Chemically-sensitive array with active and reference sensors

• US 8,519,448 B2
• Filed: 07/23/2012
• Issued: 08/27/2013
• 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): Le, Thao
• Assistant Examiner(s): GORDON, MATTHEW E
• Application Number:
  US13/556,021
• Publication Number:
  US 20120279859A1
• Time in Patent Office: 400 Days
• Field of Search: 253/253, 253/E23.08, 438/10
• US Class Current: 257/253
• 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 chemically sensitive sensors having corresponding chemical sample wells, each sensor in the plurality including a field effect transistor (FET) having a floating gate structure coupled to a corresponding chemical sample well;

at least one reference cell, the reference cell including a FET having a floating gate structure directly coupled to a reference voltage line; and

an output circuit, sensors in the array and the reference cell selectively connectable to the output circuit.

2. The apparatus of claim 1, wherein the sensors in the array are arranged in rows and columns, a column including a plurality of sensors, and the output circuit is selectively connectable via a switch to the outputs of the plurality of sensors in the column, and to the at least one reference cell.

3. The apparatus of claim 1, wherein the at least one reference cell emulates the sensors in the array.

4. The apparatus of claim 1, wherein the output circuit includes a sample and hold capacitor, and a column select switch between a node coupled to the outputs of the plurality of sensors in a column of the array and the column sample and hold capacitor.

5. The apparatus of claim 1, including a reference electrode coupled to said corresponding chemical sample wells.

6. The apparatus of claim 1, wherein the FETs in each of the sensors include a passivation layer on the floating gate structure, and have a threshold voltage that indicates an ion-concentration in an analyte solution in the chemical sample well coupled to the floating gate via the passivation layer.

7. The apparatus of claim 1, including circuitry coupled to the array and the output circuit to produce signals that connect a plurality of sensors in the array and the at least one reference cell to an output driver in a sequence.

8. The apparatus of claim 1, wherein the array is arranged in rows and columns, a column including a plurality of sensors, and wherein the at least one reference cell is disposed in the array in an extra row in the column.

9. The apparatus of claim 1, wherein the array is arranged in rows and columns, a column including a plurality of sensors, the output circuit being selectively connectable via a switch to outputs of the plurality of sensors in the column, and to the at least one reference cell, and including circuitry coupled to the array, the output circuit and the switch, which produces signals that connect the plurality of sensors in the column and the at least one reference cell to the output driver in a sequence.

10. The apparatus of claim 1, wherein the array is arranged in rows and columns, a row including a plurality of sensors, and wherein the at least one reference cell is disposed in the array in an extra column in the row.

11. The apparatus of claim 1, wherein the array arranged in rows and columns, a row including a plurality of sensors, the output circuit being selectively connectable via a switch to the outputs of the plurality of sensors in the row, and to the at least one reference cell, and including circuitry coupled to the array, the output circuit and the switch, which produces signals that connect the plurality of sensors in the row and the at least one reference cell to the output circuit in a sequence.

12. An apparatus, comprising:

a sensor array having an active portion of sensors and a reference portion of sensors, sensors in the array each having a field effect transistor (FET) with a floating gate structure, the floating gate structures being directly coupled to a reference voltage line the sensors in the reference portion being reference sensors, and the sensors in the active portion having their floating gate structures coupled to a chemical sample well; and

an output circuit selectively connectable to the sensors in the reference portion and to the sensors in the active portion.

13. The apparatus of claim 12, wherein the reference portion is around a perimeter of the sensor array.

14. The apparatus of claim 12, including reference voltage connectors connected to the floating gate structures of sensors in the reference portion of the array.

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

16. The apparatus of claim 12, wherein the array is arranged in rows and columns, and wherein the reference portion includes a column in the array, and including a plurality of column output drivers being selectively connectable to the sensors in corresponding columns of the array, including a column output circuit selectively connectable to the sensors in the column in the reference portion.

17. The apparatus of claim 12, wherein the sensor is arranged in rows and columns, and wherein the reference portion includes a row in the array.

18. The apparatus of claim 12, wherein the array is arranged in rows and columns, and wherein the reference portion includes a row in the array, and wherein the output circuit is selectively connectable to the outputs of the plurality of sensors in a column of the array, and a sensor in the row in the reference portion.

19. The apparatus of claim 12, wherein each sensor in the array is coupled to a column output buffer, coupled to a column select switch.

20. The apparatus of claim 12, including a column select switch between a node coupled to the outputs of the plurality of sensors in a column of the array and the output circuit.

21. The apparatus of claim 12, including a sample and hold capacitor and a column select switch between a node coupled to the outputs of the plurality of sensors in a column of the array and the sample and hold capacitor.

22. The apparatus of claim 12, including a reference electrode coupled to said chemical sample wells in the active portion of the array.

23. The apparatus of claim 12, wherein the FETs in the sensors in the active portion of the array have threshold voltages that indicate an ion-concentration in an analyte solution in the corresponding chemical sample well.

24. The apparatus of claim 12, including circuitry coupled to the array which produces row and column select signals for access to the sensors in the active portion and to the sensors in the reference portion.