Methods for operating chemically-sensitive sample and hold sensors

• US 8,496,802 B2
• Filed: 07/23/2012
• Issued: 07/30/2013
• 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:
  US13/555,998
• Publication Number:
  US 20120295795A1
• Time in Patent Office: 372 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, 435103-105, 435/150, 435/182, 506/1, 506/9, 436103-105, 436/150, 436/182
• US Class Current: 205/793.5
• 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. A method for operating an apparatus comprising a plurality of chemically sensitive sensors arranged in rows and columns, comprising:

generating timing signals, row select signals and column select signals;

sampling and holding signal samples indicating reactions occurring in the plurality of sensors in a row of the array in response to the timing signals;

enabling column output circuits coupled to corresponding sensors in the row in response to the column select signals; and

outputting the signal samples to the column output circuits from the plurality of sensors in the row in response to the row select signals.

2. The method of claim 1, wherein the chemically sensitive sensors include chemically-sensitive field effect transistors (chemFETs), and including generating the signal samples in the sensors by sensing respective currents in the chemFETs under conditions such that respective constant voltages across the chemFETs are maintained.

3. The method of claim 2, including using feedback circuits in each of the sensors which maintains the respective constant voltages.

4. The method of claim 3, including using a current limiting element in series with the chemFET in each of the sensors.

5. The method of claim 4, wherein the current limiting element is a transistor having a gate coupled to a bias voltage line.

6. The method of claim 1, including using a sample and hold capacitor in each of the sensors to sample a voltage at a node that indicates an ion-concentration of an analyte solution.

7. The method of claim 1, including using a sample and hold capacitor in each of the sensors to sample voltages indicating threshold voltages of the sensors.

8. The method of claim 1, further comprising:

disposing a plurality of samples in reaction volumes coupled to the plurality of sensors, the sensors to detect sequencing reactions of the samples; and

providing conditions sufficient to permit the sequencing reactions of the samples, and wherein the signal samples indicate the sequencing reactions detected by the sensors.

9. The method of claim 8, wherein:

the samples are template nucleic acids;

providing conditions sufficient to permit the sequencing reactions includes introducing a known nucleotide into the reaction volumes; and

the signal samples indicate incorporation of the introduced known nucleotides into one or more primers that are hybridized to at least one of the template nucleic acids.

10. The method of claim 9, wherein the signal samples are based on liberation of hydrogen ions detected by the sensors resulting from the incorporation of the introduced known nucleotides.

11. The method of claim 9, further comprising analyzing the signal samples to determine at least a portion of sequences of the primers.

12. A method for operating a sensor comprising a chemically-sensitive field effect transistor (chemFET), the method comprising:

applying a voltage between a first terminal and a second terminal of the chemFET;

sensing current through the chemFET in response to the applied voltage, the sensed current based on a threshold voltage of the chemFET; and

generating an output signal of the sensor indicating the sensed current, wherein

sensing current through the chemFET comprises using a sample and hold capacitor to sample a voltage at a node indicating the sensed current; and

the output signal is generated based on the sampled voltage.

13. The method of claim 12, wherein applying the voltage comprises using a feedback circuit which maintains the applied voltage as constant.

14. The method of claim 12, wherein the chemFET is coupled to a passivation layer, and the threshold voltage is based on an ion-concentration of an analyte solution coupled to the passivation layer.

15. The method of claim 14, wherein a floating gate of the chemFET is coupled to the passivation layer.

16. The method of claim 12, wherein the chemFET includes a floating gate coupled to a reaction volume, and further comprising:

disposing a plurality of samples in the reaction volume, the chemFET to detect sequencing reactions of the samples; and

providing conditions sufficient to permit the sequencing reactions of the samples to change the threshold voltage of the chemFET.

17. The method of claim 12, wherein applying a voltage between a first terminal and a second terminal of the chemFET comprises using a feedback circuit and a controllable current source, the feedback circuit having an input coupled the first terminal of the chemFET, and the controllable current source responsive to an output from the feedback circuit to provide a current to the chemFET.

18. The method of claim 17, wherein the current provided to the chemFET maintains a constant voltage at the first terminal of the chemFET.

19. The method of claim 17, wherein the controllable current source includes a transistor coupled between a first reference voltage and the chemFET, a gate of the transistor being connected to the output of the feedback circuit.