CN113740397B - Microcurrent detection circuit and gene sequencing device - Google Patents
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Abstract
The embodiment of the disclosure provides a micro-current detection circuit and a gene sequencing device, wherein the detection circuit comprises a nanopore voltage applying unit, a nanopore detection module and a detection module, wherein the nanopore voltage applying unit is used for applying voltage to a common electrode and a detection electrode of a nanopore test cavity and driving a single nucleotide molecule to pass through a nanopore; the integration circuit unit is used for carrying out integration amplification on the micro-current signal output by the detection electrode of the nanopore test cavity and converting the micro-current signal into an integrated voltage signal; the output circuit unit is used for receiving the integrated voltage signal converted by the integrating circuit unit and outputting the integrated voltage signal; and the compensation current input unit is used for applying compensation current to the detection electrode of the nanopore test cavity. The embodiment realizes the rapid response of the nanopore gene sequencing, improves the sequencing accuracy, and is convenient for large-scale integration.
Description
Technical Field
The disclosure belongs to the technical field of electronic circuits, and particularly relates to a microcurrent detection circuit and a gene sequencing device, which can be used for detecting biological microcurrent signals of gene sequencing and pA-level microcurrents in other application fields.
Background
The nanopore sequencing method adopts an electrophoresis technology, and sequencing is realized by driving single molecules to pass through the nanopores one by means of electrophoresis. The nanopores (nanopore) are channels of about 1-10 nanometers in diameter, including solid state nanopores and biological nanopores. Single-stranded DNA (or RNA) molecules spontaneously pass through the nanopore in an electric field due to their charged nature, and cause a change in the nanopore resistance during the pass, resulting in a so-called blocking current. Four different bases A, T (U), C, and G of DNA (RNA) have identifiable differences in blocking effects on current generation when they traverse the nanopore due to differences in their own chemical structures, producing respective corresponding characteristic blocking currents. The type of the corresponding base can be determined by accurately detecting the characteristic blocking current, thereby determining the nucleic acid sequence.
In the existing nanopore sequencing mode, taking a sequencing technology of Genia Technologies company as an example, a modified nucleotide analogue is adopted to sequence while synthesizing nucleic acid, the modified nucleotide analogue comprises nucleotides and linkers used for synthesis, different linkers can generate characteristic blocking current more effectively than nucleic acid, and the detection of the linkers can effectively improve the base recognition degree, but the detection of the linkers only can hardly avoid the situation that the blocking current of the linkers is read, but the nucleotides do not really participate in the synthesis reaction, so that the error (insertion error) of redundant reading of signals is caused. Therefore, there is a need for improvements in existing nanopore sequencing technologies that can detect not only the linker, but also the nucleotide itself, to increase sequencing accuracy and rapid response capability. This requires a higher sampling frequency and a stricter noise control means.
Disclosure of Invention
The embodiment of the disclosure provides a microcurrent detection circuit and a gene sequencing device, which are used for rapidly and accurately judging the type of a nucleotide molecule passing through a nanopore and completing a sequencing function.
In a first aspect, embodiments of the present disclosure provide a micro-current detection circuit, including:
The nanometer Kong Dianya applying unit is used for applying voltage to the public electrode and the detection electrode of the nanopore testing cavity and driving the single nucleotide molecules to pass through the nanopore;
The integration circuit unit is used for carrying out integration amplification on the micro-current signal output by the detection electrode of the nanopore test cavity and converting the micro-current signal into an integrated voltage signal;
The output circuit unit is used for receiving the integrated voltage signal converted by the integrating circuit unit and outputting the integrated voltage signal;
and the compensation current input unit is used for applying compensation current to the detection electrode of the nanopore test cavity.
In an optional embodiment, the nanopore voltage applying unit includes a clamping tube, a first path end of the clamping tube is connected to the detection electrode, a second path end of the clamping tube is connected to the integrating circuit unit, and a control end of the clamping tube inputs a clamping voltage.
In an optional embodiment, the nanopore voltage applying unit includes a forward clamping tube and a reverse clamping tube, a first path end of the forward clamping tube and a first path end of the reverse clamping tube are connected with the detection electrode, a second path end of the forward clamping tube and a second path end of the reverse clamping tube are connected with the integrating circuit unit, a control end of the forward clamping tube inputs a first clamping voltage, and a control end of the reverse clamping tube inputs a second clamping voltage; the current direction of the forward clamping tube flows from the detection electrode to the integration circuit unit, and the current direction of the reverse clamping tube flows from the integration circuit unit to the detection electrode.
In an alternative embodiment, the integrating circuit unit comprises an integrating capacitor and an integrating reset switch, a first end of the integrating capacitor is connected with a second path end of the clamping tube, and a second end of the integrating capacitor is grounded; the first channel end of the integral reset switch is connected with the first end of the integral capacitor, and the second channel end of the integral reset switch is connected with a reset voltage for resetting the voltage of the integral capacitor.
In an alternative embodiment, the integrating circuit unit comprises an integrating capacitor, an integrating reset switch and a reset voltage selecting circuit unit, wherein a first end of the integrating capacitor is connected with a second path end of the forward clamping tube and a second path end of the reverse clamping tube, and a second end of the integrating capacitor is grounded; the first channel end of the integral reset switch is connected with the first end of the integral capacitor, and the second channel end of the integral reset switch is connected with a reset voltage selection circuit unit and is used for resetting the voltage of the integral capacitor; the reset voltage selection circuit unit is used for switching and selecting the reset voltage connected with the second path end of the integral reset switch.
In an alternative embodiment, the compensation current input circuit comprises a current source, the negative terminal of which is connected to a power supply, and the positive terminal of which is connected to the detection electrode.
In an alternative embodiment, the compensation current input circuit includes a first current source, a second current source, a first switch, and a second switch; the negative end of the first current source is connected to the power supply, the positive end of the first current source is connected in series with the first switch to the detection electrode, the positive end of the second current source is grounded, the negative end of the second current source is connected in series with the second switch to the detection electrode, and the control ends of the first switch and the second switch are connected with the same control signal.
In an alternative embodiment, the nanopore voltage applying unit further includes a reference voltage selecting circuit unit for switching a reference voltage selectively input to the common electrode.
In an alternative embodiment, the nanopore voltage applying unit further includes a bias circuit for generating the first clamping voltage and the second clamping voltage.
In an alternative embodiment, the bias circuit includes a first bias circuit and a second bias circuit; the first bias circuit comprises a third current source and a first MOS tube, wherein the negative end of the third current source is connected with a power supply, and the positive end of the third current source is connected with the control end and the first channel end of the first MOS tube; the second bias circuit comprises a fourth current source and a second MOS tube, the positive end of the fourth current source is grounded, the negative end of the fourth current source is connected with the control end and the first channel end of the second MOS tube, and the second channel ends of the first MOS tube and the second MOS tube are connected with a common-mode voltage.
In an optional embodiment, the nanopore voltage applying unit further includes a first switch pair and a second switch pair, the first bias circuit is connected to the first switch pair to selectively provide the second clamp voltage to the control terminal of the reverse clamp tube, and the second bias circuit is connected to the second switch pair to selectively provide the first clamp voltage to the control terminal of the forward clamp tube.
In an alternative embodiment, the nanopore voltage applying unit further includes a first driving filter circuit and a second driving filter circuit, the first driving filter circuit is connected in series between the first bias circuit and the first switch pair, and the second driving filter circuit is connected in series between the second bias circuit and the second switch pair.
In an alternative embodiment, the first switch pair includes a third switch and a fourth switch for selectively outputting the second clamp voltage or shorting the output to a power source according to a control signal; the second switch pair comprises a fifth switch and a sixth switch and is used for selectively outputting the first clamping voltage or shorting the output to the ground according to a control signal.
In an optional embodiment, the nanopore voltage applying unit further comprises an input reset switch, a first path end of the input reset switch is connected with a preset voltage, a second path end of the input reset switch is connected with the detection electrode, and a control end of the input reset switch is connected with a reset control signal.
In an alternative embodiment, the output circuit unit includes a source follower and a selection switch, an input terminal of the source follower is connected to the integration capacitor, an output terminal is connected to a first terminal of the selection switch, and a second terminal of the selection switch outputs the integrated voltage signal.
In a second aspect, the presently disclosed embodiments provide a genetic sequencing device comprising a plurality of measurement units, each measurement unit comprising a nanopore test cavity and a microcurrent detection circuit as described in any of the preceding embodiments; the nanopore test cavity comprises a public electrode and a detection electrode.
In an alternative embodiment, the micro-current detection circuit further comprises a common signal line and an analog-to-digital conversion circuit connected to the common signal line, wherein the common signal line is used for receiving a voltage signal output by the micro-current detection circuit, and the analog-to-digital conversion circuit is used for converting the voltage signal into a digital signal.
In an alternative embodiment, the circuit further comprises a tail current source, wherein the negative end of the tail current source is connected to the common signal line, and the positive end of the tail current source is grounded.
The micro-current detection circuit provided by the embodiment of the disclosure provides compensation current for the detection electrode of the nanopore test cavity through the compensation current input unit, so that the characteristic current generated by the nucleotide and the connector through the nanopore can be identified simultaneously. The scheme has the beneficial effects that at least one of the following is achieved: 1) The precision is high; 2) The method can quickly respond and correctly identify; 3) The detection circuit unit is simple and small in area, and is convenient for large-scale integration.
Drawings
In order to more clearly illustrate the embodiments of the present disclosure or the solutions in the prior art, a brief description will be given below of the drawings that are needed in the embodiments or the description of the prior art, it being obvious that the drawings in the following description are some embodiments of the present disclosure, and that other drawings may be obtained from these drawings without inventive effort to a person of ordinary skill in the art.
FIG. 1 is a schematic diagram of the structure and electrical model of a nanopore test chamber 101 employed in an embodiment of the present disclosure;
FIG. 2 is a schematic circuit diagram of a detection circuit in an exemplary nanopore sequencing device;
FIG. 3 is a schematic diagram of an operational waveform of the detection circuit shown in FIG. 2;
Fig. 4 is a circuit schematic of a micro-current detection circuit according to a first embodiment of the present disclosure;
FIG. 5A is a schematic diagram of a first operational waveform of a microcurrent detection circuit according to one embodiment of the present disclosure;
FIG. 5B is a schematic diagram of a second operational waveform of a microcurrent detection circuit according to one embodiment of the present disclosure;
FIG. 6 is a circuit schematic of a microcurrent detection circuit according to second embodiment of the present disclosure;
FIG. 7 is a schematic diagram of an operating waveform of a microcurrent detection circuit according to a second embodiment of the present disclosure;
fig. 8 is a schematic structural view of a gene sequencing device according to an embodiment of the present disclosure.
Detailed Description
For the purposes of making the objects, technical solutions and advantages of the embodiments of the present disclosure more clear, the technical solutions of the embodiments of the present disclosure will be clearly and completely described below with reference to the accompanying drawings in the embodiments of the present disclosure. It will be apparent that the described embodiments are some, but not all, of the embodiments of the present disclosure. Based on the embodiments in this disclosure, all other embodiments that a person of ordinary skill in the art would obtain without making any inventive effort are within the scope of protection of this disclosure.
In this disclosure, it should be understood that terms such as "comprises" or "comprising," etc., are intended to indicate the presence of features, numbers, steps, acts, components, portions, or combinations thereof disclosed in this specification, and are not intended to exclude the possibility that one or more other features, numbers, steps, acts, components, portions, or combinations thereof are present or added.
In a nanopore sequencing device, a voltage applied to two ends of a test cavity is used for driving a nucleotide molecule and a connector for synthesis to pass through a nanopore, and the type of the nucleotide molecule passing through the nanopore is detected by detecting a micro-current characteristic signal output by the nanopore, so that sequencing is realized.
Fig. 1 is a schematic diagram of a structure and an electrical model of a nanopore test chamber 101 employed in an embodiment of the present disclosure. As shown in fig. 1, the test chamber 101 comprises a first compartment and a second compartment separated by a phospholipid bilayer membrane 105, and an electrode 103 connected to the first compartment and an electrode 102 connected to the second compartment. The phospholipid bilayer membrane 105 has a nanopore 104 thereon, and the nucleotide molecule 106 with the linker 107 attached is located in the first compartment and passes through the nanopore 104 under the application of a voltage across the electrodes 102 and 103. In fig. 1, nanopore equivalent capacitance 108 and nanopore equivalent resistance 109 may be employed to simulate the electrical characteristics of nanopore 104, and for ease of illustration, the disclosed embodiments simplify test cavity 102 to nanopore equivalent circuit model 113.
FIG. 2 is a schematic circuit diagram of a detection circuit in a nanopore sequencing device that can be implemented. As shown in fig. 2, the detection circuit includes a nanopore voltage applying unit, an integrating circuit unit, and an output circuit unit. Wherein the nanopore voltage applying unit is configured to apply a voltage to the common electrode and the detection electrode 208 of the nanopore test chamber 207, thereby driving the single nucleotide molecule through the nanopore by means of a voltage difference between the common electrode and the detection electrode 208 of the nanopore test chamber 207. In one embodiment, the nanopore voltage applying unit includes a clamping tube 201.
The integrating circuit unit is used for integrating and amplifying the micro-current signal output by the detection electrode 208 of the nanopore test cavity 207 and converting the micro-current signal into an integrated voltage signal. In one embodiment, the integrating circuit unit includes an integrating capacitor 203 and an integrating reset switch 202.
The output circuit unit receives the integrated voltage signal converted by the integrating circuit unit and outputs the integrated voltage signal. In one embodiment, the output circuit unit includes a source follower 204 and a selection switch 205 (implemented with selection tube 205 in fig. 2).
In this example of the detection circuit, a reference voltage VCMD 210 is applied to a common electrode (corresponding to the electrode 112 in fig. 1) of the nanopore test cavity 207, a source of the clamp 201 is connected to a detection electrode 208 (corresponding to the electrode 110 in fig. 1) of the nanopore test cavity 207, and a drain of the clamp 201 is connected to one end of the integrating capacitor 203. The gate of the clamping tube 201 inputs a clamping voltage VP 209, and the clamping voltage VP is a fixed voltage, so that the input voltage of the detection electrode 208 of the nanopore test cavity is ensured to be a certain fixed value. When a forward voltage is applied to the reference voltage VCMD, for example, about 100mV to 200mV higher than the voltage on the detection electrode 208, the nucleotide molecules in the nanopore test cavity pass through the nanopore under the action of the electric field, at this time, a characteristic current appears in the nanopore, the characteristic current passes through the clamping tube 201 and is input to the integrating capacitor 203, the integrating capacitor 203 performs integration amplification on the characteristic current for a certain period of time, so as to generate an integrated voltage signal 211, and the integrated voltage signal 211 is output to the common signal line 213 through the source follower 204 and the selection switch 205, and then is output to the analog-to-digital converter ADC 206 through the common signal line 213 for analog-to-digital conversion. Wherein the reset switch 202 periodically clears the charge on the integrating capacitor 203 under control of the reset signal Rst.
Fig. 3 is a schematic diagram of an operation waveform of the detection circuit. As shown in fig. 3, 301 is a voltage waveform applied by the reference voltage VCMD; 302 is the waveform of the periodic reset signal of the integrating capacitor and 303 is the waveform of the integrated voltage across the integrating capacitor. When the reference voltage applies a forward voltage, the integrated voltage is accumulated on the integrating capacitor and a periodic saw tooth signal is generated according to the reset signal period.
The operation of the detection circuit shown in fig. 2 is briefly described below.
First, when the clamp 201 operates in a subthreshold state, the clamp voltage VP thereof changes with the detected current.
The relation between the current and the voltage of the MOS tube in the subthreshold state is as follows:
Where n is a process related constant, which can take on a value of 1.5 empirically; VT is thermal voltage, and 26mV is taken at normal temperature; ids0 is a MOS transistor current parameter and is related to a process; vth is the threshold voltage of the MOS transistor; ids is the current value flowing through the MOS tube, and Vgs is the voltage value of the MOS tube corresponding to the current value.
For different currents, e.g., ids1 and Ids2, corresponding to different Vgs1 and Vgs2, respectively, the voltage difference Δvgs between the two is:
referring to FIG. 1, if the nanopore equivalent capacitance 108 is 2pF and the nanopore equivalent resistance 109 is in the range of 250MΩ -20 GΩ, a current of 5 pA-800 pA will be generated when a voltage of 200mV is applied across the nanopore, temporarily irrespective of the influence of the solution resistance 111.
As described above, when the current range to be detected by the detection circuit is in the range of 5pA to 800pA and Ids1 and Ids2 are respectively maximized and minimized, the change in Δvgs can be estimated as follows:
as described above, for the detection circuit shown in FIG. 2, there will be a maximum of about 200mV change in the detection electrode 208 during the detection process. Through simplified calculation, the final stabilization time of the structure has the following relation:
Where n is a process related constant, which can take on a value of 1.5 empirically; VT is thermal voltage, and 26mV is taken at normal temperature; c is the nanopore equivalent capacitance, referring to nanopore equivalent capacitance 108 in fig. 1; delta Vgs is the voltage change of the detection electrode caused before and after the current mutation of the nano holes; i0 is the initial current value flowing through the clamping tube, namely the current value before the current of the nano-hole suddenly changes; i1 is the final current value flowing through the clamp, here the current value after the nanopore current abrupt change.
When the detection circuit is in an unstable state, particularly for rapid current change in the detection process, taking the example that the nucleotide molecules pass through the nanopore, the residence time of the nucleotide molecules in the nanopore is shortest by about 100us, so that the rapid current change, the detection circuit shown in fig. 2 cannot ensure correct identification. In addition, different detection currents can cause different changes of voltage values Vgs of the clamping tube, and finally the voltage values are reflected at two ends of the nanopore, so that detection errors are caused.
Aiming at the defects of the detection circuit, the present disclosure provides an improved micro-current detection circuit, which can rapidly and accurately judge the type of nucleotide molecules passing through a nanopore and complete a sequencing function.
Fig. 4 is a circuit schematic of a micro-current detection circuit according to a first embodiment of the disclosure. As shown in fig. 4, the micro-current detection circuit of the embodiment of the present disclosure includes a nanopore voltage applying unit, an integrating circuit unit, an output circuit unit, and a compensation current input unit.
The nanopore voltage applying unit is used for applying voltages to the common electrode and the detection electrode 408 of the nanopore test cavity 407, so that a single nucleotide molecule is driven to pass through the nanopore by means of the voltage difference between the common electrode and the detection electrode 208 of the nanopore test cavity 407, and unidirectional microcurrent signal detection is realized.
The integrating circuit unit is used for integrating and amplifying the micro-current signal output by the detection electrode 408 of the nanopore test cavity 407, and converting the micro-current signal into an integrated voltage signal.
The output circuit unit is used for receiving the integrated voltage signal converted by the integration circuit unit and outputting the integrated voltage signal.
The compensation current input unit is configured to apply a compensation current to the detection electrode 408 of the nanopore test cavity 407, and is configured to reduce a voltage change caused by a micro-current signal output by the detection electrode 408, thereby reducing a dependence of a voltage of the detection electrode on a detection current, reducing a circuit stabilization time, and improving a response speed.
In one embodiment, the nanopore voltage applying unit includes a clamping tube 401, a first path end of the clamping tube 401 is connected to the detecting electrode 408, a second path end of the clamping tube is connected to the integrating circuit unit, a control end of the clamping tube inputs a clamping voltage VP 409, and the clamping voltage VP acts to make the voltage of the detecting electrode 408 be a fixed value. In one embodiment, the first path end may be a source electrode of the MOS transistor, the second path end may be a drain electrode of the MOS transistor, and the control end is a gate electrode of the MOS transistor.
In one embodiment, the integrating circuit unit includes an integrating capacitor 403 and an integrating reset switch 402 (illustratively implemented as reset tube 402 in fig. 4). The first end of the integrating capacitor 403 is connected to the second end of the clamping tube 401, and the second end is grounded to the ground potential, so as to integrate and amplify the microcurrent signal of the detection electrode. The first path terminal of the integral reset switch 402 is connected to the first terminal of the integral capacitor 403, and the second path terminal of the integral reset switch 402 is connected to the reset voltage Vpre, so as to reset the voltage of the integral capacitor 403 periodically under the action of the reset signal Rst.
In one embodiment, the compensation current input unit includes a current source 414. Wherein the negative terminal of the current source 414 is connected to the power supply VDD and the positive terminal is connected to the detection electrode 408 of the nanopore test cavity 407. The compensation current input unit supplies compensation current to the clamping tube 401 through the current source 414, and reduces the voltage variation of the detection electrode 408 along with the micro-current signal.
In one embodiment, the output circuit unit includes a source follower 404 and a selection switch 405 (illustratively implemented with a selection tube 405 in fig. 4). The input end of the source follower 404 is connected to the first end of the integrating capacitor 403, the output end is connected in series to the first end of the selection switch 405, and the second end of the selection switch 405 is used for outputting the integrated voltage signal 411. In one embodiment, a second terminal of the selection switch 405 may be connected to a common signal line 413, the integrated voltage signal 411 may be output to the common signal line 413, and the common signal line 413 may be connected to the analog-to-digital converter 406, further converting the integrated voltage signal 411 into a digital signal.
In this embodiment, as shown in the above formula (3), the settling time Tset of the detection circuit is positively correlated with Δvgs and I1/I0 and inversely correlated with I1, so that lowering Δvgs and raising I1 will effectively reduce the settling time.
The detection electrodes 408 are connected in parallel with the compensation current 414, and the introduced compensation current 414 can reduce the voltage variation caused by the detection current (micro-current signal) output by the detection electrodes, that is, the above-mentioned Δvgs. As an example, when the compensation current is 200pA, the detection current is 5pA to 800pA, the detection range is 205pA to 1000pA after the compensation current is added, and the voltage difference Δvgs' =59 4mV caused by the detection current is significantly reduced. At the same time, the compensation current also flows through the clamping tube 401, thereby raising the current of the clamping tube 401, i.e., I1 described above. Therefore, the compensation current 414 can effectively reduce the settling time of the detection circuit, so as to realize the detection of the rapidly-changing nanopore micro-current signal.
Fig. 5A and 5B show waveforms of response of the conventional detection circuit shown in fig. 2 and the detection circuit according to the first embodiment shown in fig. 4 to different nanopore currents, respectively.
As shown in fig. 5A, when a nanopore has a nucleotide molecule passing through, the change in resistance of the nanopore may be simulated by using curve 501A, where 1gΩ indicates that the nanopore is open, abrupt change to 20gΩ indicates that the nucleotide molecule enters the nanopore, the duration may vary from 100us to 10ms, and then abrupt change again to 5gΩ indicates that the nucleotide molecule linker is within the nanopore. The curve 502A shows an integrating capacitance reset signal, which periodically resets the integrating capacitance. Curve 503A shows the integrated voltage with the addition of the compensation current, i.e., integrated voltage 411 in the structure of fig. 4; curve 504A represents the integrated voltage of a conventional structure, i.e., integrated voltage 211 of fig. 2. Comparing the curves 503A and 504A in FIG. 5A, the compensation current is added to have a shorter stabilization time, which can distinguish the state of the nucleotide molecule entering the nanopore.
Fig. 5B shows a case where no nucleotide molecule enters the nanopore, where 1gΩ indicates that the nanopore is in an open state, abrupt change to 5gΩ indicates that only a linker enters the nanopore, corresponding curve 503B indicates the integrated voltage with the addition of compensation current, curve 504B indicates the integrated voltage of the conventional structure, and no nucleotide molecule is detected to pass through the nanopore.
Curves 504A and 504B in fig. 5A and 5B represent integrated voltage signals of a conventional detection circuit, which correspond to the case that a nucleotide molecule enters a nanopore and no nucleotide molecule enters the nanopore, respectively, and the integrated voltage signals of curves 504A and 504B are similar, it can be seen that the conventional detection circuit structure cannot effectively identify the process of the nucleotide molecule passing through the nanopore, particularly when the nucleotide molecule passes through rapidly; and comparing the curves 503A and 503B, when the compensation current is increased, the detection circuit can respond to the rapid detection current change and convert the rapid detection current change into a voltage signal, and when the nucleotide molecules enter the nanopore, the detection circuit has a lower voltage signal, and as shown in the curve 503A, whether the nucleotide molecules pass through the nanopore can be distinguished according to the voltage signal.
Fig. 6 is a circuit schematic of a micro-current detection circuit according to a second embodiment of the disclosure. As shown in fig. 6, the micro-current detection circuit of the embodiment of the present disclosure also includes a nanopore voltage applying unit, an integrating circuit unit, an output circuit unit, and a compensation current input unit.
The nanopore voltage applying unit is used for applying voltage to the public electrode and the detection electrode 608 of the nanopore test cavity 607, so that a single nucleotide molecule is driven to pass through the nanopore by means of the voltage difference between the public electrode and the detection electrode 608 of the nanopore test cavity 607, and bidirectional microcurrent signal detection is realized.
The integrating circuit unit is used for integrating and amplifying the micro-current signal output by the detection electrode 608 of the nanopore test cavity 607 and converting the micro-current signal into an integrated voltage signal.
The output circuit unit is used for receiving the integrated voltage signal converted by the integration circuit unit and outputting the integrated voltage signal.
The compensation current input unit is used for applying compensation current to the detection electrode 608 of the nanopore test cavity 607, and is used for reducing voltage variation caused by micro-current signals output by the detection electrode 608, so that the dependence of the voltage of the detection electrode on the detection current is reduced, the circuit stabilization time is shortened, and the response speed is improved. The embodiment has forward and reverse detection capability, can reduce the circuit stabilization time and improve the response speed.
In one embodiment, the nanopore voltage applying unit includes a forward clamping tube 601B and a reverse clamping tube 601A, a first path end of the forward clamping tube 601B and a first path end of the reverse clamping tube 601A are connected with the detection electrode 608, a second path end of the forward clamping tube 601B and a second path end of the reverse clamping tube 601A are connected with the integrating circuit unit, a control end of the forward clamping tube inputs a first clamping voltage VP, and a control end of the reverse clamping tube inputs a second clamping voltage VN, so that forward and reverse clamping functions are respectively completed. The current direction of the forward clamp 601B flows from the detection electrode 608 to the integration circuit unit, and the current direction of the reverse clamp 601A flows from the integration circuit unit to the detection electrode 608. In one embodiment, the first path end may be a source electrode of the MOS transistor, the second path end may be a drain electrode of the MOS transistor, and the control end is a gate electrode of the MOS transistor.
In one embodiment, the integrating circuit unit includes an integrating capacitor 603, an integrating reset switch 602 (illustratively implemented as a reset tube 602 in fig. 6), and a reset voltage selection circuit unit 609. A first end of the integrating capacitor 603 is connected to the second path ends of the forward clamping tube 601B and the reverse clamping tube 601A, and a second end of the integrating capacitor 603 is grounded. A first path terminal of the integral reset switch 602 is connected to the first terminal of the integral capacitor, and a second path terminal of the integral reset switch 602 is connected to the reset voltage selection circuit unit 609. The reset voltage selection circuit 609 is used to switch and select the reset voltages (Vpre 1 and Vpre2 in fig. 6) input to the second path terminal of the integral reset switch 602.
In one embodiment, the nanopore voltage applying unit further includes a reference voltage selecting circuit unit 610 for switching the reference voltages (VCMD 1 and VCMD2 in fig. 6) selected for input to the common electrode of the nanopore test cavity 607.
In one embodiment, the compensation current input unit includes current sources 614B and 614A, selection switches 615B and 615A. Wherein the negative terminal of the current source 614B is connected to the power supply VDD, and the positive terminal is connected in series with the selection switch 615B to the detection electrode 608 of the nanopore test cavity 607. The positive terminal of the current source 614A is connected to ground, the negative terminal is connected in series with the selection switch 615A to the detection electrode 608 of the nanopore test cavity 607, and the control terminals of the selection switches 615B and 615A are connected to the same control signal CMD. The compensation current input unit supplies compensation current through current sources 614B, 614A when performing forward and reverse clamping functions for the forward clamp and the reverse clamp, respectively.
In one embodiment, the nanopore voltage applying unit further comprises a biasing circuit for generating the first clamping voltage VP and the second clamping voltage VN. The bias circuits may include a first bias circuit 619A and a second bias circuit 619B, among other things. The first bias circuit 619A includes a first current source and a first MOS transistor, and the second bias circuit 619B includes a second current source and a second MOS transistor. The first MOS tube and the second MOS tube are in diode configuration, the respective control ends are connected with the second path ends, and the first path ends of the first MOS tube and the second MOS tube are connected with a common-mode voltage VCM; the negative end of the first current source is connected with the power supply VDD, the positive end of the first current source is connected with the control end and the second path end of the first MOS tube, the positive end of the second current source is connected with the ground, and the negative end of the second current source is connected with the control end and the second path end of the second MOS tube. In one embodiment, the first path end may be a source electrode of the MOS transistor, the second path end may be a drain electrode of the MOS transistor, and the control end is a gate electrode of the MOS transistor. In one embodiment, the first MOS transistor and the second MOS transistor may be NMOS transistors or PMOS transistors.
In one embodiment, the nanopore voltage applying unit further includes a first selection switch pair 617A and a second selection switch pair 617B, the first bias circuit 619A is connected to the first selection switch pair 617A, the second bias circuit 619B is connected to the second selection switch pair 617B, and the first selection switch pair 617A and the second selection switch pair 617B are matched to output the first clamping voltage VP and the second clamping voltage VN to the control terminals of the forward clamping tube 601B and the reverse clamping tube 601A, respectively, so as to realize switching between forward detection and reverse detection. The control terminals of the first 617A and the second 617B pair are connected to the same control signal CMD. Each of the first selection switch pair 617A and the second selection switch pair 617B includes a pair of selection switches, one of the selection switches of the first selection switch pair 617A being configured to selectively output the second clamping voltage VN according to a control signal CMD, the other selection switch being configured to short the output to a power supply; one of the second pair of selection switches 617B is configured to selectively output the first clamp voltage VP according to a control signal CMD, and the other is configured to short the output to ground.
In one embodiment, as shown in fig. 6, considering that the voltage driving capability generated by the first bias circuit 619A and the second bias circuit 619B is weaker, a first driving filter circuit 618A may be further added between the first bias circuit 619A and the first selection switch pair 617A, and a second driving filter circuit 618B may be added between the second bias circuit 619B and the second selection switch pair 617B, so as to implement the driving enhancement and noise reduction function, and the specific circuit may adopt the existing embodiment and will not be described in detail.
In one embodiment, the nanopore voltage applying unit further includes an input reset switch 616, a first path terminal of the input reset switch 616 is connected to the preset voltage VCM, a second path terminal is connected to the detection electrode 608 of the nanopore test cavity, and a control terminal of the input reset switch 616 is connected to the reset control signal rst_cmd. The input reset switch 616 is used to fix the detection electrode 608 at the preset voltage VCM during the forward and reverse detection switching, so as to improve the response speed of the detection circuit during the forward and reverse detection switching, and facilitate the quick establishment of the circuit operating point.
In one embodiment, the output circuit unit includes a source follower 604 and a selection switch 605 (illustratively implemented as a selection tube 605 in fig. 6). The input end of the source follower 604 is connected to the first end of the integrating capacitor 603, the output end is connected in series with the first end of the selection switch 605, and the second end of the selection switch 605 outputs the integrated voltage signal 611. In one embodiment, a second terminal of the selection switch 605 may be connected to a common signal line 613, and the common signal line 613 may be connected to an analog-to-digital converter 606, further converting the integrated voltage signal 611 into a digital signal.
Fig. 7 is a schematic diagram of an operation waveform of a micro-current detection circuit according to a second embodiment of the present disclosure, as shown in fig. 7, 701 is a waveform of an integrated reset signal Rst, 702 is a waveform of a control signal CMD for switching a detection direction, 703 is a waveform of a reset control signal rst_cmd input to a reset switch, 704 is a waveform of a reset voltage Vpre, and 705 is a waveform of a reference voltage VCMD. The reference voltage VCMD is synchronously switched along with the control signal CMD, and when the detection direction is switched, the input reset switch 616 in fig. 6 is controlled by rst_cmd to fix the detection electrode of the nanopore to the preset voltage VCM.
Fig. 8 is a schematic structural view of a gene sequencing device according to an embodiment of the present disclosure. As shown in fig. 8, the gene sequencing device of the present embodiment includes a plurality of measurement units, each of which includes a nanopore test cavity 802 and a detection circuit unit 805 correspondingly connected; wherein the nanopore test chamber 802 comprises an electrode 808 connected to the common electrode 801 in a first compartment and a detection electrode 809 in a second compartment. The plurality of detection circuit units 805 are implemented using the micro-current detection circuit described in the first or second embodiment.
In one embodiment, the output voltage of the detection circuit unit 805 is output to the shared common signal line 806 through a selection switch in the detection circuit unit, and is converted into a digital signal by the analog-to-digital converter 807 and then output.
In one embodiment, the genetic sequencing device may further comprise a tail current source 810, the negative terminal of the tail current source 810 being connected to the common signal line 806, the positive terminal being grounded.
It should be noted that, the above embodiments may be freely combined according to needs, and in addition, devices involved in the circuit are described according to CMOS devices, and other devices, such as BJTs, JFETs, and the like, may also implement the technical solutions of the present disclosure. The foregoing is merely a preferred embodiment of the present disclosure, and it should be noted that variations and modifications could be made by those skilled in the art without departing from the principles of the present disclosure, which would also be considered to fall within the scope of the present disclosure.
Claims (18)
1. A microcurrent detection circuit, comprising:
The nanometer Kong Dianya applying unit is used for applying voltage to the public electrode and the detection electrode of the nanopore testing cavity and driving the single nucleotide molecules to pass through the nanopore;
The integration circuit unit is used for carrying out integration amplification on the micro-current signal output by the detection electrode of the nanopore test cavity and converting the micro-current signal into an integrated voltage signal;
The output circuit unit is used for receiving the integrated voltage signal converted by the integrating circuit unit and outputting the integrated voltage signal;
and the compensation current input unit is used for applying compensation current to the detection electrode of the nanopore test cavity and reducing voltage change caused by micro-current signals output by the detection electrode.
2. The micro-current detection circuit as claimed in claim 1, wherein the nanopore voltage applying unit comprises a clamping tube, a first path end of the clamping tube is connected to the detection electrode, a second path end of the clamping tube is connected to the integrating circuit unit, and a control end of the clamping tube inputs a clamping voltage.
3. The micro-current detection circuit as claimed in claim 1, wherein the nanopore voltage applying unit comprises a forward clamping tube and a reverse clamping tube, a first path end of the forward clamping tube and a first path end of the reverse clamping tube are connected with the detection electrode, a second path end of the forward clamping tube and a second path end of the reverse clamping tube are connected with the integrating circuit unit, a control end of the forward clamping tube inputs a first clamping voltage, and a control end of the reverse clamping tube inputs a second clamping voltage; the current direction of the forward clamping tube flows from the detection electrode to the integration circuit unit, and the current direction of the reverse clamping tube flows from the integration circuit unit to the detection electrode.
4. The micro-current detection circuit as claimed in claim 2, wherein the integrating circuit unit comprises an integrating capacitor and an integrating reset switch, a first end of the integrating capacitor is connected to a second path end of the clamping tube, and a second end of the integrating capacitor is grounded; the first channel end of the integral reset switch is connected with the first end of the integral capacitor, and the second channel end of the integral reset switch is connected with a reset voltage for resetting the voltage of the integral capacitor.
5. The micro-current detection circuit as claimed in claim 3, wherein the integrating circuit unit comprises an integrating capacitor, an integrating reset switch and a reset voltage selection circuit unit, a first end of the integrating capacitor is connected with a second path end of the forward clamping tube and the reverse clamping tube, and a second end of the integrating capacitor is grounded; the first channel end of the integral reset switch is connected with the first end of the integral capacitor, and the second channel end of the integral reset switch is connected with a reset voltage selection circuit unit and is used for resetting the voltage of the integral capacitor; the reset voltage selection circuit unit is used for switching and selecting the reset voltage input by the second path end of the integral reset switch.
6. The micro-current detection circuit as set forth in claim 2, wherein the compensation current input unit includes a current source having a negative terminal connected to a power source and a positive terminal connected to the detection electrode.
7. The micro-current detection circuit as set forth in claim 3, wherein the compensation current input unit includes a first current source, a second current source, a first switch, and a second switch; the negative end of the first current source is connected to the power supply, the positive end of the first current source is connected in series with the first switch to the detection electrode, the positive end of the second current source is grounded, the negative end of the second current source is connected in series with the second switch to the detection electrode, and the control ends of the first switch and the second switch are connected with the same control signal.
8. The micro-current detection circuit as claimed in claim 3, wherein the nanopore voltage applying unit further comprises a reference voltage selecting circuit unit for switching a reference voltage selectively input to the common electrode.
9. The micro-current detection circuit as set forth in claim 3, wherein the nanopore voltage applying unit further comprises a biasing circuit for generating the first clamping voltage and the second clamping voltage.
10. The microcurrent detection circuit of claim 9 wherein said bias circuit includes a first bias circuit and a second bias circuit; the first bias circuit comprises a third current source and a first MOS tube, wherein the negative end of the third current source is connected with a power supply, and the positive end of the third current source is connected with the control end and the first channel end of the first MOS tube; the second bias circuit comprises a fourth current source and a second MOS tube, the positive end of the fourth current source is grounded, the negative end of the fourth current source is connected with the control end and the first channel end of the second MOS tube, and the second channel ends of the first MOS tube and the second MOS tube are connected with a common-mode voltage.
11. The micro-current detection circuit of claim 10, wherein the nanopore voltage applying unit further comprises a first switch pair and a second switch pair, the first bias circuit being connected to the first switch pair to selectively provide a second clamp voltage to the control terminal of the reverse clamp, the second bias circuit being connected to the second switch pair to selectively provide a first clamp voltage to the control terminal of the forward clamp.
12. The micro-current detection circuit as claimed in claim 11, wherein the nanopore voltage applying unit further comprises a first driving filter circuit and a second driving filter circuit, the first driving filter circuit being connected in series between the first bias circuit and the first switch pair, the second driving filter circuit being connected in series between the second bias circuit and the second switch pair.
13. The micro-current detection circuit of claim 11, wherein the first switch pair comprises a third switch and a fourth switch for selectively outputting the second clamp voltage or shorting the output to a power supply according to a control signal; the second switch pair comprises a fifth switch and a sixth switch and is used for selectively outputting the first clamping voltage or shorting the output to the ground according to a control signal.
14. The micro-current detection circuit as claimed in claim 3, wherein the nanopore voltage applying unit further comprises an input reset switch, a first path terminal of the input reset switch is connected to a preset voltage, a second path terminal is connected to the detection electrode, and a control terminal is connected to a reset control signal.
15. The micro-current detection circuit as set forth in claim 4 or 5, wherein the output circuit unit includes a source follower and a selection switch, an input terminal of the source follower is connected to a first terminal of the integration capacitor, an output terminal is connected to a first terminal of the selection switch, and a second terminal of the selection switch outputs the integrated voltage signal.
16. A genetic sequencing device comprising a plurality of measurement units, each measurement unit comprising a nanopore test chamber and a microcurrent detection circuit according to any one of claims 1-15; the nanopore test cavity comprises a public electrode and a detection electrode.
17. The genetic sequencing apparatus of claim 16, further comprising a common signal line for receiving the voltage signal output by the microcurrent detection circuit and an analog-to-digital conversion circuit connected to the common signal line for converting the voltage signal to a digital signal.
18. The genetic sequencing apparatus of claim 17, further comprising a tail current source, a negative terminal of the tail current source being connected to the common signal line, a positive terminal of the tail current source being grounded.
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