CN111662971A - Correction method and device of gene sequencing chip - Google Patents

Correction method and device of gene sequencing chip Download PDF

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Publication number
CN111662971A
CN111662971A CN202010501336.1A CN202010501336A CN111662971A CN 111662971 A CN111662971 A CN 111662971A CN 202010501336 A CN202010501336 A CN 202010501336A CN 111662971 A CN111662971 A CN 111662971A
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output voltage
input
voltage
input voltage
hole
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张志峰
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Chengdu Wanzhong One Core Biotechnology Co ltd
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Chengdu Wanzhong One Core Biotechnology Co ltd
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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6869—Methods for sequencing
    • C12Q1/6874—Methods for sequencing involving nucleic acid arrays, e.g. sequencing by hybridisation

Abstract

The invention discloses a correction method and a correction device of a gene sequencing chip, wherein the correction method comprises the steps of determining a reference curve, correcting input voltage and standard holes according to the position distribution of the maximum slope point of an input-output characteristic curve of each detection hole; calculating a first slope of the reference curve at the corrected input voltage; calculating a second slope of the input-output characteristic curve corresponding to the effective hole at the corrected input voltage; normalizing the input voltage variation caused by the hydrogen ion concentration index change according to the output voltage variation before and after the hydrogen ion concentration index change in the effective hole and the second slope; the output voltage corresponding to the standard aperture at the corrected input voltage and the first output voltage variation are determined as the corrected output voltage corresponding to the effective aperture after the hydrogen ion concentration index in the effective aperture is changed. According to the technical scheme, the output deviation caused by the deviation in the gene sequencing chip manufacturing process can be corrected, and the accuracy of the gene sequencing result is further ensured.

Description

Correction method and device of gene sequencing chip
Technical Field
The embodiment of the invention relates to the technical field of chip correction, in particular to a method and a device for correcting a gene sequencing chip.
Background
With the development of gene detection technology, the detection precision requirement of gene sequencing chips is higher and higher.
In the chip manufacturing process, process deviation inevitably occurs, so that the detection precision of the gene sequencing chip is influenced, and the sequencing result has deviation.
Disclosure of Invention
The invention provides a method and a device for correcting a gene sequencing chip, which are used for correcting a sequencing output result of the gene sequencing chip caused by process deviation, so that the detection precision of the gene sequencing chip is improved, and the accuracy of the sequencing result is ensured.
In a first aspect, the embodiments of the present invention provide a method for calibrating a gene sequencing chip, where a side surface of the gene sequencing chip includes a plurality of detection holes; the correction method comprises the following steps:
determining a reference curve, correcting input voltage, a standard hole and a non-standard hole according to the position distribution of the maximum slope point of the input-output characteristic curve of each detection hole, wherein the reference curve is the input-output characteristic curve corresponding to the standard hole;
calculating a first slope of the reference curve at the correction input voltage;
calculating a second slope of an input-output characteristic curve corresponding to an effective hole in the non-standard holes at the corrected input voltage;
when the voltage provided by the excitation source is the correction input voltage, normalizing the input voltage variation caused by the hydrogen ion concentration index variation according to the output voltage variation before and after the hydrogen ion concentration index variation in the effective hole and the second slope;
when the voltage that the excitation source provided is the correction input voltage, will the standard hole is in the output voltage that corresponds under the correction input voltage and first output voltage variation are determined to be in after the hydrogen ion concentration index changes in the effective pore the correction output voltage that the effective pore corresponds, wherein first output voltage variation is positive correlation with second output voltage variation, second output voltage variation is the output voltage variation before and after the hydrogen ion concentration index changes in the effective pore, first output voltage variation with first slope positive correlation, first output voltage variation with second slope negative correlation.
In a second aspect, the embodiments of the present invention further provide a calibration apparatus for a gene sequencing chip, configured to perform the calibration method for a gene sequencing chip provided in the first aspect, where a side surface of the gene sequencing chip includes a plurality of detection holes; the correction device includes:
the determining module is used for determining a reference curve, a correction input voltage, a standard hole and a non-standard hole according to the position distribution of the maximum slope point of the input-output characteristic curve of each detection hole, wherein the reference curve is the input-output characteristic curve corresponding to the standard hole;
a first slope calculation module for calculating a first slope of the reference curve at the correction input voltage;
the second slope calculation module is used for calculating a second slope of an input-output characteristic curve corresponding to an effective hole in the non-standard holes at the corrected input voltage;
the normalization processing module is used for performing normalization processing on input voltage variation caused by hydrogen ion concentration index variation according to output voltage variation before and after the hydrogen ion concentration index variation in the effective hole and a second slope when the voltage provided by the excitation source is the correction input voltage;
an output voltage correction module, configured to determine, when the voltage provided by the excitation source is the correction input voltage, the output voltage corresponding to the standard aperture under the correction input voltage and a first output voltage variation as being in after the hydrogen ion concentration index changes in the effective aperture the correction output voltage corresponding to the effective aperture, wherein the first output voltage variation is positively correlated with the second output voltage variation, the second output voltage variation is the output voltage variation before and after the hydrogen ion concentration index changes in the effective aperture, the first output voltage variation is positively correlated with the first slope, and the first output voltage variation is negatively correlated with the second slope.
According to the correction method and device for the gene sequencing chip, when the voltage provided by the excitation source is the correction input voltage, the input voltage variation caused by the change of the hydrogen ion concentration index is normalized according to the output voltage variation before and after the change of the hydrogen ion concentration index in the effective hole and the second slope, so that the input voltage variation caused by the pH change corresponding to the effective holes with different input and output characteristic curves is unified to the same standard, and the accuracy of judging the gene sequencing result according to the input voltage variation of each effective hole before and after the pH change can be further ensured. And the actual output voltage variation (second output voltage variation) corresponding to the effective pore before and after the pH of the solution changes is calculated to correspond to the output voltage variation (namely, the first output voltage variation) on the reference curve, then the reference output voltage (namely, the output voltage corresponding to the reference point) and the first output voltage variation of the reference curve under the corrected input voltage are determined as the corrected output voltage corresponding to the effective pore, namely, the point on the input/output characteristic curve corresponding to the effective pore is corrected to the reference curve, so that the corrected output voltage corresponding to the effective pore and the output voltage corresponding to the standard pore are unified to the same standard (both on the reference curve), further, when the pH of the solution in the effective pore and the solution in the standard pore changes to be the same, the corrected output voltage corresponding to the effective pore is the same as the output voltage corresponding to the standard pore, the output voltage corresponding to the effective hole is corrected, so that the detection result of the effective hole and the standard hole for gene sequencing is consistent when the gene sequencing is carried out, and the accuracy of the gene sequencing result is ensured.
Drawings
FIG. 1 is a flow chart of a method for calibrating a gene sequencing chip according to an embodiment of the present invention;
FIG. 2 is a schematic diagram of an input-output characteristic curve of a detection hole according to an embodiment of the present invention;
FIG. 3 is a statistical histogram of the number of input/output characteristic curves with maximum slope points at various input voltages according to an embodiment of the present invention;
FIG. 4 is a schematic diagram of two input-output characteristic curves provided by an embodiment of the present invention;
FIG. 5 is a flow chart of another method for calibrating a gene sequencing chip according to an embodiment of the present invention;
FIG. 6 is a flowchart of another method for calibrating a gene sequencing chip according to an embodiment of the present invention;
FIG. 7 is a top view of a gene sequencing chip according to an embodiment of the present invention;
FIG. 8 is a cross-sectional view of FIG. 7 taken along line M-M';
FIG. 9 is a schematic structural diagram of a calibration apparatus for a gene sequencing chip according to an embodiment of the present invention.
Detailed Description
The present invention will be described in further detail with reference to the accompanying drawings and examples. It is to be understood that the specific embodiments described herein are merely illustrative of the invention and are not limiting of the invention. It should be further noted that, for the convenience of description, only some of the structures related to the present invention are shown in the drawings, not all of the structures.
As described in the background art, process deviation inevitably occurs in the chip manufacturing process, so that the detection precision of the gene sequencing chip is affected, and the sequencing result has deviation. The inventor finds that the above problems occur because the surface of one side of the existing gene sequencing chip usually includes a plurality of detection holes, sensing electrodes are exposed in the detection holes, and when gene sequencing is performed, a solution to be detected is injected into each detection hole, an external excitation source supplies excitation voltage to the solution to be detected, and the determination of a gene sequencing result is performed according to the measurement of the output voltage of the sensing electrodes. Each detection hole of the gene sequencing chip corresponds to an input-output characteristic curve, and ideally, the input-output characteristic curves corresponding to all the detection holes are consistent, however, the size, shape, sensing electrodes and the like of different detection holes may have slight differences due to process deviation in the chip manufacturing process, so that the input-output characteristic curves corresponding to different detection holes may be different. Because the input/output characteristic curve generally corresponds to a certain fixed hydrogen ion concentration index (pH) solution, and the input/output characteristic curve is nonlinear, the change of the pH of the solution is equivalent to adding an input voltage variation on the basis of an excitation voltage provided by an external excitation source, and the amplification factors of detection holes corresponding to different input/output characteristic curves for the voltage variation are different, so that the output voltage variations of different detection holes are different for the same input voltage variation, and finally, the gene sequencing result is deviated when the gene result is determined according to the output voltage.
In view of the above problems, an embodiment of the present invention provides a method for calibrating a gene sequencing chip, wherein a side surface of the gene sequencing chip includes a plurality of detection holes, fig. 1 is a flowchart of a method for calibrating a gene sequencing chip provided in an embodiment of the present invention, and with reference to fig. 1, the method for calibrating a gene sequencing chip includes:
step 110, determining a reference curve, correcting input voltage, a standard hole and a non-standard hole according to the position distribution of the maximum slope point of the input-output characteristic curve of each detection hole, wherein the reference curve is the input-output characteristic curve corresponding to the standard hole;
specifically, the input/output characteristic curve may represent a relationship between an excitation voltage applied to the solution in the detection hole by the external excitation source at a fixed PH and an output voltage corresponding to the sensing electrode exposed in the detection hole. Fig. 2 is a schematic diagram of input-output characteristic curves of a detection hole provided by an embodiment of the present invention, where fig. 2 schematically shows 6 input-output characteristic curves, namely, a curve 11, a curve 12, a curve 13, a curve 14, a curve 15, and a curve 16, where each input-output characteristic curve may correspond to at least one detection hole. As can be seen from fig. 2, the input/output characteristic curves corresponding to different detection holes may be different, and taking the 6 input/output characteristic curves shown in fig. 5 as an example, the input voltages corresponding to the maximum slope points on the different input/output characteristic curves may be different, for example, the maximum slope point on the curve 11 is a point, and the corresponding input voltage is VtThe point of maximum slope on the curve 14 is point B, and the corresponding input voltage is Vt-ΔVaThe point of maximum slope on the curve 13 is the point C, and the corresponding input voltage is Vt+ΔVb。
Optionally, the step 110 may include:
and step 111, counting the number of input and output characteristic curves of which the maximum slope points appear under each input voltage.
Specifically, a side surface of the gene sequencing chip includes a large number of detection holes, for example, for some gene sequencing chips, including 26 thousands of detection holes, a plurality of detection holes may correspond to the same input/output characteristic curve, in this step, the number of input/output characteristic curves in which the maximum slope point occurs at each input voltage may be counted to obtain a histogram shown in fig. 3, and fig. 3 is a statistical histogram of the number of input/output characteristic curves in which the maximum slope point occurs at each input voltage according to an embodiment of the present invention, where an abscissa in fig. 3 represents the input voltage of the excitation source, and an ordinate represents the number of curves in which the maximum slope point occurs at the corresponding input voltage.
Step 112, determining an input/output characteristic curve of the maximum slope point under the first input voltage as a reference curve; the number of input/output characteristic curves with the maximum slope points appearing at the first input voltage is larger than that with the maximum slope points appearing at any other input voltage.
Specifically, although there is a deviation in the size, shape, and the like of some detection holes due to process variations and the like in the manufacturing process of the gene sequencing chip, parameters such as the size, shape, and the like of most detection holes on the gene sequencing chip are still standard (that is, parameters such as the size, shape, and the like of most detection holes on the gene sequencing chip are still the same), and correspondingly, input and output characteristic curves corresponding to most detection holes are the same (should be overlapped in the schematic diagram shown in fig. 2, the maximum slope points of the input and output characteristic curves corresponding to most detection holes appear at the same positions of the input and output characteristic curves, that is, the input voltages corresponding to the maximum slope points on the input and output characteristic curves corresponding to most detection holes are the same, so that in this step, the number of input and output characteristic curves appearing at different input voltages by comparing the maximum slope points is compared, the number of input and output characteristic curves with the maximum slope points under the first input voltage is more than that with the maximum slope points under any other input voltage, and the input and output characteristic curves with the maximum slope points under the first input voltage are determined as reference curves, so that the reference curves correspond to most of detection holes in the gene sequencing chip, and the most of detection holes are standard holes.
That is, since the maximum slope points are the largest in the number of input/output characteristic curves at the first input voltage, it can be said that the hole corresponding to the input/output characteristic curve at the maximum slope point at the first input voltage is the standard hole, and the input/output characteristic curve at the maximum slope point at the first input voltage is determined as the reference curve, that is, the input/output characteristic curve corresponding to the standard hole is the reference curve. As can be seen from fig. 3, the number of input/output characteristic curves occurring at the maximum slope point at the input voltage Vt is the largest, and thus the first input voltage is Vt.
Step 113, determining the first input voltage as a correction input voltage;
specifically, most of the input and output characteristic curves have the maximum slope point under the first input voltage, that is, the input and output characteristic curves corresponding to most of the detection holes are most sensitive to the input voltage change near the first input voltage, that is, the amplification factor of most of the detection holes to the input voltage near the first input voltage is the maximum, so that in subsequent gene sequencing, detection is usually performed when the voltage provided by the excitation source is the first input voltage, and the detection sensitivity in gene sequencing is further ensured. Therefore, the first input voltage is used as a correction input voltage, and the nonstandard detection holes are corrected under the correction working voltage, so that the output result of the nonstandard detection holes can be corrected during gene sequencing, and the accuracy of the sequencing structure of the gene sequencing chip is ensured.
And step 114, determining the detection hole corresponding to the input-output characteristic curve with the maximum slope point under the first input voltage as a standard hole, and determining other detection holes as non-standard holes.
As explained in step 112, since most of the gene sequencing chips are standard wells and the number of the input/output characteristic curves having the maximum slope point at the first input voltage is the largest, it can be said that the parameters of the wells corresponding to the input/output characteristic curves having the maximum slope point at the first input voltage are consistent, the detection wells corresponding to the input/output characteristic curves having the maximum slope point at the first input voltage are determined as standard wells, and the other detection wells are determined as non-standard wells.
Step 120, calculating a first slope of the reference curve at the corrected input voltage;
in this embodiment and the following embodiments, the point of maximum slope on the reference curve is taken as the reference point, the coordinates corresponding to the reference point are the correction input voltage (on the horizontal axis in fig. 2) and the reference output voltage (on the vertical axis in fig. 2), and the first slope at the reference point, that is, the first slope of the reference curve at the correction voltage can be calculated by calculating the adjacent points of the reference point and the reference point on the reference curve. The adjacent point of the reference point can be obtained by scanning the standard hole filled with the solution through a sawtooth wave, and the adjacent point can correspond to the data (including the input voltage provided by the excitation source and the output voltage of the standard hole) of the previous frame or the next frame of the corrected input voltage.
Step 130, calculating a second slope of the input/output characteristic curve corresponding to the effective hole in the non-standard hole at the position of the corrected input voltage;
in this embodiment and the following embodiments, a point of the input/output characteristic curve corresponding to the effective hole in the non-standard hole at the corrected input voltage is referred to as a point to be corrected, and a second slope at the reference point, that is, a second slope of the input/output characteristic curve corresponding to the effective hole at the corrected input voltage can be calculated by calculating a point to be corrected on the input/output characteristic curve corresponding to the effective hole and a neighboring point of the point to be corrected. The adjacent point of the point to be corrected can be obtained by scanning the effective hole injected with the solution through the sawtooth wave, and the adjacent point can correspond to the data (including the input voltage provided by the excitation source and the output voltage of the effective hole) of the frame before or after the correction input voltage.
Step 140, when the voltage provided by the excitation source is the correction input voltage, normalizing the input voltage variation caused by the hydrogen ion concentration index variation according to the output voltage variation before and after the hydrogen ion concentration index variation in the effective hole and the second slope;
specifically, when the input voltage changes, the output voltage of the sensing electrode corresponding to the detection hole into which the solution is injected changes along the input/output characteristic curve corresponding to the detection hole. As is known in the art, a pH change causes a change in the input voltage to the sensor electrode, and for example, when the voltage supplied from the excitation source is the correction input voltage Vt, if the pH of the solution in the detection hole is the same as the pH of the solution at the time of obtaining the input/output characteristic curve of the detection hole, the input voltage to the sensor electrode is Vt. However, when the pH of the solution in the sensing well changes, the input voltage to the sensing electrode is actually based on the corrected input voltage Vt provided by the excitation source, plus the amount of change in the input voltage caused by the pH change, which is denoted as Δ VpH.
Fig. 4 is a schematic diagram of two input/output characteristic curves provided by an embodiment of the present invention, referring to fig. 4, where a curve 11 may represent a reference curve, and a curve 12 may represent an input/output characteristic curve corresponding to a certain effective aperture, and according to fig. 4, when an excitation voltage provided by an excitation source is a corrected input voltage Vt, output voltage variations on the curves 11 and 12 are different for the same Δ VpH, for example, before a pH change, an output voltage corresponding to the curve 11 is 400mV, and an output voltage corresponding to the curve 11 is 320mV, and then an output voltage variation is-80 mV; the corresponding output voltage on curve 12 is 600mV before the pH change and 550mV after the pH change, the change in the output voltage is-50 mV.
Since the input voltage variation caused by the pH change cannot be directly measured, the input voltage variation caused by the pH change is calculated and normalized by the output voltage of the sensing electrode which can be directly measured in this step. That is, when the voltage provided by the excitation source is the correction input voltage, the variation of the input voltage caused by the variation of the hydrogen ion concentration index is normalized according to the variation of the output voltage before and after the variation of the hydrogen ion concentration index in the effective hole and the second slope, specifically, when the normalization is performed, the input voltage variation caused by the hydrogen ion concentration index change can be obtained by the ratio of the output voltage variation before and after the hydrogen ion concentration index change in the effective hole to the second slope of the input-output characteristic curve corresponding to the effective hole at the corrected input voltage Vt, thereby obtaining the real input voltage variation caused by the pH variation of the solution in any effective hole, so that the input voltage variation caused by the pH variation corresponding to the effective holes corresponding to different input/output characteristic curves is unified to the same standard, and then the accuracy of judging the gene sequencing result according to the input voltage variation of each effective hole before and after the pH is changed can be ensured.
Specifically, the step 140 may include:
step 141, normalization processing is performed by using the following formula:
ΔVin＝ΔVout/k2，
ΔVout＝V1-V2；
ΔVindenotes the input voltage variation, Δ V, obtained after normalizationoutRepresenting the amount of change, k, in output voltage before and after the change of the hydrogen ion concentration index in the effective hole2Represents a second slope, V1Represents the output voltage, V, corresponding to the effective hole after the hydrogen ion concentration index in the effective hole changes2And the output voltage corresponding to the effective hole before the hydrogen ion concentration index in the effective hole changes is shown.
Step 150, when the voltage provided by the excitation source is the corrected input voltage, determining the output voltage corresponding to the standard aperture under the corrected input voltage and the first output voltage variation as the corrected output voltage corresponding to the effective aperture after the hydrogen ion concentration index in the effective aperture changes, where the first output voltage variation is positively correlated with the second output voltage variation, the second output voltage variation is the output voltage variation before and after the hydrogen ion concentration index in the effective aperture changes, the first output voltage variation is positively correlated with the first slope, and the first output voltage variation is negatively correlated with the second slope.
Optionally, this step 150 may include:
step 151, calculating a correction output voltage by adopting the following formula:
Vout-correct＝Vout-ref+ΔVout1wherein Δ Vout1＝ΔVout2*(k1/k2)，ΔVout2＝V1-V2；
Vout-correctIndicating the corrected output voltage, Vout-refDenotes the corresponding output voltage, Δ V, of the reference hole at the corrected input voltageout1Indicates the first output voltage variation, Δ Vout2Representing the amount of change, k, of the second output voltage1Represents a first slope, k2Represents a second slope, V1Represents the output voltage, V, corresponding to the effective hole after the hydrogen ion concentration index in the effective hole changes2And the output voltage corresponding to the effective hole before the hydrogen ion concentration index in the effective hole changes is shown.
Specifically, in this step, the output voltage corresponding to the effective pore is corrected by calculating how much the actual output voltage variation (second output voltage variation) corresponding to the effective pore corresponds to the output voltage variation (i.e., first output voltage variation) on the reference curve before and after the pH of the solution changes, determining the reference output voltage (i.e., the output voltage corresponding to the reference point) and the first output voltage variation of the reference curve under the corrected input voltage as the corrected output voltage corresponding to the effective pore, i.e., correcting the point on the input/output characteristic curve corresponding to the effective pore to the reference curve, so that the corrected output voltage corresponding to the effective pore and the output voltage corresponding to the standard pore are unified to a unified standard (both on the reference curve), and further correcting the output voltage corresponding to the effective pore, thereby ensuring that when the gene sequencing result analysis is performed according to the corrected output voltage, the accuracy of judging the gene sequencing result can be ensured. Referring to fig. 4, for example, when the voltage provided by the excitation source is the corrected input voltage Vt, the point on the input/output characteristic curve (i.e., curve 12) corresponding to the effective pore before the pH change is the point D; the point on the input/output characteristic curve corresponding to the effective pore before the pH change is point D1. When the voltage provided by the excitation source is the correction input voltage Vt, a point on the input/output characteristic curve (i.e., the reference curve 11) corresponding to the standard hole before the pH change is the point E; the point on the input/output characteristic curve corresponding to the effective pore before the pH change is point E1. After the pH changes, the output voltage corresponding to the effective pore is corrected, after the correction in step 150, the point D1 is corrected to the point E1 on the reference curve, so that when the pH changes of the solution in the effective pore and the solution in the standard pore are the same, the corrected output voltage corresponding to the effective pore is the same as the output voltage corresponding to the standard pore, and further, when the gene sequencing is performed, the detection results of the effective pore and the standard pore for the gene sequencing are consistent, thereby ensuring the accuracy of the gene sequencing result.
According to the correction method of the gene sequencing chip provided by the embodiment, when the voltage provided by the excitation source is the correction input voltage, the input voltage variation caused by the change of the hydrogen ion concentration index is normalized according to the output voltage variation before and after the change of the hydrogen ion concentration index in the effective hole and the second slope, so that the input voltage variation caused by the pH change corresponding to the effective holes of different input and output characteristic curves is unified to the same standard, and the accuracy of judging the gene sequencing result according to the input voltage variation of each effective hole before and after the pH change can be further ensured. And the actual output voltage variation (second output voltage variation) corresponding to the effective pore before and after the pH of the solution changes is calculated to correspond to the output voltage variation (namely, the first output voltage variation) on the reference curve, then the reference output voltage (namely, the output voltage corresponding to the reference point) and the first output voltage variation of the reference curve under the corrected input voltage are determined as the corrected output voltage corresponding to the effective pore, namely, the point on the input/output characteristic curve corresponding to the effective pore is corrected to the reference curve, so that the corrected output voltage corresponding to the effective pore and the output voltage corresponding to the standard pore are unified to a unified standard (both on the reference curve), further, when the pH of the solution in the effective pore and the solution in the standard pore changes the same, the corrected output voltage corresponding to the effective pore is the same as the output voltage corresponding to the standard pore, the output voltage corresponding to the effective hole is corrected, so that the detection result of the effective hole and the standard hole for gene sequencing is consistent when the gene sequencing is carried out, and the accuracy of the gene sequencing result is ensured.
FIG. 5 is a flowchart of another method for calibrating a gene sequencing chip according to an embodiment of the present invention, and referring to FIG. 5, the method for calibrating a gene sequencing chip includes:
step 210, determining a reference curve, correcting input voltage, a standard hole and a non-standard hole according to the position distribution of the maximum slope point of the input-output characteristic curve of each detection hole, wherein the reference curve is the input-output characteristic curve corresponding to the standard hole; this step is the same as step 110 in the above embodiment, and is not described herein again;
step 220, calculating a first slope of the reference curve at the corrected input voltage; the procedure of this step is the same as that of step 120 in the above embodiment, and is not described herein again;
step 230, determining a non-standard hole with an output voltage within a preset range obtained according to the input and output characteristic curve under the condition of correcting the input voltage as an effective hole, wherein the preset range is greater than or equal to a first threshold voltage and less than or equal to a second threshold voltage;
specifically, the number of detection holes included in the gene sequencing chip is large, so that a small amount of detection hole process deviation is inevitably large, and effective gene sequencing cannot be performed even if correction is performed.
Referring to fig. 2, for example, if the first threshold voltage is 200mV and the second threshold voltage is 700mV, the non-standard holes corresponding to the curves 12, 13 and 14 are valid holes, the non-standard holes corresponding to the curves 15 and 16 are invalid holes, and the curves 14 and 13 can be boundary curves, i.e., the curves between the curves 14 and 13 can both correspond to valid holes, and the curves on the left side of the curve 14 and the curves on the right side of the curve 13 correspond to invalid holes. The first threshold voltage and the second threshold voltage may be set according to an output voltage (referred to as a reference output voltage) of the input/output characteristic curve (i.e., the reference curve 11) corresponding to the standard hole at the corrected input voltage, for example, a difference between the first threshold voltage and the reference output voltage is set to be 200mV, a difference between the second threshold voltage and the reference input voltage is set to be 300mV, and when a difference between the first threshold voltage and the reference output voltage and a difference between the second threshold voltage and the reference output voltage are specifically set, the setting may be performed according to actual needs, which is not specifically limited herein.
Step 240, calculating a second slope of the input/output characteristic curve corresponding to the effective hole in the non-standard hole at the position of the corrected input voltage; this step is the same as step 130 in the above embodiment, and is not described herein again;
step 250, when the voltage provided by the excitation source is the correction input voltage, normalizing the input voltage variation caused by the hydrogen ion concentration index variation according to the output voltage variation before and after the hydrogen ion concentration index variation in the effective hole and the second slope; this step is the same as step 140 in the above embodiment, and is not described herein again;
step 260, when the voltage provided by the excitation source is the corrected input voltage, determining the output voltage corresponding to the standard aperture under the corrected input voltage and the first output voltage variation as the corrected output voltage corresponding to the effective aperture after the hydrogen ion concentration index in the effective aperture is changed, wherein the first output voltage variation is positively correlated with the second output voltage variation, the second output voltage variation is the output voltage variation before and after the hydrogen ion concentration index in the effective aperture is changed, the first output voltage variation is positively correlated with the first slope, and the first output voltage variation is negatively correlated with the second slope; this step is the same as step 150 in the above embodiment, and will not be described again.
FIG. 6 is a flowchart of another method for calibrating a gene sequencing chip according to an embodiment of the present invention, and referring to FIG. 6, the method for calibrating a gene sequencing chip includes:
step 310, obtaining an input/output characteristic curve of each detection hole, wherein the steps include injecting a solution with the same hydrogen ion concentration index into each detection hole, electrifying the solution in each detection hole through an excitation source, obtaining the measured output voltage of the sensing electrode exposed in each detection hole, and obtaining the input/output characteristic curve corresponding to each detection hole according to the input voltage electrified by the excitation source and the output voltage corresponding to each detection hole; the excitation source energizes each detection hole with a sawtooth wave shape.
Specifically, for each detection hole, the corresponding input and output characteristic curve can be obtained by adopting the above mode, so that the subsequent steps can be conveniently carried out.
Optionally, the voltage range of the sawtooth wave is 300mV-1000mV, and the step size is 0.8 mV.
Specifically, too long step length of the sawtooth wave may result in a long time for acquiring the input/output characteristic curve, and too short step length may result in incomplete acquisition of the input/output characteristic curve, and the set step length is) 0.8mV, which may ensure that the input/output characteristic curve is acquired within a short time, and may also ensure the integrity of the input/output characteristic curve.
Step 320, determining a reference curve, correcting input voltage, a standard hole and a non-standard hole according to the position distribution of the maximum slope point of the input-output characteristic curve of each detection hole, wherein the reference curve is the input-output characteristic curve corresponding to the standard hole; this step is the same as step 110 in the above embodiment, and is not described herein again;
step 330, calculating a first slope according to the output voltage corresponding to the calibrated hole under the corrected input voltage and the output voltage corresponding to the calibrated hole under the input voltage of the previous frame of the corrected input voltage;
or calculating the first slope according to the output voltage corresponding to the standard hole under the corrected input voltage and the output voltage corresponding to the standard hole under the input voltage of the frame after the corrected input voltage.
Specifically, in step 130, the detection hole filled with the solution is scanned by using a sawtooth wave, so that in each frame of the sawtooth wave scanning, the detection hole corresponds to an input voltage and an output voltage, and the first slope, i.e. a differential value of the reference curve at the corrected input voltage, can calculate the first slope according to the output voltage corresponding to the reference hole under the corrected input voltage and the output voltage corresponding to the reference hole under the input voltage of the frame before the corrected input voltage, according to the following specific formula:
Figure BDA0002524793260000151
wherein k is1Represents a first slope, VtIndicating the corrected input voltage, Vout-refDenotes the corresponding output voltage, V, of the reference hole at the corrected input voltaget0Is indicated in the corrected input voltage VtInput voltage, V, of the previous frameout0Indicating the output voltage of the standard aperture for the frame preceding the corrected input voltage. Wherein, Vt-Vt0I.e. the step length of the sawtooth wave. Specifically, with reference to fig. 2, point a on the reference curve is enlarged, where the coordinate corresponding to point a is (V)t，Vout-ref) That is, the coordinates corresponding to point a are (corrected input voltage, output voltage corresponding to reference hole under corrected input voltage), and the coordinates corresponding to point a1 are (V)t0，Vout0) That is, the coordinate corresponding to the point a1 is (the input voltage of the frame before the correction input voltage, and the output voltage corresponding to the reference hole under the input voltage of the frame before the correction input voltage), and further, the first slope may be calculated according to the coordinate of the point a1 and the coordinate of the point a. The coordinates of point a and the coordinates of point a1 are obtained from the data obtained when the input/output characteristic curves of the respective detection holes are acquired.
Or calculating the first slope according to the output voltage corresponding to the standard hole under the corrected input voltage and the output voltage corresponding to the standard hole under the input voltage of the frame after the corrected input voltage. The first slope may be calculated by using the following formula, and the specific calculation method is similar to the method of calculating according to the previous frame data of the corrected input voltage, and is not described herein again.
Step 340, calculating a second slope according to the output voltage corresponding to the effective aperture under the corrected input voltage and the output voltage corresponding to the effective aperture under the input voltage of the previous frame of the corrected input voltage;
or calculating the second slope according to the output voltage corresponding to the effective hole under the corrected input voltage and the output voltage corresponding to the effective hole under the input voltage of a frame after the corrected input voltage.
The specific calculation formula for calculating the second slope according to the output voltage corresponding to the effective aperture under the corrected input voltage and the output voltage corresponding to the effective aperture under the input voltage of the frame before the corrected input voltage is as follows:
Figure BDA0002524793260000161
wherein k is2Represents a second slope, VtIndicating the corrected input voltage, Vout-yIndicating the corresponding output voltage, V, of the effective aperture at the corrected input voltaget0Is indicated in the corrected input voltage VtInput voltage, V, of the previous frameouty0Indicating the output voltage of the effective aperture one frame prior to the corrected input voltage. Wherein, Vt-Vt0I.e. the step length of the sawtooth wave. With reference to fig. 2, the point F on the reference curve is enlarged, wherein the coordinate corresponding to the point F is (V)t，Vout-y) That is, the coordinate corresponding to the F point is (correcting the input voltage, correcting the output voltage corresponding to the effective hole under the input voltage), and the coordinate corresponding to the F1 point is (V)t0，Vouty0) That is, the coordinate corresponding to the point F1 is (the input voltage of the frame before the correction input voltage, and the output voltage corresponding to the effective aperture under the input voltage of the frame before the correction input voltage), and further, the first slope may be calculated according to the coordinate of the point F1 and the coordinate of the point F. The coordinates of point F and the coordinates of point F1 are obtained from the data obtained when the input/output characteristic curve of each detection hole is acquired.
Step 350, when the voltage provided by the excitation source is the correction input voltage, normalizing the input voltage variation caused by the hydrogen ion concentration index variation according to the output voltage variation before and after the hydrogen ion concentration index variation in the effective hole and the second slope; this step is the same as step 140 in the above embodiment, and is not described herein again;
step 360, when the voltage provided by the excitation source is the correction input voltage, determining the output voltage corresponding to the standard aperture under the correction input voltage and the first output voltage variation as the correction output voltage corresponding to the effective aperture after the hydrogen ion concentration index in the effective aperture changes, wherein the first output voltage variation is positively correlated with the second output voltage variation, the second output voltage variation is the output voltage variation before and after the hydrogen ion concentration index in the effective aperture changes, the first output voltage variation is positively correlated with the first slope, and the first output voltage variation is negatively correlated with the second slope; this step is the same as step 150 in the above embodiment, and will not be described again.
Fig. 7 is a top view of a gene sequencing chip according to an embodiment of the present invention, fig. 8 is a cross-sectional view taken along M-M' of fig. 7, and referring to fig. 7 and 8, optionally, the gene sequencing chip includes sensing electrodes 510 arranged in an array, an insulating layer 520 disposed on one side of the sensing electrodes 510, and a driving electrode 530 disposed on the insulating layer 520 away from the entire surface of the sensing electrodes 510, the driving electrode 530 and the insulating layer 520 include via structures, the via structures serve as detection holes 540, and the detection holes 540 expose the sensing electrodes 510; the sensor further comprises a plurality of amplifying circuits 550, and the sensing electrodes 510 are in one-to-one correspondence with and electrically connected with the amplifying circuits 550; the driving electrode 530 is used for externally connecting a voltage signal, and the sensing electrode 510 is used for generating a sensing signal according to the voltage signal on the driving electrode 530 and transmitting the sensing signal to the amplifying circuit 550.
During gene sequencing, the solution to be detected may be added into the detecting hole, and the externally applied voltage signal may be applied to the solution to be detected or applied to the driving electrode. When the driving electrode 530 is externally connected with a voltage signal, an induced charge is formed on the sensing electrode 510, so that an induced signal is generated and transmitted to the sub-amplifying circuit 550, and the determination of the gene sequencing result is performed by measuring the output voltage of the amplifying circuit 550. The amplifying circuit 550 may be any device having signal amplifying or converting functions, such as a transistor and an amplifier, and may convert a slight variation of a voltage (current) signal into an obvious variation of a current (voltage) signal, which is not limited in the embodiment of the present invention.
Alternatively, the method for calibrating a gene sequencing chip according to any of the above embodiments may be used for calibrating a gene sequencing chip shown in fig. 7 and 8.
The present embodiment further provides a calibration apparatus for a gene sequencing chip, which is used to perform the calibration method for a gene sequencing chip provided in any of the above embodiments of the present invention, wherein a surface of one side of the gene sequencing chip includes a plurality of detection holes; FIG. 9 is a schematic structural diagram of a calibration apparatus for a gene sequencing chip according to an embodiment of the present invention, referring to FIG. 9, the calibration apparatus includes:
the determining module 410 is configured to determine a reference curve, a corrected input voltage, a standard hole and a non-standard hole according to the position distribution of the maximum slope point of the input/output characteristic curve of each detection hole, where the reference curve is an input/output characteristic curve corresponding to the standard hole;
a first slope calculation module 420 for calculating a first slope of the reference curve at the corrected input voltage;
a second slope calculation module 430, for calculating a second slope of the input/output characteristic curve corresponding to the effective hole in the non-standard hole at the corrected input voltage;
the normalization processing module 440 is configured to, when the voltage provided by the excitation source is the correction input voltage, perform normalization processing on the input voltage variation caused by the hydrogen ion concentration index variation according to the output voltage variation before and after the hydrogen ion concentration index variation in the effective hole and the second slope;
the output voltage correction module 450 is configured to determine, when the voltage provided by the excitation source is the correction input voltage, an output voltage corresponding to the standard aperture under the correction input voltage and a first output voltage variation as the correction output voltage corresponding to the effective aperture after the hydrogen ion concentration index in the effective aperture changes, where the first output voltage variation is positively correlated with a second output voltage variation, the second output voltage variation is an output voltage variation before and after the hydrogen ion concentration index in the effective aperture changes, the first output voltage variation is positively correlated with a first slope, and the first output voltage variation is negatively correlated with a second slope.
The correction device of the gene sequencing chip provided by the embodiment of the invention can execute the correction method of the gene sequencing chip provided by any embodiment of the invention, and has corresponding functional modules and beneficial effects of the execution method.
It is to be noted that the foregoing is only illustrative of the preferred embodiments of the present invention and the technical principles employed. It will be understood by those skilled in the art that the present invention is not limited to the particular embodiments described herein, but is capable of various obvious changes, rearrangements and substitutions as will now become apparent to those skilled in the art without departing from the scope of the invention. Therefore, although the present invention has been described in greater detail by the above embodiments, the present invention is not limited to the above embodiments, and may include other equivalent embodiments without departing from the spirit of the present invention, and the scope of the present invention is determined by the scope of the appended claims.

Claims (11)

1. A correction method of a gene sequencing chip is characterized in that one side surface of the gene sequencing chip comprises a plurality of detection holes; the correction method comprises the following steps:
determining a reference curve, correcting input voltage, a standard hole and a non-standard hole according to the position distribution of the maximum slope point of the input-output characteristic curve of each detection hole, wherein the reference curve is the input-output characteristic curve corresponding to the standard hole;
calculating a first slope of the reference curve at the correction input voltage;
calculating a second slope of an input-output characteristic curve corresponding to an effective hole in the non-standard holes at the corrected input voltage;
when the voltage provided by the excitation source is the correction input voltage, normalizing the input voltage variation caused by the hydrogen ion concentration index variation according to the output voltage variation before and after the hydrogen ion concentration index variation in the effective hole and the second slope;
when the voltage that the excitation source provided is the correction input voltage, will the standard hole is in the output voltage that corresponds under the correction input voltage and first output voltage variation are determined to be in after the hydrogen ion concentration index changes in the effective pore the correction output voltage that the effective pore corresponds, wherein first output voltage variation is positive correlation with second output voltage variation, second output voltage variation is the output voltage variation before and after the hydrogen ion concentration index changes in the effective pore, first output voltage variation with first slope positive correlation, first output voltage variation with second slope negative correlation.
2. The method for calibrating gene sequencing chips of claim 1, wherein when the voltage provided by the excitation source is the calibration input voltage, normalizing the input voltage variation caused by the hydrogen ion concentration index change according to the output voltage variation before and after the hydrogen ion concentration index change in the effective hole and the second slope, comprises:
the normalization process is performed using the following formula:
ΔVin＝ΔVout/k2，
ΔVout＝V1-V2；
ΔVindenotes the input voltage variation, Δ V, obtained after normalizationoutRepresenting the amount of change, k, in output voltage before and after the change of the hydrogen ion concentration index in the effective hole2Represents the second slope, V1Represents the output voltage, V, corresponding to the effective hole after the hydrogen ion concentration index in the effective hole changes2And the output voltage corresponding to the effective hole before the hydrogen ion concentration index in the effective hole changes is represented.
3. The method of calibrating a gene sequencing chip according to claim 1, wherein when the voltage supplied from the excitation source is the calibration input voltage, determining a first output voltage variation and a first output voltage variation of the standard well at the calibration input voltage as the calibration output voltage corresponding to the effective well after the hydrogen ion concentration index in the effective well has changed, wherein the first output voltage variation is positively correlated with the second output voltage variation, the second output voltage variation is the output voltage variation before and after the hydrogen ion concentration index in the effective well has changed, the first output voltage variation is positively correlated with the first slope, and the first output voltage variation is negatively correlated with the second slope, the method comprising:
calculating the corrected output voltage using the following equation:
Vout-correct＝Vout-ref+ΔVout1wherein Δ Vout1＝ΔVout2*(k1/k2)，ΔVout2＝V1-V2；
Vout-correctRepresenting said corrected output voltage, Vout-refRepresents the corresponding output voltage, Δ V, of the standard hole at the corrected input voltageout1Indicates the first output voltage variation, Δ Vout2Representing the amount of change, k, of the second output voltage1Represents the first slope, k2Represents the second slope, V1Represents the output voltage, V, corresponding to the effective hole after the hydrogen ion concentration index in the effective hole changes2And the output voltage corresponding to the effective hole before the hydrogen ion concentration index in the effective hole changes is represented.
4. The method of calibrating a gene sequencing chip of claim 1, wherein prior to calculating a second slope of the input-output characteristic curve corresponding to the valid well of the non-standard wells at the calibration input voltage, the method comprises:
and determining a non-standard hole with an output voltage within a preset range obtained according to the input and output characteristic curve under the corrected input voltage as an effective hole, wherein the preset range is greater than or equal to a first threshold voltage and less than or equal to a second threshold voltage.
5. The method of calibrating a gene sequencing chip according to claim 1, further comprising, before determining a reference curve, a calibration input voltage, and standard wells and non-standard wells based on a position distribution of maximum slope points of an input-output characteristic curve of each of the detection wells:
acquiring an input/output characteristic curve of each detection hole, wherein the input/output characteristic curve comprises injecting a solution with the same hydrogen ion concentration index into each detection hole, electrifying the solution in each detection hole through the excitation source, acquiring the measured output voltage of the sensing electrode exposed in each detection hole, and acquiring the input/output characteristic curve corresponding to the detection hole according to the input voltage electrified by the excitation source and the output voltage corresponding to the detection hole; the excitation source energizes each detection hole with a sawtooth wave shape.
6. The method of claim 5, wherein the sawtooth voltage ranges from 300mV to 1000mV and the step size is 0.8 mV.
7. The method of calibrating a gene sequencing chip of claim 5, wherein said calculating a first slope of said reference curve at said calibration input voltage comprises:
calculating the first slope according to the output voltage corresponding to the standard hole under the correction input voltage and the output voltage corresponding to the standard hole under the input voltage of the frame before the correction input voltage;
or calculating the first slope according to the output voltage corresponding to the standard hole under the corrected input voltage and the output voltage corresponding to the standard hole under the input voltage of a frame after the corrected input voltage.
8. The method of claim 5, wherein calculating a second slope of the input-output characteristic curve corresponding to the valid well of the non-standard wells at the calibration input voltage comprises:
calculating the second slope according to the output voltage corresponding to the effective hole under the corrected input voltage and the output voltage corresponding to the effective hole under the input voltage of the frame before the corrected input voltage;
or calculating the second slope according to the output voltage corresponding to the effective hole under the corrected input voltage and the output voltage corresponding to the effective hole under the input voltage of a frame after the corrected input voltage.
9. The method of calibrating a gene sequencing chip according to claim 1, wherein said determining a reference curve, a calibration input voltage, and standard wells and non-standard wells based on a position distribution of maximum slope points of an input-output characteristic curve of each of said test wells comprises:
counting the number of input and output characteristic curves of the maximum slope point under each input voltage;
determining an input-output characteristic curve of the maximum slope point under the first input voltage as a reference curve;
wherein the number of input/output characteristic curves of which the maximum slope points appear at a first input voltage is greater than that of input/output characteristic curves of which the maximum slope points appear at any other input voltage;
determining the first input voltage as a corrected input voltage;
and determining the detection hole corresponding to the input and output characteristic curve of which the maximum slope point appears under the first input voltage as the standard hole, and determining the other detection holes as the non-standard holes.
10. The method for calibrating a gene sequencing chip according to any one of claims 1 to 9, wherein the gene sequencing chip comprises sensing electrodes arranged in an array, an insulating layer disposed on one side of the sensing electrodes, and driving electrodes disposed on the insulating layer away from the sensing electrodes, wherein the driving electrodes and the insulating layer comprise via hole structures serving as the detection holes exposing the sensing electrodes;
the sensing electrodes are in one-to-one correspondence with and electrically connected with the amplifying circuits;
the driving electrode is used for being externally connected with a voltage signal, and the sensing electrode is used for generating a sensing signal according to the voltage signal on the driving electrode and transmitting the sensing signal to the amplifying circuit.
11. A calibration device for a gene sequencing chip, which is used for performing the calibration method for a gene sequencing chip according to any one of claims 1 to 10, wherein one side surface of the gene sequencing chip comprises a plurality of detection holes; the correction device includes:
the determining module is used for determining a reference curve, a correction input voltage, a standard hole and a non-standard hole according to the position distribution of the maximum slope point of the input-output characteristic curve of each detection hole, wherein the reference curve is the input-output characteristic curve corresponding to the standard hole;
a first slope calculation module for calculating a first slope of the reference curve at the correction input voltage;
the second slope calculation module is used for calculating a second slope of an input-output characteristic curve corresponding to an effective hole in the non-standard holes at the corrected input voltage;
the normalization processing module is used for performing normalization processing on input voltage variation caused by hydrogen ion concentration index variation according to output voltage variation before and after the hydrogen ion concentration index variation in the effective hole and a second slope when the voltage provided by the excitation source is the correction input voltage;
an output voltage correction module, configured to determine, when the voltage provided by the excitation source is the correction input voltage, the output voltage corresponding to the standard aperture under the correction input voltage and a first output voltage variation as being in after the hydrogen ion concentration index changes in the effective aperture the correction output voltage corresponding to the effective aperture, wherein the first output voltage variation is positively correlated with the second output voltage variation, the second output voltage variation is the output voltage variation before and after the hydrogen ion concentration index changes in the effective aperture, the first output voltage variation is positively correlated with the first slope, and the first output voltage variation is negatively correlated with the second slope.
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Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20130090860A1 (en) * 2010-12-30 2013-04-11 Life Technologies Corporation Methods, systems, and computer readable media for making base calls in nucleic acid sequencing
US20170089858A1 (en) * 2015-09-24 2017-03-30 Genia Technologies, Inc. Encoding state change of nanopore to reduce data size
US20170370902A1 (en) * 2016-06-23 2017-12-28 Roche Sequencing Solutions, Inc. Period-to-period analysis of ac signals from nanopore sequencing
US20170370903A1 (en) * 2016-06-23 2017-12-28 Roche Sequencing Solutions, Inc. Formation and calibration of nanopore sequencing cells
CN109791138A (en) * 2016-10-12 2019-05-21 豪夫迈·罗氏有限公司 Nano-pore voltage method
WO2019129555A1 (en) * 2017-12-28 2019-07-04 F. Hoffmann-La Roche Ag Measuring and removing noise in stochastic signals from a nanopore dna sequencing system driven by an alternating signal
CN110741097A (en) * 2017-04-19 2020-01-31 豪夫迈·罗氏有限公司 Phased nanopore array

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20130090860A1 (en) * 2010-12-30 2013-04-11 Life Technologies Corporation Methods, systems, and computer readable media for making base calls in nucleic acid sequencing
US20170089858A1 (en) * 2015-09-24 2017-03-30 Genia Technologies, Inc. Encoding state change of nanopore to reduce data size
US20170370902A1 (en) * 2016-06-23 2017-12-28 Roche Sequencing Solutions, Inc. Period-to-period analysis of ac signals from nanopore sequencing
US20170370903A1 (en) * 2016-06-23 2017-12-28 Roche Sequencing Solutions, Inc. Formation and calibration of nanopore sequencing cells
CN109791138A (en) * 2016-10-12 2019-05-21 豪夫迈·罗氏有限公司 Nano-pore voltage method
CN110741097A (en) * 2017-04-19 2020-01-31 豪夫迈·罗氏有限公司 Phased nanopore array
WO2019129555A1 (en) * 2017-12-28 2019-07-04 F. Hoffmann-La Roche Ag Measuring and removing noise in stochastic signals from a nanopore dna sequencing system driven by an alternating signal

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
章寅: "固态纳米孔单分子传感器设计制造及关键技术研究" *

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