Methods and apparatus for measuring analytes using large scale FET arrays

• US 9,951,382 B2
• Filed: 07/21/2016
• Issued: 04/24/2018
• 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): Ball, J. Christopher
• Application Number:
  US15/216,242
• Publication Number:
  US 20160326580A1
• Time in Patent Office: 642 Days
• 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:

providing an array of chemical sensors, the chemical sensors comprising field-effect transistors having floating gates coupled to sensitive areas arranged along a substantially planar surface, a receptor covalently coupled to the sensitive areas, the receptor to reversibly bind a phosphate;

delivering template nucleic acids proximate to the sensitive areas of the sensors;

introducing a nucleotide, the nucleotide incorporating into a nucleic acid strand complementary to the template nucleic acid and releasing the phosphate, the phosphate reversibly binding to the receptor; and

detecting output signals from the chemical sensors indicating incorporation of the introduced nucleotide into the template nucleic acids, the output signal responsive to the reversible binding of the phosphate to the receptor.

2. The method of claim 1, wherein the phosphate is a pyrophosphate or an orthophosphate.

3. The method of claim 2, wherein the phosphate is a pyrophosphate.

4. The method of claim 1, wherein the sensitive area includes a passivation layer.

5. The method of claim 4, wherein the receptor is covalently attached to the passivation layer.

6. The method of claim 1, wherein the receptor is covalently attached to the sensitive area via silanol chemistry.

7. The method of claim 1, wherein a silanation layer is bonded to the sensitive area by reactive surface groups.

8. The method of claim 7, wherein the reactive surface groups are silanol groups.

9. The method of claim 7, wherein the receptor is bound to the silanation layer with a bifunctional linker.

10. The method of claim 9, wherein the bifunctional linker includes an amine specific linker.

11. The method of claim 10, wherein the amine specific linker is bis(sulfosuccinimidyl) suberate, bis[2-(succinimidooxycarbonyloxy)ethyl] sulfone, disuccinimidyl suberate, disuccinimidyl tartarate, dimethyl adipimate.2 HCI, dimethyl pimelimidate.2 HCI, dimethyl suberimidate.2 HCI, or ethylene glycolbis-[succinimidyl-[succinate]].

12. The method of claim 9, wherein the bifunctional linker includes a carbohydrate reactive group.

13. The method of claim 12, wherein the carbohydrate reactive group includes azidobenzoyl hydrazine.

14. The method of claim 9, wherein the bifunctional linker includes N-succinimidyl-3-[2-pyridyldithio] propionate, succinimidyl [4-iodoacetyl] aminobenzoate, succinimidyl 4-[N-maleimidomethyl] cyclohexane-1- carboxylate, m-maleimidobenzoyl-N-hydroxysuccinimide ester, sulfosuccinimidyl 6-[3-[2-pyridyldithio ]propionamido ]hexanoate, or sulfosuccinimidyl 4-[N-maleimidomethyl] cyclohexane-1-carboxylate.

15. The method of claim 9, wherein the bifunctional linker includes 1-ethyl-3-[3-dimethylaminopropyl]-carbodiimide hydrochloride, 4-[N -maleimidomethyl]-cyclohexane-1-carboxylhydrazide.2 HCI, 4-(4-N-maleimidophenyl)-butyric acid hydrazide.2 HCI, or 3-[2-pyridyldithio] propionyl hydrazide.

16. The method of claim 1, further comprising introducing apyrase following detecting, the apyrase converting a remaining nucleotide to a monophosphate nucleotide.

17. The method of claim 1, wherein the field-effect transistor is a chemically sensitive field-effect transistor (ChemFET).

18. The method of claim 1, further comprising an array of wells operably connected to the array of chemical sensors and exposing the sensitive areas.

19. The method of claim 18, wherein delivering the template nucleic acid includes securing the template nucleic acid in a well of the array of wells.

20. The method of claim 1, further comprising a structure disposed over the array of chemical sensors and defining a flow cell between the structure and the array of chemical sensors.