Methods and apparatus for measuring analytes using large scale FET arrays

• US 8,535,513 B2
• Filed: 09/14/2012
• Issued: 09/17/2013
• 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): Ball, J. Christopher
• Application Number:
  US13/616,454
• Publication Number:
  US 20130017959A1
• Time in Patent Office: 368 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- 15, 436/150, 436/182, 506/1, 506/9
• US Class Current: 205/793.5
• CPC Class Codes: C12Q 1/6869 Methods for sequencing
• 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 27/414 Ion-sensitive or chemical field-effect transistors, i.e. ISFETS or CHEMFETS
• 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: H01L 21/306 Chemical or electrical treatment, e.g. electrolytic etching to form insulating layers H01L21/31
• CPC Class Codes: H01L 2224/04105 Bonding areas formed on an encapsulation of the semiconductor or solid-state body, e.g. bonding areas on chip-scale packages
• CPC Class Codes: H01L 2224/16 of an individual bump connector
• CPC Class Codes: H01L 2224/76155 Jetting means, e.g. ink jet
• CPC Class Codes: H01L 2224/82102 using jetting, e.g. ink jet
• CPC Class Codes: H01L 24/18 High density interconnect [HDI] connectors; Manufacturing methods related thereto interconnection structure between a plurality of semiconductor chips H01L23/5389
• CPC Class Codes: H01L 24/20 Structure, shape, material or disposition of high density interconnect preforms
• CPC Class Codes: H01L 24/82 by forming build-up interconnects at chip-level, e.g. for high density interconnects [HDI] interconnection structure between a plurality of semiconductor chips H01L23/5389
• CPC Class Codes: H01L 27/088 the components being field-effect transistors with insulated 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 2924/00 Indexing scheme for arrangements or methods for connecting or disconnecting semiconductor or solid-state bodies as covered by H01L24/00
• CPC Class Codes: H01L 2924/01005 Boron [B]
• CPC Class Codes: H01L 2924/01006 : Carbon [C]
• CPC Class Codes: H01L 2924/01011 : Sodium [Na]
• CPC Class Codes: H01L 2924/01012 : Magnesium [Mg]
• CPC Class Codes: H01L 2924/01013 : Aluminum [Al]
• CPC Class Codes: H01L 2924/01015 : Phosphorus [P]
• CPC Class Codes: H01L 2924/01019 : Potassium [K]
• CPC Class Codes: H01L 2924/0102 : Calcium [Ca]
• CPC Class Codes: H01L 2924/01023 : Vanadium [V]
• CPC Class Codes: H01L 2924/01024 : Chromium [Cr]
• CPC Class Codes: H01L 2924/01027 : Cobalt [Co]
• CPC Class Codes: H01L 2924/01029 : Copper [Cu]
• CPC Class Codes: H01L 2924/0103 : Zinc [Zn]
• CPC Class Codes: H01L 2924/01033 : Arsenic [As]
• CPC Class Codes: H01L 2924/01046 : Palladium [Pd]
• CPC Class Codes: H01L 2924/01047 : Silver [Ag]
• CPC Class Codes: H01L 2924/01052 : Tellurium [Te]
• CPC Class Codes: H01L 2924/01056 : Barium [Ba]
• CPC Class Codes: H01L 2924/01059 : Praseodymium [Pr]
• CPC Class Codes: H01L 2924/01073 : Tantalum [Ta]
• CPC Class Codes: H01L 2924/01074 : Tungsten [W]
• CPC Class Codes: H01L 2924/01075 : Rhenium [Re]
• CPC Class Codes: H01L 2924/01082 : Lead [Pb]
• CPC Class Codes: H01L 2924/1306 : Field-effect transistor [FET]
• CPC Class Codes: H01L 2924/13091 : Metal-Oxide-Semiconductor Field-Effect Transistor [MOSFET]
• CPC Class Codes: H01L 2924/14 : Integrated circuits
• CPC Class Codes: H01L 2924/1433 : Application-specific integrated circuit [ASIC]
• CPC Class Codes: H01L 2924/19041 : being a capacitor
• CPC Class Codes: H01L 2924/19042 : being an inductor
• CPC Class Codes: H01L 2924/19043 : being a resistor
• CPC Class Codes: H01L 2924/30105 : Capacitance
• CPC Class Codes: H01L 2924/3011 : Impedance
• CPC Class Codes: H01L 2924/3025 : Electromagnetic shielding

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 for nucleic acid sequencing, comprising:

disposing a bead attached to at least one template nucleic acid in a reaction well communicating with a chemical sensor, wherein the chemical sensor comprises an ion-sensitive field-effect transistor (ISFET) including a floating gate coupled to the reaction well via a passivation layer;

introducing a nucleotide into the reaction well;

detecting an output pulse from the chemical sensor in response to a transient change in ion concentration within the reaction well pending incorporation of the nucleotide into the template nucleic acid; and

determining at least a portion of a sequence corresponding to a portion of the template nucleic acid based on the detected output pulse.

2. The method of claim 1, wherein the output pulse is based on a threshold voltage of the ISFET.

3. The method of claim 1, wherein the output pulse is based on a voltage at a terminal of the ISFET.

4. The method of claim 1, wherein the output pulse is based on a voltage generated by the chemical sensor in response to the transient change in ion concentration.

5. The method of claim 1, wherein the introduced nucleotide is a plurality of nucleotides of a single type.

6. The method of claim 1, wherein the change in ion-concentration is due at least in part to liberation of ions resulting from the incorporation of the nucleotide.

7. The method of claim 1, further including amplifying the at least one template nucleic acid in the reaction well prior to the introducing.

8. The method of claim 7, wherein the amplifying includes isothermally amplifying the at least one template nucleic acid in the reaction volume.

9. The method of claim 1, wherein the reaction well is defined by a surface having a primer attached thereto.

10. The method of claim 9, wherein the at least one nucleic acid template includes an adapter that is complementary to at least some portion of the primer.

11. A method for nucleic acid sequencing, comprising:

disposing at least one template nucleic acid in a reaction well communicating with a chemical sensor, wherein the reaction well is defined by a surface having a primer attached thereto;

introducing a nucleotide into the reaction well;

detecting an output pulse from the chemical sensor in response to a transient change in ion concentration pending incorporation of the nucleotide into the template nucleic acid due at least in part to liberation of ions;

determining at least a portion of a sequence corresponding to a portion of the template nucleic acid based on the detected output pulse.

12. The method of claim 11, wherein the chemical sensor is an ion-sensitive field-effect transistor (ISFET).

13. The method of claim 12, wherein the output pulse is based on a threshold voltage of the ISFET.

14. The method of claim 12, wherein the output pulse is based on a voltage at a terminal of the ISFET.

15. The method of claim 11, wherein the output pulse is based on a voltage generated by the chemical sensor in response to the transient change in ion concentration.

16. The method of claim 11, further including amplifying the at least one template nucleic acid in the reaction well prior to the introducing.

17. The method of claim 16, wherein the amplifying includes isothermally amplifying the at least one template nucleic acid in the reaction volume.

18. The method of claim 11, wherein the at least one nucleic acid template includes an adapter that is complementary to at least some portion of the primer.

19. A method for nucleic acid sequencing, comprising:

disposing at least one template nucleic acid in a reaction well communicating with a chemically-sensitive field-effect transistor (chemFET) having a floating gate;

introducing a nucleotide into the reaction well;

detecting an output pulse from the chemFET in response to a transient change in ion concentration within the reaction well pending incorporation of the nucleotide into the template nucleic acid; and

determining at least a portion of a sequence corresponding to a portion of the template nucleic acid based on the detected output pulse.

20. The method of claim 19, wherein the floating gate of the chemically-sensitive field-effect transistor (chemFET) is coupled to the reaction well via a passivation layer.

21. The method of claim 19, wherein the output pulse is based on a threshold voltage of the ISFET.

22. The method of claim 19, wherein the output pulse is based on a voltage at a terminal of the ISFET.

23. The method of claim 19, further including amplifying the at least one template nucleic acid in the reaction well prior to the introducing.

24. The method of claim 23, wherein the amplifying includes isothermally amplifying the at least one template nucleic acid in the reaction volume.

25. The method of claim 19, wherein the reaction well is defined by a surface having a primer attached thereto.

26. The method of claim 25, wherein the at least one nucleic acid template includes an adapter that is complementary to at least some portion of the primer.