JP6401588B2 - Current measuring device, base sequence analyzing device, measuring chip - Google Patents

Description

  The present invention relates to a current measuring device.

  In order to analyze a base sequence such as DNA (deoxyribonucleic acid) or RNA (ribonucleic acid), a base sequence analyzer (sequencer) is used. Various methods are being sought by research institutions and companies as next-generation (fourth generation) sequencers, and gating nanopore sequencing technology is attracting attention as one of them.

  In gating nanopore sequencing technology, when DNA or RNA passes between a pair of nanometer-order electrodes (nanoelectrodes), the tunnel current that flows between the electrodes is the type of base (A, G, T, C) The base sequence is determined by utilizing the change depending on. According to this method, it is expected that the base sequence can be analyzed with a very inexpensive and small device. In this specification, the nanoelectrode is used as including a sub-microelectrode or microelectrode larger than that.

  Similarly to the gating nanopore sequencing technology, the MCBJ method (Mechanically Controllable Break Junction) has been developed as a method using a tunnel current. In the MCBJ method, a nanoelectrode is formed by breaking a metal wire.

  One of the important elemental technologies in these sequencers is a current measuring device that can measure the tunnel current flowing between nanoelectrodes with sufficient accuracy. That is, the order of the tunnel current is several tens of pA, and in order to determine the type of base, a difference in conductance of the order of several pS must be detected.

JP 2003-240747 A JP 2009-133762 A JP 2013-257334 A

The present inventors examined using a transimpedance amplifier as a weak current measuring device. FIG. 1 is a circuit diagram of a current measuring device 900 including a transimpedance amplifier 800. The transimpedance amplifier 800 includes an operational amplifier 802, the inverting input of the operational amplifier 802 - comprising a resistor _{R F} provided between the output, a (). A predetermined potential V _REF (for example, ground voltage) is input to the non-inverting input terminal (+) of the operational amplifier 802. Capacitor C _F is connected in parallel with resistor R _F for circuit stability.

  A DUT (device under test) 810 includes a sample such as DNA or RNA (hereinafter collectively referred to as DNA) and a chip that accommodates the sample. The chip is formed with nanochannels and nanopillars through which DNA molecules separated from the sample pass, electrode pairs, and the like. A cable 820 connects between the DUT 810 and the transimpedance amplifier 800.

FIG. 2 is an equivalent circuit diagram of the current measuring apparatus 900 of FIG. The _DUT 810 is modeled as a current source 812 that generates a tunnel current I _DUT , a parasitic parallel resistance R _DUT , and a parasitic parallel capacitor C _DUT .

Cable 820 includes a first line 822 that connects one end 814 of DUT 810 and the inverting input terminal of operational amplifier 802, and a second line 824 that connects the other end 816 of DUT 810 and the non-inverting input terminal of operational amplifier 802. C _CAB is a parasitic capacitance between the two lines 822 and 824. In the case of a coaxial cable, a parasitic capacitance of 10 pF is generated per 10 cm.

Various parasitic capacitances exist in the input stage of the transimpedance amplifier 800. C _PRO is a parasitic capacitance such as a protection element for ESD, for example, a diode or an ESD suppressor. The operational amplifier 802 is represented by an ideal amplifier 804 and various parasitic capacitances. CMN and CMP are common input capacitors, and CD is a differential input capacitor. Note that the resistance values and capacitance values shown in FIG. 2 are merely examples.

The DC transimpedance of the transimpedance amplifier 800 is given by the following equation.
20 × Log ₁₀ (R _F ) (dB) (1)
For example, when R _F = 1 GΩ, the transimpedance is 180 dB.

  A DNA sequencer needs to identify a huge number of types of billions of base pairs. In the fourth generation, a measurement time of about 1 ms per base is required, but it is difficult to specify a base due to the influence of noise in one measurement. Therefore, statistical methods are used such as measuring the tunnel current a plurality of times in 1 ms and specifying the base based on the resulting histogram. For example, in order to measure the tunnel current 100 times in 1 ms, a sampling rate of 100 ksps is required. In this case, the band required for the transimpedance amplifier is several hundred kHz to several MHz in consideration of the margin. .

Here, the frequency characteristics of the transimpedance amplifier 800 of FIG. 2 will be examined. The cut-off frequency f2 is given by equation (2).
f2 = 1 / {2πR _F × (C _F + C _S / A _OL )} (2)
However, C _S = C _DUT + C _CAB + C _PRO + CD, and A _OL is an open loop gain of the operational amplifier. It can be seen from equation (2) that in order to increase the cutoff frequency f2, an approach can be taken in which C _F is decreased, C _S is decreased, and A _OL is increased in gain and bandwidth. The C _S is referred to as an input shunt capacitance. Open-loop gain _{A OL} is sufficiently large, if the input shunt capacitance _{C S} is small, equation (2) can be approximated by equation (3).
f2≈1 / {2πR _F × C _F } (3)
For example _R F = 1 _G.OMEGA, when the C F = 10 fF, comprising the formula (3) and f2 = 15.9kHz.

On the other hand, since the tunnel current is weak, noise in the measurement system also becomes a problem. FIG. 3 is a diagram illustrating noise characteristics of the transimpedance amplifier. In order to detect a minute current, the order of several tens of MΩ to several TΩ is required as R _F , and therefore thermal noise due to the resistance R _F is dominant in the low frequency region.
V _NOISE = √ (4 × k × T × R _F ) [V / √Hz]
T is temperature and k is Boltzmann constant. This equation represents the voltage noise density per unit frequency.
In the case of R _F = 1 GΩ and T = 27 ° C., V _NOISE = 4.1 μV / √Hz (also referred to as V / rtHz).

With respect to thermal noise, since band limitation is applied to the cut-off frequency f2 of the above as a boundary, in the high frequency region above the cutoff frequency f2, than the thermal noise of the R _F, the noise of the transimpedance amplifier 800 is dominant. In the high frequency region, the noise gain of the amplifier is (C _F + C _S + CM + CD) / C _F times, so in order to reduce noise, C _S , CM, CD must be reduced and C _F must be increased. . However, increasing C _F means lowering the cut-off frequency f 2, which is contrary to the demand for wider bandwidth, and therefore it is necessary to design C _F as small as possible within the range in which the stability of the system is ensured. As described above, in the transimpedance amplifier of FIG. 1, there is a trade-off relationship between a wide band (cutoff frequency) and low noise, and it is difficult to achieve both.

  In particular, the transimpedance amplifier is sensitive to electric field noise because the input impedance of the operational amplifier is very high. In order to reduce noise, there is a technique of covering a signal line with a shield and controlling the potential of the shield. However, if a shield is added to a transimpedance amplifier that requires high speed, the parasitic capacitance of the signal line increases and the capacitance of the amplifier that drives the shield is added. descend.

  SUMMARY OF THE INVENTION The present invention has been made in view of the above problems, and one of exemplary purposes of an aspect thereof is to provide a current measuring device with reduced noise.

One embodiment of the present invention relates to a current measurement device. The current measuring device includes a current generating unit that generates a current signal to be measured, and a transimpedance amplifier that converts the current signal into a voltage signal. The transimpedance amplifier includes an inverting amplifier circuit and a feedback resistor provided between the inverting input terminal and the output terminal of the amplifier circuit. The amplifier circuit is integrated on the same semiconductor chip as the current generator.
According to this aspect, the signal line extending from the current generation unit to the inverting input terminal of the amplifier circuit can be formed by the wiring on the semiconductor substrate, and the length thereof can be shortened to reduce the grounding capacitance of the input line. Thereby, the noise gain of the transimpedance amplifier can be reduced, and a low noise current measuring device can be provided. The transimpedance amplifier is very sensitive to electric field noise because of its very high input impedance, and can shorten the signal line that is an interference path, thereby reducing the influence of electric field noise. Further, by integrating the amplifier circuit, the influence of electric field noise or the like can be reduced because the high resistance amplifier input end is not exposed to the outside.

According to one aspect of the current measuring apparatus, a first contact pad formed on a semiconductor chip and connected to an inverting input terminal of an amplifier circuit, and a second contact formed on the semiconductor chip and connected to an output terminal of the amplifier circuit. You may further provide a head unit which has a pad and the 1st, 2nd probe which contacts the 1st, 2nd contact pad. The feedback resistor may be built in the head unit and connected between the first and second probes.
In this aspect, the feedback resistor is not integrated into the semiconductor chip, but the feedback resistor is configured by using a chip component, a SiP component, or a resistor module in the head unit. Because it is not restricted, it can be enlarged. Here, while the gain (transimpedance) of the current measuring device is proportional to the feedback resistance, the thermal noise generated by the resistance is given by V _NOISE = √ (4 × k × T × R _F ) [V / √Hz] Since it is proportional to the square root of the feedback resistance, the S / N ratio can be increased as the resistance value of the feedback resistance increases. In addition, when the feedback resistor is integrated in the semiconductor chip, there arises a problem that the resistance value fluctuates due to process variations and the transimpedance (gain) varies. According to this aspect, the feedback resistor is incorporated in the head unit and used. Thus, variations in transimpedance can be suppressed.

A current measuring device according to an aspect is formed on a semiconductor chip, a third contact pad formed on the semiconductor chip, a driving guard metal formed on the semiconductor chip and connected to the third contact pad, A guard amplifier that supplies the voltage of the non-inverting input terminal of the amplifier circuit to the driving guard metal may be further provided. The head unit further includes a third probe that comes into contact with the third contact pad, and a cable having a shield that is connected to the core wire and the third probe, which are part of the wiring from the first probe to the feedback resistor. May be.
According to this aspect, by using the driving guard function, the space between the feedback resistor and the amplifier input is protected, thereby providing an electric field shield and reducing stray capacitance.

  Another aspect of the present invention also relates to a current measuring device. The current measuring device includes a current generating unit that generates a current signal to be measured, and a transimpedance amplifier that converts the current signal into a voltage signal. The transimpedance amplifier includes an inverting amplifier circuit and a feedback resistor provided between the inverting input terminal and the output terminal of the amplifier circuit. The amplifier circuit includes an input stage and an amplifier stage. A part including the input stage of the amplifier circuit is integrated on the same semiconductor chip as the current generator.

  According to this aspect, the signal line extending from the current generation unit to the inverting input terminal of the amplifier circuit can be formed by the wiring on the semiconductor substrate, and the length thereof can be shortened to reduce the grounding capacitance of the input line. Thereby, the noise gain of the transimpedance amplifier can be reduced, and a low noise current measuring device can be provided. The transimpedance amplifier is very sensitive to electric field noise because of its very high input impedance, and can shorten the signal line that is an interference path, thereby reducing the influence of electric field noise. Further, by integrating the amplifier circuit, the influence of electric field noise or the like can be reduced because the high resistance amplifier input end is not exposed to the outside.

  According to one aspect of the current measuring apparatus, a first contact pad formed on a semiconductor chip and connected to an inverting input terminal of an amplifier circuit, and a second contact formed on the semiconductor chip and connected to an output terminal of an input stage You may further provide a head unit which has a pad and the 1st, 2nd probe which contacts the 1st, 2nd contact pad. The feedback resistor and the amplification stage may be built in the head unit, the input terminal of the amplification stage may be connected to the second probe, and the feedback resistor may be connected between the first probe and the output terminal of the amplification stage.

  Another embodiment of the present invention relates to a base sequence analyzer. The base sequence analyzer includes any one of the above-described current measuring devices.

  Another aspect of the present invention relates to a measurement chip. The measuring chip includes a first electrode and a second electrode, an electrode pair configured to allow a sample to pass between the first electrode and the second electrode, and an inverting input terminal connected to the first electrode. Type amplifier circuit, a first contact pad connected to the inverting input terminal of the amplifier circuit, and a second contact pad connected to the output terminal of the amplifier circuit, integrated on one semiconductor substrate Is done. In use, the measurement chip can be configured as a transimpedance amplifier by connecting a feedback resistor between the first contact pad and the second contact pad.

  Another aspect of the present invention relates to a measurement chip. The measuring chip includes a first electrode and a second electrode, an electrode pair configured to allow a sample to pass between the first electrode and the second electrode, and a part of an inverting amplifier circuit, An input stage having an input terminal connected to the first electrode, a first contact pad connected to the input terminal of the input stage, and a second contact pad connected to the output terminal of the input stage. Integrated on the semiconductor substrate. In use, a transimpedance amplifier can be configured by connecting a feedback resistor and an amplification stage of an amplifier circuit between the first contact pad and the second contact pad.

  Note that any combination of the above-described constituent elements and the constituent elements and expressions of the present invention replaced with each other between methods and apparatuses are also effective as an aspect of the present invention.

  According to an aspect of the present invention, a current measuring device with reduced noise can be provided.

It is a circuit diagram of a current measuring device including a transimpedance amplifier. FIG. 2 is an equivalent circuit diagram of the current measuring device of FIG. 1. It is a figure which shows the noise characteristic of a transimpedance amplifier. It is a figure which shows the electric current measurement apparatus which concerns on 1st Embodiment. FIG. 5A is a diagram showing a current measuring apparatus according to the second embodiment, and FIG. 5B is a circuit diagram showing another configuration example of the amplifier circuit. It is a figure which shows the electric current measurement apparatus which concerns on a 1st modification. It is a figure which shows the electric current measurement apparatus which concerns on a 2nd modification. It is a figure which shows the electric current measuring apparatus which concerns on a 3rd modification. It is a block diagram of a base sequence analyzer provided with a current measuring device.

  The present invention will be described below based on preferred embodiments with reference to the drawings. The same or equivalent components, members, and processes shown in the drawings are denoted by the same reference numerals, and repeated descriptions are omitted as appropriate. The embodiments do not limit the invention but are exemplifications, and all features and combinations thereof described in the embodiments are not necessarily essential to the invention.

In this specification, “the state in which the member A is connected to the member B” means that the member A and the member B are electrically connected in addition to the case where the member A and the member B are physically directly connected. It includes the case of being indirectly connected through another member that does not affect the connection state.
Similarly, “the state in which the member C is provided between the member A and the member B” refers to the case where the member A and the member C or the member B and the member C are directly connected, as well as an electrical condition. It includes the case of being indirectly connected through another member that does not affect the connection state.

(First embodiment)
FIG. 4 is a diagram illustrating the current measuring apparatus 100 according to the first embodiment. The current measuring apparatus 100 detects a weak current signal I _DUT such as a tunnel current or an ion current, and converts it into a voltage signal _VOUT .

The current measuring device 100 includes a current generator 110 and a transimpedance amplifier 120. The current generator 110 generates a current signal I _{DUT to} be measured. The transimpedance amplifier 120 converts the current signal I _DUT into a voltage signal _VOUT .

The transimpedance amplifier 120 includes an inverting amplifier circuit 122, a feedback resistor R _F , and a feedback capacitor C _F. The feedback resistor _RF is provided between the inverting input terminal (−) and the output terminal of the amplifier circuit 122. The feedback capacitor C _F is connected in parallel with the feedback resistor R _F.

  In the present embodiment, the components of the current generator 110 and the transimpedance amplifier 120 are separately mounted on the measurement chip 102 and the head unit 104.

  The amplifier circuit 122 is integrated on the same semiconductor chip (measurement chip) 102 as the current generator 110. On the measurement chip 102, a first contact pad Pd1 and a second contact pad Pd2 are formed. The first contact pad Pd1 is electrically connected to the inverting input terminal of the amplifier circuit 122, and the second contact pad Pd2 is electrically connected to the output terminal of the amplifier circuit 122. The plurality of measuring chips 102 are sequentially carried directly under the head unit 104 by the transport device 106 and are carried out after the measurement.

  The head unit 104 includes first probes Pb1 and Pb2. The first probe Pb1 and the second probe Pb2 are arranged at locations where they can contact the first contact pad Pd1 and the second contact pad Pd2, respectively. The head unit 104 can be moved up and down by a lifting device 108.

Feedback resistor _{R F} of the transimpedance amplifier 120 is built in the head unit 104, it is electrically connected between the first probe Pb1 of the second probe Pb2. The feedback capacitor _{CF is} also electrically connected between the first probe Pb1 and the second probe Pb2.

  The measurement chip 102 is further provided with a contact pad Pd 2 ′ and an output buffer 124. The output buffer 124 receives the output of the amplifier circuit 122. The contact pad Pd <b> 2 ′ is electrically connected to the output terminal of the output buffer 124. The head unit 104 further includes a probe Pb 2 ′ and a measurement unit 126, a power supply circuit 128, a signal generator 130, and a calibrator 132.

  The probe Pb2 'is disposed at a location where it can come into contact with the contact pad Pd2'. The measurement unit 126 is configured to be able to measure the voltages of the second probe Pb2 and the probe Pb2 '. Measuring unit 126 includes, for example, a digitizer (A / D converter). The power supply circuit 128 generates a power supply voltage to be supplied to the circuit elements in the head unit 104 and the circuit elements in the measurement chip 102. The signal generator 130 generates various signals used for measurement and calibration. The calibrator 132 performs calibration such as DC offset of the amplifier circuit 122 of the measurement chip 102 prior to measurement of the measurement chip 102.

  If the output impedance of the amplifier circuit 122 is sufficiently small, the output buffer 124 may be omitted. In this case, the contact pad Pd2 'and the probe Pb2' may be omitted. The power supply circuit 128, the signal generator 130, and the calibrator 132 may be provided outside the head unit 104.

The above is the configuration of the current measuring apparatus 100.
According to the current measuring apparatus 100, since the amplifier circuit 122 is integrated on the measurement chip 102, the signal line 112 extending from the current generator 110 to the inverting input terminal of the amplifier circuit 122 is connected to the measurement chip 102 (semiconductor substrate). It can be formed with the upper wiring. Thereby, the length of the signal line 112 can be shortened, and the grounding capacity (C _{S in} FIG. 2) of the signal line 112 can be reduced. Also since the signal line 112 becomes short, may be omitted protection element (ESD element), it can be reduced further capacitance to ground C _S in this case. As a result, the noise gain of the transimpedance amplifier corresponding to (C _F + C _S + CM + CD) / C _F can be reduced, and a low noise current measuring device can be provided.

  Further, the transimpedance amplifier 120 is sensitive to electric field noise because of its very high input impedance, and can shorten the signal line 112 that is an interference path, thereby reducing the influence of electric field noise. When the amplifier circuit 122 uses SiP parts, DiP parts, or the like, the high resistance amplifier input terminal is exposed to the outside. However, by integrating the amplifier circuit 122, the high resistance amplifier input terminal is externally connected. By not exposing to the effect, the influence of electric field noise and the like can be reduced.

In addition current measurement device 100 of FIG. 4, the feedback resistor R _F a without integrated on a semiconductor chip (measurement chip) 102, chip components and SiP parts in the head unit 104, a feedback resistor using a resistor module R _F It was decided to constitute. The practical upper limit of the resistance element on the semiconductor substrate is about several MΩ, and a resistance of several hundred MΩ to several GΩ requires a huge chip size. In this embodiment, the feedback resistor R _F With external components, an increase in the chip size of the measurement chip 102 may also be on the order of a few hundred MΩ~ number GΩ while suppressing.

Here, the gain (transimpedance) of the current measuring device is proportional to the feedback resistor R _F , while the thermal noise generated by the resistor is V _NOISE = √ (4 × k × T × R _F ) [V / √Hz] Since it is proportional to the square root of the feedback resistance, the S / N ratio can be increased as the resistance value of the feedback resistance increases.

Moreover, when integrating the feedback resistor R _F in the semiconductor chip, the resistance value varies with process variations, but a problem that the transimpedance (Gain) varies occurs repeatedly the built-in feedback resistor R _F in the head unit 104 using By doing so, variation in transimpedance can be suppressed. This eliminates the need for calibration for each semiconductor chip.

Consider the band of the transimpedance amplifier. By this current measuring device 100, the input capacitance C _S is small, the bandwidth (cutoff frequency) of the transimpedance amplifier is given by the above equation (3), the function of the feedback resistor R _F feedback capacitor C _F only Become. Therefore, by providing the feedback capacitor C _F in the head unit 104 in addition to the feedback resistor R _F , variation in the cut-off frequency f2 can be suppressed, and a plurality of measurement chips 102 can be measured in the same band.

An open loop gain can be cited as a parameter that greatly varies among the operational amplifiers constituting the amplifier circuit 122. Here, the sensitivity of the cut-off frequency f2 to the open loop gain is given by Equation (3), which can be made sufficiently small because the grounding capacitance _CS is small.

The DC offset of the operational amplifier can be calibrated by the following method. Output impedance of the current generator 110 to be measured is assumed higher than the feedback resistor R _F. In this case, the feedback resistor _RF is contacted so that the current generator 110 does not generate a current, and the output voltage of the transimpedance amplifier is measured by the measuring unit 126, thereby measuring the DC offset of the operational amplifier (amplifier circuit 122). it can. When the DC offset thus measured is held and the current signal I _DUT is measured, the influence of the DC offset can be eliminated by subtracting (adding) the DC offset from the measured value.

  Thus, even if the operational amplifier characteristics fluctuate due to manufacturing variations, the current measuring apparatus 100 according to the embodiment can ignore the influence of the fluctuations or can easily cope with it, and thus the operational amplifier can be dealt with. It can be said that the performance requirement is not high. When the operational amplifier is configured by a complementary metal oxide semiconductor (CMOS) process, since the CMOS has a high gate input resistance, there is an advantage that a low-leakage amplifier can be configured.

  In addition, since only the measurement chip 102 is portable, automatic continuous high sensitivity measurement is possible.

(Second Embodiment)
FIG. 5A shows a current measuring apparatus 100a according to the second embodiment. The current measuring device 100a further includes a guard amplifier 134, an ESD protection element 136, a driving guard metal 138, and a coaxial wiring (cable) 140 in addition to the current measuring device 100 of FIG.

  The driving guard metal 138 is disposed in the vicinity of the signal line 112. For example, the two driving guard metals 138a and 138b may be formed so as to sandwich the feedback line 113 connecting the signal line 112 and the first contact pad Pd1.

The driving guard metal 138a / b is connected to the third contact pad Pd3a / b. The head unit 104 includes a third probe Pb3a / b provided at a position corresponding to the third contact pad Pd3a / b. The third probe Pb3a / b is connected to the shield 144 of the coaxial wiring 140. The first probe Pb1 is connected to the core wire 142 of the coaxial wiring 140. The shield 144 of the coaxial wiring 140 covers at least a part of the feedback capacitor C _F and the feedback resistor R _F.

The guard amplifier 134 receives the voltage V _REF at the non-inverting input terminal (+) of the amplifier circuit 122 and applies it to the driving guard metal 138. The reference voltage V _REF may be a voltage generated by the reference voltage source 123 or a ground voltage.

  The ESD protection element 136 is provided between the signal line 112 and the driving guard metal 138, and is formed of, for example, a diode.

The above is the configuration of the current measuring device 100a.
According to the current measuring device 100a, by using the driving guard function, the space between the feedback resistance and the amplifier input is protected, thereby providing an electric field shield and reducing stray capacitance. By arranging the ESD protection element 136 in the driving guard, the parasitic capacitance of the ESD protection element 136 is also reduced. When the stray capacitance is C _STRAY , the effective capacitance is reduced to C _STRAY / A _OL .

  FIG. 5B is a circuit diagram illustrating another configuration example of the amplifier circuit 122. The amplifier circuit 122 may be composed of a single operational amplifier, but is composed of a combination of a non-inverting amplifier 150 and an inverting amplifier 152. Non-inverting amplifier 150 includes, for example, an operational amplifier 154 and resistors R1 and R2. The inverting amplifier 152 inverts and amplifies the output of the non-inverting amplifier 150. The non-inverting input terminal of the operational amplifier 154 corresponds to the inverting input terminal of the amplifier circuit 122, and the inverting input terminal of the operational amplifier 154 corresponds to the inverting input terminal of the amplifier circuit 122.

According to this modification, the following effects can be obtained.
The amplifier circuit 122 has a two-stage configuration of a non-inverting amplifier 150 and an inverting amplifier 152. In Figure 2, the differential input capacitance CD of the operational amplifier 802 is connected in parallel with the cable capacitance C _CAB like to become a part of the input shunt capacitance C _S, a factor to lower the cut-off frequency f2 of the transimpedance amplifier 800 ing. On the other hand, in the configuration of FIG. 5B, the differential input capacitance of the operational amplifier 154 does not exist in parallel with the cable capacitance _CCAB or the like of FIG. 2, and therefore the cutoff frequency f2 of the transimpedance amplifier is A drop due to the differential input capacitance of the operational amplifier 154 can be prevented.

  The present invention has been described based on the embodiments. This embodiment is an exemplification, and it will be understood by those skilled in the art that various modifications can be made to combinations of the respective constituent elements and processing processes, and such modifications are within the scope of the present invention. is there. Hereinafter, such modifications will be described.

(First modification)
In the embodiment, the measurement chip 102 is transported by the transport device 106 and the measurement chips 102 are measured one by one. However, the present invention is not limited to this. FIG. 6 is a diagram showing a current measuring device 100b according to the first modification. In this modification, the current measuring apparatus 100b measures part or all of the plurality of measuring chips 102 on the wafer 160 before dicing on the wafer at the same time.

  On the probe card 162, a plurality of the above-described head units 104 are arranged so as to correspond to the plurality of measurement chips 102 on the wafer 160. The wafer 160 is transferred to a position directly below the head unit 104 by a handler (not shown). The wafer 160 and the probe card 162 are close to each other, and the probe Pb of each head unit 104 and the corresponding contact pad Pd of the measurement chip 102 come into contact with each other, whereby a plurality of measurement chips 102 can be collectively measured. Alternatively, the quality of the amplifier circuit 122 on the measuring chip 102 can be determined collectively.

  The probe card 162 does not need to measure all the measurement chips 102 on the wafer 160 at the same time, and it is sufficient that a plurality of measurement chips 102 such as eight or sixteen can be measured simultaneously.

(Second modification)
FIG. 7 is a diagram showing a current measuring device 100c according to the second modification. The current measuring device 100c is a case-type measuring device that can be handled manually. The jig 170 includes a probe unit 172 that is an upper lid portion and a mounter 174 that is a lower base portion. The mounter 174 is provided with one or a plurality of sockets 176, and the measuring chip 102 can be attached to each socket 176. One or a plurality of head units 104 are provided in the probe unit 172.

  The user manually places the measurement chip 102 on the socket 176 and then covers the probe unit 172 on the mounter 174 to bring the head unit 104 and the corresponding pad of the measurement chip 102 into contact with the probe.

(Third Modification)
In the embodiment, the case where the entire amplifier circuit 122 is integrated in the measurement chip 102 has been described, but the present invention is not limited thereto. FIGS. 8A to 8D are diagrams showing a current measuring device according to a third modification. As shown in FIG. 8A, the amplifier circuit 122 includes an input stage 122a and an amplifier stage 122b. A part including the input stage 122a is integrated in the measurement chip 102, and the amplifier stage 122b is connected to the head unit 104. Built in. FIGS. 8B to 8C show specific examples of the input stage 122a. FIG. 8B shows a source follower circuit, FIG. 8C shows a buffer (voltage follower), and FIG. 8D shows a non-inverting amplifier.

  Returning to FIG. The input terminal of the input stage 122a of the amplifier circuit 122, that is, the inverting input terminal of the amplifier circuit 122 is connected to the current generator 110 (first electrode 310a in FIG. 9). The first contact pad Pd1 is connected to the input terminal of the input stage 122a. The second contact pad Pd2 is connected to the output terminal of the input stage 122a.

The first probe Pb1 and the second probe Pb2 are disposed so as to be in contact with the first contact pad Pd1 and the second contact pad Pd2. The input terminal of the amplification stage 122b is connected to the second probe Pb2. Feedback resistor _{R F} is provided between the output terminal of the amplifier stage pb2122b and first probe Pb1.

That is, in use, between a first contact pad Pd1 of the second contact pad Pd2, by amplifying stage 122b of the feedback resistor R _F and the amplifier circuit 122 is connected, by the transimpedance amplifier 110 is enabled configuration Yes.

  Also by this modification, the same effect as the embodiment can be obtained.

(Fourth modification)
In the embodiment, the case where the digitizer (A / D converter) is mounted on the head unit 104 has been described. However, the digitizer may be integrated on the measurement chip 102. In this case, an interface circuit for transmitting digital data and a contact pad for outputting digital data are further formed on the measurement chip 102. A probe and an interface circuit that receives digital data via the probe may be provided on the head unit 104 side.

(5th modification)
In the embodiment, the first contact pad Pd1 and the signal line 112 are directly connected. However, a resistor may be formed between the first contact pad Pd1 and the signal line 112 for circuit protection. Similarly, a resistor may be formed between the second contact pad Pd 2 and the output of the amplifier circuit 122.

(Use)
Finally, the use of the current measuring device 100 will be described. The current measurement device 100 according to the embodiment can be used for a base sequence analysis device (DNA sequencer or RNA sequencer) 300. FIG. 9 is a block diagram of a base sequence analyzing apparatus 300 including the current measuring apparatus 100. The nanopore chip 302 corresponds to the measurement chip 102 described above. Note that the chip in FIG. 9 is a schematic diagram, and the size of each member is different from the actual size.

  The nanopore chip 302 is a semiconductor chip such as silicon, on which a nanochannel 304, a nanopillar 306, an electrode pair 310, a nanopore 312, an amplifier circuit 122, a first contact pad Pd1 to a third contact pad Pd3 are provided. Integrated. In addition, the measurement chip 102 includes an electrophoresis electrode (not shown), a contact pad for supplying a voltage to the electrophoresis electrode, and a contact pad for supplying a power supply voltage generated by the power supply circuit 128. Etc. are also formed.

  As the DNA sample passes through the nanochannel 304, one molecule of DNA is separated and extracted. When the DNA molecule passes through the nanopillar 306, the DNA molecule is linearized.

  The head unit 104 is provided with a drive amplifier 180. The drive amplifier 180 controls a voltage applied to the electrode pair for electrophoresis and controls an electric field generated between the electrode pair for electrophoresis. This electric field is applied to the DNA molecule, and the DNA molecule passes between the electrode pair 310 formed in the nanopore 312.

The electrode pair 310 includes a first electrode 310a and a second electrode 310b. The electrode pair 310 is connected to the inverting input terminal of the amplifier circuit 122 and the first contact pad Pd1. Between the electrode pair 310, a tunnel current I _DUT corresponding to the type of base of the DNA molecule passing at that time flows. The current measuring apparatus 100 detects the tunnel current (current signal) I _DUT and converts it into a voltage signal _VOUT . That is, in the base sequence analyzer 300, it is understood that the electrode pair 310 and the nanopore 312 correspond to the current generator 110 in FIG.

The voltage signal _VOUT is converted into a digital value by the measurement unit (A / D converter) 126. The digital value is input to the data processing device 314. The data processing device 314 is a computer including a memory and a processor, and specifies a base sequence of a DNA molecule by signal processing.

The resistance thermal noise in terms of current by the resistor R _F is I _NOISE = √ (4 × k × T / R _F ). When R _F = 1MΩ and 129 fA / √Hz in an environment of 27 ° C. and the transimpedance has a band of 100 kHz, noise of 40.7 pA _RMS is generated. Therefore, for high-precision measurement, a large number of samplings and statistical processing will be required. From this point of view, the current measuring apparatus 100 according to the embodiment has low noise characteristics and high speed, so that the accuracy is increased by increasing the number of samplings per base, or the number of bases to be analyzed per unit time is increased. be able to. Or since the noise of the current measuring device 100 can be reduced, the number of samplings per base can be reduced.

  Although the gating nanopore type sequencer has been described with reference to FIG. 9, the current measuring device 100 can also be used for an MCBJ type sequencer. In this case, instead of the nanopore chip 302, an MCBJ chip is used. Instead of the nanopore 312, the MCBJ chip is integrated with an electrode material such as a gold wire and a breaking mechanism for breaking the electrode material.

  Although the present invention has been described based on the embodiments, the embodiments merely show the principle and application of the present invention, and the embodiments depart from the idea of the present invention defined in the claims. Many modifications and changes in the arrangement are allowed within the range not to be performed.

DESCRIPTION OF SYMBOLS 100 ... Current measuring device, 102 ... Measuring chip, 104 ... Head unit, 106 ... Conveying device, 108 ... Lifting device, 110 ... Current generating part, 112 ... Signal line, 120 ... Transimpedance amplifier, 122 ... Amplifying circuit, 124 DESCRIPTION OF SYMBOLS ... Output buffer 126 ... Measurement part 128 ... Power supply circuit 130 ... Signal generator 132 ... Calibrator 134 ... Guard amplifier 136 ... ESD protection element 138 ... Driving guard metal 140 ... Coaxial wiring 142 ... Core wire , 144 ... shield, R F _... feedback resistor, C F _... feedback capacitor, 150 ... non-inverting amplifier, 152 ... inverting amplifier, 154 ... op, Pd1 ... first contact pad, Pd2 ... second contact pad, Pd3 ... Third contact pad, Pb1... First probe, Pb2... Second probe, P b3 ... third probe, 112 ... signal line, 160 ... wafer, 162 ... probe card, 170 ... jig, 172 ... probe unit, 174 ... mounter, 176 ... socket, 180 ... drive amplifier, 300 ... base sequence analyzer, 302 ... Nanopore chip, 304 ... Nanochannel, 306 ... Nanopillar, 310 ... Electrode pair, 310a ... First electrode, 310b ... Second electrode, 312 ... Nanopore.

Claims (3)

A current generator for generating a current signal to be measured; and
A transimpedance amplifier that converts the current signal into a voltage signal;
With
The transimpedance amplifier is
An inverting amplifier circuit;
A feedback resistor provided between an inverting input terminal and an output terminal of the amplifier circuit;
Including
The amplifier circuit includes an input stage and an amplifier stage,
A part including the input stage of the amplifier circuit is integrated on the same semiconductor chip as the current generator,
A first contact pad formed on the semiconductor chip and connected to the inverting input terminal of the amplifier circuit;
A second contact pad formed on the semiconductor chip and connected to the output terminal of the input stage;
A head unit having first and second probes in contact with the first and second contact pads;
Further comprising
The feedback resistor and the amplification stage are built in the head unit,
An input terminal of the amplification stage is connected to the second probe;
The feedback resistor, characterized current measurement device that is connected between the output terminal of the amplifier stage and the first probe. A base sequence analyzing apparatus comprising the current measuring apparatus according to claim 1 . An electrode pair including a first electrode and a second electrode, and configured to allow a sample to pass between the first electrode and the second electrode;
An input stage that is part of an inverting amplifier circuit, the input terminal of which is connected to the first electrode;
A first contact pad connected to an input terminal of the input stage;
A second contact pad connected to the output terminal of the input stage;
Integrated into a single semiconductor substrate,
In use, a transimpedance amplifier can be configured by connecting a feedback resistor and an amplification stage of the amplifier circuit between the first contact pad and the second contact pad. Measuring chip to be used.

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