Nanogap chemical and biochemical sensors

• US 8,500,979 B2
• Filed: 12/31/2009
• Issued: 08/06/2013
• Est. Priority Date: 12/31/2009
• Status: Active Grant

• Current Assignee: Intel Corporation
• Original Assignee: Intel Corporation
• Inventors: Elibol, Oguz H., Daniels, Jonathan S., Credo, Grace M., Su, Xing
• Primary Examiner(s): Ball, J. Christopher
• Application Number:
  US12/655,578
• Publication Number:
  US 20110155586A1
• Time in Patent Office: 1,314 Days
• Field of Search: 20440301-40315, 204/409, 204/242, 205/777.5, 205/792, 422/82.01
• US Class Current: 204/409
• CPC Class Codes: G01N 27/3278 involving nanosized elements, e.g. nanogaps or nanoparticles nanopores G01N33/48721; magnetic beads G01N27/745

Abstract

Devices and methods are presented for electronic sensing of chemical and biochemical analytes. An electronic sensor having a at least two electrodes separated by a nanoscale gap wherein the separation between the first electrode and the second electrode forms a cavity capable of containing a fluid wherein two or more posts comprised of an insulating material extend into the cavity from the face of the first electrode to the face of the second electrode. Optionally, the cavity is closed with a bead. Devices according to embodiments of the invention are capable of detecting chemicals and biochemicals through redox cycling events. Additionally, devices and methods according to embodiments of the invention are adapted to identify and sequence nucleic acid molecules.

Claims

1. An electronic sensor comprising,

a substrate wherein a first and a second electrode are attached to the substrate,

wherein the first electrode has a face and wherein the second electrode has a face and there is a distance separating the face of the first electrode from the face of the second electrode that is defined by a point on the face of the first electrode and the nearest point on the face of the second electrode and the distance is less than 100 nm,

wherein the separation between the first electrode and the second electrode forms a cavity capable of containing a fluid,

wherein two or more posts comprised of an insulating material extend from the face of the first electrode to the face of the second electrode, and

wherein the electrodes are coupled to conducting elements through which voltage can be applied to the electrodes and a current measured from the electrodes.

4. The device of claim 1 wherein the electrodes are comprised of a metal selected from the group consisting of gold, platinum, palladium, and combinations thereof.

5. The device of claim 1 wherein there are five or more posts.

6. The device of claim 1 wherein there are ten or more posts.

7. The device of claim 1 wherein the substrate is a silicon wafer.

8. An array of electronic sensors according to the device of claim 1 wherein the array comprises 10³ electronic sensors.

9. An array of electronic sensors according to the device of claim 1 wherein the array comprises 10⁵ electronic sensors.

10. The device of claim 1 wherein at least one of the electrodes is in contact with a passivation layer.

11. The device of claim 1 additionally comprising an attachment site that is specific for an analyte of interest in the cavity of the electronic sensor.

12. The device of claim 1 additionally comprising a nucleic acid attachment site comprising a nucleic acid in the cavity of the electronic sensor.

13. The device of claim 7 additionally comprising electronics housed in the substrate that are capable of placing a first voltage on the first electrode and a second voltage on the second electrode and measuring a current flow between the first electrode and the second electrode.

2. The device of claim wherein the distance is between 10 nm and 80 nm.

3. The device of claim wherein the distance is between 10 nm and 50 nm.

14. A method for analyzing a nucleic acid in an electronic sensor comprising:

placing a nucleic acid molecule to be sequenced in a sensing cavity of the electronic sensor wherein the sensing cavity of the electronic sensor comprises at least two electrodes and a plurality of posts in the cavity comprised of an insulating material that extend from a face of the first electrode to a face of the second electrode,

terminating a growing complementary nucleic acid polymer hybridized to the nucleic acid molecule to be sequenced with a nuclease resistant nucleotide,

providing, to the sensing cavity of the electronic sensor, a solution comprising a polymerase enzyme, an exonuclease enzyme, and a nucleotide triphosphate comprising a redox group attached to a phosphate group of the nucleotide triphosphate, under conditions that allow a complementary nucleotide triphosphate comprising a redox group to be incorporated into the growing complementary polymer by the polymerase enzyme and excised from the growing, complementary strand by the exonuclease enzyme a plurality of times, and

detecting, the presence of redox molecules that are a product of the incorporation and excision of a nucleotide triphosphate comprising a redox group into and out of the complementary polymer, wherein detection occurs through the detection of a current that is the product of redox cycling of the product redox molecules.

15. The method of claim 14 wherein the redox group is selected from the group consisting of an aminophenyl, a hydroxyphenyl, a napthyl, a ferrocene, an anthraquinone, and a methylene blue molecule.

16. The method of claim 14 wherein the solution comprising a polymerase enzyme, an exonuclease enzyme, and a nucleotide triphosphate comprising a redox group, also comprises a phosphatase enzyme that is capable of removing phosphate groups from a redox group attached to a pyrophosphate group.

17. The method of claim 14 wherein the terminating, providing, and detecting are performed a plurality of times and sequence information is determined for a section of the nucleic acid molecule to be sequenced comprising a plurality of bases.

18. The method of claim 14 wherein the method is performed a plurality of times on an array of electronic sensors.

19. The method of claim 14 wherein there is a distance separating the face of the first electrode from the face of the second electrode that is defined by a point on the face of the first electrode and the nearest point on the face of the second electrode and the distance is less than 100 nm.

20. The method of claim 19 wherein the distance is between 10 nm and 80 nm.

21. The method of claim 19 wherein the distance is between 10 nm and 80 nm.

22. The method of claim 19 wherein there are five or more posts.

23. The method of claim 19 wherein there are ten or more posts.

24. The method of claim 19 wherein the electrodes are comprised of platinum, palladium, gold or combinations thereof.