Methods and apparatus for measuring analytes using large scale FET arrays

• US 9,269,708 B2
• Filed: 09/26/2011
• Issued: 02/23/2016
• Est. Priority Date: 12/14/2006
• Status: Active Grant

• Current Assignee: Life Technologies Corporation (Thermo Fisher Scientific Incorporated)
• Original Assignee: Life Technologies Corporation (Thermo Fisher Scientific Incorporated)
• Inventors: Rothberg, Jonathan M., Hinz, Wolfgang, Johnson, Kim L., Bustillo, James
• Primary Examiner(s): GORDON, MATTHEW E
• Application Number:
  US13/245,675
• Publication Number:
  US 20120034607A1
• Time in Patent Office: 1,611 Days
• Field of Search: 257/253, 257/E23.08, 438/10
• US Class Current: 1/1
• CPC Class Codes: C12Q 1/6818 involving interaction of two or more labels, e.g. resonant energy transfer
• CPC Class Codes: C12Q 1/6874 involving nucleic acid arrays, e.g. sequencing by hybridisation
• CPC Class Codes: C12Q 2533/101 Primer extension
• CPC Class Codes: C12Q 2565/301 Pyrophosphate (PPi)
• CPC Class Codes: C12Q 2565/607 being a sensor, e.g. electrode
• CPC Class Codes: G01N 27/4145 specially adapted for biomolecules, e.g. gate electrode with immobilised receptors
• CPC Class Codes: G01N 27/4148 Integrated circuits therefor, e.g. fabricated by CMOS processing CMOS processing per se H01L21/82
• CPC Class Codes: G01N 33/54373 involving physiochemical end-point determination, e.g. wave-guides, FETS, gratings
• CPC Class Codes: G01N 33/5438 Electrodes
• CPC Class Codes: H01L 27/088 the components being field-effect transistors with insulated gate
• CPC Class Codes: H01L 29/42324 Gate electrodes for transistors with a floating gate
• CPC Class Codes: H01L 29/78 with field effect produced by an insulated gate H01L29/7725, H01L29/775, H01L29/778 take precedence
• CPC Class Codes: H01L 2924/01006 Carbon [C]
• CPC Class Codes: H01L 2924/01013 Aluminum [Al]
• CPC Class Codes: H01L 2924/01015 Phosphorus [P]
• CPC Class Codes: H01L 2924/01073 Tantalum [Ta]
• CPC Class Codes: H01L 2924/14 Integrated circuits
• CPC Class Codes: H01L 2924/1433 Application-specific integrated circuit [ASIC]
• CPC Class Codes: Y10T 436/22 Hydrogen, per se

Abstract

Methods and apparatus relating to very large scale FET arrays for analyte measurements. ChemFET (e.g., ISFET) arrays may be fabricated using conventional CMOS processing techniques based on improved FET pixel and array designs that increase measurement sensitivity and accuracy, and at the same time facilitate significantly small pixel sizes and dense arrays. Improved array control techniques provide for rapid data acquisition from large and dense arrays. Such arrays may be employed to detect a presence and/or concentration changes of various analyte types in a wide variety of chemical and/or biological processes. In one example, chemFET arrays facilitate DNA sequencing techniques based on monitoring changes in hydrogen ion concentration (pH), changes in other analyte concentration, and/or binding events associated with chemical processes relating to DNA synthesis.

Claims

1. An apparatus, comprising:

an array of sensors arranged in a plurality of rows and a plurality of columns, sensors in the array of sensors including a corresponding chemically-sensitive field-effect transistor (chemFET);

a plurality of microwells associated with the array of sensors;

circuitry for accessing sensors in the array of sensors, the circuitry including;

a row select circuit responsive to a first input signal to apply a sequence of shifted row select signals, wherein a given row select signal is applied to enable reading of one or more sensors in a corresponding row in the plurality of rows, and

a column select circuit responsive to a second input signal to apply a sequence of shifted column select signals during application of the row select signals, wherein a given column select signal is applied to acquire an output signal produced by an enabled sensor in a corresponding column in the plurality of columns; and

readout circuitry including;

a buffer amplifier having an input and an output, and

a plurality of switches coupled between at least two columns of the plurality of columns and the input of the buffer amplifier, wherein switches in the plurality of switches are responsive to corresponding column select signals to selectively provide output signals generated by enabled sensors in the at least two columns to the input of the buffer amplifier.

2. The apparatus of claim 1, wherein:

the row select circuit includes at least one row select shift register to produce the row select signals sequentially shifted by a first time interval;

the column select circuit includes at least one column shift register to produce the column select signals sequentially shifted by a second time interval.

3. The apparatus of claim 2, wherein the at least one row select shift register comprises a plurality of row select shift registers that simultaneously select sensors in at least two rows from the plurality of rows.

4. The apparatus of claim 2, wherein the at least one column shift register comprises a plurality of column shift registers that simultaneously acquire output signals from sensors in at least two columns of the plurality of columns.

5. The apparatus of claim 1, wherein the output of the buffer amplifier upon applying the shifted row select signals and the shifted column select signals constitutes at least a portion of a frame of data, and wherein the data is generated at a rate of at least 10 frames per second.

6. The apparatus of claim 1, wherein the output signal is a voltage signal measured with respect to a voltage of a reference electrode.

7. The apparatus of claim 1, wherein output signals produced by the array of sensors upon applying the shifted row select signals and the shifted column select signals constitutes a frame of data, and wherein the data is generated at a rate of at least 10 frames per second.

8. The apparatus of claim 1, wherein the chemFET is an ion-sensitive field-effect transistor (ISFET) with a threshold voltage that changes based on a chemical reaction occurring in at least one associated microwell in the plurality of microwells.

9. The apparatus of claim 8, wherein the chemical reaction comprises liberation of hydrogen ions, and an output signal of the ISFET indicates changes in hydrogen ion concentration in the at least one associated microwell.

10. The apparatus of claim 1, wherein the plurality of rows comprises at least 512 rows and the plurality of columns comprises at least 512 columns.

11. The apparatus of claim 1, wherein each of the columns in the plurality of columns is coupled to a corresponding column circuit that provides a drain current and a drain-to-source voltage to each of the FETs of the sensors in a column of the array of sensors.

12. The apparatus of claim 1, wherein each column select signal in the sequence of shifted column select signals is applied during application of each of the row select signals.

13. The apparatus of claim 1, further comprising readout circuitry to read output signals corresponding to voltage levels at first terminals of chemFETs of sensors in the array of sensors, and wherein respective sensors in the array of sensors further include a corresponding first switch responsive to a corresponding row select signal in the sequence of row select signals to couple the first terminal of the corresponding chemFET to the readout circuitry.

14. The apparatus of claim 13, wherein respective sensors in the array of sensors further include a corresponding second switch responsive to the corresponding row select signal to couple the corresponding chemFET to a current source that provides a bias current, the bias current establishing the voltage level at the first terminal of the corresponding chemFET based on a threshold voltage of the corresponding chemFET.

15. The apparatus of claim 14, wherein the first switch and the second switch of respective sensors are each single-transistor switches having channel types the same as that of the corresponding chemFET.

16. The apparatus of claim 1, wherein the given row select signal enables reading of a plurality of sensors in the corresponding row.

17. The apparatus of claim 1, wherein the given row select signal enables reading of each sensor in the corresponding row.

18. An apparatus comprising:

an array of sensors arranged in a plurality of rows and a plurality of columns, sensors in the array of sensors including a corresponding chemically-sensitive field-effect transistor (chemFET);

a plurality of microwells associated with the array of sensors;

circuitry for accessing sensors in the array of sensors, the circuitry including;

a row select circuit responsive to a first input signal to apply a sequence of shifted row select signals, wherein a given row select signal is applied to enable reading of one or more sensors in a corresponding row in the plurality of rows, and

a column select circuit responsive to a second input signal to apply a sequence of shifted column select signals during application of the row select signals, wherein a given column select signal is applied to acquire an output signal produced by an enabled sensor in a corresponding column in the plurality of columns; and

bias circuitry including a plurality of amplifiers and a diode-connected FET arranged in a Kelvin bridge configuration to establish a voltage difference between sources and drains of chemFET of sensors in the array of sensors.