WO2013052825A1 - Bypass for r-c filter in chemical sensor arrays - Google Patents

Bypass for r-c filter in chemical sensor arrays Download PDF

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Publication number
WO2013052825A1
WO2013052825A1 PCT/US2012/058996 US2012058996W WO2013052825A1 WO 2013052825 A1 WO2013052825 A1 WO 2013052825A1 US 2012058996 W US2012058996 W US 2012058996W WO 2013052825 A1 WO2013052825 A1 WO 2013052825A1
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chemical
voltage
output terminal
sensor
method
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PCT/US2012/058996
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French (fr)
Inventor
Todd Rearick
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Life Technologies Corporation
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Priority to US61/543,635 priority
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Publication of WO2013052825A1 publication Critical patent/WO2013052825A1/en

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    • GPHYSICS
    • G01MEASURING; TESTING
    • G01NINVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N27/00Investigating or analysing materials by the use of electric, electro-chemical, or magnetic means
    • G01N27/26Investigating or analysing materials by the use of electric, electro-chemical, or magnetic means by investigating electrochemical variables; by using electrolysis or electrophoresis
    • G01N27/403Cells and electrode assemblies
    • G01N27/414Ion-sensitive or chemical field-effect transistors, i.e. ISFETS or CHEMFETS
    • G01N27/4148Integrated circuits therefor, e.g. fabricated by CMOS processing

Abstract

In one implementation, a method is described for operating a chemical sensor. The method includes initiating a chemical reaction proximate to the chemical sensor. The method further includes, during a first time interval of the chemical reaction, closing a bypass switch placed in parallel with a resistor and arranged between an output terminal of the chemical sensor and a capacitor, thereby charging the capacitor to a first voltage based on a voltage at the output terminal due to the chemical reaction. The method further includes opening the bypass switch during a second time interval of the chemical reaction, thereby charging the capacitor to a second voltage based on the voltage at the output terminal. The method further includes generating an output signal for the chemical sensor based on the second voltage on the capacitor.

Description

BYPASS FOR R-C FILTER IN CHEMICAL SENSOR ARRAYS

BACKGROUND

[0001] The present disclosure relates to sensors for chemical analysis, and more particularly to low-noise, high-speed sensor arrays for nucleic acid sequencing.

[0002] A variety of types of sensors have been used in the detection of various chemical and/or biological processes. One type of sensor is a chemically-sensitive field effect transistor (chemFET). A chemFET includes a source and a drain separated by channel region, and a chemically sensitive area coupled to the channel region. The operation of the chemFET is based on the modulation of channel conductance due to a chemical reaction which causes changes in charge near the sensitive area. The modulation of the channel conductance affects the threshold voltage of the chemFET, and the threshold voltage can be measured to indicate characteristics of the chemical reaction. The threshold voltage may for example be measured by applying appropriate bias voltages to the source and drain of the chemFET, and measuring a current through the chemFET. As another example, the threshold voltage may be measured by applying an appropriate bias voltage to one of the source or drain and driving a known current through the chemFET, and measuring the voltage at the other of the source or drain of the chemFET.

[0003] An ion-sensitive field effect transistor (ISFET) is a type of chemFET that includes an ion-sensitive layer at the sensitive area. The presence of ions in an analyte solution alters the surface potential at the interface between the ion-sensitive layer and the analyte solution, usually due to the dissociation of oxide groups by the ions in the analyte solution. The change in surface potential at the sensitive area of the ISFET affects the threshold voltage of the device, which can be measured to indicate the presence and/or concentration of ions within the analyte solution.

[0004] Arrays of ISFETs may be used for monitoring chemical reactions, such as DNA sequencing reactions, based on the detection of ions present, generated, or used during a reaction. See, for example, U.S. Patent No. 7,948,015 to Rothberg et al., which is incorporated by reference herein. More generally, large arrays of chemFETs or other types of chemical sensors may be employed to detect and measure static and/or dynamic amounts or concentrations of a variety of analytes (e.g. hydrogen ions, other ions, compounds, etc.) in a variety of chemical and/or biological processes, through which valuable information may be obtained based on such analyte measurements. The processes may for example be biological or chemical reactions, cell or tissue cultures or monitoring, neural activity, nucleic acid sequencing, etc. [0005] A specific issue that arises in the operation of sensor arrays is the susceptibility of the sensor output signals to noise. Specifically, the noise affects the accuracy of downstream signal processing used to determine the characteristics of the chemical and/or biological process being detected by the sensors.

[0006] In addition, the operation speed may be limited by the number of sensors in the array, because a certain amount of time is required to read out the output signal of each sensor. A low operation speed limits the use of large scale sensor arrays that simultaneously detect reactions produce transient sensor output signal pulses, because these reactions may be completed before all the output signal pulses can be read out.

[0007] It is therefore desirable to provide devices include low noise, high speed sensor arrays, and methods for operating such device.

SUMMARY

[0008] In one implementation, a chemical detection circuit is described. The circuit includes a chemical sensor comprising a chemically-sensitive transistor having an output terminal, and a row-select switch coupled to the output terminal of the chemically-sensitive transistor. The circuit also includes an R-C filter coupled to the output terminal of the chemically-sensitive transistor via the row-select switch. The circuit also includes a bypass circuit comprising a bypass switch arranged in parallel with a resistor of the R-C filter.

[0009] This circuit and other implementations of the technology disclosed can each optionally include one or more of the following features.

[0010] The chemically-sensitive transistor can be an ion-sensitive field effect transistor (ISFET).

[0011] The chemical sensor can be one of a column of chemical sensors in an array. A current source can be shared by all chemical detection pixels of the column in the array.

[0012] The R-C filter and the bypass circuit can be shared by all chemical detection pixels of the column.

[0013] The R-C filter can include a capacitor that samples a voltage at the output terminal of the chemically-sensitive transistor.

[0014] The resistor of the R-C filter can include multiple segments, and the bypass circuit can include respective bypass switches for resistors in each segment.

[0015] In another implementation, a method for operating a chemical sensor is described.

The method includes initiating a chemical reaction proximate to the chemical sensor. The method further includes, during a first time interval of the chemical reaction, closing a bypass switch placed in parallel with a resistor and arranged between an output terminal of the chemical sensor and a capacitor, thereby charging the capacitor to a first voltage based on a voltage at the output terminal due to the chemical reaction. The method further includes opening the bypass switch during a second time interval of the chemical reaction, thereby further charging the capacitor to a second voltage based on the voltage at the output terminal. The method further includes generating an output signal for the chemical sensor based on the second voltage on the capacitor.

[0016] This method and other implementations of the technology disclosed can each optionally include one or more of the following features.

[0017] The capacitor can be charged at a first time constant while the bypass switch is closed, and charged at a second time constant while the bypass switch is open.

[0018] Initiating the chemical reaction can include initiating a sequencing reaction.

[0019] Initiating the sequencing reaction can include disposing a plurality of template nucleic acids in a reaction well coupled to the chemical sensor, and introducing known nucleotides into the reaction well.

[0020] The voltage at the output terminal of the chemical sensor can indicate incorporation of the introduced known nucleotides into at least one of the template nucleic acids.

[0021] The method can further include analyzing the output signal to determine at least a portion of sequences corresponding to a portion of the template nucleic acids.

[0022] The voltage at the output terminal of the chemical sensor can be due to byproducts from the chemical reaction.

[0023] The chemical reaction can occur within a solution coupled to the chemical sensor.

[0024] The chemical sensor can be a chemically-sensitive field effect transistor (chemFET), and the voltage at the output terminal is based on a threshold voltage of the chemFET.

[0025] The chemFET can include a floating gate coupled to a reaction well containing the chemical reaction.

[0026] The voltage at the output terminal can be due to a change in ion-concentration within a solution containing the chemical reaction.

[0027] Other implementations may include a non-transitory computer readable storage medium storing instructions executable by a processor to perform a method as described above. Yet another implementation may include a system including memory and one or more processors operable to execute instructions, stored in the memory, to perform a method as described above. [0028] Particular aspects of one more implementations of the subject matter described in this specification are set forth in the drawings and the description below. Other features, aspects, and advantages of the subject matter will become apparent from the description, the drawings, and the claims.

BRIEF DESCRIPTION OF THE DRAWINGS

[0029] FIG. 1 illustrates a schematic diagram of a portion of a chemical detection circuit according to an exemplary embodiment.

[0030] FIG. 2 illustrates a simplified signal timing diagram for operating the chemical detection circuit of FIG. 1 according to an exemplary embodiment.

[0031] FIG. 3 illustrates a simplified signal timing diagram for operating the chemical detection circuit of FIG. 1 according to a second exemplary embodiment.

[0032] FIG. 4 illustrates a schematic diagram of a chemical detection circuit according to a second exemplary embodiment that includes multiple resistors.

[0033] FIG. 5 illustrates a block diagram of components of a system for nucleic acid sequencing according to an exemplary embodiment.

[0034] FIG. 6 illustrates cross-sectional and expanded views of a portion of the integrated circuit device and flow cell of FIG. 5.

[0035] FIG. 7 illustrates a simplified block diagram of an integrated circuit device including a chemical detection circuit as described herein.

[0036] FIG. 8 is a flow chart of an example process for generating an output signal from a chemical sensor according to an exemplary embodiment.

DETAILED DESCRIPTION

[0037] Techniques are described herein for high speed, low noise operation of sensor arrays used for chemical analysis, so that the values of the sensor output signals can be quickly and accurately read out. The sensors in the sensor arrays may be chemically-sensitive field effect transistors (chemFETs), such as ion-sensitive field effect transistors (ISFETS). Examples of sensors that may be used in embodiments are described in U.S. Patent Application Publication No. 2010/0300559, No. 2010/0197507, No. 2010/0301398, No. 2010/0300895, No. 2010/0137143, and No. 2009/0026082, and U.S. Patent No. 7,575,865, each which are incorporated by reference herein.

[0038] In various exemplary embodiments, the methods, systems, and computer readable media described herein may advantageously be used to process and/or analyze data and signals obtained from electronic or charged-based nucleic acid sequencing. In electronic or charged- based sequencing (such as, pH-based sequencing), a nucleotide incorporation event may be determined by detecting ions (e.g., hydrogen ions) that are generated as natural by-products of polymerase-catalyzed nucleotide extension reactions. This may be used to sequence a sample or template nucleic acid, which may be a fragment of a nucleic acid sequence of interest, for example, and which may be directly or indirectly attached as a clonal population to a solid support, such as a particle, microparticle, bead, etc. The sample or template nucleic acid may be operably associated to a primer and polymerase and may be subjected to repeated cycles or "flows" of deoxynucleoside triphosphate ("dNTP") addition (which may be referred to herein as "nucleotide flows" from which nucleotide incorporations may result) and washing. The primer may be annealed to the sample or template so that the primer's 3' end can be extended by a polymerase whenever dNTPs complementary to the next base in the template are added. Then, based on the known sequence of nucleotide flows and on measured output signals of the sensors indicative of ion concentration during each nucleotide flow, the identity of the type, sequence and number of nucleotide(s) associated with a sample nucleic acid present in a reaction confinement region coupled to a sensor can be determined.

[0039] FIG. 1 illustrates a schematic diagram of a portion of a chemical detection circuit 100 according to an exemplary embodiment. The chemical detection circuit 100 includes a plurality of chemical sensors 101.1 -101. N (N may be an integer number larger than one, e.g., 1024, . 4096, etc.), a current source 108, an R-C filter formed by a resistor Rf 110 and a capacitor 1 12, a bypassing circuit for the resistor Rf 110 that may include a bypass switch 114 responsive to a Shunt Enable signal, a sample and hold switch 120, a bias resistor 122, a reference bias voltage 124, an output source-follower transistor 126, an output current source 128, a column select switch 130 and a column capacitor 132. Alternatively, other array configurations may be used.

[0040] In the schematic diagram, the bias resistor 122 represents the bulk resistance of a fluid flowing on top of the chemical detection circuit 100. The reference bias voltage 124 may provide a reference bias voltage to the fluid via a reference electrode (not shown). The output transistor 126 generates an output signal VOUT of a selected chemical sensor based on the voltage VSH on capacitor 112 when the column select switch 130 is closed (i.e., enabled). [0041] In some embodiments, the sample and hold switch 120 may be omitted. When the sample and hold switch 120 is provided, it may be switched on (i.e., closed) to connect the filter capacitor 112 to the output terminal of the selected chemical sensor in a selected row, and it provides isolation of the filter capacitor 112 from the selected chemical sensor during readout of the voltage VSH on the capacitor 112. The column capacitor 132 stores a voltage VOUT

representing the output signal of the selected chemical sensor and is generated by the output source-follower transistor 126 based on the voltage VSH- The column capacitor 132 may be a discrete capacitor, and/or represent inherent capacitance for the column bus.

[0042] In the illustrated embodiment, each chemical sensor (e.g., 101.1, ..., 101. N) includes a chemically-sensitive transistor (e.g., 102.1, ..., or 102.N, respectively) and two row select switches (e.g., 104.1 and 106.1 for sensor 101.1, or 104.N and 106.N for sensor 101. N, respectively). Each chemically-sensitive transistor 102.1-102.N has a gate terminal that may be covered by a chemically-sensitive passivation layer. In some embodiments, the gate terminal includes a floating gate structure sandwiched between a passivation layer and a gate oxide overlying the channel. During operation, the passivation layer may be exposed to an analyte solution (e.g., the fluid flowing on top of the chemical detection circuit 100) to be analyzed. Overlying the gate terminal of each chemical sensor (e.g., on top of the passivation layer), there may be a respective microwell for holding the fluid.

[0043] In the schematic diagram of FIG. 1 , the resistors 116.1-116.N represent the resistance of the fluid in each respective microwell. The capacitors 118.1—118.N represent the capacitance between the passivation layer and the gate terminal.

[0044] Each chemically-sensitive transistor 102.1-102.N has a first terminal coupled to a first side of a respective first row select switch 104.1-104.N, and a second terminal coupled to ground. In the example shown in Figure 1, the transistor 102.1 is PMOS with a first terminal (e.g., the source) connected to a first side of the first row select switch 104.1 and a second terminal (e.g., the drain) connected to ground. Each first row select switch (e.g., 104.1, ..., or 104.N) of each chemical detection pixel has a second side connected to the current source 108.

[0045] The first terminal of each chemically-sensitive transistor 102.1-102.N also serves as an output terminal of the respective sensors 101.1-101. N and are coupled to a second row select switch 106 (e.g., 106.1 to 106.N). Each pair of row select switches 104 and 106 (e.g., 104.1 and 106.1) may be controlled by a single row select signal.

[0046] When the bypass switch 114 is open, the resistor 110 and capacitor 112 form an R-C low pass filter which filters out fluidic noise and noise from other sources that could appear in the voltage VSH- The capacitor 112 of the R-C filter also serves as a sample and hold capacitor to accumulate charges to establish the voltage VSH based on the voltage at the output terminal of the selected sensor.

[0047] When the bypass switch 114 is open, the settling time for sampling the voltage at the output terminal of the selected sensor onto the capacitor 112 can be significantly slower than the settling time when the bypass switch 114 is closed, due to the resistor 110. In general, the settling time depends on the overall capacitance (e.g., capacitance of the capacitor 112, capacitance of the gate terminal of the output transistor 126, the column bus capacitance represented by the column capacitor 132) and the overall resistance (e.g., source impedance of the selected chemically-sensitive transistor of the chemical detection pixel and the resistor value of the filter resistor Rf 110). Closing the bypass switch 114 bypasses the resistor Rf 110 by provides a low resistance current path around the resistor 110. Doing so reduces the resistance of the signal path and thus the voltage VSH reaches the voltage at the output terminal of the selected sensor more quickly. This faster settling time can be, for example, for the first 1-2 micro-seconds of the sensor selection process.

[0048] FIG. 2 illustrates a simplified signal diagram for operating the chemical detection circuit of FIG. 1 according to an exemplary embodiment. In this example, the sensor 101.1 is the sensor selected for read out. As shown in Figure 2, a Shunt Enable signal that controls the bypass switch 114 may change from a logic low to high (i.e. to close the bypass switch 114 to bypass the resistor 110) at substantially at the same time as a Row Select signal that controls the row select switches 104.1 and 106.2 of the sensor 101 (i.e. to close the row select switches 104.1 and 106.2).

[0049] Also shown is a Sample and Hold (S/H) signal that controls the sample and hold switch 120. In the example in Figure 2, the S/H signal is enabled (e.g., set at a logic high state to close the switch 120) for substantially the same time period as the Row Select signal. Thus, in this embodiment, when a Row Select signal selects the sensor 101.1 to be read, the sample and hold switch 120 is closed to also allow charge to accumulate at the capacitor 112 to produce the voltage VSH based on the output terminal of the selected sensor 101.1. During the time the Shunt Enable signal is logic high, the bypass switch 114 is closed to bypass the resistor 110, which allows for fast settling of VSH to a first voltage value that may be close to the actual voltage at the output terminal of the selected sensor 101.1.

[0050] The relatively fast time constant (xfast) for settling while the bypass switch 114 is closed is determined by the source impedance of the transistor 102.1, the total capacitance of capacitors 112 and 132, and the capacitance of the gate terminal of the of the output transistor 126. In one embodiment, the total capacitance may be Ctotai 7.5pF, the source impendence may be 40k at a 3.8uA bias current and fast time constant Tfast may be 0.3 μ8.

[0051] The fast settling region during a first time interval of the chemical reaction detected by the sensor 101.1 (e.g., Tfast time period in Figure 2) may be used to quickly get the voltage VSH "close" to the actual value of the voltage at the source terminal of the transistor 102.1. For example, a 0.3 μ8 time constant may allow for 7 time constant settling in about 2 μ8. Further, the voltage on capacitor 112 after the fast settling region may be within 0.1% of the actual value, plus root mean square (RMS) noise at full bandwidth of a filter with the ¾st time constant. The RMS noise may be a statistical value of noise (e.g., a standard deviation).

[0052] As shown in FIG. 2, the bypass switch 114 is then opened during a second time interval by returning the Shunt Enable signal to a logic low. The opening of the bypass switch 114 forces the charge to flow through the resistor 110, which increases the setting time constant during this second time interval. However, since the voltage VSH at the start of the slow settling region (i.e. xsiow time period in Figure 2) may be very close to the actual value at the output terminal of the sensor 101.1, the overall settling time for reading the sensor 101.1 can still be quite fast. Also, 3 time-constants may decay away, for example, 95% of any residual error. Since residual error at the start of the slow settling region may be only, for example, 0.1%, residual error at the end of slow settling region may be only, for example, 0.005%. Further, the slow settling region may allow excess noise from the end of the fast settling to decay away. For example, RMS noise at the end of the fast settling region may be ~1 lOuV. After 3 time- constants of in the slow settling region, only 5.5uV RMS of this excess noise may remain on the sample and hold capacitor 112. In doing so, the chemical detection circuit 100 can allow more complete settling for each signal output and more tolerance to process variability in Rf value.

[0053] The bypass switch 114 may inject charge when it is disabled, but in embodiments this effect may be minimal. Any charge injected may decay away in the slow settling region.

Further, on-resistance of the bypass switch is small compared to the source impedance of the ISFET.

[0054] Operating the bypass switch 114 in parallel with the resistor 110 as described above enables a relatively quick overall setting time of the voltage VSH while the bypass switch is closed, while also allowing noise due to the fast settling to decay away when the bypass switch is open. In doing so, low-noise output signals of the sensors can be read out quickly and accurately. [0055] FIG. 3 illustrates a simplified signal diagram for operating the chemical detection circuit of FIG. 1 according to a second exemplary embodiment. In contrast to Figure 2, in Figure 3 both the transition of the S/H signal and Shunt Enabled signal may be delayed by a time tO after the Row Select signal. The sample and hold switch 120 is switched on (i.e., closed) so the filter capacitor 112 can respond to the selected row, and is switched off to provides isolation of the filter capacitor 112 from the chemical sensor during readout of the voltage VOUT to generate the voltage VOUT of the output signal. In an embodiment, the sample and hold switch 120 may be switched on (e.g., closed) when the Shunt Enabled signal goes from logic low to logic high. As a result, the output signal of a selected chemical sensor sampled on the capacitor 112 may start rising after the period of time tO from when the Row Select signal is enabled.

[0056] In one embodiment, the value of the resistor may be tuned by splitting the R-C filter resistor (e.g., the resistor 110 in FIG. 1) into two or more segments, with a shunt bypass switch across each one. FIG. 4 illustrates a schematic diagram of a chemical detection circuit according to a second exemplary embodiment that includes multiple resistors. As shown in Figure 4, the filter resistor 110 of the chemical detection circuit 100 may be replaced by multiple filter resistors 110'.1 to HO' .M, where M is an integer number larger than one. Each filter resistor 110' has a corresponding bypass circuit that includes a corresponding bypass switch 114'.

Programmatically enabling of one or more of these bypass switches may allow tuning of Rf- e.g., helping with process variability. Other components of the chemical detection circuit 400 corresponding to similar components of the chemical detection circuit 100 have the same reference numerals.

[0057] FIG. 5 illustrates a block diagram of components of a system for nucleic acid sequencing according to an exemplary embodiment. The components include a flow cell 501 on an integrated circuit device 500 including sensor array with chemical detection circuits as described herein, a reference electrode 508, a plurality of reagents 514 for sequencing, a valve block 516, a wash solution 510, a valve 512, a fluidics controller 518, lines 520/522/526, passages 504/509/511, a waste container 506, an array controller 524, and a user interface 528. The integrated circuit device 500 includes a microwell array 507 overlying a sensor array that includes sensors arranged in rows and columns. The flow cell 501 includes an inlet 502, an outlet 503, and a flow chamber 505 defining a flow path of reagents over the microwell array 507.

[0058] The reference electrode 508 may be of any suitable type or shape, including a concentric cylinder with a fluid passage or a wire inserted into a lumen of passage 511. The reagents 514 may be driven through the fluid pathways, valves, and flow cell 501 by pumps, gas pressure, or other suitable methods, and may be discarded into the waste container 506 after exiting the outlet 503 of the flow cell 501. The fluidics controller 518 may control driving forces for the reagents 514 and the operation of valve 512 and valve block 516 with suitable software.

[0059] The microwell array 507 may include an array of defined spaces or reaction confinement regions, referred to herein as microwells, which are operationally associated with corresponding sensors in the sensor array. For example, each microwell may be coupled to a sensor suitable for detecting an analyte or reaction property of interest within that microwell. The microwell array 507 may be integrated in the integrated circuit device 500, so that the microwell array 507 and the sensor array are on a single device or chip.

[0060] The flow cell 501 may have a variety of configurations for controlling the path and flow rate of reagents 514 over the microwell array 507. The array controller 524 provides bias voltages and timing and control signals to the integrated circuit 500 for reading the output signals of sensors of the sensor array using the techniques described herein. The array controller 524 also provides a reference bias voltage to the reference electrode 508 to bias the reagents 514 flowing over the microwell array 507.

[0061] The array controller 524 also collects and processes output signals from the sensors of the sensor array received through output ports on the integrated circuit device 500 via bus 527. The array controller 524 may be a computer or other computing means. The array controller 524 may include memory for storage of data and software applications, a processor for accessing data and executing applications, and components that facilitate communication with the various components of the system in FIG. 5.

[0062] The user interface 528 may display information about the flow cell 501 and the output signals received from the integrated circuit device 500, as well as instrument settings and controls, and allow a user to enter or set instrument settings and controls.

[0063] In an exemplary embodiment, the fluidics controller 518 may control delivery of the individual reagents 514 to the flow cell 501 and integrated circuit device 500 in a predetermined sequence, for predetermined durations, at predetermined flow rates. The array controller 524 can then collect and store the output signals of the sensors due to reactions occurring in response to the delivery of the reagents 514. The output signals indicate physical and/or chemical parameters of one or more reactions taking place in the corresponding microwells in the microwell array 507. In operation, the system may also monitor and control the temperature of the integrated circuit device 500, so that reactions take place and measurements are made at a known predetermined temperature. [0064] The system may be configured to let a single fluid or reagent contact the reference electrode 508 throughout an entire multi-step reaction. The valve 512 may be shut to prevent any wash solution 510 from flowing into passage 509 as the reagents 514 are flowing. Although the flow of wash solution may be stopped, there may still be uninterrupted fluid and electrical communication between the reference electrode 508, passage 509, and the microwell array 507. The distance between the reference electrode 508 and the junction between passages 509 and 511 may be selected so that little or no amount of the reagents flowing in passage 509 and possibly diffusing into passage 511 reach the reference electrode 508. In an exemplary embodiment, the wash solution 510 may be selected as being in continuous contact with the reference electrode 508, which may be especially useful for multi-step reactions using frequent wash steps.

[0065] FIG. 6 illustrates cross-sectional and expanded views of a portion of the integrated circuit device 500 and flow cell 501. During operating, the flow chamber 505 of the flow cell 501 confines a reagent flow 608 of delivered reagents across open ends of the microwells in the microwell array 507. The volume, shape, aspect ratio (such as base width-to-well depth ratio), and other dimensional characteristics of the microwells may be selected based on the nature of the reaction taking place, as well as the reagents, byproducts, or labeling techniques (if any) that are employed.

[0066] The expanded view of FIG. 6 illustrates a representative microwell 601 in the microwell array 607, and a corresponding sensor 614 in the sensor array 605. The sensor 614 can be a chemical field-effect transistor (chemFET), more specifically an ion-sensitive FET (ISFET), with a floating gate 618 having a sensor plate 620 separated from the microwell interior by an ion-sensitive layer 616. The sensor plate 620 may for example include multiple layers of conductive material. The ion-sensitive layer 616 may for example be an oxide of an upper layer of conductive material of the sensor plate 620.

[0067] The sensor 614 can be responsive to (and generate an output signal related to) the amount of a charge 624 present on ion-sensitive layer 616 opposite the sensor plate 620.

Changes in the charge 624 can cause changes in the threshold voltage of the chemFET. The change in threshold voltage can be measured by measuring the current between a source 621 and a drain 622 of the chemFET. As a result, the chemFET can be used directly to provide a current- based output signal on an array line connected to the source 621 or drain 622, or indirectly with additional circuitry to provide a voltage-based output signal. Reactants, wash solutions, and other reagents may move in and out of the microwells by a diffusion mechanism 640. [0068] In an embodiment, reactions carried out in the microwell 601 can be analytical reactions to identify or determine characteristics or properties of an analyte of interest. Such reactions can generate directly or indirectly byproducts that affect the amount of charge adjacent to the sensor plate 620. If such byproducts are produced in small amounts or rapidly decay or react with other constituents, multiple copies of the same analyte may be analyzed in the microwell 601 at the same time in order to increase the output signal generated. In an embodiment, multiple copies of an analyte may be attached to a solid phase support 612, either before or after deposition into the microwell 601. The solid phase support 612 may be microparticles, nanoparticles, beads, solid or porous comprising gels, or the like. For simplicity and ease of explanation, solid phase support 612 is also referred herein as a particle. For a nucleic acid analyte, multiple, connected copies may be made by rolling circle amplification (RCA), exponential RCA, or like techniques, to produce an amplicon without the need of a solid support.

[0069] FIG. 7 illustrates a block diagram of a chemical detection circuit 700 according to an embodiment of the present invention. The chemical detection circuit 700 may comprise a sensor array 702, a row select circuit 706, top and bottom column interfaces 704.1 and 704.2, and a data output circuit 708. The sensor array 702 may comprise a plurality of chemical sensors formed in columns and rows. Each column may include a plurality of chemical sensors as shown in Figure 1. The row select circuit 706 generate row select signals to selectively enable the row select switches of the chemical detection pixels. The top and bottom column interfaces 704.1 and 704.2 include circuits to read the output signals of the selected sensors from column buses using the techniques described herein and send the data to the data output circuit 708. These circuits include bypass switches arranged in parallel with resistors of R-C filter and operated as described herein.

[0070] In the illustrated embodiment, the sensor array 702 is divided into a top half and a bottom half (e.g., split arrays). For columns in the top half, output signals may be read out from the top column interface 704.1 and for columns in the bottom half, output signals may be read out from the bottom column interface 704.2. The data output circuit 708 may include multiplexers (e.g., one or more levels) to select data from one or more columns to serve as outputs of the chemical detection circuit 700.

[0071] The values of the output signals can then be analyzed by a computer or other computing means as described above to identify or determine characteristics or properties of an analyte of interest. For example, in an exemplary embodiment, the data processing system may be process the values of the output signals using the techniques disclosed in Rearick et al., U.S. Pat. Appl. No. 13/339,846, filed December 29, 2011, based on U.S. Prov. Pat. Appl. Nos.

61/428,743, filed December 30, 2010, and 61/429,328, filed January 3, 2011, and in Hubbell, U.S. Pat. Appl. No. 13/339,753, filed December 29, 2011, based on U.S. Prov. Pat. Appl. No 61/428,097, filed December 29, 2010, which are all incorporated by reference herein in their entirety.

[0072] The techniques described herein may be used with various nucleic acid sequencing techniques and apparatuses, including those described in U.S. Patent Application Publication No. 2010/0300559, No. 2010/0197507, No. 2010/0301398, No. 2010/0300895, No. 2010/0137143, and No. 2009/0026082, and U.S. Patent No. 7,575,865. Such sequencing platforms may involve sequencing-by-synthesis techniques that operate by the detection of inorganic pyrophosphate or hydrogen ions produced by nucleotide incorporation reactions. In some cases, the sensor array is a chemFET sensor array. In some cases, the chemFET sensors of the sensor array detect hydrogen ions. In some cases, flowing of the reagent(s) onto the sensor array causes chemical reactions that release hydrogen ions. In some cases, the amplitude of the signals from the chemFET sensors is related to the amount of hydrogen ions detected. In some cases, the sensor array is a light-sensing array. In some cases, flowing of the reagent(s) onto the sensor array causes chemical reactions that release inorganic pyrophosphate, which causes the emission of light via an enzyme cascade initiated by the inorganic pyrophosphate.

[0073] FIG. 8 is a flow chart of an example process for generating an output signal from a chemical sensor according to an exemplary embodiment. Other embodiments may perform the steps in different orders and/or perform different or additional steps than the ones illustrated in FIG. 8.

[0074] At step 802, a chemical reaction is initiated in proximity to a chemical sensor. The chemical sensor may be a chemFET as described above, and the chemical reaction may be a sequencing reaction as described above.

[0075] At step 804, a bypass switch placed in parallel with a resistor and arranged between an output terminal of the chemical sensor and a capacitor is closed during a first time interval of the chemical reaction. In doing so, the capacitor is charged to a first voltage based on a voltage at the output terminal due to the chemical reaction.

[0076] At step 806, the bypass switch is opened during a second time interval of the chemical reaction. In doing do, the capacitor is further charged to a second voltage based on the voltage at the output terminal. [0077] At step 808, an output signal is generated for the chemical sensor based on the second voltage on the capacitor. The value of the output signal can then be collected, stored and analyzed by a data processing system as described above to identify or determine characteristics or properties of the chemical reaction.

[0078] Various embodiments may be implemented using hardware elements, software elements, or a combination of both. Examples of hardware elements may include processors, microprocessors, circuits, circuit elements (e.g., transistors, resistors, capacitors, inductors, and so forth), integrated circuits, application specific integrated circuits (ASIC), programmable logic devices (PLD), digital signal processors (DSP), field programmable gate array (FPGA), logic gates, registers, semiconductor device, chips, microchips, chip sets, and so forth. Examples of software may include software components, programs, applications, computer programs, application programs, system programs, machine programs, operating system software, middleware, firmware, software modules, routines, subroutines, functions, methods, procedures, software interfaces, application program interfaces (API), instruction sets, computing code, computer code, code segments, computer code segments, words, values, symbols, or any combination thereof. Determining whether an embodiment is implemented using hardware elements and/or software elements may vary in accordance with any number of factors, such as desired computational rate, power levels, heat tolerances, processing cycle budget, input data rates, output data rates, memory resources, data bus speeds and other design or performance constraints.

[0079] Some embodiments may be implemented, for example, using a computer-readable medium or article which may store an instruction or a set of instructions that, if executed by a machine, may cause the machine to perform a method and/or operations in accordance with the embodiments. Such a machine may include, for example, any suitable processing platform, computing platform, computing device, processing device, computing system, processing system, computer, processor, or the like, and may be implemented using any suitable combination of hardware and/or software. The computer-readable medium or article may include, for example, any suitable type of memory unit, memory device, memory article, memory medium, storage device, storage article, storage medium and/or storage unit, for example, memory, removable or non-removable media, erasable or non-erasable media, writeable or re-writeable media, digital or analog media, hard disk, floppy disk, read-only memory compact disc (CD-ROM), recordable compact disc (CD-R), rewriteable compact disc (CD-RW), optical disk, magnetic media, magneto-optical media, removable memory cards or disks, various types of Digital Versatile Disc (DVD), a tape, a cassette, or the like. The instructions may include any suitable type of code, such as source code, compiled code, interpreted code, executable code, static code, dynamic code, encrypted code, and the like, implemented using any suitable high-level, low-level, object-oriented, visual, compiled and/or interpreted programming language.

[0080] Those skilled in the art may appreciate from the foregoing description that the present teachings may be implemented in a variety of forms, and that the various embodiments may be implemented alone or in combination. Therefore, while the embodiments of the present teachings have been described in connection with particular examples thereof, the true scope of the embodiments and/or methods of the present teachings should not be so limited since other modifications will become apparent to the skilled practitioner upon a study of the drawings, specification, and following claims.

Claims

CLAIMS What is claimed is:
1. A chemical detection circuit, comprising:
a chemical sensor comprising:
a chemically-sensitive transistor having an output terminal; and
a row-select switch coupled to the output terminal of the chemically-sensitive transistor;
an R-C filter coupled to the output terminal of the chemically-sensitive transistor via the row-select switch; and
a bypass circuit comprising a bypass switch arranged in parallel with a resistor of the R-C filter.
2. The chemical detection circuit of claim 1, wherein the chemically-sensitive transistor is an ion-sensitive field effect transistor (ISFET).
3. The chemical detection circuit of claim 1, wherein the chemical sensor is one of a column of chemical sensors in an array.
4. The chemical detection circuit of claim 3, wherein a current source is shared by all chemical detection pixels of the column in the array.
5. The chemical detection circuit of claim 3, wherein the R-C filter and the bypass circuit are shared by all chemical detection pixels of the column.
6. The chemical detection circuit of claim 1, wherein the R-C filter comprises a capacitor that samples a voltage at the output terminal of the chemically-sensitive transistor.
7. The chemical detection circuit of claim 1, wherein the resistor of the R-C filter comprises multiple segments and the bypass circuit comprises respective bypass switches for resistors in each segment.
8. A method for operating a chemical sensor, the method comprising:
initiating a chemical reaction proximate to the chemical sensor; during a first time interval of the chemical reaction, closing a bypass switch placed in parallel with a resistor and arranged between an output terminal of the chemical sensor and a capacitor, thereby charging the capacitor to a first voltage based on a voltage at the output terminal due to the chemical reaction;
opening the bypass switch during a second time interval of the chemical reaction, thereby further charging the capacitor to a second voltage based on the voltage at the output terminal; and
generating an output signal for the chemical sensor based on the second voltage on the capacitor.
9. The method of claim 8, wherein the capacitor is charged at a first time constant while the bypass switch is closed, and charged at a second time constant while the bypass switch is open.
10. The method of claim 8, wherein initiating the chemical reaction comprises initiating a sequencing reaction.
11. The method of claim 10, wherein initiating the sequencing reaction comprises:
disposing a plurality of template nucleic acids in a reaction well coupled to the chemical sensor; and
introducing known nucleotides into the reaction well.
12. The method of claim 11, wherein the voltage at the output terminal of the chemical sensor indicates incorporation of the introduced known nucleotides into at least one of the template nucleic acids.
13. The method of claim 12, further comprising analyzing the output signal to determine at least a portion of sequences corresponding to a portion of the template nucleic acids.
14. The method of claim 8, wherein the voltage at the output terminal of the chemical sensor is due to byproducts from the chemical reaction
15. The method of claim 8, wherein the chemical reaction occurring within a solution coupled to the chemical sensor.
16. The method of claim 8, wherein the chemical sensor is a chemically-sensitive field effect transistor (chemFET), and the voltage at the output terminal is based on a threshold voltage of the chemFET.
17. The method of claim 16, wherein the chemFET includes a floating gate coupled to a reaction well containing the chemical reaction.
18. The method of claim 8, wherein the voltage at the output terminal is due to a change in ion-concentration within a solution containing the chemical reaction.
PCT/US2012/058996 2011-10-05 2012-10-05 Bypass for r-c filter in chemical sensor arrays WO2013052825A1 (en)

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