CN111090002A - Nanopore gene sequencing micro-current detection device and current stability compensation method - Google Patents
Nanopore gene sequencing micro-current detection device and current stability compensation method Download PDFInfo
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Abstract
The invention provides a nanopore gene sequencing micro-current detection device, which comprises a detection circuit for detecting current change generated when DNA molecules flow through a nanopore on a thin film, wherein the detection circuit comprises a first electrode, a second electrode, a third electrode and a constant potential circuit; when the working electrode deflects, the constant potential circuit makes the ground potential of the counter electrode pair always follow the ground potential of the reference electrode pair, so that a stable voltage difference is kept between the first electrode and the second electrode. The invention also relates to a compensation method for the stability of the micro-current in the nanopore gene sequencing. The invention changes the current signal detected by the working electrode into a voltage signal through the integral amplifier, the integral amplifier takes a capacitor as a feedback element, and two sampling and holding circuits are adopted to realize related double sampling, thereby having lower noise performance, improving the bandwidth and the linearity of the signal, simultaneously carrying out filtering, denoising, compensation and other processing on the current signal, and greatly improving the accuracy of current detection.
Description
Technical Field
The invention relates to the technical field of electronics, in particular to a nanopore gene sequencing micro-current detection device.
Background
The third generation nanopore gene sequencing technology which is characterized by single molecule, synthesis and sequencing has more obvious advantages in reading length, cost and speed, and is one of the current research hotspots. The principle of nanopore sequencing is to detect the weak characteristic current change generated when a uncoiled DNA single strand passes through a nanopore to judge the base sequence of the DNA single strand. Therefore, the accurate measurement of the characteristic current is one of the key technologies for realizing high-accuracy gene sequencing, while the current nanopore gene sequencing widely uses a two-electrode electrochemical system, a certain voltage is applied between two electrodes for driving DNA to pass through a nanopore, but due to the existence of a non-Faraday process, the pressure difference between the two electrodes is easy to fluctuate so as to cause potential deviation, and because the current is very weak and is generally in the picoampere level, the change of the pressure difference greatly influences the detection accuracy of the current and the accuracy of the sequencing.
Disclosure of Invention
In order to overcome the defects of the prior art, the invention provides a nanopore gene sequencing micro-current detection device.
The third electrode is added between the first electrode and the second electrode, and the third electrode enables a constant potential to be formed between the first electrode and the second electrode, so that the technical problem is solved.
The invention provides a nanopore gene sequencing micro-current detection device, which comprises a detection circuit for detecting current change generated when DNA molecules flow through a nanopore on a thin film, and is characterized in that the detection circuit comprises a first electrode, a second electrode, a third electrode and a constant potential circuit, wherein the first electrode and the second electrode are arranged at two sides of the thin film, voltage is applied between the first electrode and the second electrode to drive a DNA single chain on the thin film to pass through the nanopore, and the second electrode is used for detecting a current signal generated when the DNA molecules pass through the nanopore;
the third electrode is arranged between the first electrode and the second electrode, the third electrode is connected with the constant potential circuit, and the constant potential circuit is connected with the first electrode; the constant potential circuit adjusts the first electrode pair ground potential to always follow the change of the third electrode pair ground potential, so that a stable voltage difference is kept between the first electrode and the second electrode.
Preferably, the constant potential circuit comprises a constant potential generator and a data processing component, the constant potential generator is connected with the first electrode, and the data processing component is positioned between the constant potential generator and the second electrode; and the data processing component sends an instruction according to the detected potential offset of the second electrode to configure the constant potential generator so as to form a constant potential between the first electrode and the second electrode.
Preferably, an integrating amplifier is arranged between the second electrode and the data processing component and is used for converting the current signal detected by the second electrode into a voltage signal; wherein the integrating amplifier employs a high input stage impedance.
Preferably, at least one sample holder is included between the integrating amplifier and the data processing assembly for holding sample values.
Preferably, the second electrode is at zero potential with respect to ground.
Preferably, the constant potential generator comprises an operational amplifier for supplying a current to the first electrode, an inverting input of the operational amplifier being connected to the third electrode.
Preferably, the constant potential generator further includes a bias source, the bias source is electrically connected to the data processing component, the data processing component sends an instruction to the bias source, and the bias source is configured to set a constant potential between the first electrode and the second electrode.
The invention also provides a compensation method for stabilizing the micro-current in nanopore gene sequencing, which is used for carrying out high-frequency compensation on the output signal amplified by the integral amplifier, wherein the high-frequency compensation is used for weakening the high-frequency component of the output signal amplified by the integral amplifier.
Preferably, zero overshoot compensation is performed by a low pass filter before the high frequency compensation is performed; and adding offset voltage for post compensation while performing the zero overshoot compensation, wherein the offset voltage post compensation is used for eliminating the offset voltage output in the integrating amplifier.
Preferably, compensation of electrode capacitance, membrane capacitance and nanopore series resistance is also included; wherein the content of the first and second substances,
the compensation of the electrode capacitor and the membrane capacitor comprises the steps that a first compensation branch and a second compensation branch are respectively connected to the inverting input end of the integrating amplifier, and the first compensation branch and the second compensation branch are respectively used for providing current for the electrode capacitor and the membrane capacitor; the first compensation branch and the second compensation branch are simultaneously connected with a step voltage, and the step voltage enables the currents passing through the first compensation branch and the electrode capacitor and the currents passing through the second compensation branch and the membrane capacitor to be equal in magnitude and opposite in direction;
the compensation of the nanopore series resistance comprises taking out a certain proportion of the output voltage of the integrating amplifier to offset the voltage drop caused by the nanopore series resistance and form a compensation circuit of a correction loop.
Compared with the prior art, the invention has the beneficial effects that:
the invention discloses a nanopore gene sequencing micro-current detection device, which comprises a counter electrode and a working electrode which are arranged on two sides of a lipid membrane, wherein a reference electrode is arranged between the counter electrode and the working electrode, a bias voltage is applied between the working electrode and the reference electrode through a constant potential generator, when the working electrode deviates, the constant potential generator enables the ground potential of the counter electrode to always change along with the ground potential of the reference electrode, and the constant potential formed between the counter electrode and the working electrode is ensured to be used for driving DNA molecules to pass through a nanopore. In addition, the current signal detected by the working electrode is changed into a voltage signal through the integrating amplifier, the integrating amplifier takes a capacitor as a feedback element, and two sampling and holding circuits are adopted to realize related double sampling, so that the double sampling circuit has lower noise performance, improves the bandwidth and the linearity of the signal, and simultaneously performs filtering, denoising, compensation and other processing on the current signal, thereby greatly improving the accuracy of current detection.
The invention also discloses a compensation method for the stability of the micro-current for the nanopore gene sequencing, which can accurately and stably detect the fluctuation of the picoampere-level current signal generated when DNA molecules pass through the nanopore, the detection precision can be as low as less than 10 picoamperes, and the nanopore gene sequencing with high accuracy can be realized.
The foregoing description is only an overview of the technical solutions of the present invention, and in order to make the technical solutions of the present invention more clearly understood and to implement them in accordance with the contents of the description, the following detailed description is given with reference to the preferred embodiments of the present invention and the accompanying drawings. The detailed description of the present invention is given in detail by the following examples and the accompanying drawings.
Drawings
The accompanying drawings, which are included to provide a further understanding of the invention and are incorporated in and constitute a part of this application, illustrate embodiment(s) of the invention and together with the description serve to explain the invention without limiting the invention. In the drawings:
FIG. 1 is an overall structural view of a nanopore gene sequencing micro-current detection device of the present invention;
FIG. 2 is a detailed structural diagram of the nanopore gene sequencing micro-current detection device of the present invention;
FIG. 3 is a diagram of a constant potential generator of the nanopore gene sequencing micro-current detection device of the present invention;
FIG. 4 is a schematic illustration of a compensation method for nanopore gene sequencing micro-current stabilization of the present invention;
reference numerals: 10. lipid membrane, 20, DNA molecule, 30, nanopore, 40, second electrode, 50, first electrode, 60, third electrode, 70, constant potential circuit, 710, constant potential generator, 720, integrating amplifier, 730, denoising unit, 740, first sample holder, 750, second sample holder, 760, data processing component, 711, first capacitor, 712, first resistor, 713, second resistor, 714, second capacitor, 715, operational amplifier, 716, bias source, 800, boost overshoot circuit, 810, high frequency compensation, 820, zero overshoot compensation, 830, offset compensation, 840, offset voltage post compensation, 850, low pass filter, 860, first compensation branch, 870, step voltage, 880, second compensation branch, 890, compensation circuit of the correction loop.
Detailed Description
The present invention will be further described with reference to the accompanying drawings and the detailed description, and it should be noted that any combination of the embodiments or technical features described below can be used to form a new embodiment without conflict.
The invention provides a nanopore gene sequencing micro-current detection device, which comprises a detection circuit for detecting current change generated when DNA molecules flow through a nanopore on a thin film, wherein the detection circuit comprises a first electrode 50, a second electrode 40, a third electrode 60 and a constant potential circuit 70, the first electrode 50 and the second electrode 40 are arranged at two sides of the thin film, voltage is applied between the first electrode 50 and the second electrode 40 to drive a DNA single chain on the thin film to pass through the nanopore 30, and the second electrode 40 is used for detecting a current signal generated when the DNA molecules 20 pass through the nanopore 30;
the third electrode 60 is disposed between the first electrode 50 and the second electrode 40, the third electrode 60 is connected to the constant potential circuit 70, and the constant potential circuit 70 is connected to the first electrode 50; the constant potential circuit 70 adjusts the first electrode 50 to the ground potential to always follow the change of the third electrode 60 to the ground potential, so that a stable voltage difference is maintained between the first electrode 50 and the second electrode 40. In one embodiment, the DNA molecule 20 is driven through the nanopore 30 by applying a voltage between the first electrode 50 and the second electrode 40, the first electrode 50 being a counter electrode and the second electrode 40 being a working electrode for detecting a weak current signal generated by the DNA molecule 20 as it passes through the nanopore 30. A reference electrode is arranged between the counter electrode and the working electrode, the reference electrode is connected with a constant potential circuit 70, the constant potential circuit 70 enables the ground potential of the counter electrode to always follow the change of the ground potential of the reference electrode, so as to ensure that a constant potential is formed between the counter electrode and the working electrode to drive the DNA molecules 20 to pass through the nanometer pore canal 30.
The constant potential circuit 70 comprises a constant potential generator 710 and a data processing component 760, wherein the constant potential generator 710 is connected with the first electrode 50, and the data processing component 760 is positioned between the constant potential generator 710 and the second electrode 40; the data processing component 760 will send instructions for configuring the constant potential generator 710 to cause a constant potential to be formed between the first electrode 50 and the second electrode 40 based on the detected amount of potential offset of the second electrode 40. In one embodiment, the thin film is preferably a lipid membrane 10, the nanopore 30 is embedded between two lipid membranes 10, the nanopore 30 is communicated with the upper and lower regions of the lipid membrane 10, the constant potential generator 710 is used for forming a bias voltage between a working electrode and a counter electrode in a three-electrode system so as to drive the DNA molecules 20 to pass through the nanopore 30 and simultaneously form an ion current, and the ground potential of the counter electrode always changes along with the potential of the reference electrode; the constant potential generator 710 is used to maintain a stable, constant driving voltage between the working electrode and the counter electrode.
In one embodiment, the ground potential of the second electrode 40, i.e., the working electrode, is zero, which can achieve the purpose of stable and controllable driving voltage between the reference electrode and the working electrode, and current only flows between the counter electrode and the working electrode, and no current flows through the reference electrode, thereby avoiding polarization.
The second electrode 40 and the data processing component 760 comprise an integral amplifier 720, and the integral amplifier 720 is used for converting the current signal detected by the second electrode 40 into a voltage signal; wherein the integrating amplifier 720 employs a high input stage impedance. In one embodiment, the integrating amplifier 720 is used to convert the detected current signal into a voltage signal, and the integrating amplifier 720 uses a high input stage impedance and uses a small capacitor as a feedback element to form an integrating circuit, but since the capacitor needs to be periodically discharged, a switch connected in parallel with the capacitor needs to be placed to control the charging and discharging process of the capacitor. The integrating amplifier 720 is connected to a denoising unit 730, and the denoising unit 730 is used for denoising noise generated in the current signal detection process.
At least one sample holder is included between the integrating amplifier 720 and the data processing assembly 760 for holding sample values. In one embodiment, in order to prevent the integrating amplifier 720 from being unable to process signals in the feedback capacitor discharge device, a sample holder is configured to hold sample values, the sample holder employs a correlated double sampling technique, the sample holder includes a first sample holder 740 and a second sample holder 750, the first sample holder 740 is connected in parallel with the second sample holder 750, the noise is reduced, and the accuracy of current signal detection is improved, and the sample holder generally comprises an analog switch, a storage capacitor and a buffer amplifier, and is controlled to be in a sampling state or a holding state by the analog switch.
The constant potential generator 710 comprises an operational amplifier 715, wherein the operational amplifier 715 is used for providing current to the first electrode 50, and the inverting input of the operational amplifier 715 is connected with the third electrode 60. The constant potential generator 710 further comprises a bias source 716, wherein the bias source 716 is electrically connected to the data processing element 760, the data processing element 760 sends a command to the bias source 716, and the bias source 716 is configured to set a constant potential between the first electrode 50 and the second electrode 40. In one embodiment, an operational amplifier 715 supplies current to the counter electrode to balance the current demand of the working electrode, and the inverting input is connected to the reference electrode, the operational amplifier 715 maintains the working and counter electrodes at a constant potential, the potential being supplied by a bias source 716, the bias source 716 being controlled by the data processing component 760. Because the current on the reference electrode is very small, any offset caused by the input offset voltage in the op-amp 715 will cause a sudden change in on-potential, and the op-amp 715 is selected to ensure that it has a small input bias current, typically less than 5pA, and a low offset voltage, typically less than 100 μ V, and to control the op-amp 715 to operate at a constant temperature. The circuit stability and noise reduction of the constant potential circuit 70 depend on the resistors including the first resistor 712 and the second resistor 713 and the capacitors including the first capacitor 711 and the second capacitor 714, as shown in fig. 3.
In addition, the data processing unit 760 is also used for converting the voltage signal into a digital signal, and generally comprises a single chip microcomputer, an FPGA (field programmable gate array) processor, an analog-to-digital conversion functional module and a data transmission module, so as to transmit data to an upper computer for large-scale data analysis, thereby realizing the identification and assembly of the base sequence of the DNA molecule.
The invention also provides a compensation method for micro-current stabilization in nanopore gene sequencing, which comprises the step of performing high-frequency compensation 810 on the output signal amplified by the integrating amplifier 720, wherein the high-frequency compensation 810 is used for weakening the high-frequency component of the output signal amplified by the integrating amplifier 720, as shown in FIG. 4. Zero overshoot compensation 820 by a low pass filter before the high frequency compensation 810; and adding an offset voltage post-compensation 840 at the same time of the zero overshoot compensation 820, wherein the offset voltage post-compensation 840 is used for eliminating the offset voltage output in the integrating amplifier 720. In one embodiment, to solve the problem of the reduction of the high frequency component of the output signal amplified by the integrating amplifier 720, the circuit is high frequency compensated 810 to provide bandwidth, and the zero point of the integrating amplifier 720 generates an overshoot phenomenon on the output signal of the high frequency compensated 810, so that the zero point overshoot compensation 820 is performed by using a low pass filter before the high frequency compensation 810. In addition, a certain output offset voltage exists in the integrating amplifier 720, internal or external offset zero adjustment, namely, the input offset compensation 830 of the integrating amplifier needs to be carried out on the output offset voltage, and offset voltage post-compensation 840 is added at the same time of zero overshoot compensation 820 so as to eliminate the negative effect of the offset voltage.
In the nanopore gene sequencing detection process, through hole noise is generated when DNA single molecules pass through a nanopore, the frequency range of a DNA single molecule perforation ion current signal and the frequency range of noise and interference signals are overlapped, the frequency of the noise is usually higher than that of a detection signal, the noise and the interference signals are filtered by a low-pass filter 850, and the frequency of the low-pass filter 850 is preferably 10 kHz.
The compensation of electrode capacitance, membrane capacitance and nanopore series resistance is also included; wherein the content of the first and second substances,
the compensation of the electrode capacitance and the membrane capacitance includes connecting a first compensation branch 860 and a second compensation branch 880 to the inverting input terminal of the integrating amplifier 720, respectively, where the first compensation branch 860 and the second compensation branch 880 are used to provide current to the electrode capacitance and the membrane capacitance, respectively; a step voltage 870 is connected to both the first compensating branch 860 and the second compensating branch 880, wherein the step voltage 870 enables the currents passing through the first compensating branch 860 and the electrode capacitor and the currents passing through the second compensating branch 880 and the membrane capacitor to be equal and opposite;
compensating the nanopore series resistance comprises taking the output voltage of the integrating amplifier 720 a proportion to offset the voltage drop caused by the nanopore series resistance and forming a compensation circuit 890 of a correction loop.
The electrode capacitance is not purely capacitive, and there is a resistance in series with the electrode capacitance, such as the electrode resistance and the resistance of the electrolyte solution, the electrolyte solution in the electrode, etc. The influence of the electrode capacitance on the circuit is mainly when the detection system starts to operate, because the time constant of the electrode capacitance is relatively small and is of a uS level, the generated charging and discharging current is higher than a pA level detection signal by 2 to 3 orders of magnitude after being amplified by a feedback element, the detection signal is sufficiently submerged, and the amplifier can enter a saturation region, so that the work of the detection system is seriously influenced. An electrode capacitance compensation branch, i.e. a first compensation branch 860, is connected to the inverting input terminal of the integrating amplifier 720, and is dedicated to providing current for charging and discharging the electrode capacitance, the branch uses the compensation capacitance as a charging and discharging current injection element, and a synchronous step voltage 870 is also input to the other end of the compensation capacitance, so that the current passing through the compensation capacitance is exactly equal to the charging and discharging current of the electrode capacitance to be eliminated, and the direction is opposite. Meanwhile, due to the existence of the electrode capacitance time constant, the step voltage signal applied to the compensation capacitance branch circuit also needs to be output after passing through a delay circuit with adjustable time constant, so that the compensation current is better matched with the electrode capacitance current.
The time constant of the membrane capacitance is higher than the electrode capacitance, by tens to hundreds of uS. Similar to electrode capacitance compensation during compensation, the voltage source step voltage 870 of the second compensation branch 880 serving as a film capacitance compensation path is output to the compensation capacitor through the time delay circuit and the proportional control circuit.
The nanopore series resistance has two main hazards to the measurement circuit: one is that it limits the charging and discharging time of the membrane capacitor, affects the index of DNA rapid measurement, makes the system bandwidth not as high as expected, and this part is already compensated by the previous membrane capacitor compensation path; the other is voltage drop caused by current flowing through a series resistor, for the part of the detected current, a compensation channel is applied to the output end of the integral amplifier, the output voltage of the integral amplifier which is in direct proportion to the detected current is taken out in a certain proportion, and the compensation circuit 890 is used for offsetting partial voltage drop to form a correction loop, so that the time resolution of the detected current signal can be improved, and the system bandwidth capability can also be improved; for the charge and discharge current part of the membrane capacitor, when a driving voltage is applied, a short charge or discharge pulse is added at the front edge and the rear edge of the pulse, so that the change of the membrane voltage starts to change to a level higher or lower than a preset voltage value, and the additional pulse is removed immediately once a preset value is reached, thereby obviously improving the change speed of the membrane voltage. Because the primary factors influencing the sensitivity of weak current measurement are the bias current of the integrating amplifier 720 and the drift of the integrating amplifier along with temperature or time, the pre-integrating amplifier should meet the requirements that the bias current is as smaller as possible than the weak current to be measured, the gain and common mode rejection ratio is high, the offset voltage and drift are small, the noise is small and the like, and JFET devices with low noise, high gain and low bias current such as AD549L can be selected.
The invention discloses a nanopore gene sequencing micro-current detection device, which comprises a counter electrode and a working electrode which are arranged at two sides of a lipid membrane 10, wherein a reference electrode is arranged between the counter electrode and the working electrode, a bias voltage is applied between the working electrode and the reference electrode through a constant potential generator 710, when the working electrode deviates, the constant potential generator 710 enables the ground potential of the counter electrode to change along with the ground potential of the reference electrode all the time, and the constant potential formed between the counter electrode and the working electrode is ensured to be used for driving a DNA molecule 20 to pass through a nanopore 30. In addition, the current signal detected by the working electrode is changed into a voltage signal through the integrating amplifier 720, the integrating amplifier 720 takes a capacitor as a feedback element, and two sampling and holding circuits are adopted to realize related double sampling, so that the noise performance is lower, the bandwidth and the linearity of the signal are improved, meanwhile, the current signal is also subjected to filtering, denoising, compensation and other processing, and the accuracy of current detection is greatly improved.
The invention also discloses a compensation method for the stability of the micro-current for the nanopore gene sequencing, which can accurately and stably detect the fluctuation of the picoampere-level current signal generated when DNA molecules pass through the nanopore, the detection precision can be as low as less than 10 picoamperes, and the nanopore gene sequencing with high accuracy can be realized.
The foregoing is merely a preferred embodiment of the invention and is not intended to limit the invention in any manner; those skilled in the art can readily practice the invention as shown and described in the drawings and detailed description herein; however, those skilled in the art should appreciate that they can readily use the disclosed conception and specific embodiments as a basis for designing or modifying other structures for carrying out the same purposes of the present invention without departing from the scope of the invention as defined by the appended claims; meanwhile, any changes, modifications, and evolutions of the equivalent changes of the above embodiments according to the actual techniques of the present invention are still within the protection scope of the technical solution of the present invention.
Claims (10)
1. The nanopore gene sequencing micro-current detection device comprises a detection circuit for detecting current change generated when DNA molecules flow through a nanopore on a thin film, and is characterized in that the detection circuit comprises a first electrode, a second electrode, a third electrode and a constant potential circuit, wherein the first electrode and the second electrode are arranged on two sides of the thin film, voltage is applied between the first electrode and the second electrode to drive a DNA single chain on the thin film to pass through the nanopore, and the second electrode is used for detecting a current signal generated when the DNA molecules pass through the nanopore;
the third electrode is arranged between the first electrode and the second electrode, the third electrode is connected with the constant potential circuit, and the constant potential circuit is connected with the first electrode; the constant potential circuit adjusts the first electrode pair ground potential to always follow the change of the third electrode pair ground potential, so that a stable voltage difference is kept between the first electrode and the second electrode.
2. The nanopore gene sequencing micro-current detection device of claim 1, wherein the constant potential circuit comprises a constant potential generator and a data processing component, the constant potential generator is connected with the first electrode, and the data processing component is located between the constant potential generator and the second electrode; and the data processing component sends an instruction according to the detected potential offset of the second electrode to configure the constant potential generator so as to form a constant potential between the first electrode and the second electrode.
3. The nanopore gene sequencing micro-current detection device of claim 2, comprising an integrating amplifier between the second electrode and the data processing component, the integrating amplifier being configured to convert a current signal detected by the second electrode into a voltage signal; wherein the integrating amplifier employs a high input stage impedance.
4. The nanopore gene sequencing microcurrent detection device of claim 3, comprising at least one sample holder between the integrating amplifier and the data processing assembly for holding sample values.
5. The nanopore gene sequencing microcurrent detection device of claim 1, wherein said second electrode is at zero ground potential.
6. The nanopore gene sequencing micro-current detection device of claim 2, wherein the constant potential generator comprises an operational amplifier for providing current to the first electrode, an inverting input of the operational amplifier being connected to the third electrode.
7. The nanopore gene sequencing micro-current detection device of claim 6, wherein the constant potential generator further comprises a bias source, the bias source is electrically connected to the data processing component, the data processing component sends a command to the bias source, and the bias source is used for setting a constant potential between the first electrode and the second electrode.
8. A compensation method for micro-current stabilization in nanopore gene sequencing is characterized by comprising the step of carrying out high-frequency compensation on an output signal amplified by an integrating amplifier, wherein the high-frequency compensation is used for weakening a high-frequency component of the output signal amplified by the integrating amplifier.
9. The method for compensating for the stability of nanopore gene sequencing microcurrents according to claim 8, wherein the zero overshoot compensation is performed by a low pass filter before the high frequency compensation is performed; and adding offset voltage for post compensation while performing the zero overshoot compensation, wherein the offset voltage post compensation is used for eliminating the offset voltage output in the integrating amplifier.
10. The method for compensating for the stability of nanopore gene sequencing microcurrents according to claim 8, further comprising compensating for electrode capacitance, membrane capacitance, and nanopore series resistance; wherein the content of the first and second substances,
the compensation of the electrode capacitor and the membrane capacitor comprises the steps that a first compensation branch and a second compensation branch are respectively connected to the inverting input end of the integrating amplifier, and the first compensation branch and the second compensation branch are respectively used for providing current for the electrode capacitor and the membrane capacitor; the first compensation branch and the second compensation branch are simultaneously connected with a step voltage, and the step voltage enables the currents passing through the first compensation branch and the electrode capacitor and the currents passing through the second compensation branch and the membrane capacitor to be equal in magnitude and opposite in direction;
the compensation of the nanopore series resistance comprises taking out a certain proportion of the output voltage of the integrating amplifier to offset the voltage drop caused by the nanopore series resistance and form a compensation circuit of a correction loop.
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| CN113740397A (en) * | 2020-05-27 | 2021-12-03 | 成都今是科技有限公司 | Micro-current detection circuit and gene sequencing device |
| CN113759162A (en) * | 2021-08-31 | 2021-12-07 | 陕西科技大学 | Weak current amplification circuit of biological nanometer pore |
| WO2023051665A1 (en) * | 2021-09-30 | 2023-04-06 | 成都今是科技有限公司 | Nanopore sequencing circuit unit and gene sequencing apparatus |
| WO2023051666A1 (en) * | 2021-09-30 | 2023-04-06 | 成都今是科技有限公司 | Ultra-small area micro-current detection circuit unit and system |
| US20230258593A1 (en) * | 2022-02-16 | 2023-08-17 | Western Digital Technologies, Inc. | Low noise amplifiers with feedback for nanopore applications |
| WO2023158452A1 (en) * | 2022-02-16 | 2023-08-24 | Western Digital Technologies, Inc. | Low noise amplifiers with shields for nanopore applications |
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