System and apparatus for nanopore sequencing

Patent metadata

Field	Value
Publication number	US-9322820-B2
Application number	US-201313828230-A
Country	US
Kind code	B2
Filing date	Mar 14, 2013
Priority date	Mar 14, 2013
Publication date	Apr 26, 2016
Grant date	Apr 26, 2016

Abstract

A piezoelectric substrate having a nanopore opening that separates two reservoirs of conductive fluid may provide for sensitive biological measurements by allowing control of the size of the nanopore according to piezoelectric stimulation of the substrate. Multiple embodiments are provided of monolithic piezoelectric substrates and nanopores for this purpose as well as a control system for controlling the nanopore dimensions electrically using AC or DC waveforms.

First claim

We claim:

1. An apparatus for a study of biological molecules comprising:
a piezoelectric substrate positionable between reservoirs of conductive fluid;
a nanopore opening in the piezoelectric substrate between the reservoirs;
at least one electrode pair applying an electrical field to the piezoelectric substrate to change a dimension of the piezoelectric substrate holding the nanopore; and
at least one electrical sensor measuring a change in the electrical environment of the nanopore
wherein the at least one electrode pair is electrically insulated from the piezoelectric substrate and from the reservoirs.

2. The apparatus of claim 1 wherein at least one electrode pair is displaced outside of an area between the reservoirs.

3. The apparatus of claim 1 wherein the nanopore is provided by a non-piezoelectric material coating an inner surface of an opening in the piezoelectric substrate.

4. The apparatus of claim 3 wherein the non-piezoelectric material includes first and second electrically independent sensing electrodes across the nanopore communicating with the electrical sensor.

5. The apparatus of claim 1 wherein the at least one electrode pair provides a change in dimension of the piezoelectric substrate to change at least one diameter of the nanopore.

6. The apparatus of claim 5 wherein electrical field produces a shear of the substrate along a plane of the substrate.

7. The apparatus of claim 6 including multiple electrode pairs positioned on opposite sides of the nanopore providing countervailing thickness shear on opposite sides of the nanopore.

8. The apparatus of claim 1 wherein the piezoelectric substrate is quartz.

9. The apparatus of claim 1 wherein the at least one electrical sensor is a current sensor measuring ion flow through the nanopore as obstructed by the molecules in the nanopore.

10. The apparatus of claim 1 wherein the at least one electrical sensor is a capacitance sensor measuring capacitive coupling across the nanopore as changed by different molecules in the nanopore.

11. The apparatus of claim 1 wherein the at least one electrical sensor is a current sensor measuring a resistive flow across the nanopore changed by molecules in the nanopore.

12. The apparatus of claim 1 further including an electrical controller communicating with the at least one electrode pair on the substrate to operate the at least one electrode pair to excite the substrate in a mechanical resonant mode of the substrate to provide a periodic change in nanopore dimension.

13. The apparatus of claim 1 further including an electrical controller communicating with the at least one electrode pair on the substrate to operate the at least one electrode pair to provide a change in dimension of the nanopore over a time period compatible to a time between passage of different molecules through the nanopore.

14. The apparatus of claim 1 further including an electrical controller communicating with the at least one electrode pair on the substrate to operate the at least one electrode pair on the substrate as a function of signals received from the at least electrical sensor.

15. The apparatus of claim 1 wherein the at least one electrode pair on the substrate is operated to increase a measurement time of the molecules and decrease a time between measurements when molecules are passing through the nanopore.

Assignees

• Wisconsin Alumni Res Found
• Univ Hamburg

Inventors

• Blick Robert H
• Stava Eric James

Classifications

• G01N33/48721 Primary

  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 title

• G01N15/1218

  Physics · mapped topic

• G01N15/12

  by observing changes in resistance or impedance across apertures when traversed by individual particles, e.g. by using the Coulter principle · CPC title

• G01N15/1227

  Physics · mapped topic

• C12Q1/6869

  Methods for sequencing · CPC title