Methods and apparatus for measuring analytes using large scale FET arrays

• US 8,269,261 B2
• Filed: 02/08/2011
• Issued: 09/18/2012
• 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): Le, Thao
• Assistant Examiner(s): GORDON, MATTHEW E
• Application Number:
  US13/022,694
• Publication Number:
  US 20120040844A1
• Time in Patent Office: 588 Days
• Field of Search: 257/253, 257/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:

a sensor array of at least 10⁵ sensors formed in the substrate, the sensors having a pitch distance of not more than 10 microns;

at least one of the sensors in the array defining a chemFET having a gate oxide with a characteristic thickness, a floating gate, and a characteristic threshold voltage;

wherein the characteristic threshold voltage of the chemFET is affected by a trapped charge; and

wherein the characteristic thickness of the gate oxide is selected to reduce the trapped charge in the sensor by allowing a trapped charge to pass through the gate oxide onto the substrate.

2. The apparatus of claim 1, wherein the gate oxide thickness is permissible to trapped charge flowing to the substrate.

3. The apparatus of claim 1, where the thickness of the gate oxide is approximately 75 Angstroms.

4. The apparatus of claim 1, where the characteristic threshold voltage of a respective chemFET sensor is similar to that of characteristic threshold voltages for at least one other chemFETs in the sensor array.

5. The apparatus of claim 1, further comprising a control circuitry configured to detect a plurality of output signals corresponding to a plurality of the sensors, wherein the output signal depends at least in part on the characteristic threshold voltage for a respective sensor of the sensor array.

6. The apparatus of claim 5, wherein the output signals from the plurality of sensors are substantially similar in response.

7. The apparatus of claim 5, wherein the plurality of sensors of the sensor array are substantially similar in sensitivity.

8. The apparatus of claim 5, wherein the control circuitry further comprises at least one analog-to-digital converter.

9. The apparatus of claim 5, wherein the sensor array and at least a portion of the control circuitry are formed on a single substrate.

10. The apparatus of claim 1, further comprising an array of reaction chambers coupled to the sensor array.

11. The apparatus of claim 10, wherein the plurality of output signals are generated in response to the presence of analytes in the corresponding reaction chambers.

12. The apparatus of claim 11, wherein the analytes comprise hydrogen ions.

13. The apparatus of claim 11, wherein the analytes comprise byproducts of a chemical reaction.

14. The apparatus of claim 13, wherein the chemical reaction comprises nucleotide incorporation into a sample nucleic acid template.

15. A detection system, comprising:

an array of at least 10⁵ FET sensors forming a FET sensor array arranged in columns and rows, each FET sensor separated from an adjacent FET sensor by a pitch distance of not more than 10 microns;

an array of wells formed on a substrate, a plurality of the wells in the array of wells corresponding to a plurality of sensors in the FET array;

wherein the array of wells is not more than 7 mm by 7 mm in surface area; and

wherein at a first well is coupled to a first FET sensor such that a reaction by-product in the first well is communicated to the first sensor.

16. The detection system of claim 15, wherein the reaction by-product is one of an electromagnetic charge or a chemical.

17. The detection system of claim 15, wherein the first FET sensor further comprises a floating gate, a gate oxide layer and a source electrode.

18. The detection system of claim 15, further comprising a controller for receiving a signal from the first FET, the signal generated as a result of the reaction by-product communicated to the first FET.

20. The detection system of claim 18, further comprising a passivation layer formed on a first detection well, the passivation layer detecting presence of an analyte and communicating the presence to a corresponding first sensor.

19. A detection system, comprising:

a control circuit in communication with a CMOS detector formed in a substrate, the CMOS detector having an array of at least 10⁵ sensors arranged to correspond with and communicate with an array of detection wells in which the wells are arranged to have a pitch distance of about 10 microns or less; and

a gate oxide layer interposed between a source electrode and a floating gate of a first sensor of the array;

wherein the characteristic thickness of the gate oxide is selected to reduce a trapped charge in the sensor by allowing a trapped charge to pass through the gate oxide onto the substrate.