Sensor circuit for controlling, detecting, and measuring a molecular complex

• US 8,986,629 B2
• Filed: 02/26/2013
• Issued: 03/24/2015
• Est. Priority Date: 02/27/2012
• Status: Active Grant

• Current Assignee: Roche Sequencing Solutions, Inc. (Roche Holding AG)
• Original Assignee: Genia Technologies, Inc. (Roche Holding AG)
• Inventors: Deierling, Kevin, Chen, Roger J. A., Fullagar, David J.
• Primary Examiner(s): Sines, Brian J
• Application Number:
  US13/777,879
• Publication Number:
  US 20130237460A1
• Time in Patent Office: 756 Days
• Field of Search: 422/50, 422/68.1, 422/82.01, 422/502, 422/503, 422/509
• US Class Current: 422/503
• 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 2565/607 being a sensor, e.g. electrode
• CPC Class Codes: C12Q 2565/631 being a biochannel or pore
• CPC Class Codes: G01N 27/4473 by electric means
• CPC Class Codes: G01N 27/44782 of a plurality of samples
• CPC Class Codes: G01N 27/44791 Microapparatus sample containers with integrated microfluidic structures B01L3/5027
• CPC Class Codes: G01N 33/48721 Investigating individual macromolecules, e.g. by translocation through nanopores Coulter counters in general G01N15/12; fabrication methods for nanoscale apertures B81B1/00; sequencing of nucleic acids C12Q1/68
• CPC Class Codes: Y10T 436/11 Automated chemical analysis

Abstract

A device for controlling, detecting, and measuring a molecular complex is disclosed. The device comprises a common electrode. The device further comprises a plurality of measurement cells. Each measurement cell includes a cell electrode and an integrator electronically coupled to the cell electrode. The integrator measures the current flowing between the common electrode and the cell electrode. The device further comprises a plurality of analog-to-digital converters, wherein an integrator from the plurality of measurement cells is electrically coupled to one analog-to-digital converter of the plurality of analog-to-digital converters.

Claims

1. A device comprising:

a plurality of measurement cells, each measurement cell including a cell electrode above which a nanopore is formed, the cell electrode configurable to apply a distinct potential that is independent from cell electrodes in other measurement cells, each measurement cell including an integrator electronically coupled to the cell electrode;

a common electrode, the common electrode configured to apply a common potential to a liquid above the nanopores formed above the cell electrodes in the plurality of measurement cells, wherein the common potential is common to all of the measurement cells, and wherein the integrator in each measurement cell measures the current flowing between the common electrode and the cell electrode in the measurement cell;

a plurality of analog-to-digital converters, wherein an integrator from the plurality of measurement cells is electrically coupled to one analog-to-digital converter of the plurality of analog-to-digital converters.

2. The device of claim 1, wherein each measurement cell further includes a liquid chamber containing the liquid.

3. The device of claim 2, wherein,

the common electrode supplies a common electric potential when the liquid chamber contains an electrolyte,

the cell electrode supplies a variable electric potential when the liquid chamber contains the electrolyte, wherein the voltage between the common electrode and the cell electrode equals the variable electric potential minus the common electric potential,

the integrator includes an integrating capacitor, the voltage across the integrating capacitor is a measure of the current flowing between the common electrode and the cell electrode during a measurement period, and

the variable electric potential of the cell electrode is controlled by an applied voltage.

4. The device of claim 3, wherein the variable electric potential of the cell electrode is controlled by the applied voltage via a buffering means.

5. The device of claim 1, wherein the integrator further includes:

a buffering component, wherein the buffer component is electrically coupled to the analog-do-digital converter to buffer an output of the integrator before being connected to the analog-do-digital converter.

6. The device of claim 1, wherein the analog-to-digital converter coupled to the integrator measures a first voltage at an output of the integrator at a beginning of a measurement period and a second voltage at the output of the integrator at an end of the measurement period, and wherein a difference of the second voltage and the first voltage corresponds to a measurement of the current.

7. The device of claim 6, wherein the measurement period is adjusted based at least in part on the current and how much time the current would take to cause a saturation.

8. The device of claim 1, wherein,

more than one integrators send their output to a coupled analog-to-digital converter corresponding to the more than one integrators via a time-division multiplexing channel.

9. The device of claim 1, wherein at least one of the analog-to-digital converters includes a comparator.

10. The device of claim 9, wherein the analog-to-digital converter includes a controlling analog input, and the controlling analog input controls a variable sample rate of the current measurement by varying a voltage at the controlling analog input.

11. The device of claim 10, wherein the variable sample rate increases when the current increases.

12. The device of claim 10, wherein the varied voltage comprises a comparator threshold.

13. The device of claim 10, wherein the varied voltage comprises an initial voltage at an output of one of the integrators.

14. The device of claim 13, wherein a time measurement of the output of one of the integrators to reach a comparator threshold from the initial voltage corresponds to a measurement of the current.

15. The device of claim 1, wherein,

a column of integrators from the plurality of measurement cells is electrically coupled to one analog-to-digital converter of the plurality of analog-to-digital converters, and

the column of integrators share the coupled analog-to-digital converter via a time-division multiplexing channel.

16. The device of claim 2, wherein the device is configured to retain at least one lipid, one nanopore protein, and one molecular complex in the liquid chamber of at least one measurement cell of the plurality of measurement cells.

17. The device of claim 16, wherein the molecular complex comprises one of the following:

a single stranded DNA, a single stranded RNA, and a tagged nucleotide.

18. The device of claim 16, wherein the device is configured to supply an electrical stimulus to the lipid, the nanopore protein, and the molecular complex in the liquid chamber of at least one measurement cell of the plurality of measurement cells.

19. The device of claim 16, wherein,

the device is configured to individually detect a physical state and individually transpose the physical state from a plurality of possible physical states of a material in the liquid chamber of each measurement cell of the plurality of measurement cells, by modulating the voltage and measuring the current between the common electrode and the cell electrode, and

the plurality of possible physical states comprises:

no formation of a lipid bilayer,

formation of a lipid bilayer,

insertion of a nanopore protein in a lipid bilayer, forming a nanopore, and

interaction of a molecular complex with the nanopore.

20. The device of claim 19, wherein each measurement cell progresses through the plurality of possible physical states at an own pace of said measurement cell, independently of the physical states of other measurement cells of the plurality of measurement cells.

21. The device of claim 16, wherein the device is configured to recognize a specific base type corresponding to the molecular complex in the liquid chamber of one measurement cell of the plurality of measurement cells by measuring the current flowing between the common electrode and the cell electrode.

22. The device of claim 2, wherein the current between the common electrode and the cell electrode flows in either direction depending on a controlling potential applied to a terminal of the integrator.