordingly has the potential to cause a problem in detecting the output signal thereof as a correct result.

To such a problem with such a small particle measurement system 1R To avoid according to a conventional technique, only a part of the generated raw data can be used for the particle diameter measurement and the measurement of the number of particles. That means the remaining data is superfluous. In other words, such an arrangement is able to use only part of the data as effective data. This leads to difficulties in using such data for development applications such as particle shape analysis, transit phenomenon analysis when a particle passes through a nanopore, etc. It should be noted that this problem is in no way within the general understanding of one of ordinary skill in the art.

The present invention has been made in view of such a situation. Accordingly, an exemplary purpose of an embodiment of the present invention is to provide a small particle measurement system that is capable of measuring an absolute value of a current or a voltage.

THE SOLUTION OF THE PROBLEM

One embodiment of the present invention relates to a measuring device which is designed to measure a signal which corresponds to a resistance of a nanopore device which has an opening and a pair of electrodes. The measuring device has the following: an output connection pair which can be connected to the electrode pair of the nanopore device; a front-end circuit which is designed to generate an analog detection signal which corresponds to a resistance between the output connection pair; and an A / D converter, which is designed to convert the analog detection signal into a digital detection signal. A calibration device which has a known resistance value can be connected between the output connection pair instead of the nanopore device. The measuring device can be calibrated in a state in which the calibration device is connected.

Another embodiment of the present invention relates to a calibration method for a measuring device which is designed to measure a signal which corresponds to a resistance of a nanopore device which has an opening and a pair of electrodes. The measuring device has the following: an output connection pair which can be connected between the electrode pair of the nanopore device; a bias voltage source configured to apply a DC bias voltage to the output terminal pair; a transimpedance amplifier configured to convert a current signal flowing between the pair of output terminals into a voltage signal; and an A / D converter which is designed to convert an output signal of the transimpedance amplifier into a digital value. The calibration method has the following steps: connecting a known resistor instead of the nanopore device to the output connection pair; Detecting an output signal of the A / D converter in a state in which a known DC bias voltage is applied to the known resistor; and acquiring a calibration parameter based on an output signal of the A / D converter.

It should be noted that any combination of the components described above, any component of the present invention or any aspect thereof can be mutually replaced between a method, an apparatus, etc., which are also effective as an embodiment of the present invention.

ADVANTAGEOUS EFFECT OF THE INVENTION

An embodiment of the present invention has a measuring device in which the accuracy of a current signal or a voltage signal is ensured.

Figure list

• 1 ein Blockdiagramm, das ein Kleinpartikelmesssystem, welches das „electrical sensing zone Verfahren“ verwendet;
• 2 ein Wellenformdiagramm, das ein Beispiel für einen von einer Messvorrichtung gemessenen Mikrostrom Is zeigt;
• 3 ein Beispiel für ein Histogramm einer Signalintensität, welche bei einer internationalen-Standard-Partikelmessung erfasst wurde;
• 4 ein Blockdiagram, welches ein Kleinpartikelmesssystem gemäß einer Ausführungsform zeigt;
• 5 ein Blockdiagram, welches ein Kleinpartikelmesssystem in einem Strom-Kalibrierungsmodus zeigt;
• 6A und 6B Diagramme zum Erläutern der Kalibrierung eines Strom-Messsystems;
• 7 ein Blockdiagramm, welches ein Kleinpartikelmesssystem in einem Spannungs-Kalibrierungsmodus zeigt;
• 8 ein Diagramm zum Erläutern der Kalibrierung eines Spannungs-Anlege-Systems;
• 9 ein Blockdiagramm, welches eine Messvorrichtung zeigt;
• 10 ein Flussdiagramm, welches bei dem Kleinpartikelmesssystem gemäß einer Ausführungsform verwendet Kalibrierung zeigt;
• 11 ein Blockdiagramm, welches ein Strom-Messsystem einer Messvorrichtung gemäß Modifikation 3 zeigt;
• 12 ein Blockdiagramm, welches eine Messvorrichtung gemäß Modifikation 4 zeigt; und
• 13 ein Blockdiagramm, welches eine Messvorrichtung gemäß Modifikation 5 zeigt.

The figures show:

• 1 a block diagram showing a small particle measurement system using the "electrical sensing zone method";
• 2nd FIG. 4 is a waveform diagram showing an example of a microcurrent Is measured by a measuring device;
• 3rd an example of a histogram of a signal intensity, which was recorded in an international standard particle measurement;
• 4th 3 is a block diagram showing a small particle measurement system according to an embodiment;
• 5 a block diagram showing a small particle measurement system in a current calibration mode;
• 6A and 6B Diagrams for explaining the calibration of a current measuring system;
• 7 a block diagram showing a small particle measurement system in a voltage calibration mode;
• 8th a diagram for explaining the calibration of a voltage application system;
• 9 a block diagram showing a measuring device;
• 10th 3 is a flowchart showing calibration used in the small particle measurement system according to an embodiment;
• 11 a block diagram showing a current measuring system of a measuring device according to modification 3;
• 12th a block diagram showing a measuring device according to modification 4; and
• 13 a block diagram showing a measuring device according to modification 5.

PREFERRED EMBODIMENT OF THE INVENTION

The present invention is described below on the basis of preferred embodiments with reference to the drawings. Identical or similar components, elements and processes are provided with the same reference symbols, and redundant descriptions thereof may be omitted. The embodiments have been described for exemplary purposes only and are in no way intended to limit the present invention. In addition, it is not absolutely necessary for the present invention that all features or a combination thereof are arranged as described in the embodiments.

In the present description, the state expressed by the sentence "the element A is connected to the element B" includes a state in which the element A is indirectly connected to the element B via another element which is the electrical connection between them not significantly affected or the functions or effects of the connection between them, as well as a state in which they are physically and directly connected.

Likewise, the reference to the element C. is between the element A and the element B arranged “expressed state with a state in which the element A indirectly with the element C. connected, or the element B indirectly with the element C. is connected via another element that does not significantly affect the electrical connection between them or does not impair the functions or effects of the connection between them, and a state in which they are directly connected.

BASIC VERSION

4th Fig. 3 is a block diagram showing a small particle measurement system 1 according to one embodiment. The small particle measurement system 1 has a nanopore device 100 , a measuring device 200 and a data processing device 300 on.

As for 1 describes the nanopore device 100 a nanopore chip 102 with an opening 104 is provided, and a pair of electrodes 106 and 108 on. An interior of the nanopore chip 102 is filled with an electrolyte solution such as a KCI solution (potassium chloride), PBS solution (phosphate buffered saline) or the like.

The measuring device 200 has an output connector pair OUT1 and OUT2 , a front-end circuit 202 , a digitizer 230 , an interface 240 and a calibration controller 250 on. The nanopore device 100 can be detached from the output connector pair OUT1 and OUT2 connected. In a state in which the nanopore device 100 to the output connector pair OUT1 and OUT2 is connected, is the output connector pair OUT1 and OUT2 electrically to the pair of electrodes 106 and 108 via pens P1 and P2 the nanopore device 100 connected. In a state in which the nanopore device 100 to the front-end circuit 202 is attached is the front end circuit 202 capable of an analog detection signal V _p to generate, which has a correlation with a resistance which is between the output terminal pair OUT1 and OUT2 is present.

The digitizer 230 has an A / D converter and converts the analog detection signal V _p into a digital detection signal D _S around.

In the present embodiment, the front-end circuit is 202 designed to have a bias voltage Vb to the output connector pair OUT1 and OUT2 to put on and around a stream I _S to measure which flows in this state. The front-end circuit 202 has a transimpedance amplifier 210 and a voltage source 220 on.

The data processing device 300 acts as an interface with the user. In addition, the data processing device controls 300 integral the small particle measurement system 1 and has functions for recording, storing and displaying measurement results. The data processing device 300 can be designed as a universal computer or workstation. In addition, the data processing device 300 be designed as a dedicated hardware component for the small particle measurement system 1 is set up.

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

The operation supported in normal measurement mode is the same as that in 1 shown measuring device 200R supported operation. The nanopore device 100 is between the output connector pair OUT1 and OUT2 the measuring device 200 connected. In the normal measuring mode, the voltage source 220 a DC bias voltage Vb on the pair of electrodes 106 and 108 on. For example, the voltage source 220 a D / A converter and generates a bias voltage Vb, which corresponds to digital input data. The transimpedance amplifier 210 converts the current I _S which through the nanopore device 100 flows into a voltage signal V _p around. The digitizer 230 converts the voltage signal V _p into digital data D _S around. the interface 240 transmits the digital data D _S to the data processing device 300 . The digital data obtained as time series data D _S represent a waveform of the current. The data processing device 300 processes the digital data acquired in the normal measurement mode D _S and detects the number of in an electrolytic solution 2nd containing particles 4th and their particle diameter. In addition, the calibration mode described later ensures the measurement accuracy of the current signal or the voltage signal. Accordingly, such an arrangement is capable of detecting detailed features such as a particle shape etc. based on the waveform of the current.

Next, the calibration mode will be described. If the interface predetermined control data from the data processing device 300 receives, the measuring device 200 set in a current calibration mode. In the current calibration mode, the calibration controller controls 250 the operation of the measuring device 200 .

5 Fig. 3 is a block diagram showing a small particle measurement system 1C in the current Calibration mode shows. In the current calibration mode is a calibration facility 400 between the output connector pair OUT1 and OUT2 the measuring device 200 connected. The calibration facility 400 has a standard resistance R, which has a known resistance value. The measuring device 200 is configured to be able to calibrate at least a part of the internal configuration thereof in a state in which the calibration device 400 to the measuring device 200 connected.

The measuring device 200 can have a device holder. The device holder is designed to be the nanopore device 100 to attach. As in 4th shown shows the nanopore device 100 the pencil P1 and P2 on which to the pair of electrodes 106 and 108 should be connected. The device holder is formed so that the output connector pair OUT1 and OUT2 are so exposed that they are in contact with the pens P1 and P2 the nanopore device 100 can come. In this case, the calibration device 400 to the device holder of the measuring device 200 be attached. In addition, the calibration facility 400 the pencils P1 and P2 which are configured to contact the output connector pair in a state where the calibration device is attached to the device holder OUT1 and OUT2 can come. That is, the calibration facility 400 and the nanopore device are preferably designed to have compatibility in terms of shape and size. This arrangement provides the signal path with uniform resistance etc. for both the particle measurement which the nanopore device 100 used, as well as the calibration, which the calibration facility 400 used. This enables improved calibration accuracy.

Above was the configuration of a small particle measurement system 1 described. Next, the operation thereof will be described.

Calibration of a current measuring system

First the calibration of the current measuring system, eg the calibration of the transimpedance amplifier 210 and the digitizer 230 described. This calibration is described on the assumption that the voltage application system and the voltage source 220 have already been calibrated and that the accuracy of the bias voltage Vb is ensured. Then the calibration of the voltage source 220 described.

The calibration facility is as described above 400 to the measuring device in current calibration mode 200 connected. When the current measuring system is calibrated, the data processing device performs 300 a calibration program. The data processing device 300 transmits control data to the measuring device 200 so the measuring device 200 to put in the current calibration mode. The data processing device then transmits 300 a default value Db of the bias voltage Vb to the measuring device 200 while this sets the default value Db of the bias voltage Vb to multiple N values x ₁ , x ₂ , ... x _N toggles. The calibration control 250 passes that from the data processing device 300 received default value x _i the voltage source 220 so the voltage source 220 to instruct a bias voltage Vb _i to create.

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

The digital detection signal D _Si is preferably measured several times for each bias voltage Vb. In this case, an average m _i for the digital detection signals recorded during the multiple measurements D _Si calculated.

6 and 6B are diagrams for explaining the calibration of the current measuring system. In 6A the horizontal axis represents the bias voltage thus applied Vb _i and the vertical axis represents the digital detection signal value thus measured m _i . An example will now be described in which N = 2. The data processing device 300 calculates the average m ₁ the multiple digital detection signals detected when Vb = Vb ₁ D _S1 . In addition, the data processing device calculates 300 the average m ₂ the multiple digital detection signals detected when Vb = Vb ₂ D _S2 .

In one case where Vb _i is applied to the standard resistor R, the current I _i , which flows through the standard resistor R, is represented by I _i = Vb _i / R. The horizontal axis can be represented by means of the current I using this relation, which is shown in 6B will be shown.

The calibration of the current measuring system is equivalent to the determination of a function which represents the relation between the measured value m and the current I. If m ₁ , m ₂ , I ₁ and I ₂ are known values, the current I, which one corresponds to any measured value w, are represented by the following expression (4). $$\text{I.}=\left({\text{I.}}_1-{\text{I.}}_{\mathrm{2nd}}\right)/\left({\text{m}}_{\mathrm{2nd}}-{\text{m}}_1\right)\times \left(\text{m}-{\text{m}}_1\right)+{\text{I.}}_1$$

If the measured value m as a digital detection signal value D _S as a result of the measurement of the nanopore device 100 was detected in the normal measurement mode, the true value of the current level, which corresponds to the measurement value m, can be calculated based on expression (1).

Preferably the value of Vb ₁ set to 0 [V], which enables calibration processing to be simplified. That is, if the relation Vb ₁ = 0 [V] is true, the relation I ₁ = 0 [A] is true. Accordingly, expression (4) can be transformed into the following expression (5). $$\text{I.}={\text{I.}}_{\mathrm{2nd}}/\left({\text{m}}_{\mathrm{2nd}}-{\text{m}}_1\right)\times \left(\text{m}-{\text{m}}_1\right)$$

By inserting the relation I ₂ = Vbz / R in expression (5), the following expression (6) is obtained. $$\text{I.}={\text{Vb}}_{\mathrm{2nd}}/\{\text{R}\times \left({\text{m}}_{\mathrm{2nd}}-{\text{m}}_1\right)\times \left(\text{m}-{\text{m}}_1\right)$$

After acquiring the measured values m ₁ and m ₂ calculates the data processing device 300 based on the following expression the gain GAIN_CUR. In addition, the data processing device stores 300 the measured value m ₁ as offset OFS_CUR. $$\begin{array}{l}\text{GAIN\_CUR}={\text{Vb}}_{\mathrm{2nd}}/\{\text{R}\times \left({\text{m}}_{\mathrm{2nd}}-{\text{m}}_1\right)\}\\ \text{OFS\_CUR}={\text{m}}_1\end{array}$$

Then, in the normal measurement mode, the true value of the current can be calculated based on the following expression (7) using the GAIN_CUR and OFS_CUR thus detected in the current calibration mode. $$\text{I.}=\text{GAIN\_CUR}\times \left(\text{m}-\text{OFS\_CUR}\right)$$

CALIBRATION OF THE VOLTAGE APPLICATION SYSTEM

7 Fig. 3 is a block diagram showing a small particle measurement system 1D shows in voltage calibration mode. Before the voltage application system (voltage source 220 ) is calibrated instead of the nanopore device 100 a voltage measuring device such as a digital multimeter 500 or the like between the output connector pair OUT1 and OUT2 the measuring device 200 connected.

When the voltage application system is calibrated, the data processing device performs 300 a calibration program. The data processing device 300 transmits control data to the measuring device 200 so the measuring device 200 to put in the voltage calibration mode. The data processing device then transmits 300 a default value Db of the bias voltage Vb to the measuring device 200 while this sets the default value Db to multiple N values x ₁ , x ₂ , ... x _n toggles. The calibration control 250 passes that from the data processing device 300 received default value x _i the voltage source 220 so the voltage source 220 to instruct a bias voltage Vb _i to create.

The digital multimeter 500 measures the bias voltage Vb _i (i = 1, 2, ..., N). The measured values b _i the bias voltage Vb _i are sent to the data processing device 300 to hand over.

The digital multimeter 500 preferably measures each bias voltage several times Vb . The data processing device 300 calculates an average b _i the multiple measurements of each bias voltage Vb _i .

8th Fig. 10 is a diagram for explaining the calibration of the voltage application system. In 8th the horizontal axis represents that of the voltage source 220 provided default value Db and the vertical axis represents the measured value b _i that of the digital multimeter 500 measured bias voltage Vb. An example will now be described in which N = 2.

The data processing device 300 records the measured value b ₁ the bias voltage Vb ₁ which was captured as a default value x ₁ was selected. In addition, the data processing device detects 300 the measured value b ₂ the bias voltage Vb ₂ which was recorded as the default value x ₂ was selected.

A function g (x) which is defined by the two in 8th points shown is represented by the following expression (8). $$\text{y}=\text{G}\left(\text{x}\right)=\left({\text{b}}_{\mathrm{2nd}}-{\text{b}}_1\right)/\left({\text{x}}_{\mathrm{2nd}}-{\text{x}}_1\right)·\left(\text{x}-{\text{x}}_1\right)+{\text{b}}_1$$

With the measuring device 200 becomes the value x ' the default data Db, which is an arbitrary value y of the bias voltage Vb should provide, represented by the following expression (9). $$\text{x '}={\text{G}}^{-1}\left(\text{y}\right)=\left({\text{x}}_{\mathrm{2nd}}-{\text{x}}_1\right)/\left({\text{b}}_{\mathrm{2nd}}-{\text{b}}_1\right)·\left(\text{x}-{\text{x}}_1\right)+{\text{x}}_1$$

The data processing device 300 calculates GAIN_V = (x ₂ - x ₁ ) / (b ₂ - b ₁ ), OFS_y = b ₁ and OFS_x = x ₁ , and saves the values calculated in this way. If any bias voltage y is to be generated in the normal operating mode after the calibration is complete x ' as D _S Value generated as follows. $$\text{x '}=\text{GAIN\_V}·\left(\text{y}-\text{OFS\_y}\right)+\text{OFS\_x}$$

This enables an accurate bias voltage Vb to be generated.

$$\text{OFS\_y}={\text{b}}_1$$

$$\text{OFS\_x}=0$$

Preferably, an arrangement can be made in which Vb _i = 0 [V], which makes it possible to simplify the calibration processing. In this case x _i = 0 is true. Accordingly, the gain and the offset to be calculated are modified, represented by the following expressions. $$\text{GAIN\_V}={\text{x}}_{\mathrm{2nd}}/\left({\text{b}}_{\mathrm{2nd}}-{\text{b}}_1\right)$$

$$\text{OFS\_y}={\text{b}}_1$$

$$\text{OFS\_x}=0$$

If any bias voltage y is to be generated, x 'may preferably be as D _S Value can be generated as follows. $$\text{x '}=\text{GAIN\_V}·\left(\text{y}-\text{OFS\_y}\right)$$

The calculation for the current measuring system, which corresponds to the expression (7), and the calculation for the voltage application system, which corresponds to the expression (11), can be carried out by means of an internal component of the measuring device 200 be supported. 9 Fig. 3 is a block diagram showing a measuring device 200D shows.

In the voltage calibration mode described above, the two parameters GAIN_CUR and OFS_CUR are generated. These parameters are stored in a non-volatile manner 256 written, which in the measuring device 200 is arranged.

A calibration control 250D has a first calculation unit 252 on. In the normal operating mode, the first calculation unit converts 252 the value m of the digital data DS in the current value I. which is represented based on expression (7) of expression (7). the interface 240 transmits digital data D _S ' , which represent the correct value of the current I thus converted, to the data processing device 300 .

In addition, the two parameters GAIN_V and OFS_y are generated in the current calibration mode described above. These parameters are also stored in non-volatile memory 256 the measuring device 200 written. The calibration control 250D has a second calculation unit 254 on. In the normal operating mode, the second calculation unit converts 254 the value x of that from the data processing device 300 received default data D _S in value x ' which is represented by expression (11) based on expression (11), and represents the value thus converted x ' for the voltage source 220 ready.

10th Fig. 3 is a flowchart showing the process of the small particle measurement system 1 shows calibration based on the embodiment. First, the voltage calibration mode ( S100 ), which calibrates the voltage application system. This operation restores the accuracy of the voltage source 220 generated bias voltage Vb for sure.

Then the current calibration mode ( S102 ), which calibrates the current measuring system. This operation restores the accuracy of that of the transimpedance amplifier 210 and the digitizer 230 measured current signal safely. After the calibration procedures described above, the normal measurement and the resistance of the nanopore device can be carried out 100 is being measured.

The same calibration parameters are then used in the normal measurement ("NO" in S104 ). After the specified time has elapsed ("YES" in S104 ) the calibration is carried out again ( S100 , S102 ).

In the present embodiment, this ensures that the output signal (digital data D _S ) received input signal (current signal I _S ) can be recorded within a specified accuracy range. The absolute value thereof can thus be used in development applications such as particle shape analysis, transit phenomenon analysis etc.

In addition, since it is ensured that the output signal value is based on the Input signal is detected, the reliability of this arrangement is ensured as a measuring device.

The present invention has been described above with reference to the embodiment. The embodiment described above has only been described for exemplary purposes and is in no way intended to be interpreted in a restricted manner. Rather, it will be readily apparent to those skilled in the art that various modifications can be made by combining the above-described components or operations in various combinations that also fall within the technical scope of the present invention. Such modifications are described below.

MODIFICATION 1

The parameters obtained during the calibration can be stored in an integrated memory of the data processing device 300 stored in a non-volatile manner. The parameters stored in this way can be used every time the measuring device 200 is started for the measuring device 200 Loading.

MODIFICATION 2

An embodiment has been described with respect to an arrangement in which the data processing apparatus 300 the calibration is provided by executing a program control operation. However, the present invention is not limited to such an arrangement. For example, the measuring device can have an integrated processor such as an FPGA (“Field Programmable Gate Array”), a microcontroller, ASIC (“Application Specific Integrated”) or the like. In addition, the measuring device can be instructed to execute a calibration program.

MODIFICATION 3

11 Fig. 3 is a block diagram showing a current measuring system of a measuring device 200E according to modification 3 shows. With reference to 9 An arrangement has been described in which the measuring device 200D digital data corrected using digital signal processing. 11 shows the measuring device 200E , which is designed to correct digital data by means of analog signal processing. A calibration hardware component 270 has an adder 272 , an offset correction D / A converter 274 and a gain correction D / A converter 276 on. The offset correction D / A converter 274 converts the offset correction value OFS-CUR detected in the current calibration mode described above into an analog offset voltage V _OFS around. The adder 272 adds the offset voltage V _OFS to the output voltage V _p from the transimpedance amplifier 210 to. The gain correction D / A converter 276 converts the gain correction value detected in the current calibration mode GAIN_CUR to an analog reference voltage VREF and sets the reference voltage VREF thus obtained for a reference connection of the digitizer 230 (A / D converter) ready.

MODIFICATION 4

12th Fig. 3 is a block diagram showing a measuring device 200F according to modification 4 shows. The measuring device 200F is designed to be connected to an external voltage source 510 which has already been calibrated can be connected. In addition, instead of using an output voltage VINT, the internal voltage source 220 an output voltage V _EXT the external voltage source 510 to the calibration facility 400 be created. For example, the measuring device 200F have an external power supply (EXT) connection pin and a multiplexer (selector). The multiplexer is in current calibration mode 260 by selecting the external voltage VEXT will be able to calibrate the current measurement system before the calibration of the voltage application system is complete.

MODIFICATION 5

13 Fig. 3 is a block diagram showing a measuring device 200 G according to modification 5 shows. In this modification is a front end circuit 202G designed to pass a current Ib through the output connector pair OUT1 and OUT2 pretend and the tension V _p to measure which on the output connector pair OUT1 and OUT2 is present. The front-end circuit 202G has a bias current source 280 and an amplifier 282 on. The bias power source 280 provides a DC bias current Ib through the output connector pair OUT1 and OUT2 ready. The amplifier 282 amplifies the voltage signal V _p which on the output connector pair OUT1 and OUT2 is applied, and provides the voltage signal thus amplified V _p for the digitizer 230 ready.

The calibration of the measuring device 200 G can be divided into two steps, that is, the calibration of the voltage measurement system, which is the amplifier 282 and the digitizer 230 and the calibration of a current application system using the bias current source 280 having. The calibration device can be used to calibrate the voltage measuring system 400 , which has a standard resistance, preferably between the output connector pair OUT1 and OUT2 be connected. On the other hand, when calibrating the current application system, an external current measuring device can preferably be located between the output connection pair OUT1 and OUT2 be connected. The calibration to be supported is the same as that described above.

The measuring device 200 G can also have a connecting pin ("EXT pin") to which an external power source 520 can be connected. The measuring device 200 G is designed to be in the calibration mode instead of one from the bias current source 280 generated bias current Ib on from the external power source 520 generated electricity I _EXT can be provided for a device which is connected between the output connector pair. The measuring device 200 G can be a selector 262 have, which is designed to switch the power source.

MODIFICATION 6

In the present description, a small particle measuring device has been described. However, the present invention is not limited to such an application. In addition, the present invention is widely applicable to various types of measuring devices that support microcurrent measurement using a nanopore device, including, for example, DNA sequencers.

The present invention has been described with reference to embodiments. However, the above-described embodiments show only the operation and applications of the present invention for exemplary purposes only, and the embodiments are in no way intended to be interpreted restrictively. Rather, various modifications and changes in design may be made without departing from the spirit and scope of the present invention, which is defined in the appended claims.

Reference list

1

Small particle measurement system

2nd

Electrolyte solution

4th

particle

100

Nanopore device

102

Nanopore chip

104

opening

106, 108

electrode

110

Protective cover

200

Measuring device

202

Front end circuit

210

Transimpedance amplifier

220

Voltage source

230

Digitizer

240

interface

250

Calibration control

260

multiplexer

270

Bias power source

272

amplifier

300

Data processing device

400

Calibration facility

500

digital multimeter

510

external voltage source

520

external power source

QUOTES INCLUDE IN THE DESCRIPTION

This list of documents listed by the applicant has been generated automatically and is only included for the better information of the reader. The list is not part of the German patent or utility model application. The DPMA assumes no liability for any errors or omissions.

Patent literature cited

• JP 2011513739 [0011]
• JP H04040373 [0011]
• JP H07504989 [0011]
• JP 2004510980 [0011]

Claims (13)

Measuring device which is designed to measure a signal which corresponds to a resistance of a nanopore device which has an opening and a pair of electrodes, the measuring device having the following: an output connection pair which is to be connected to the electrode pair of the nanopore device; a front-end circuit which is designed to generate an analog detection signal which corresponds to a resistance between the output connection pair; and an A / D converter which is designed to convert the analog detection signal into a digital detection signal, wherein instead of the nanopore device, a calibration device, which has a known resistance value, between the output connector pair can be connected, and wherein the measuring device can be calibrated in a state in which the calibration device is connected. Measuring device according to Claim 1 , wherein the front-end circuit is configured to specify a voltage at the output connection pair and to measure a current which flows through the calibration device. Measuring device according to Claim 2 , wherein the front-end circuit comprises: a bias voltage source, which is designed to apply a DC bias voltage to the output connection pair; and a transimpedance amplifier, which is designed to convert a current signal flowing through the output connection pair into a voltage signal, and wherein the voltage signal is designed as an analog detection signal. Measuring device according to Claim 3 , wherein the bias voltage is set to a plurality of values in a calibration operation, and wherein the measuring device is calibrated based on a plurality of digital detection signals which have been detected in accordance with the plurality of values. Measuring device according to Claim 3 or 4th , In a calibration operation instead of the nanopore device or the calibration device, an external voltage measuring device can be connected between the output connection pair. Measuring device according to one of the Claim 3 to 5 , wherein the measuring device further comprises a connection terminal to which an external voltage source can be connected, wherein during a calibration operation instead of the bias voltage generated by the bias voltage source, a voltage generated by the external voltage source can be applied to the output connection pair . Measuring device according to Claim 1 , wherein the front-end circuit is configured to specify a current between the output connection pair and to measure a voltage which is present at the output connection pair. Measuring device according to Claim 7 , wherein the front-end circuit has a bias current source which is designed to specify a DC bias current between the output connection pair, and wherein the analog detection signal corresponds to a voltage which is present at the output Connection pair is present. Measuring device according to Claim 8 wherein the bias current is set to a plurality of values in a calibration operation, and wherein the measuring device is calibrated based on a plurality of detected digital detection signals which correspond to the plurality of values. Measuring device according to Claim 8 or 9 , in a calibration operation instead of the nanopore device or the calibration device, an external current measuring device can be connected between the output connection pair. Measuring device according to one of the Claims 8 to 10th , wherein the measuring device further comprises a connection terminal to which an external current source can be connected, wherein during a calibration operation instead of a bias current generated by the bias current source, a current generated by the external current source can be predetermined between the output connection pair . Calibration method for a measuring device which is designed to measure a signal which corresponds to a resistance of a nanopore device which has an opening and a pair of electrodes, the measuring device having the following: an output connection pair which is connected to the pair of electrodes the nanopore device is to be connected; a bias voltage source which is designed to specify a DC bias voltage at the output connection pair; - a transimpedance amplifier configured to convert a current signal flowing through the pair of output terminals into a voltage signal; and an A / D converter, which is designed to convert an output of the transimpedance amplifier into a digital value, and the calibration method comprises the following steps: connecting a known resistor instead of the nanopore device between the output connection pair; - Detecting an output of the A / D converter in a state in which a known DC bias voltage is specified across the known resistor; and acquiring a calibration parameter based on an output of the A / D converter. Calibration procedure according to Claim 12 wherein an external power supply device is used in the detection of the output from the A / D converter instead of the bias voltage source.

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