CN113699223B - Nanopore sequencing circuit, sequencing method and device - Google Patents
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Abstract
The application discloses a nanopore sequencing circuit, a sequencing method and a device. The nanopore sequencing circuit comprises at least one signal detection circuit and an analog-to-digital conversion circuit, wherein the input end of the signal detection circuit is connected with a nanopore sequencing channel, and the output end of the signal detection circuit is connected with the input end of the analog-to-digital conversion circuit; wherein the signal detection circuit comprises: the input end of the current amplification circuit is connected with the nanopore sequencing channel and is used for amplifying a current signal generated in the nanopore sequencing channel; the input end of the voltage conversion circuit is connected with the output end of the current amplification circuit, and the output end of the voltage conversion circuit is connected with the input end of the analog-to-digital conversion circuit and used for converting the amplified current signal into a voltage signal; the analog-to-digital conversion circuit is used for converting the voltage signal into a digital signal. Through the circuit, sequencing signals can be accurately acquired.
Description
Technical Field
The application belongs to the technical field of nanopore sequencing, and particularly relates to a nanopore sequencing circuit, a nanopore sequencing method and a nanopore sequencing device.
Background
Currently, nanopore gene sequencers presume the sequence of genes passing through a thin film nanopore by measuring the current signal flowing through the thin film nanopore. The current signal is very weak, typically on the order of tens of picoamps. Generally, in a nanopore sequencing circuit, a transimpedance amplification circuit is used to convert a micro-current signal into a voltage signal for amplification, and an analog-to-digital conversion circuit is used to sample the amplified voltage signal to obtain a corresponding measurement result.
However, in general, in a transimpedance amplifier circuit, a high-resistance resistor (of the order of several hundred megaohms to several gigaohms) is used to place a minute current flowing through a nanopore from several tens of picovolts to several hundreds of millivolts. However, in integrated circuit designs, it is difficult to achieve resistors with values on the order of gigaohms using passive devices.
Disclosure of Invention
In view of this, the nanopore sequencing circuit, the nanopore sequencing method, and the nanopore sequencing device provided in the embodiments of the present application can amplify a current signal flowing through a thin-film nanopore, avoid transimpedance amplification of the current signal by using a high-resistance resistor, and accurately acquire a sequencing signal.
In a first aspect, embodiments of the present application provide a nanopore sequencing circuit comprising at least one signal detection circuit and an analog-to-digital conversion circuit.
The input end of the signal detection circuit is connected with the nanopore sequencing channel, and the output end of the signal detection circuit is connected with the input end of the analog-to-digital conversion circuit.
The signal detection circuit comprises the following circuits.
And the input end of the current amplification circuit is connected with the nanopore sequencing channel and is used for amplifying a current signal generated in the nanopore sequencing channel.
And the input end of the voltage conversion circuit is connected with the output end of the current amplification circuit, and the output end of the voltage conversion circuit is connected with the input end of the analog-to-digital conversion circuit and is used for converting the amplified current signal into a voltage signal.
The analog-to-digital conversion circuit is used for converting the voltage signal into a digital signal.
In some implementations, the current amplification circuit includes at least one current amplification unit including a first current amplification unit.
The first current amplification unit comprises a first transistor, a second transistor and a first operational amplifier, wherein the area of a PN junction of the second transistor is M times of the area of the PN junction of the first transistor, and M is a positive number.
And the inverting input end of the first operational amplifier is connected with the nanopore sequencing channel, and the non-inverting input end of the first operational amplifier is connected with a bias voltage.
The input end of the first transistor is connected with the output end of the first operational amplifier, and the output end of the first transistor is connected with the inverting input end of the first operational amplifier.
And the input end of the second transistor is connected with the output end of the first operational amplifier.
In some embodiments, the current amplifying unit further comprises a second current amplifying unit.
The second current amplifying unit includes a third transistor, a fourth transistor, and a second operational amplifier, where a PN junction area of the fourth transistor is N times the PN junction area of the third transistor, and N is a positive number.
And the inverting input end of the second operational amplifier is connected with the output end of the first current amplification unit, and the non-inverting input end of the second operational amplifier is connected with the bias voltage.
The input end of the third transistor is connected with the inverting input end of the second operational amplifier, and the output end of the third transistor is connected with the output end of the second operational amplifier.
In a case where the number of the second current amplifying units is equal to the number of the first current amplifying units, the output terminal of the fourth transistor is connected to the output terminal of the second operational amplifier.
In some embodiments, when the number of the first current amplifying units is one more than the number of the second current amplifying units, and the number of the second current amplifying units is L, an output terminal of an lth one of the first current amplifying units is connected to an input terminal of an lth one of the second current amplifying units, an output terminal of an lth one of the second current amplifying units is connected to an input terminal of an L +1 th one of the first current amplifying units, and L is a positive integer;
and the output end of the L +1 th first current amplification unit is connected with the input end of the voltage conversion circuit.
In some embodiments, the first and second transistors, the third and fourth transistors are each one of a diode, a triode, and a metal oxide semiconductor field effect transistor.
In some embodiments, the circuit further comprises: a multi-channel selection circuit.
Each input end of the multi-channel selection circuit is connected with the output end of one signal detection circuit, and the output end of the multi-channel selection circuit is connected with the analog-to-digital conversion circuit.
In some embodiments, the voltage conversion circuit includes a passive element and a third operational amplifier;
the inverting input end of the third operational amplifier is connected with the output end of the current amplifying circuit, the non-inverting input end of the third operational amplifier is connected with the bias voltage, and the output end of the third operational amplifier is connected with the input end of the analog-to-digital conversion circuit;
and the first end of the passive element is connected with the inverting input end of the third operational amplifier, and the second end of the passive element is connected with the output end of the third operational amplifier.
In a second aspect, embodiments of the present application provide a nanopore sequencing method applied to the nanopore sequencing circuit according to the first aspect, the method including:
amplifying a current signal in the nanopore sequencing channel through a current amplification circuit in the signal detection circuit;
converting the amplified current signal into a voltage signal through a voltage conversion circuit in the signal detection circuit;
and converting the voltage signal into a digital signal through an analog-to-digital conversion circuit.
In some embodiments, the nanopore sequencing circuit further comprises a multichannel selection circuit;
and selecting a target signal detection circuit from a plurality of input ends of a multi-channel selection circuit through the multi-channel selection circuit, and inputting a voltage signal of the target signal detection circuit into the analog-to-digital conversion circuit.
In a third aspect, embodiments of the present application provide a nanopore sequencing device comprising nanopore sequencing circuitry comprising a nanopore sequencing circuitry as described in the first aspect.
According to the nanopore sequencing circuit, the nanopore sequencing method and the nanopore sequencing device, the nanopore sequencing circuit comprises at least one signal detection circuit and an analog-to-digital conversion circuit, a micro-current signal in a nanopore sequencing channel is amplified through a current amplification circuit in the signal detection circuit, so that a current signal flowing through a thin film nanopore is amplified and measured, the amplified current signal is converted into a voltage signal through a voltage conversion circuit in the signal detection circuit, and the voltage signal is converted into a digital signal through the analog-to-digital conversion circuit. Therefore, the micro-current signal flowing through the nanopore is directly amplified, the current signal is converted into the voltage signal for sampling, and the sequencing result is obtained, so that the sequencing result is more accurate, and the trans-resistance amplification of the micro-current signal by using a high-resistance resistor is not needed.
Drawings
In order to more clearly illustrate the technical solutions of the embodiments of the present application, the drawings needed to be used in the embodiments of the present application will be briefly described below, and for those skilled in the art, other drawings can be obtained according to the drawings without creative efforts.
Fig. 1 shows a schematic structural diagram of a nanopore sequencing circuit provided in an embodiment of the present application.
Fig. 2 shows a schematic structure diagram of another nanopore sequencing circuit provided in an embodiment of the present application.
Fig. 3 shows a schematic structure diagram of another nanopore sequencing circuit provided in an embodiment of the present application.
Fig. 4a shows a schematic structural diagram of a first current amplifying unit provided in an embodiment of the present application.
Fig. 4b shows a schematic structural diagram of another first current amplifying unit provided in the embodiment of the present application.
Fig. 4c is a schematic structural diagram of another first current amplifying unit provided in the embodiment of the present application.
Fig. 5 shows a schematic structure diagram of another nanopore sequencing circuit provided in an embodiment of the present application.
Fig. 6a shows a schematic structural diagram of a second current amplifying unit provided in an embodiment of the present application.
Fig. 6b shows a schematic structural diagram of a further second current amplifying unit provided in the embodiment of the present application.
Fig. 6c is a schematic structural diagram of a further second current amplifying unit provided in the embodiment of the present application.
Fig. 7a shows a schematic structural diagram of a multi-stage amplified current amplifying circuit provided in an embodiment of the present application.
Fig. 7b is a schematic structural diagram of a further multi-stage amplified current amplifying circuit provided in the embodiment of the present application.
Fig. 8 shows a schematic structure diagram of another nanopore sequencing circuit provided in an embodiment of the present application.
FIG. 9 shows a schematic flow diagram of a nano-sequencing method provided in an embodiment of the present application.
FIG. 10 shows a schematic structural diagram of a nano-sequencing apparatus provided in an embodiment of the present application.
Detailed Description
Features and exemplary embodiments of various aspects of the present application will be described in detail below, and in order to make objects, technical solutions and advantages of the present application more apparent, the present application will be further described in detail below with reference to the accompanying drawings and specific embodiments. It should be understood that the specific embodiments described herein are intended to be illustrative only and are not intended to be limiting. It will be apparent to one skilled in the art that the present application may be practiced without some of these specific details. The following description of the embodiments is merely intended to provide a better understanding of the present application by illustrating examples thereof.
For a better understanding of the present application, the related art will first be summarized before describing the specific implementations of the present application.
In the cavity filled with electrolyte, the insulating permeable membrane with nano-scale pores divides the cavity into 2 chambers, and when voltage is applied to the electrolyte chamber, ions or other small molecules can pass through the nano-pores to form stable detectable ionic current.
Because the four bases adenine (a), guanine (G), cytosine (C) and thymine (T) constituting DeoxyriboNucleic Acid (DNA) have different molecular structures and volume sizes, when single-stranded DNA (ssdna) passes through a nanopore under the driving of an electric field, the current variation amplitude caused when the single-stranded DNA (ssdna) passes through the nanopore is different due to the difference of different bases, thereby obtaining the sequence information of the detected DNA.
Specifically, the nanopore gene sequencing device presumes a gene sequence passing through a thin film nanopore by measuring a current signal flowing through the thin film nanopore. The current signal is very weak, typically on the order of tens of picoamps. In a sequencing circuit, a transimpedance amplification circuit is generally used to convert a current signal into a voltage signal and amplify the voltage signal. The amplified voltage signal is sampled by an analog-to-digital conversion circuit to obtain a corresponding measurement result.
However, since the current signal flowing through the thin film nanopore is very weak, the transimpedance amplification circuit in the sequencing circuit usually needs to amplify the micro-current signal to more than several hundred millivolts, and then perform voltage acquisition and measurement. Thus, in the transimpedance amplifier circuit, a resistor with a sufficiently large resistance value, for example, a resistance value of several hundred mega ohms to several giga ohms, is usually required to amplify the micro-current signal of the thin film nanopore to several hundred millivolts. In the design of an integrated circuit, a resistor with the resistance up to giga ohm is difficult to realize by using a passive device; if an active device, such as a Metal-Oxide-Semiconductor Field-Effect Transistor (MOSFET), is used as the resistor, although the resistance value can reach giga-ohm order, the active device will bring more noise compared with a passive device, thereby reducing the signal-to-noise ratio of the system and the current measurement accuracy.
In addition, a capacitance transimpedance amplifier circuit is also used by those skilled in the art to amplify the current. Although the capacitor transimpedance amplifier circuit is convenient to realize in an integrated circuit without using a high-resistance resistor, the capacitor transimpedance amplifier circuit has infinite gain, and the capacitor is required to be discharged periodically, so that the highest sampling frequency of a sequencing circuit is limited. Meanwhile, the instantaneous current formed by the discharge operation of the capacitor may interfere with the adjacent current signals to be measured, thereby affecting the current measurement accuracy.
In view of this, embodiments of the present disclosure provide a nanopore sequencing circuit, a nanopore sequencing method, and a nanopore sampling device, which can amplify a micro-current flowing through a nanopore through a current amplification circuit in a signal detection circuit, convert the amplified current into a voltage through a voltage conversion circuit in the signal detection circuit, and sample a voltage signal through an analog-to-digital conversion circuit. Therefore, the micro-current signal flowing through the nanopore is directly amplified, the current signal is converted into the voltage signal for sampling, and the sequencing result is obtained, so that the sequencing result is more accurate, and the trans-resistance amplification of the micro-current signal by using a high-resistance resistor is not needed. Meanwhile, the signal measurement bandwidth of the nanopore sequencing circuit is higher than that of a common transimpedance amplification circuit.
In addition, compared with a capacitor transimpedance amplification circuit, the nanopore sequencing circuit provided by the embodiment of the application does not need frequent discharging operation on a capacitor, so that the interference of capacitor discharging on adjacent current signals is eliminated, the measurement precision of the sequencing circuit is improved, and the sequencing circuit and a thin film nanopore are conveniently integrated.
In addition, the capacitor transimpedance amplifying circuit is a discrete time amplifying circuit, and the nanopore sequencing circuit provided by the embodiment of the application belongs to a continuous time amplifying circuit, so that the limitation of the discrete time amplifying circuit on the highest sampling frequency of the sequencing device can be eliminated.
A nanopore sequencing circuit provided in embodiments of the present application is described in detail below. Fig. 1 shows a schematic structural diagram of a nanopore sequencing circuit provided in an embodiment of the present application. As shown in fig. 1, the nanopore sequencing circuit includes at least one signal detection circuit 10 and an analog-to-digital conversion circuit 20.
The signal detection circuit is used for detecting a current signal generated in the nanopore sequencing channel 30 and inputting the current signal to the analog-to-digital conversion circuit 20.
In the embodiment of the present application, the nanopore sequencing channel 30 is a plurality of nanopore structures distributed on the insulating film, and the plurality of nanopore structures form a nanopore array, and each nanopore can be used as a nanopore sequencing channel. It should be noted that, the embodiments of the present application refer to "sequencing" and may refer to sequencing a nucleic acid strand that passes through a nanopore sequencing channel.
Here, the nanopore sequencing channel 30 may include a nanopore sensor. The nanopore sensor is used for collecting an electric signal generated when a biomolecule passes through a nanopore. In some embodiments, the electrical signal may be a current signal.
Here, the input of the signal detection circuit 10 is connected to a nanopore sequencing channel 30. An output terminal of the signal detection circuit 10 is connected to an input terminal of the analog-to-digital conversion circuit 20.
Specifically, the signal detection circuit 10 includes a current amplification circuit 11 and a voltage conversion circuit 12.
Here, the input of the current amplification circuit 11 is connected to the nanopore sequencing channel 30. The current amplification circuit 11 is used to amplify the current signal generated in the nanopore sequencing channel.
An input terminal of the voltage conversion circuit 12 is connected to an output terminal of the current amplification circuit 11. An output terminal of the voltage conversion circuit 12 is connected to an input terminal of the analog-to-digital conversion circuit 20. The voltage conversion circuit 12 is configured to convert the amplified current signal into a voltage signal.
Here, the voltage conversion circuit 12 may be any circuit that converts a current signal into a voltage signal. In the embodiment of the present application, the structure of the voltage conversion circuit is not limited.
The analog-to-digital conversion circuit 20 is configured to convert the voltage signal output by the voltage conversion circuit 12 into a digital signal. The input end of the analog-to-digital conversion circuit 20 is connected with the output end of the voltage conversion circuit 12.
Here, the analog-to-digital conversion circuit 20 samples the voltage signal output from the voltage conversion circuit 12, and converts the sampled voltage signal into a digital signal.
In the above embodiments, the nanopore sequencing circuit comprises at least one signal detection circuit and an analog-to-digital conversion circuit, the micro-current signal in the nanopore sequencing channel is amplified by a current amplification circuit in the signal detection circuit, so as to amplify and measure a current signal flowing through the thin film nanopore, and the amplified current signal is converted into a voltage signal by a voltage conversion circuit in the signal detection circuit, and the voltage signal is converted into a digital signal by the analog-to-digital conversion circuit. Therefore, the micro-current signal flowing through the nanopore is directly amplified, the current signal is converted into the voltage signal for sampling, and the sequencing result is obtained, so that the sequencing result is more accurate, and the trans-resistance amplification of the micro-current signal by using a high-resistance resistor is not needed.
In some embodiments, the analog-to-digital conversion circuit 20 may include an analog-to-digital converter. The analog-to-digital converter may be used by at least one signal detection circuit. In the embodiment of the present application, the specific form of the analog-to-digital conversion circuit 20 is not limited.
In the actual sequencing process, the nanopore array of the nanopore sequencer has hundreds of nanopores, but not every nanopore is generated or remains available in the sequencing process, so that the data acquisition efficiency is improved, the cost is reduced, and the space is saved.
Fig. 2 shows a schematic structure diagram of another nanopore sequencing circuit provided in an embodiment of the present application. As shown in fig. 2, the nanopore sequencing circuit includes at least one signal detection circuit 10, a multi-channel selection circuit 40, and an analog-to-digital conversion circuit 20.
The multi-channel selection circuit 40 is provided between the signal detection circuit 10 and the analog-to-digital conversion circuit. Specifically, each input terminal of the multi-channel selection circuit 40 is connected to an output terminal of one of the signal detection circuits 10. The output of the multi-channel selection circuit 40 is connected to the analog-to-digital conversion circuit 20.
Here, the multi-channel selection circuit 40 is configured to select one signal detection circuit as a target signal detection circuit from at least one signal detection circuit connected to an input terminal in the multi-channel selection circuit 40, and input a voltage signal of the target signal detection circuit to the analog-to-digital conversion circuit 20.
In some implementations, as shown in FIG. 2, the multi-channel selection circuit 40 may include a Multiplexer (Mux).
Here, the output voltages of the plurality of signal detection circuits 10 are input to the analog-to-digital conversion circuit 20 via the multi-channel selection circuit 40. During a period of time, the analog-to-digital conversion circuit 20 performs sampling measurement on a signal of one signal detection circuit 10 output by the multi-channel selection circuit 40.
It should be noted that the multi-channel selection circuit 40 may also be a multiplexing circuit composed of other circuit elements. In the embodiment of the present application, the type of the multi-channel selection circuit 40 is not limited.
In the above embodiment, the multi-channel selection circuit 40 may multiplex a plurality of signal detection circuits and select a voltage signal output by one target signal detection circuit from the multiplexed signal detection circuits for sampling, so that the sampling efficiency may be improved and the space size of the circuit may be reduced.
The inventor has found in practice that the magnitude of the current signal flowing through the transistor is proportional to the PN junction area of the transistor, and thus the current signal flowing through the transistor can be controlled by controlling the PN junction area of the transistor. The specific relationship between the current signal magnitude and the PN junction area is as follows:
wherein A is the PN junction area of the transistor, and the input voltage of the transistor is
The output voltage of the transistor is
I is the magnitude of the current signal flowing through the transistor, VTIs the thermal voltage constant.
In the embodiments of the present application, the term "PN junction" refers to a space charge region formed at an interface between a P-type semiconductor and an N-type semiconductor fabricated on the same semiconductor (typically, silicon or germanium) substrate.
In some embodiments, the current amplifying circuit 11 may be formed by a transistor to achieve the purpose of accurately controlling the current amplification factor.
The "transistor" according to the embodiment of the present application refers to a transistor formed of a P-type semiconductor and an N-type semiconductor. Here, the type of the transistor is not limited, and the transistor may be a diode, a transistor, and a MOSFET.
Note that, when the transistor is a triode, the PN junction includes a collector junction and an emitter junction. When the transistor is a MOSFET, the PN junction can be a space charge region formed by the interface between the drain region and the semiconductor, and a space charge region formed by the interface between the source region and the semiconductor.
In the embodiment of the present application, when the diode, the transistor, and the MOSFET are in the on state, the diode, the transistor, and the MOSFET may be equivalent to a switch.
Fig. 3 shows a schematic structure diagram of another nanopore sequencing circuit provided in an embodiment of the present application. As shown in fig. 3, the current amplification circuit 11 includes at least one current amplification unit 111. The current amplifying unit 111 includes a first current amplifying unit 111 a.
As shown in fig. 3, the first current amplifying unit 111a includes a first transistor 1111a, a second transistor 1112a, and a first operational amplifier 1113a, wherein the PN junction area of the second transistor 1112a is M times the PN junction area of the first transistor 1111a, and M is a positive number.
The inverting input of the first operational amplifier 1113a is connected to the nanopore sequencing channel 30. The non-inverting input terminal of the first operational amplifier 1113a and a bias voltage VbiasAre connected.
The first transistor 1111a may be inversely connected between the inverting input terminal and the output terminal of the first operational amplifier 1113 a. Specifically, an input terminal of the first transistor 1111a is connected to an output terminal of the first operational amplifier 1113 a. The output of the first transistor 1111a is coupled to the inverting input of the first operational amplifier 1113a and to the nanopore sequencing channel 30. That is, the output of the first transistor 1111a is connected to the connection between the inverting input of the first operational amplifier 1113a and the nanopore sequencing channel 30.
The input terminal of the second transistor 1112a is connected to the output terminal of the first operational amplifier 1113a and also connected to the input terminal of the first transistor 1111 a. That is, the input terminal of the second transistor 1112a is connected to a connection line between the output terminal of the first operational amplifier 1113a and the input terminal of the first transistor 1111 a. An output terminal of the second transistor 1112a serves as an output terminal of the first current amplifying unit.
In the embodiment of the present application, the output terminal of the first current amplifying unit 111a may be connected to the input terminal of the voltage converting circuit. Or the output end of the first current amplifying unit 111a may be connected to the second current amplifying unit 111b, and the specific connection relationship may be determined according to the number of the first current amplifying unit and the second current amplifying unit included in the current amplifying circuit.
Since the first transistor 1111a, the second transistor 1112a, and the first operational amplifier 1113a constitute a current amplification circuit, the PN junction area of the second transistor 1112a is M times the PN junction area of the first transistor 1111 a. Thus, the second current signal I flowing through the second transistor2Is a first current signal I flowing through a first transistor1M times of.
Wherein the content of the first and second substances,
therefore, the current signal generated in the nanopore sequencing channel can be amplified by M times after passing through the first current amplification unit 111 a.
The above calculation represents only the magnitude of each current signal, and does not relate to the current direction.
In the above-described embodiment, the first current amplifying unit is configured based on two transistors and one operational amplifier, and the purpose of accurately amplifying the current signal can be achieved by controlling the ratio of the PN junction areas of the two transistors. At the same time, the current signal generated in the nanopore sequencing channel does not need to be amplified by a high-impedance resistor.
In some embodiments, as shown in fig. 3, nanopore sequencing channel 30 may comprise a nanopore equivalent resistance R1 and an equivalent capacitance C1, wherein the equivalent resistance and the equivalent capacitance are connected in parallel and then grounded.
In some embodiments, the first transistor 1111a and the second transistor 1112a may be one of a diode, a transistor, and a MOSFET, respectively. That is, the first transistor 1111a and the second transistor 1112a may be the same type. For example, the first transistor 1111a and the second transistor 1112a may both be diodes. Alternatively, the first transistor 1111a and the second transistor 1112a may be both transistors. Alternatively, the first transistor 1112a and the second transistor 1112a are both MOSFETs.
Here, the types of the first transistor 1111a and the second transistor 1112a may be different. For example, the first transistor is a diode, and the second transistor 1112a is a transistor. Alternatively, the first transistor is a transistor, and the second transistor 1112a is a MOSFET. Alternatively, the first transistor is a MOSFET, the second transistor 1112a is a diode, and so on.
A specific circuit configuration of the first current amplifying unit configured by a diode will be described with an example in which the first transistor 1111a and the second transistor 1112a are both diodes. Fig. 4a shows a schematic structural diagram of a first current amplifying unit provided in an embodiment of the present application. As shown in fig. 4a, the first transistor 1111a is a diode D1, the second transistor 1112a is a diode D2, and the first operational amplifier 1113a is an operational amplifier U1.
Here, the inverting input of the operational amplifier U1 is connected to the nanopore sequencing channel 30 as the input of the first current amplification unit 111 a. The non-inverting input of the operational amplifier U1 is connected to the bias voltage Vbias.
The anode of the diode D1 is connected to the output of the operational amplifier U1. The cathode of diode D1 is connected to the inverting input of operational amplifier U1 and also to nanopore sequencing channel 30.
The anode of the diode D2 is connected to the output of the operational amplifier U1 and also to the anode of the diode D1. The cathode of the diode D2 serves as the output terminal of the first current amplifying unit.
Taking the first transistor 1111a and the second transistor 1112a as an example, a specific circuit structure of the first current amplifying unit configured by a triode will be described. Fig. 4b shows a schematic structural diagram of another first current amplifying unit provided in the embodiment of the present application. As shown in fig. 4b, the first transistor 1111a is a transistor VT1, the second transistor 1112a is a transistor VT2, and the first operational amplifier 1113a is an operational amplifier U1.
The inverting input of the operational amplifier U1 is connected to the nanopore sequencing channel 30 as the input of the first current amplification unit 111 a. The non-inverting input of the operational amplifier U1 is connected to the bias voltage Vbias.
The base of the transistor VT1 and the collector of the transistor VT1 are connected together and are connected with the output end of the operational amplifier U1. The emitter of the transistor VT1 is connected to the inverting input of the operational amplifier U1 and to the nanopore sequencing channel 30.
The base of the transistor VT2 is connected with the collector of the transistor VT2, and is connected with the output end of the operational amplifier U1, and is also connected with the base of the transistor VT1 and the collector of the transistor VT 1. The emitter of the transistor VT2 serves as the output terminal of the first current amplifying unit.
A specific circuit configuration of the first current amplifying unit configured by MOS transistors will be described with the first transistor 1111a and the second transistor 1112a both being MOSFETs as an example. Fig. 4c is a schematic structural diagram of another first current amplifying unit provided in the embodiment of the present application. As shown in fig. 4c, the first transistor 1111a is a MOS transistor T1, the second transistor 1112a is a MOS transistor T2, and the first operational amplifier 1113a is an operational amplifier U1.
The inverting input of the operational amplifier U1 is connected to the nanopore sequencing channel 30 as the input of the first current amplification unit 111 a. The non-inverting input of the operational amplifier U1 is connected to the bias voltage Vbias.
The gate of the MOS transistor T1 and the drain of the MOS transistor T1 are connected to the output terminal of the operational amplifier U1. The source of MOS transistor T1 is connected to the inverting input of operational amplifier U1 and to nanopore sequencing channel 30.
The gate of the MOS transistor T2 and the drain of the MOS transistor T2 are connected to the output terminal of the operational amplifier U1, and are also connected to the gate of the MOS transistor T1 and the drain of the MOS transistor T1. The source of the MOS transistor T2 serves as the output terminal of the first current amplifying unit.
Meanwhile, since the PN area ratio between the transistors is limited, the amplification capability of the first current amplifying unit 111a is limited. Therefore, in order to increase the current amplification factor, a two-stage current amplification circuit may be employed to amplify the current. Fig. 5 shows a schematic structure diagram of another nanopore sequencing circuit provided in an embodiment of the present application. As shown in fig. 5, the current amplification circuit 11 includes at least one current amplification unit 111. The current amplifying unit 111 may include a first current amplifying unit 111a and a second current amplifying unit 111 b.
As shown in fig. 5, the output terminal of the first current amplifying unit 111a is connected to the input terminal of the second current amplifying unit 111b, and the second current amplifying unit 111b is connected to the voltage converting circuit 12, so that the current amplifying unit realizes two-stage amplification.
Specifically, the second current amplifying unit 111b may include a third transistor 1111b, a fourth transistor 1112b, and a second operational amplifier 1113b, wherein the PN junction area of the fourth transistor 1112b is N times the PN junction area of the third transistor 1111b, and N is a positive number.
The inverting input terminal of the second operational amplifier 1113b is connected to the output terminal of the first current amplifying unit 111a, that is, to the output terminal of the second transistor 1112 a. The non-inverting input terminal of the second operational amplifier 1113b and the bias voltage VbiasAre connected.
The third transistor 1111b may be coupled in a forward direction between the inverting input terminal and the output terminal of the second operational amplifier 1113 b. Specifically, the input terminal of the third transistor 1111b is connected to the inverting input terminal of the second operational amplifier 1113b, and also connected to the output terminal of the first current amplifying unit 111 a. That is, the input terminal of the third transistor 1111b is connected to the connection line between the inverting input terminal of the second operational amplifier 1113b and the output terminal of the first current amplifying unit 111 a.
An output terminal of the third transistor 1111b is connected to an output terminal of the second operational amplifier 1113 b.
An output terminal of the fourth transistor 1112b is connected to an output terminal of the second operational amplifier 1113b and also to an output terminal of the third transistor 1111 b. That is, the output terminal of the fourth transistor 1112b is connected to the connection between the output terminal of the second operational amplifier 1113b and the output terminal of the third transistor 1111 b. An input terminal of the fourth transistor 1112b serves as an output terminal of the second current amplifying unit.
In the embodiment of the present application, the output terminal of the second current amplifying unit 111b may be connected to the input terminal of the voltage converting circuit 12. Or the output end of the second current amplifying unit 111b may be connected to the first current amplifying unit 111a, and the specific connection relationship may be determined according to the number of the first current amplifying unit and the second current amplifying unit included in the current amplifying circuit.
Since the third transistor 1111b, the fourth transistor 1112b, and the second operational amplifier 1113b constitute the second current amplifying unit 111b, and the PN junction area of the fourth transistor 1112b is N times the PN junction area of the third transistor 1111 b. Therefore, the fourth current signal I flowing through the fourth transistor4Is a third current signal I flowing through a third transistor3N times.
Wherein the content of the first and second substances,
therefore, the current signal generated in the nanopore sequencing channel can be amplified after passing through the first current amplification unit 111a and the second current amplification unit 111b
And (4) doubling.
The above calculation represents only the magnitude of each current signal, and does not relate to the current direction.
In the above-described embodiment, the current amplifying unit 111 may include the first current amplifying unit 111a and the second current amplifying unit 111 b. The current signal generated in the nanopore sequencing channel can be subjected to 2-stage amplification through the current amplification unit. Therefore, the amplification factor of the current signal can be increased, the amplification factor can be accurately controlled by controlling the area ratio of PN junctions between the transistors, and the current is prevented from being amplified by adopting a high-impedance resistor.
In some embodiments, the third and fourth transistors 1112b may be one of a diode, a triode, and a MOSFET, respectively.
Here, the type of the third transistor 1111b and the fourth transistor 1112b may be the same. For example, the third transistor 1111b and the fourth transistor 1112b may both be diodes. Alternatively, the third transistor 1111b and the fourth transistor 1112b may be both triodes. Alternatively, the third transistor 1111b and the fourth transistor 1112b may be both MOSFETs.
And, the types of the third transistor 1111b and the fourth transistor 1112b may be different. For example, the third transistor 1111b is a diode, and the fourth transistor 1112b is a transistor. Alternatively, the third transistor 1111b is a triode and the fourth transistor 1112b is a MOSFET. Alternatively, the third transistor 1111b is a MOSFET, the fourth transistor 1112b is a diode, or other combinations thereof.
A specific circuit configuration of the second current amplifying unit configured by a diode will be described with the third transistor 1111b and the fourth transistor 1112b both being diodes as an example. Fig. 6a shows a schematic structural diagram of a second current amplifying unit provided in an embodiment of the present application. As shown in fig. 6a, the third transistor 1111b is a diode D3, the fourth transistor 1112b is a diode D4, and the second operational amplifier 1113b is an operational amplifier U2.
An inverting input terminal of the operational amplifier U2 is connected to an output terminal of the first current amplifying unit 111 a. The non-inverting input of the operational amplifier U2 is connected to the bias voltage Vbias.
The anode of the diode D3 is connected to the inverting input terminal of the operational amplifier U2 and also to the output terminal of the first current amplifying unit 111 a. The cathode of the diode D3 is connected to the output of the operational amplifier U2.
The cathode of the diode D4 is connected to the output of the operational amplifier U2 and also to the cathode of the diode D3. The anode of the diode D4 serves as the output terminal of the second current amplifying unit.
A specific circuit configuration of the second current amplifying unit configured by a triode will be described with an example in which the third transistor 1111b and the fourth transistor 1112b are both N-type triodes. Fig. 6b shows a schematic structural diagram of a further second current amplifying unit provided in the embodiment of the present application. As shown in fig. 6b, the third transistor 1111b is a transistor VT3, the fourth transistor 1112b is a transistor VT4, and the second operational amplifier 1113b is an operational amplifier U2.
An inverting input terminal of the operational amplifier U2 is connected to an output terminal of the first current amplifying unit 111 a. The non-inverting input of the operational amplifier U2 is connected to the bias voltage Vbias.
The base of the transistor VT3 and the collector of the transistor VT3 are connected together, and are connected to the inverting input terminal of the operational amplifier U2, and also to the output terminal of the first current amplifying unit 111 a. The emitter of the transistor VT3 is connected to the output of the operational amplifier U2.
The base of the transistor VT4 is connected with the collector of the transistor VT4 and is used as the output end of the second current amplification unit. The emitter of the transistor VT4 is connected to the output of the operational amplifier U2 and also to the emitter of the transistor VT 3.
A specific circuit configuration of the second current amplifying unit configured by MOS transistors will be described with the third transistor 1111b and the fourth transistor 1112b both being MOSFETs as an example. Fig. 6c is a schematic structural diagram of a further second current amplifying unit provided in the embodiment of the present application. As shown in fig. 6c, the third transistor 1111b is a MOS transistor T3, the fourth transistor 1112b is a MOS transistor T4, and the second operational amplifier 1113b is an operational amplifier U2.
An inverting input terminal of the operational amplifier U2 is connected to an output terminal of the first current amplifying unit 111 a. The non-inverting input of the operational amplifier U2 is connected to the bias voltage Vbias.
The gate of the MOS transistor T3 and the drain of the MOS transistor T3 are connected together, and are connected to the inverting input terminal of the operational amplifier U2 and also to the output terminal of the first current amplifying unit 111 a. The source of the MOS transistor T3 is connected to the output terminal of the operational amplifier U2.
The gate of the MOS transistor T4 is connected to the drain of the MOS transistor T4 as the output terminal of the second current amplifying unit. The source of the MOS transistor T4 is connected with the output end of the operational amplifier U2 and is also connected with the source of the MOS transistor T3.
In order to increase the current amplification factor, a multi-stage current amplification circuit may be used, and in some embodiments, the current amplification circuit 11 may include a plurality of current amplification units. Among them, the current amplifying units are of two types, the first current amplifying unit may include a first current amplifying unit 111a, and the second current amplifying unit may include a first current amplifying unit 111a and a second current amplifying unit 111 b.
Fig. 7a shows a schematic structural diagram of a multi-stage amplified current amplifying circuit provided in an embodiment of the present application, and as shown in fig. 7a, the current amplifying circuit 11 may include L second current amplifying units. In the current amplifying circuit 11, the number of the first current amplifying units 111a is equal to the number of the second current amplifying units 111b, and the number of the first current amplifying units 111a is L, where L is a positive integer.
Here, in the case where L is equal to 1, the input terminal of the first current amplifying unit 111a of the current amplifying units is connected to the nanopore sequencing channel 30, and the output terminal of the second current amplifying unit 111b of the current amplifying units is connected to the input terminal of the voltage converting circuit 12 as the output terminal of the current amplifying unit.
In the case where L is greater than 1, the input terminal of the first current amplification unit 111a in the 1 st current amplification unit is connected to the nanopore sequencing channel 30. The output end of the 1 st current amplification unit is connected with the input end of the second current amplification unit. By analogy, the input end of the L-th current amplification unit is connected to the output end of the L-1 th current amplification unit, and the output end of the second current amplification unit 111b in the L-th current amplification unit is used as the output end of the L-th current amplification unit and is also used as the output end of the current amplification circuit 11 and is connected to the input end of the voltage conversion circuit 12.
Fig. 7b shows a schematic structural diagram of another multi-stage current amplifying circuit provided in the embodiment of the present application, and as shown in fig. 7b, the current amplifying circuit 11 may include L second current amplifying units and 1 first current amplifying unit. In the current amplifying circuit 11, the number of the first current amplifying means 111a is one more than the number of the second current amplifying means 111b, and the number of the first current amplifying means 111a is L + 1.
Here, in the case where L is equal to 1, the input terminal of the 1 st first current amplifying unit 111a is connected to the nanopore sequencing channel 30. An output terminal of the 1 st first current amplifying unit 111a is connected to an input terminal of the 1 st second current amplifying unit 111 b. The output terminal of the 1 st second current amplifying unit 111b is connected to the input terminal of the 2 nd first current amplifying unit 111 a. The output terminal of the 2 nd first current amplifying unit 111a is connected to the input terminal of the voltage converting circuit 12 as the output terminal of the current amplifying unit.
In the case where L is greater than 1, the input terminal of the first current amplification unit 111a in the 1 st current amplification unit is connected to the nanopore sequencing channel 30. The output end of the 1 st current amplification unit is connected with the input end of the second current amplification unit. By analogy, the input end of the L-th current amplification unit is connected to the output end of the L-1 th current amplification unit, and in the L-th current amplification unit, the output end of the L-th first current amplification unit 111a is connected to the input end of the L-th second current amplification unit 111 b.
Here, the output terminal of the L-th second current amplifying unit is connected to the input terminal of the L + 1-th first current amplifying unit. The output end of the L +1 th first current amplifying unit is used as the output end of the current amplifying circuit 11 and is connected with the input end of the voltage converting circuit 12.
In the above-described embodiments, the current amplification circuit includes a plurality of current amplification units, and multistage amplification of current can be realized. Therefore, the micro-current signal can be amplified to a required current value, so that the micro-current signal is prevented from being amplified by a resistor with high resistance.
In order to further amplify the current signal output from the current amplifying circuit, the voltage converting circuit 12 may also have a function of amplifying the current signal. That is, the voltage conversion circuit 12 may be an amplification circuit. Fig. 8 is a schematic diagram of a nanopore sequencing circuit provided in an embodiment of the present application, as shown in fig. 8. The voltage conversion circuit includes a passive element 121 and a third operational amplifier 122.
Here, the inverting input terminal of the third operational amplifier 122 is connected to the output terminal of the current amplification circuit 11. The non-inverting input of the third operational amplifier 122 is connected to the bias voltage Vbias. The output terminal of the third operational amplifier 122 serves as the output terminal of the voltage conversion circuit 12.
It should be noted that in the case where the nanopore sequencing circuit does not include the multi-channel selection circuit 40, the third operational amplifier 122 may be connected to the input of the analog-to-digital conversion circuit 20. Where the nanopore sequencing circuit includes the multi-channel selection circuit 40, the third operational amplifier 122 may be connected to one input of the multi-channel selection circuit 40.
And the first terminal of the passive element 121 is connected to the inverting input terminal of the third operational amplifier 122. A second terminal of the passive element 121 is connected to an output terminal of the third operational amplifier 122.
Here, the passive element 121 and the third operational amplifier 122 constitute an amplification circuit for amplifying again the current signal output from the current amplification circuit 11 and generating a voltage signal.
In the above embodiment, based on the voltage conversion circuit formed by the passive element 121 and the third operational amplifier 122, the current signal output by the current amplification circuit 11 may be amplified again, and the amplified current signal may be converted into a voltage signal, which is convenient for the acquisition of the subsequent analog-to-digital conversion circuit.
In some examples, as shown in fig. 8, the passive element 121 may include a resistor R2. The third operational amplifier 122 may include an operational amplifier U3. The resistor R2 and the operational amplifier U3 form a transimpedance amplifier circuit.
In the above embodiment, the nanopore sequencing circuit amplifies the current signal generated in the nanopore sequencing channel through the current amplification circuit, so that the voltage conversion circuit does not need to amplify the current signal by using a high-resistance resistor.
In addition, the passive element 121 may include a capacitor and a resistor. The capacitor transimpedance amplification circuit consists of a capacitor, a resistor and an operational amplifier.
It should be noted that the passive element 121 and the third operational amplifier 122 may also constitute other types of amplifying circuits. In the embodiment of the present application, the circuit formed by the passive element 121 and the third operational amplifier 122 is not limited.
Based on the nanopore sequencing circuit provided by the above embodiment, a corresponding nanopore sequencing method is also provided by the embodiment of the application. Fig. 9 shows a schematic flow diagram of a nanopore sequencing method provided in an embodiment of the present application. As shown in fig. 9, the nanopore sequencing method may include the following steps.
And S91, amplifying the current signal in the nanopore sequencing channel through a current amplification circuit in the signal detection circuit.
S92, the amplified current signal is converted into a voltage signal by a voltage conversion circuit in the signal detection circuit.
S93, converting the voltage signal into a digital signal through an analog-to-digital conversion circuit.
In the above-described embodiment, the micro-current signal in the nanopore sequencing channel is amplified by the current amplification circuit in the signal detection circuit, thereby amplifying the current signal flowing through the thin film nanopore, and the amplified current signal is converted into a voltage signal by the voltage conversion circuit in the signal detection circuit, and the voltage signal is converted into a digital signal by the analog-to-digital conversion circuit. Therefore, the micro-current signal flowing through the nanopore is directly amplified, the current signal is converted into the voltage signal for sampling, and the sequencing result is obtained, so that the sequencing result is more accurate, and the trans-resistance amplification of the micro-current signal by using a high-resistance resistor is not needed.
In some embodiments, in the case that the current amplification circuit includes at least one current amplification unit including the first current amplification unit, S91 may specifically include:
amplifying the current signal generated by the nanopore sequencing channel by M times under the condition that the PN junction area of the second transistor is M times of the PN junction area of the first transistor.
In the above embodiment, the purpose of accurately amplifying the current signal can be achieved by controlling the ratio of the PN junction areas of the two transistors. At the same time, the current signal generated in the nanopore sequencing channel does not need to be amplified by a high-impedance resistor.
In some implementations, in the case where the current amplifying unit includes a first current amplifying unit and a second current amplifying unit, S91 may specifically include:
amplifying the current signal generated by the nanopore sequencing channel by N x M times under the condition that the PN junction area of the second transistor is M times of the PN junction area of the first transistor, and the PN junction area of the fourth transistor is N times of the PN junction area of the third transistor.
In the above-described embodiment, the current amplifying unit 111 may include the first current amplifying unit 111a and the second current amplifying unit 111 b. The current signal generated in the nanopore sequencing channel can be subjected to 2-stage amplification through the current amplification unit. Therefore, the amplification factor of the current signal can be increased, the amplification factor can be accurately controlled by controlling the area ratio of PN junctions between the transistors, and the current is prevented from being amplified by adopting a high-impedance resistor.
Similarly, in the case that the current amplification unit comprises L +1 first current amplification units and L second current amplification units, the current signal generated by the nanopore sequencing channel is amplified by N(L+1)*MLAnd (4) doubling.
Amplifying the current signal generated by the nanopore sequencing channel by N under the condition that the current amplification unit comprises L first current amplification units and L second current amplification unitsL*MLAnd (4) doubling.
In some embodiments, where the nanopore sequencing circuit comprises a multichannel selection circuit, the nanopore sequencing method may further comprise: a target signal detection circuit is selected from a plurality of input ends of the multi-channel selection circuit through a multi-channel selection circuit, and a voltage signal of the target signal detection circuit is input to the analog-to-digital conversion circuit.
In the above embodiment, a plurality of signal detection circuits can be multiplexed by the multi-channel selection circuit, and a voltage signal output by one target signal detection circuit is selected from the multiplexed signal detection circuits for sampling, so that the sampling efficiency can be improved, and the space size of the circuit can be reduced.
The nanopore sequencing circuit and the nanopore sequencing method provided by the embodiment of the application can also be suitable for collecting dense multipath weak current signals. In addition, the circuit can be used for various industrial controllers, high-precision instruments, medical products and the like.
Fig. 10 shows a schematic structural diagram of a nanopore sequencing device provided in an embodiment of the present application. As shown in fig. 10, a nanopore sequencing device 1200 may include a nanopore sequencing circuit 1201 and a nanopore sequencing channel 1202 as described in any of the embodiments herein.
It is to be understood that the present application is not limited to the particular arrangements and instrumentality described above and shown in the attached drawings. A detailed description of known methods is omitted herein for the sake of brevity. In the above embodiments, several specific steps are described and shown as examples. However, the method processes of the present application are not limited to the specific steps described and illustrated, and those skilled in the art can make various changes, modifications, and additions or change the order between the steps after comprehending the spirit of the present application.
The functional blocks shown in the above-described structural block diagrams may be implemented as hardware, software, firmware, or a combination thereof. When implemented in hardware, it may be, for example, an electronic circuit, an Application Specific Integrated Circuit (ASIC), suitable firmware, plug-in, function card, or the like.
It should also be noted that the exemplary embodiments mentioned in this application describe some methods or systems based on a series of steps or devices. However, the present application is not limited to the order of the above-described steps, that is, the steps may be performed in the order mentioned in the embodiments, may be performed in an order different from the order in the embodiments, or may be performed simultaneously.
Aspects of the present application are described above with reference to flowchart illustrations and/or block diagrams of nanopore sequencing circuitry, nanopore sequencing methods, nanopore sequencing devices, according to embodiments of the present application. It will be understood that each block of the flowchart illustrations and/or block diagrams, and combinations of blocks in the flowchart illustrations and/or block diagrams, can be implemented by computer program instructions. These computer program instructions may be provided to a processor of a general purpose computer, special purpose computer, or other programmable data processing apparatus to produce a machine, such that the instructions, which execute via the processor of the computer or other programmable data processing apparatus, enable the implementation of the functions/acts specified in the flowchart and/or block diagram block or blocks. Such a processor may be, but is not limited to, a general purpose processor, a special purpose processor, an application specific processor, or a field programmable logic circuit. It will also be understood that each block of the block diagrams and/or flowchart illustration, and combinations of blocks in the block diagrams and/or flowchart illustration, can be implemented by special purpose hardware for performing the specified functions or acts, or combinations of special purpose hardware and computer instructions.
As described above, only the specific embodiments of the present application are provided, and it can be clearly understood by those skilled in the art that, for convenience and brevity of description, the specific working processes of the system, the module and the unit described above may refer to the corresponding processes in the foregoing method embodiments, and are not described herein again. It should be understood that the scope of the present application is not limited thereto, and any person skilled in the art can easily conceive various equivalent modifications or substitutions within the technical scope of the present application, and these modifications or substitutions should be covered within the scope of the present application.
Claims (10)
1. A nanopore sequencing circuit, comprising at least one signal detection circuit and an analog-to-digital conversion circuit,
the input end of the signal detection circuit is connected with the nanopore sequencing channel, and the output end of the signal detection circuit is connected with the input end of the analog-to-digital conversion circuit;
wherein the signal detection circuit comprises:
the input end of the current amplification circuit is connected with the nanopore sequencing channel and is used for amplifying a current signal generated in the nanopore sequencing channel;
the input end of the voltage conversion circuit is connected with the output end of the current amplification circuit, and the output end of the voltage conversion circuit is connected with the input end of the analog-to-digital conversion circuit and used for converting the amplified current signal into a voltage signal;
the analog-to-digital conversion circuit is used for converting the voltage signal into a digital signal;
the current amplifying circuit comprises
At least one current amplifying unit including a first current amplifying unit;
the first current amplification unit comprises a first transistor, a second transistor and a first operational amplifier, wherein the PN junction area of the second transistor is M times of that of the first transistor, and M is a positive number;
the inverting input end of the first operational amplifier is connected with the nanopore sequencing channel, and the non-inverting input end of the first operational amplifier is connected with a bias voltage;
the input end of the first transistor is connected with the output end of the first operational amplifier, and the output end of the first transistor is connected with the inverting input end of the first operational amplifier;
and the input end of the second transistor is connected with the output end of the first operational amplifier.
2. The circuit of claim 1, wherein the current amplification unit further comprises a second current amplification unit;
the second current amplifying unit comprises a third transistor, a fourth transistor and a second operational amplifier, wherein the PN junction area of the fourth transistor is N times of that of the third transistor, and N is a positive number;
the inverting input end of the second operational amplifier is connected with the output end of the first current amplifying unit, and the non-inverting input end of the second operational amplifier is connected with the bias voltage;
the input end of the third transistor is connected with the inverting input end of the second operational amplifier, and the output end of the third transistor is connected with the output end of the second operational amplifier;
in a case where the number of the second current amplifying units is equal to the number of the first current amplifying units, the output terminal of the fourth transistor is connected to the output terminal of the second operational amplifier.
3. The circuit of claim 2,
when the number of the first current amplifying units is one more than that of the second current amplifying units and the number of the second current amplifying units is L, the output end of the L-th first current amplifying unit is connected with the input end of the L-th second current amplifying unit, the output end of the L-th second current amplifying unit is connected with the input end of the L + 1-th first current amplifying unit, and L is a positive integer;
and the output end of the L +1 th first current amplification unit is connected with the input end of the voltage conversion circuit.
4. The circuit of any of claims 1 to 3, wherein the first transistor and the second transistor are each one of a diode, a triode, and a metal oxide semiconductor field effect transistor.
5. The circuit according to any one of claims 2 to 3, wherein the third transistor and the fourth transistor are each one of a diode, a triode, and a metal oxide semiconductor field effect transistor.
6. The circuit of claim 1, further comprising: a multi-channel selection circuit;
each input end of the multi-channel selection circuit is connected with the output end of one signal detection circuit, and the output end of the multi-channel selection circuit is connected with the analog-to-digital conversion circuit.
7. The circuit of claim 1, wherein the voltage conversion circuit comprises a passive component and a third operational amplifier;
the inverting input end of the third operational amplifier is connected with the output end of the current amplifying circuit, the non-inverting input end of the third operational amplifier is connected with the bias voltage, and the output end of the third operational amplifier is connected with the input end of the analog-to-digital conversion circuit;
and the first end of the passive element is connected with the inverting input end of the third operational amplifier, and the second end of the passive element is connected with the output end of the third operational amplifier.
8. A nanopore sequencing method applied to the nanopore sequencing circuit of any of claims 1 to 7, the method comprising:
amplifying a current signal in the nanopore sequencing channel through a current amplification circuit in the signal detection circuit;
converting the amplified current signal into a voltage signal through a voltage conversion circuit in the signal detection circuit;
and converting the voltage signal into a digital signal through an analog-to-digital conversion circuit.
9. The method of claim 8, wherein the nanopore sequencing circuit further comprises a multichannel selection circuit;
and selecting a target signal detection circuit from a plurality of input ends of a multi-channel selection circuit through the multi-channel selection circuit, and inputting a voltage signal of the target signal detection circuit into the analog-to-digital conversion circuit.
10. A nanopore sequencing device, wherein said device comprises nanopore sequencing circuitry comprising nanopore sequencing circuitry according to any of claims 1-7.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103275867A (en) * | 2013-05-02 | 2013-09-04 | 华中科技大学 | Detection and acquisition system for solid-state nano-pore nucleic acid sequencing electric signals |
| CN107462765A (en) * | 2017-09-07 | 2017-12-12 | 昆山龙腾光电有限公司 | A kind of signal deteching circuit and device |
Family Cites Families (15)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4980650A (en) * | 1988-08-19 | 1990-12-25 | U.S. Philips Corporation | Current amplifier |
| EP0613243A1 (en) * | 1993-02-26 | 1994-08-31 | STMicroelectronics S.r.l. | Anti-logarithmic converter with temperature compensation |
| JP2002123320A (en) * | 2000-10-12 | 2002-04-26 | Advantest Corp | Voltage generator with current limiting function |
| JP3917595B2 (en) * | 2003-02-26 | 2007-05-23 | 株式会社東芝 | Nucleic acid concentration quantitative analysis chip, nucleic acid concentration quantitative analysis device, and nucleic acid concentration quantitative analysis method |
| WO2013012940A1 (en) * | 2011-07-20 | 2013-01-24 | The Regents Of The University Of California | Compensated patch-clamp amplifier for nanopore polynucleotide sequencing and other applications |
| CN202548093U (en) * | 2012-03-26 | 2012-11-21 | 上海市计算技术研究所 | Micro-current chemical signal pickup device |
| CN103970359A (en) * | 2013-01-29 | 2014-08-06 | 北京博汇信通科技有限公司 | Photoelectric signal processing circuit used for infrared touch screen |
| DE102013215666A1 (en) * | 2013-08-08 | 2015-02-12 | Siemens Aktiengesellschaft | Method for sequencing biopolymers |
| US10316355B2 (en) * | 2014-07-25 | 2019-06-11 | Kalim Mir | Nanopipette analysis of polymers |
| US10246742B2 (en) * | 2015-05-20 | 2019-04-02 | Quantum-Si Incorporated | Pulsed laser and bioanalytic system |
| CN206369977U (en) * | 2016-12-13 | 2017-08-01 | 厦门宇电自动化科技有限公司 | The alternating voltage input module of artificial intelligence instrument |
| WO2020061967A1 (en) * | 2018-09-27 | 2020-04-02 | 深圳市大疆创新科技有限公司 | Ranging device and time measuring method based on ranging device |
| CN112708544A (en) * | 2019-10-25 | 2021-04-27 | 成都今是科技有限公司 | Measuring device and measuring method for gene sequencing |
| US10956687B1 (en) * | 2019-12-12 | 2021-03-23 | Texas Instruments Incorporated | Logarithmic amplifier |
| CN212518919U (en) * | 2020-08-28 | 2021-02-09 | 深圳市儒翰基因科技有限公司 | Low-power-consumption low-noise front-end sensing amplifier suitable for DNA sequencing signals |
-
2021
- 2021-10-29 CN CN202111266944.XA patent/CN113699223B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103275867A (en) * | 2013-05-02 | 2013-09-04 | 华中科技大学 | Detection and acquisition system for solid-state nano-pore nucleic acid sequencing electric signals |
| CN107462765A (en) * | 2017-09-07 | 2017-12-12 | 昆山龙腾光电有限公司 | A kind of signal deteching circuit and device |
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