CN114414635A - Nanopore DNA sequencing circuit based on nonlinear slope quantization - Google Patents

Nanopore DNA sequencing circuit based on nonlinear slope quantization Download PDF

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CN114414635A
CN114414635A CN202111546908.9A CN202111546908A CN114414635A CN 114414635 A CN114414635 A CN 114414635A CN 202111546908 A CN202111546908 A CN 202111546908A CN 114414635 A CN114414635 A CN 114414635A
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靳刚
严加智
汤华莲
包军林
刘伟峰
王一润
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Xidian University
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Abstract

The invention discloses a nanopore DNA sequencing circuit based on nonlinear slope quantization, which comprises: the detection array comprises a plurality of detection units which are arranged in an array; a plurality of nanopore sensing cells; each nanopore sensing unit comprises a common electrode, a unit electrode and a biological cavity which are oppositely arranged; the biological cavity comprises a biological membrane, the biological membrane comprises a nanopore, and the input ends of the plurality of detection units are respectively and correspondingly connected with the plurality of unit electrodes; the detection unit is used for converting current signals generated when different basic groups pass through the nanopore into voltage signals; the quantization module comprises a signal generation unit, a comparison unit and a conversion unit; because the voltage signal is converted into the pulse signal, namely the pulse signal is converted from the voltage domain to the time domain, the noise and the offset generated in the quantization stage can be reduced; meanwhile, the time domain signal processing also avoids the need of a capacitor array or an analog module with larger area when the voltage domain is processed, and reduces the power consumption and occupied layout area when in quantization.

Description

Nanopore DNA sequencing circuit based on nonlinear slope quantization
Technical Field
The invention belongs to the technical field of biological microelectronics, and particularly relates to a nanopore DNA sequencing circuit based on nonlinear slope quantization.
Background
With the rapid development of molecular biology and microelectronics, the nanopore-based molecular detection technology is also becoming a fourth generation sequencing technology which becomes a research hotspot in the field. Nanopores can be used to sequence DNA, and when single-stranded DNA passes through a nanopore, the four nitrogenous bases that make up the DNA molecule: adenine (a), cytosine (C), guanine (G) and thymine (T) influence the ionic current flowing through the nanopore, and the characteristic currents produced when different bases pass through are also different. Therefore, the DNA base sequence can be determined by detecting and reading the characteristic current signal by an integrated circuit and quantizing the signal into a number.
The core of nanopore-based DNA sequencing technology can be attributed to the sensing and quantification process of weak signals. At present, when a voltage domain quantization scheme mainly based on an ADC (analog to digital converter) is applied to DNA sequencing quantization based on a nanopore, a quantization mode data processing circuit has large power consumption, a sample-and-hold circuit is generally composed of a capacitor array, the area of a quantization module is multiplied when the sequencing array is expanded, and errors generated in a signal quantization process are increased due to the influence of capacitor mismatch in the process; in addition, the small-swing analog voltage signal output in the sequencing unit is susceptible to switch, and is susceptible to damage to sensitive signals by introducing noise and distortion in the module, for example, non-ideal effects are introduced in the sample-and-hold stage and the quantization comparison stage in the ADC.
Further, there is a cell structure for quantifying a sensing signal by using a Single-Slope ADC (Single-Slope ADC) quantification method, which can save a part of area, but still has a sampling comparison process, and the quantification time thereof varies with the amplitude of a sampling voltage, and nanopore DNA sequencing controls the speed of base puncture by a biochemical method, and the detection period and the quantification time are determined, so that the quantification method of the Single-Slope ADC is not suitable for nanopore DNA sequencing.
Disclosure of Invention
In order to solve the above problems in the prior art, the present invention provides a nanopore DNA sequencing circuit based on nonlinear ramp quantization. The technical problem to be solved by the invention is realized by the following technical scheme:
the invention provides a nanopore DNA sequencing circuit based on nonlinear slope quantization, which comprises:
the detection array comprises a plurality of detection units which are arranged in an array;
a plurality of nanopore sensing cells; each nanopore sensing unit comprises a common electrode and a unit electrode which are oppositely arranged, and a biological cavity positioned between the common electrode and the unit electrode; the biological cavity comprises a biological film, the biological film comprises a nanopore, and the input ends of the detection units are respectively and correspondingly connected with the unit electrodes; the detection unit is used for converting current signals generated when different basic groups pass through the nanopore into voltage signals;
a quantization module comprising: the device comprises a signal generating unit, a comparing unit and a converting unit; wherein the content of the first and second substances,
the signal generating unit is used for generating a ramp signal;
the comparison unit is used for generating a pulse signal according to the ramp signal and the voltage signal;
and the conversion unit is used for converting the time domain width of the pulse signal into a digital code to obtain base sequence information.
In one embodiment of the present invention, the detection unit includes an integrating amplifier, the comparison unit includes a first comparator, the signal generation unit includes a first ramp generator, and the conversion unit includes a first time-to-digital converter; wherein the content of the first and second substances,
for each detection unit, the input end of the integrating amplifier is connected with the corresponding unit electrode, the output end of the integrating amplifier is connected with the first input end of the first comparator, the second input end of the first comparator is connected with the first ramp generator, and the output end of the first comparator is connected with the input end of the first time-to-digital converter.
In one embodiment of the present invention, in the detection array, the detection unit includes an integrating amplifier, and the comparison units are arranged in an array in the same manner as the detection unit; wherein the content of the first and second substances,
the comparison unit comprises second comparators, the input end of each integration amplifier is connected with the corresponding unit electrode, the output end of each integration amplifier is connected with the first input end of the corresponding second comparator, and a plurality of first sub-modules arranged in an array are formed.
In one embodiment of the present invention, the signal generation unit includes a second ramp generator; wherein the content of the first and second substances,
and in the first sub-module in the same row, the second input end of each second comparator is connected to the same second ramp generator.
In one embodiment of the invention, the conversion unit comprises a second time-to-digital converter; wherein the content of the first and second substances,
and the output ends of the second comparators are connected to the corresponding row selection switches and are connected with the same second time-to-digital converter through the corresponding row selection switches.
In one embodiment of the invention, the plane of the biological membrane is parallel to both the common electrode and the unit electrode, and the biological membrane divides the biological cavity into a first cavity and a second cavity;
wherein the first cavity is located between the unit electrode and the biological membrane, and the second cavity is located between the biological membrane and the common electrode.
In one embodiment of the invention, the biological chamber comprises an ionic solution having electrical conductivity.
In one embodiment of the invention, the diameter of the nano-pores is 1-3 nm.
Compared with the prior art, the invention has the beneficial effects that:
the invention provides a nanopore DNA sequencing circuit based on nonlinear slope quantization, which comprises: the detection array comprises a plurality of detection units which are arranged in an array; the nanopore sensing device comprises a plurality of nanopore sensing units, wherein each nanopore sensing unit comprises a common electrode and a unit electrode which are oppositely arranged, and a biological cavity positioned between the common electrode and the unit electrode, the biological cavity comprises a biological membrane, the biological membrane comprises a nanopore, and the input ends of a plurality of detection units are respectively and correspondingly connected with the plurality of unit electrodes; the quantization module includes: the device comprises a signal generating unit, a comparing unit and a converting unit; the detection unit is used for converting current signals generated when different bases penetrate through the nanopore into voltage signals, the signal generation unit is used for generating ramp signals, the comparison unit is used for generating pulse signals according to the ramp signals and the voltage signals, and the conversion unit is used for measuring the time domain width of the pulse signals into digital codes to obtain base sequence information. Because the voltage signal is converted into the pulse signal, namely the pulse signal is converted from the voltage domain to the time domain, the time domain signal has the characteristic of a digital signal, and the time domain resolution of the edge transition of the digital signal is superior to the voltage domain resolution of an analog signal, so that the noise and the offset generated in the quantization stage can be reduced; meanwhile, the time domain signal processing also avoids the need of a capacitor array or an analog module with larger area when the voltage domain is processed, thereby further reducing the power consumption consumed during quantization and the occupied layout area.
The present invention will be described in further detail with reference to the accompanying drawings and examples.
Drawings
FIG. 1 is a schematic diagram of a nanopore DNA sequencing circuit based on nonlinear ramp quantization according to an embodiment of the present invention;
fig. 2 is a circuit diagram of a quantization module according to an embodiment of the present invention;
FIG. 3 is a timing diagram illustrating an embodiment of the present invention for non-linear ramp quantization based nanopore DNA sequencing;
FIG. 4a is a diagram illustrating a quantization process provided by an embodiment of the present invention;
FIG. 4b is another schematic diagram of a quantization process provided by an embodiment of the invention;
FIG. 4c is another schematic diagram of a quantization process provided by an embodiment of the invention;
FIG. 5 is a schematic structural diagram of a detection array and a quantization module according to an embodiment of the present invention;
FIG. 6 is another timing diagram illustrating the operation of a nanopore DNA sequencing circuit based on non-linear ramp quantization according to an embodiment of the present invention;
Detailed Description
The present invention will be described in further detail with reference to specific examples, but the embodiments of the present invention are not limited thereto.
At present, a nanopore-based molecular detection method is used for detecting a base sequence of DNA, and because a current signal required to be detected by a read circuit for sequencing the nanopore DNA is usually in the picoampere (pA) level, and is very weak and noisy, a voltage signal (mV level) read according to the current signal is easily interfered when being accessed to a post-stage quantization module, so that information loss is caused, and the quantization precision is influenced. In addition, because the layout area occupied by the existing quantization module is large, when a detection array for nanopore DNA sequencing is formed, the density of the detection array is difficult to increase.
In view of the above, the present invention provides a nanopore DNA sequencing circuit based on nonlinear ramp quantization.
FIG. 1 is a schematic diagram of a nanopore DNA sequencing circuit based on nonlinear ramp quantization according to an embodiment of the present invention. Referring to fig. 1, the present invention provides a nanopore DNA sequencing circuit 1 based on nonlinear ramp quantization, including:
the detection array 10, the detection array 10 includes a plurality of detection units arranged in an array;
a plurality of nanopore sensing cells 20; each nanopore sensing cell 20 comprises a common electrode 201 and a cell electrode 202 which are oppositely arranged, and a biological cavity 203 which is positioned between the common electrode 201 and the cell electrode 202; the biological cavity 203 comprises a biological membrane 204, the biological membrane 204 comprises a nanopore 205, and the input ends of the plurality of detection units are respectively connected with the plurality of unit electrodes 202; a detection unit for converting a current signal generated when different bases pass through the nanopore 205 into a voltage signal;
a quantization module 30 comprising: the device comprises a signal generating unit, a comparing unit and a converting unit; wherein the content of the first and second substances,
a signal generation unit for generating a ramp signal;
the comparison unit is used for generating a pulse signal according to the ramp signal and the voltage signal;
and the conversion unit is used for converting the time domain width of the pulse signal into a digital code to obtain the base sequence information.
In this embodiment, the nanopore DNA sequencing circuit based on nonlinear ramp quantization includes: a detection array 10, a plurality of nanopore sensing cells 20, and a quantification module 30. Specifically, the detection array 10 is composed of a plurality of detection units, the plurality of detection units are arranged in a matrix, and each nanopore sensing unit 20 includes: the electrode assembly comprises a common electrode 201, a unit electrode 202 and a biological cavity 203 positioned between the common electrode 201 and the unit electrode 202, wherein the common electrode 201 is arranged opposite to the unit electrode 202, a biological film 204 is arranged in the biological cavity 203, and the biological film 204 comprises a nanopore 205. When a potential difference Δ V exists between the common electrode 201 and the unit electrode 202, an ionic current flows through the nanopore 205, and the single-stranded DNA changes the amplitude of the ionic current through the nanopore 205 under the action of a pressure difference; when different bases pass through the nanopore 205, the current amplitude changes differently, and then a current signal is generated, and since the input ends of the plurality of detection units are connected with the unit electrodes 202 in the plurality of nanopore 205 sensing units 20 in a one-to-one correspondence manner, the detection units can convert the current signal into a voltage signal.
Alternatively, the perforation rate of the bases in this example is one base per period Ts, which is 100 μ s.
It will be appreciated that the voltage signal read by the detection unit during nanopore DNA sequencing is a periodic triangular wave with a period that is the same as the period of the reset signal to which the detection unit is connected, and an amplitude that is related to the base species passing through the nanopore 205. Further, the quantization module 30 includes: the device comprises a signal generating unit, a comparing unit and a converting unit; in the process of quantizing the voltage signal into the digital code, the comparing unit compares the voltage signal with the ramp signal generated by the signal generating unit to generate a pulse signal, and then converts the time domain width of the pulse signal into the digital code, wherein different digital codes output by the converting unit represent that different bases are detected to pass through the nanopore 205. Because the voltage signal is converted into the pulse signal, namely the pulse signal is converted from the voltage domain to the time domain, the time domain signal has the characteristic of a digital signal, and the time domain resolution of the edge transition of the digital signal is superior to the voltage domain resolution of an analog signal, so that the noise and the offset generated in the quantization stage can be reduced. In addition, the time domain signal processing also avoids the need of a capacitor array or an analog module with larger area when the voltage domain is processed, thereby further reducing the power consumption consumed during quantization and the occupied layout area.
It should be noted that, in order to implement DNA sequencing, the nanopore DNA sequencing circuit 1 further includes peripheral circuits, such as: the digital-to-analog converter generates an electrode driving signal, and includes a band gap reference circuit, a bias circuit, a power management circuit, a phase-locked loop, and the like.
Fig. 2 is a circuit diagram of a quantization module according to an embodiment of the present invention. As shown in fig. 2, the detection unit includes an integrating amplifier 301, the comparison unit includes a first comparator CMP1, the signal generation unit includes a first ramp generator 302, and the conversion unit includes a first time-to-digital converter TDC 1; wherein the content of the first and second substances,
for each detection cell, the input terminal of the integrating amplifier 301 is connected to the corresponding cell electrode 202, the output terminal is connected to the first input terminal of the first comparator CMP1, the second input terminal of the first comparator CMP1 is connected to the first ramp generator 302, and the output terminal is connected to the input terminal of the first time-to-digital converter TDC 1.
In the present embodiment, each detection cell in the detection array 10 is correspondingly connected to one quantization module 30, and for each detection cell, for example, the input terminal of the integrating amplifier 301 is connected to the corresponding cell electrode 202, the output terminal is connected to the first input terminal of the first comparator CMP1, the second input terminal of the first comparator CMP1 is connected to the first ramp generator 302, and the output terminal is connected to the input terminal of the first time-to-digital converter TDC 1.
FIG. 3 is a timing diagram illustrating the operation of a nanopore DNA sequencing circuit based on non-linear ramp quantization according to an embodiment of the present invention. Specifically, please refer to FIGS. 2-3, TquantizationAs a voltage signal VcQuantization time of (T)sFor integration period, IsignalRepresenting the current signals generated when different bases pass through the nanopore 205, and after being sensed and detected by the detection unit, the detection unit reads the current signals into voltage signals VcAnd is fed to a first input of a first comparator CMP1, a second input of the first comparator CMP1 being a ramp signal VRAMP generated by a ramp generator. The first comparator CMP1 converts the voltage signal VcIs compared with the voltage amplitude of the ramp signal VRAMP to output a pulse signal V with different time domain widthso. Further, the first time-to-digital converter TDC1 converts the different pulse signals VoThe different pulse widths of (a) are measured as different digital codes, DOUT representing the different digital codes output by the first time-to-digital converter TDC1, representing the detection of different bases through the nanopore 205, in order to distinguish the type of base passing through the nanopore 205, i.e. adenine (a), cytosine (C), guanine (G) or thymine (T).
In this embodiment, the voltage signal read by the detection unit is a periodic triangular wave, the period of the periodic triangular wave is the same as the period of the reset signal RST, the amplitude of the periodic triangular wave is related to the base type passing through the nanopore, and the triangular waves with different voltage domain amplitudes can be converted into pulse square waves with different time domain widths by the first comparator CMP1, so that the conversion of the voltage signal to the time signal is realized.
In addition, after the first comparator CMP1 converts the analog signal into the pulse signal, the delay, phase or frequency of the pulse signal is used as the information carrier, and then the pulse signal is sent to the conversion unit, because the conversion unit adopts the first time-to-digital converter TDC1, the signal can be processed into the digital signal by using the switching characteristic of the digital circuit transistor, and the digital process does not need a large-area capacitor array, so that the consumed power consumption is greatly reduced compared with the analog circuit. Furthermore, the time domain resolution of the edge transition of the digital signal is better than the voltage resolution of the analog signal, and the noise resistance of the digital signal is stronger than that of an analog circuit and the noise performance is better, so that the accuracy and the anti-interference capability of a quantization result can be obviously improved by adopting the quantization method of the time domain ADC during quantization.
Fig. 4a, 4b and 4c are schematic diagrams of a quantization process provided by an embodiment of the present invention. Referring to fig. 4a, 4b and 4c, when the constant voltage is used as the ramp signal, the accuracy and performance of the quantization module 30 are affected if the constant voltage is not properly selected. Specifically, if the constant voltage value amplitude is high, then at the integration voltage VcAt very low amplitudes, the first comparator CMP1 cannot produce a valid comparison, i.e., part of the information may be missed in the process of converting the voltage signal into a pulse signal, which is a fatal defect for sequencing, as shown by VREF2 in fig. 4 (a); on the contrary, if the constant voltage value is low in amplitude, the pulse signal V isoThe large pulse width of (a) increases the bit requirement for the first time to digital converter TDC1, thereby increasing area and power consumption, as shown by VREF1 in fig. 4 (a).
In addition, T in the ramp signalquantizationThe difference also affects the number of bits and the accuracy of the first time to digital converter TDC 1. When T is reached as shown in FIG. 4(b)quantizationClose to an integration period, and facing two limit conditions of low integration amplitude and high integration amplitude, the obtained pulse signal VoThe pulse width difference of (a) is large, that is, the number of bits required for the first time-to-digital converter TDC1 is relatively large. When T is reached as shown in FIG. 4(c)quantizationVery small, the pulse signal V obtained by conversionoThe pulse width difference of (a) is small, thus requiring a high accuracy of the first time to digital converter TDC1, increasing the requirement for clock frequency. Thus selecting a suitable TquantizationIs crucial to the quantization process.
In the nanopore DNA sequencing circuit based on nonlinear slope quantization provided by the invention, when the voltage signal read out by the detection unit is quantized, only four bases constituting the DNA need to be distinguished: adenine (A), cytosine (C), guanine (G) and thymine (T), so that a nonlinear slope quantization method can be used, the anti-interference capability of a read signal during quantization is improved, and simultaneously the layout area occupied by a quantization circuit and the consumed power consumption during array formation are reduced.
Fig. 5 is a schematic structural diagram of a detection array and a quantization module according to an embodiment of the present invention. As shown in fig. 5, in the detection array 10, the detection unit includes an integrating amplifier 301, and the comparison units are arrayed in the same manner as the detection unit; wherein the content of the first and second substances,
the comparing unit comprises second comparators CMP2, each integrating amplifier 301 having an input connected to a corresponding CELL electrode 202 and an output connected to a first input of a corresponding second comparator CMP2, forming a plurality of first sub-modules CELL _ s arranged in an array.
Optionally, the signal generation unit comprises a second ramp generator 303; wherein the content of the first and second substances,
in the first sub-module CELL _ s located in the same row, the second input terminal of each second comparator CMP2 is connected to the same second ramp generator 303;
optionally, the conversion unit comprises a second time-to-digital converter TDC 2; wherein the content of the first and second substances,
in the first sub-module CELL _ s in the same column, the output terminal of each second comparator CMP2 is connected to a corresponding row selection switch, and is connected to the same second time-to-digital converter TDC2 through the corresponding row selection switch.
In particular, the non-linear ramp quantization method is applied to nanopore DNA sequencing arrays due to the quantization time TquantizationWith the adjustability, each column of detecting units in the detecting array 10 can share one second time-to-digital converter TDC 2. Optionally, each integrating amplifier 301 has an input connected to the corresponding cell electrode 202 and an output connected to a first input of a corresponding second comparator CMP2, the second comparator being connected to the first input of the second comparator CMP2The CMP2 and the detection unit are correspondingly integrated together to form a plurality of first sub-modules CELL _ s arranged in an array, and the second comparator CMP2 can be arranged outside the detection array 10 to further save power consumption and layout area. Further, with continued reference to fig. 6, the first sub-modules CELL _ s are arranged as an M × N array, each row of the first sub-modules CELL _ s shares a second ramp generator 303, and the quantization result in each row of the first sub-modules CELL _ s is within an integration period TsThe internal serial outputs are stored in corresponding storage units, and at the same time, the N second time-to-digital converters TDC2 output data in parallel at the same time.
The quantization time T of the second comparator CMP2 when the ramp signal is used as the quantization reference signalquantizationOccupying only the integration period TsSo that at a TsThe remaining time in the clock signal, the second comparator CMP2 and the second time-to-digital converter TDC2 are both inactive, so the column-shared second time-to-digital converter TDC2 does not need to output M quantization results at the same time. Illustratively, TquantizationAnd TsCan be adjusted according to the number of rows in the array formed by the first submodule CELL _ s, so that the two satisfy Ts＝M*TquantizationWherein M denotes the number of rows of the array formed by the first sub-modules CELL _ s, i.e. the number of the first sub-modules CELL _ s in each column, and the M first sub-modules CELL _ s in each column may multiplex the same quantization channel in a time-sharing manner. It will be appreciated that the column-shared second time-to-digital converter TDC2 quantisation channel is every other TquantizationA group of data is output, and the effect of time-sharing multiplexing is achieved.
FIG. 6 is another timing diagram of the operation of a nanopore DNA sequencing circuit based on non-linear ramp quantization provided by an embodiment of the invention. Since the reset signal is shared with the row of the ramp signal, the reset signal RST in the m +1 th row is exemplified by the m +1 th row in the n-th column and the m +1 th row<m+1>And an integration signal Vc m +1, n]Reset signal RST of row m<m>And an integration signal Vc m, n]Delayed by one Tquantization. With RST<m>Reset time point t0At time, the cells of the m-th row are at t0+Ts-TquantizationOccupying a quantization channel, and quantizing and comparing the pulse width output by the TDC 2; the cells in row m +1 are at t0+TsOccupying the quantization channel. The time that two adjacent rows of cells occupy the common TDC2 differs by exactly one Tquantization. Then at a TsDuring the period, the cells in the nth row are serially quantized by the TDC2 from the 1 st row to the Mth row according to row selection switching, the TDC2 is provided every TquantizationThe detection information of one unit is output in series, so that the TDC2 is always in a working state, and the effect of time division multiplexing is achieved.
It can be seen that the present invention takes into account the quantization time TquantizationThe second time-to-digital converter TDC2 is shared in a time-division multiplexing mode when the nanopore DNA sequencing array is quantized, so that the throughput capacity of quantized data is improved, and the layout area and the power consumption occupied by a quantization circuit are reduced.
With continued reference to fig. 1, the plane of the biological membrane 204 is parallel to both the common electrode 201 and the unit electrode 202, and the biological membrane 204 divides the biological cavity 203 into a first cavity 203a and a second cavity 203 b; wherein the first cavity 203a is located between the unit electrode 202 and the biological film 204, and the second cavity 203b is located between the biological film 204 and the common electrode 201.
Optionally, the biological chamber 203 comprises an ionic solution having electrical conductivity.
Optionally, the diameter of the nanopore 205 is 1-3 nm.
The beneficial effects of the invention are that:
the invention provides a nanopore DNA sequencing circuit based on nonlinear slope quantization, which comprises: the detection array comprises a plurality of detection units which are arranged in an array; the nanopore sensing device comprises a plurality of nanopore sensing units, wherein each nanopore sensing unit comprises a common electrode and a unit electrode which are oppositely arranged, and a biological cavity positioned between the common electrode and the unit electrode, the biological cavity comprises a biological membrane, the biological membrane comprises a nanopore, and the input ends of a plurality of detection units are respectively and correspondingly connected with the plurality of unit electrodes; the quantization module includes: the device comprises a signal generating unit, a comparing unit and a converting unit; the detection unit is used for converting current signals generated when different bases penetrate through the nanopore into voltage signals, the signal generation unit is used for generating ramp signals, the comparison unit is used for generating pulse signals according to the ramp signals and the voltage signals, and the conversion unit is used for measuring the time domain width of the pulse signals into digital codes to obtain base sequence information. Because the voltage signal is converted into the pulse signal, namely the pulse signal is converted from the voltage domain to the time domain, the time domain signal has the characteristic of a digital signal, and the time domain resolution of the edge transition of the digital signal is superior to the voltage domain resolution of an analog signal, so that the noise and the offset generated in the quantization stage can be reduced; meanwhile, the time domain signal processing also avoids the need of a capacitor array or an analog module with larger area when the voltage domain is processed, thereby further reducing the power consumption consumed during quantization and the occupied layout area.
In the description of the present invention, the terms "first" and "second" are used for descriptive purposes only and are not to be construed as indicating or implying relative importance or implying any number of technical features indicated. Thus, a feature defined as "first" or "second" may explicitly or implicitly include one or more of that feature. In the description of the present invention, "a plurality" means two or more unless specifically defined otherwise.
In the description herein, references to the description of the term "one embodiment," "some embodiments," "an example," "a specific example," or "some examples," etc., mean that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the invention. In this specification, the schematic representations of the terms used above are not necessarily intended to refer to the same embodiment or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples. Furthermore, various embodiments or examples described in this specification can be combined and combined by those skilled in the art.
While the present application has been described in connection with various embodiments, other variations to the disclosed embodiments can be understood and effected by those skilled in the art in practicing the claimed application, from a review of the drawings, the disclosure, and the appended claims. In the claims, the word "comprising" does not exclude other elements or steps, and the word "a" or "an" does not exclude a plurality. A single processor or other unit may fulfill the functions of several items recited in the claims. The mere fact that certain measures are recited in mutually different dependent claims does not indicate that a combination of these measures cannot be used to advantage.
The foregoing is a more detailed description of the invention in connection with specific preferred embodiments and it is not intended that the invention be limited to these specific details. For those skilled in the art to which the invention pertains, several simple deductions or substitutions can be made without departing from the spirit of the invention, and all shall be considered as belonging to the protection scope of the invention.

Claims (8)

1. A nanopore DNA sequencing circuit based on non-linear ramp quantization, comprising:
the detection array comprises a plurality of detection units which are arranged in an array;
a plurality of nanopore sensing cells; each nanopore sensing unit comprises a common electrode and a unit electrode which are oppositely arranged, and a biological cavity positioned between the common electrode and the unit electrode; the biological cavity comprises a biological film, the biological film comprises a nanopore, and the input ends of the detection units are respectively and correspondingly connected with the unit electrodes; the detection unit is used for converting current signals generated when different basic groups pass through the nanopore into voltage signals;
a quantization module comprising: the device comprises a signal generating unit, a comparing unit and a converting unit; wherein the content of the first and second substances,
the signal generating unit is used for generating a ramp signal;
the comparison unit is used for generating a pulse signal according to the ramp signal and the voltage signal;
and the conversion unit is used for converting the time domain width of the pulse signal into a digital code to obtain base sequence information.
2. The non-linear ramp quantization based nanopore DNA sequencing circuit of claim 1, wherein the detection unit comprises an integrating amplifier, the comparison unit comprises a first comparator, the signal generation unit comprises a first ramp generator, and the conversion unit comprises a first time-to-digital converter; wherein the content of the first and second substances,
for each detection unit, the input end of the integrating amplifier is connected with the corresponding unit electrode, the output end of the integrating amplifier is connected with the first input end of the first comparator, the second input end of the first comparator is connected with the first ramp generator, and the output end of the first comparator is connected with the input end of the first time-to-digital converter.
3. The non-linear ramp quantization based nanopore DNA sequencing circuit of claim 1, wherein in the detection array, the detection unit comprises an integrating amplifier, and the comparison units are arrayed in the same manner as the detection unit; wherein the content of the first and second substances,
the comparison unit comprises second comparators, the input end of each integration amplifier is connected with the corresponding unit electrode, the output end of each integration amplifier is connected with the first input end of the corresponding second comparator, and a plurality of first sub-modules arranged in an array are formed.
4. The non-linear ramp quantization based nanopore DNA sequencing circuit of claim 3, wherein the signal generation unit comprises a second ramp generator; wherein the content of the first and second substances,
and in the first sub-module in the same row, the second input end of each second comparator is connected to the same second ramp generator.
5. The non-linear ramp quantization based nanopore DNA sequencing circuit of claim 4, wherein the conversion unit comprises a second time-to-digital converter; wherein the content of the first and second substances,
and the output ends of the second comparators are connected to the corresponding row selection switches and are connected with the same second time-to-digital converter through the corresponding row selection switches.
6. The nanopore DNA sequencing circuit based on nonlinear ramp quantization of claim 1, wherein the plane of the biological membrane is parallel to both the common electrode and the cell electrode, and the biological membrane divides the biological cavity into a first cavity and a second cavity;
wherein the first cavity is located between the unit electrode and the biological membrane, and the second cavity is located between the biological membrane and the common electrode.
7. The non-linear ramp quantization based nanopore DNA sequencing circuit of claim 6, wherein the biological chamber comprises an ionic solution having electrical conductivity.
8. The non-linear ramp quantization based nanopore DNA sequencing circuit of claim 1, wherein the nanopore has a diameter of 1-3 nm.
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