Methods for operating an array of chemically-sensitive sensors

• US 8,658,017 B2
• Filed: 07/20/2012
• Issued: 02/25/2014
• 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, Hinz, Wolfgang, Johnson, Kim, Bustillo, James
• Primary Examiner(s): Ball, J. Christopher
• Application Number:
  US13/554,900
• Publication Number:
  US 20120289413A1
• Time in Patent Office: 585 Days
• Field of Search: 257/253, 205/789, 205/792, 205/793.5, 422 8201- 8203, 435/6, 435/285.1, 435/287.1, 435/287.2, 436103-105, 436/150, 436/182, 506/1, 506/9
• US Class Current: 205/793.5
• 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. A method of operating an apparatus comprising an array of chemically sensitive sensors arranged in rows and columns, comprising:

producing signal samples in a plurality of sensors of the array in response to a first timing signal;

enabling an output circuit coupled to the plurality of sensors in response to a select signal;

outputting the signal samples to the output circuit from the plurality of sensors; and

applying a reference voltage to a reference cell, and outputting a reference signal to the output circuit from the reference cell.

2. The method of claim 1, including applying a chemical sample and a reference electrode to chemical sample wells coupled to the plurality of sensors.

3. The method of claim 1, wherein each sensor in the array comprises a chemically-sensitive field effect transistor (chemFET) including a floating gate and a passivation layer, and the signal samples indicate an ion-concentration in an analyte solution coupled to the corresponding floating gates via the passivation layers.

4. The method of claim 1, including performing a calibration process to determine the reference voltage.

5. The method of claim 1, wherein the plurality of sensors comprises a column of chemically-sensitive field effect transistors (chemFETs), each having a floating gate structure coupled to a corresponding chemical sample well, and wherein the reference cell comprises an extra chemFET in the column having a floating gate structure tied to a reference voltage connector.

6. The method of claim 1, wherein the plurality of sensors comprises a row of chemically-sensitive field effect transistors (chemFETs), each having a floating gate structure coupled to a corresponding chemical sample well, and wherein the reference cell comprises an extra chemFET in the row having a floating gate structure tied to a reference voltage connector.

7. The method of claim 1, further comprising:

disposing a plurality of template nucleic acids in chemical sample wells for the plurality of sensors of the array; and

synthesizing a new nucleic acid strand from at least one template nucleic acid disposed in the chemical sample wells by incorporating one or more known nucleotides to the at least one template nucleic acid, and wherein the signal samples produced by the plurality of sensors indicate incorporation of the one or more known nucleotides.

8. The method of claim 7, further comprising using the signal samples produced by the plurality of sensors to determine at least a portion of a sequence of the new nucleic acid strand.

9. The method of claim 8, further comprising using the reference signal from the reference cell to determine the portion of the sequence.

10. A method of operating an apparatus comprising an array of cells comprising field effect transistors (FETs), the method comprising:

operating FETs of cells in a reference portion of the array as dummy sensors to produce reference signals;

operating FETs of cells in an active portion of the array coupled to corresponding chemical sample wells to produce signal samples; and

using the reference signals from the FETs of cells in the reference portion to calibrate operation of the FETs of cells in the active portion of the array.

11. The method of claim 10, wherein the FETs of cells in the reference portion and in the active portion include floating gate structures, and operating FETs of the cells in the reference portion of the array includes applying a reference voltage to their floating gate structures.

12. The method of claim 10, wherein the array is arranged in rows and columns, and wherein the reference portion includes a column of cells in the array.

13. The method of claim 10, wherein the array is arranged in rows and columns, and wherein the reference portion includes a column of cells in the array, and operating the cells in the active portion and in the reference portion of the array includes selectively connecting the cells in corresponding columns of the array to column output circuits, including a column output circuit selectively connectable to the cells in the column in the reference portion.

14. The method of claim 10, wherein the array is arranged in rows and columns, and wherein the reference portion includes a row of cells in the array.

15. The method of claim 10, wherein the array is arranged in rows and columns, and wherein the reference portion includes a row of cells in the array, and operating the cells in the active portion and in the reference portion of the array includes selectively connecting the cells in rows of the array to corresponding column output circuits, including a cell in the row in the reference portion.

16. The method of claim 10, further comprising:

disposing a plurality of template nucleic acids in chemical sample wells for FETs in the active portion of the array; and

synthesizing a new nucleic acid strand from at least one template nucleic acid disposed in the chemical sample wells by incorporating one or more known nucleotides to the at least one template nucleic acid, and wherein the signal samples produced by the cells in the active region indicate incorporation of the one or more known nucleotides.

17. The method of claim 16, further comprising using the signal samples produced by the cells in the active portion to determine at least a portion of a sequence of the new nucleic acid strand.

18. The method of claim 16, further comprising using the reference signals from the cells in the reference portion to determine at least a portion of a sequence of the new nucleic acid strand.

19. The method of claim 10, including selecting a cell in a row in the array using a column select signal.

20. The method of claim 10, including activating cells in the array using a row select signal.

21. The method of claim 10, wherein operating the cells in the active portion and in the reference portion of the array includes connecting selected cells to a sample and hold capacitor using a column select switch.

22. The method of claim 10, wherein including applying a reference voltage to an analyte solution in the chemical sample wells of the cells in the active portion.

23. The method of claim 10, wherein the FETs in the cells in the active portion have thresholds that indicate an ion-concentration in an analyte solution in the chemical sample wells.