Methods and apparatus for measuring analytes using large scale FET arrays

• US 8,426,899 B2
• Filed: 02/02/2011
• Issued: 04/23/2013
• 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 M., Hinz, Wolfgang, Johnson, Kim L., Bustillo, James
• Primary Examiner(s): Le, Thao
• Assistant Examiner(s): GORDON, MATTHEW E
• Application Number:
  US13/019,692
• Publication Number:
  US 20120322054A1
• Time in Patent Office: 811 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 integrated circuit sensor for detecting byproducts of a plurality of reactions, comprising:

a sensor array comprising at least 10⁵ field-effect transistor based sensors, the sensors having a floating gate with an analyte-sensitive layer that provide threshold voltage dependent output signals wherein the trapped charge of each floating gate is such that the threshold voltage is similar for at least some of the sensors in response to detecting substantially the same amount of reaction byproduct;

a plurality of reaction chambers for containing separate reactions coupled to the sensor array.

2. The integrated circuit sensor of claim 1, further comprising control circuitry coupled to the sensor array to receive samples of the output signals from said field effect transistors at a rate of approximately twenty samples per second or more during detection of reaction.

3. The integrated circuit sensor of claim 2, wherein the sensor array detects nucleic acid sequencing byproducts and the control circuitry associates detected sequencing byproducts with the composition of the sample.

4. The integrated circuit sensor of claim 3, wherein the sensor array detects nucleic acid sequencing byproducts as known nucleotides are introduced into the plurality of reaction chambers and the control circuitry associates detected sequencing byproducts with the composition of the sample.

5. The integrated circuit sensor of claim 1, wherein said sensors of said sensor array have a pitch of 10 μ

m or less.

6. The integrated circuit sensor of claim 1, wherein said byproduct is hydrogen ions.

7. The integrated circuit sensor of claim 6, wherein said output signal of each of said sensors represents changes in said hydrogen ion concentration within a range of from approximately pH 7 to pH 9.

8. The integrated circuit sensor of claim 1, wherein the sensor array detects nucleic acid sequencing byproducts.

9. A sensor for detecting reaction byproducts of at least 10⁵ nucleic acid sequencing reactions, comprising:

a sensor array comprising a plurality of chemFET sensors each having a floating gate with an analyte-sensitive layer that provides threshold voltage dependent output signals in response to detecting substantially the same amount of reaction byproduct; and

a plurality of reaction chambers for containing separate nucleic acid sequencing reactions coupled to the sensor array.

10. The sensor of claim 9, further comprising control circuitry coupled to the sensor array to receive samples of the output signals from the chemFETs at a rate of approximately twenty samples per second or more during detection of reaction.

11. The sensor of claim 10, wherein the sensor array detects nucleic acid sequencing byproducts and the control circuitry associates detected sequencing byproducts with the sequence of a nucleic acid sample contained within a respective reaction chamber.

12. The sensor of claim 11, wherein the sensor array detects nucleic acid sequencing byproducts as known nucleotides are introduced into the plurality of reaction chambers and the control circuitry associates detected sequencing byproducts with the sequence of a nucleic acid sample contained within a respective reaction chamber.