Methods and apparatus for detecting molecular interactions using FET arrays

• US 9,404,920 B2
• Filed: 01/09/2014
• Issued: 08/02/2016
• 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
• Primary Examiner(s): CROW, ROBERT THOMAS
• Application Number:
  US14/151,182
• Publication Number:
  US 20140194297A1
• Time in Patent Office: 936 Days
• Field of Search: None
• US Class Current: 1/1
• CPC Class Codes: C12Q 1/6825 Nucleic acid detection involving sensors
• 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: G01N 27/26 by investigating electrochemical variables; by using electrolysis or electrophoresis
• 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 33/6818 Sequencing of polypeptides
• 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 29/788 with floating gate H01L29/78391 takes precedence
• CPC Class Codes: H01L 2924/01006 Carbon [C]

Abstract

Methods and apparatuses relating to large scale FET arrays for analyte detection and measurement are provided. 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.

Claims

1. A method for detecting bimolecular interactions, the method comprising:

providing a sample analyzer comprising an array of sensors, a given sensor in the array of sensors comprising;

a chemFET including a first gate dielectric between a substrate and a floating gate, and having a characteristic threshold voltage affected by trapped charge in the first gate dielectric, and a transistor including a second gate dielectric between a gate terminal and the substrate, wherein the gate terminal is coupled to the floating gate of the chemFET, and the second gate dielectric has a thickness less than that of the first gate dielectric;

removing the trapped charge via the transistor by providing an electrical path for charge from the floating gate to the substrate;

providing at least one molecular species to the array of sensors; and

detecting a molecular interaction between the at least one molecular species and a second molecular species by detecting the changes in electrical properties of the chemFET.

2. The method of claim 1, further comprising disposing the at least one molecular species and the second molecular species in proximity to or in contact with the chemFET.

3. The method of claim 1, wherein the molecular interaction between the at least one molecular species and the second molecular species is a binding or coupling interaction or a hybridization or affinity interaction.

4. The method of claim 1, wherein the change in at least one electrical property of at least a portion of the sensors of the array is the voltage or current change produced by a change in ion concentration resulting from the molecular interaction of the at least one molecular species with the second molecular species.

5. The method of claim 1, wherein the at least one molecular species and the second molecular species are selected from the following combinations:

a first protein and a second protein, a first nucleic acid and a second nucleic acid, a protein and a nucleic acid, an antibody and an antigen, an aptamer and a target, an enzyme and a substrate, an enzyme and an inhibitor, and enzyme and a cofactor.

6. The method of claim 5, wherein the at least one molecular species comprises an enzyme, the second molecular species comprises a substrate for the enzyme, and the enzyme reacts with the substrate to effectuate a change in the at least one electrical property of the sensors of the array.

7. The method of claim 1, where the characteristic threshold voltage of the chemFET of the given sensor is similar to the characteristic threshold voltages of chemFETs of other sensors in the sensor array.

8. The method of claim 1, further comprising control circuitry that detects output signals from the sensors, where the output signals are dependent on the respective threshold voltages of chemFETs of the sensors.