Active chemically-sensitive sensors with in-sensor current sources

• US 8,912,580 B2
• Filed: 03/12/2014
• Issued: 12/16/2014
• Est. Priority Date: 05/29/2009
• Status: Active Grant

• Current Assignee: Life Technologies Corporation (Thermo Fisher Scientific Incorporated)
• Original Assignee: Life Technologies Corporation (Thermo Fisher Scientific Incorporated)
• Inventors: Milgrew, Mark J.
• Primary Examiner(s): Ball, J. Christopher
• Application Number:
  US14/206,326
• Publication Number:
  US 20140194301A1
• Time in Patent Office: 279 Days
• Field of Search: 257/27, 257/192, 257213-413, 204/406, 205/789, 205/792
• US Class Current: 257/253
• 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 27/27 Association of two or more measuring systems or cells, each measuring a different parameter, where the measurement results may be either used independently, the systems or cells being physically associated, or combined to produce a value for a further parameter
• 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: G01N 33/54373 involving physiochemical end-point determination, e.g. wave-guides, FETS, gratings
• CPC Class Codes: Y10T 29/49002 Electrical device making

Abstract

Methods and apparatus relating to FET arrays for monitoring chemical and/or biological reactions such as nucleic acid sequencing-by-synthesis reactions. Some methods provided herein relate to improving signal (and also signal to noise ratio) from released hydrogen ions during nucleic acid sequencing reactions.

Claims

1. A method of operating an apparatus comprising an array of chemically sensitive sensors comprising chemically-sensitive field effect transistors (chemFETs) and source follower amplifiers arranged in rows and columns, the method comprising:

inducing a flow of current in the chemFETs in the sensors using a transistor coupled to the chemFET and biased in a current limiting mode;

amplifying a voltage on a conduction terminal of the chemFET using a source follower amplifier in the row of the sensors to produce a sensor output voltage; and

coupling the sensor output voltage to a column bus coupled to a column of sensors in the array.

2. The method of claim 1, wherein the inducing includes applying a sub-threshold voltage to the transistor in the sensor, and the amplifying includes coupling the conduction terminal of the chemFET to the gate of a second transistor in the sensor and turning on a third transistor in the sensor coupled between a conduction terminal of the second transistor and the column bus in response to a row select signal.

3. The method of claim 1, wherein the inducing includes biasing the transistor in the sensor in a reverse bias diode mode, and the amplifying includes coupling the conduction terminal of the chemFET to the gate of a second transistor in the sensor and turning on a third transistor in the sensor coupled between a conduction terminal of the second transistor and the output conductor in response to a row select signal.

4. The method of claim 1, including applying a chemical sample in chemical sample wells coupled to the plurality of sensors to produce voltages on conduction terminals of the chemFETs.

5. The method of claim 4, wherein the voltages on the conduction terminals of the chemFETs indicate sequencing reactions detected by the sensors.

6. The method of claim 4, wherein:

disposing the chemical sample includes disposing a plurality of template nucleic acids in the chemical sample wells, and introducing a known nucleotide into the chemical sample wells; and

the voltages on the conduction terminals of the chemFETs indicate incorporation of the introduced known nucleotide into one or more primers that are hybridized to at least one of the template nucleic acids.

7. The method of claim 1, wherein the chemFET includes a floating gate and a passivation layer, and a sensor surface on the passivation layer over the floating gate.

8. The method of claim 7, wherein a voltage on the column bus indicates an ion-concentration of an analyte solution coupled to the floating gate via the passivation layer.

9. The method of claim 1, wherein the sensors in the array including chemical sample wells, and including applying an analyte solution to the chemical sample wells, and coupling a reference electrode to the analyte solution.