DESIGN AND METHODS FOR MEASURING ANALYTES USING NANOFABRICATED DEVICE

• US 20180120287A1
• Filed: 12/21/2017
• Published: 05/03/2018
• Est. Priority Date: 06/30/2015
• Status: Active Grant

• Current Assignee: Roche Molecular Systems (Roche Holding AG)
• Original Assignee: Roche Sequencing Solutions, Inc. (Roche Holding AG)
• Inventors: Henck, Steven
• Granted Patent: US 11,391,719 B2
• Time in Patent Office: Days
• CPC Class Codes: C12Q 1/6869 Methods for sequencing
• CPC Class Codes: C12Q 2565/631 being a biochannel or pore
• 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

Abstract

Devices for sequencing linear biomolecules (e.g., DNA, RNA, polypeptides, proteins, and the like) using quantum tunneling effects, and methods of making and using such devices, are provided. A nanofabricated device can include a small gap formed by depositing a thin film between two electrodes, and subsequently removing the film using an etching process. The width of the resulting gap can correspond with the size of a linear biomolecule such that when a part of the biomolecule (e.g., a nucleobase or amino acid) is present in the gap, a change in tunneling current, voltage, or impedance can be measured and the part of the biomolecule identified. The gap dimensions can be precisely controlled at the atomic-scale by, for example, atomic layer deposition (ALD) of the sacrificial film. The device can be made using existing integrated circuit fabrication equipment and facilities, and multiple devices can be formed on a single chip.

Claims

1. A device for sequencing a linear biomolecule using quantum tunneling, the device comprising:

a substrate having a top surface;

a first electrode disposed on a first portion of the top surface of the substrate;

a first dielectric layer disposed on a second portion of the top surface of the substrate;

a second electrode disposed on the first dielectric layer and suspended over the first electrode; and

a gap defined by a top surface of the first electrode and a bottom surface of the second electrode, wherein a width of the gap corresponds to a size of the linear biomolecule such that a quantum tunneling current is transmitted between the first electrode and the second electrode when;

a voltage is applied across the first electrode and the second electrode; and

a part of the linear biomolecule is present in the gap.

2. The device of claim 1 wherein the substrate comprises a second dielectric layer disposed on a semiconductor substrate.

3. The device of claim 1, wherein the width of the gap is about 0.8 to 5.0 nm.

4. The device of claim 1, wherein the gap is further defined by a top surface of the first dielectric layer and a side surface of the second electrode.

5. The device of claim 4, wherein the top surface of the first dielectric layer and the top surface of the first electrode are substantially coplanar.

6. The device of claim 1, wherein the first electrode and the second electrode are oriented orthogonally to one another.

7. The device of claim 1, further comprising circuitry electrically coupled to the first electrode and the second electrode, wherein the circuitry is configured to:

apply the voltage across the first electrode and the second electrode; and

measure;

the quantum tunneling current transmitted between the first electrode and the second electrode;

the voltage across the first electrode and the second electrode;

or

an impedance between the first electrode and the second electrode.

8. The device of claim 1, wherein the first electrode and the second electrode individually comprise a material selected from a group consisting of metals, semiconductors, carbon, conductive ceramics, and conductive polymers.

9. The device of claim 1, wherein the first dielectric layer comprises a material selected from the group consisting of oxides, dielectric ceramics, polymers, carbonates, glasses, minerals, and air.

15. A sequencing method comprising:

a) providing a device according to claim 1;

b) applying a voltage across the first electrode and the second electrode;

c) introducing a part of a linear biomolecule into the gap;

d) measuring;

a quantum tunneling current transmitted between the first electrode and the second electrode; and

/or

the voltage across the first electrode and the second electrode; and

/or

an impedance between the first electrode and the second electrode; and

e) identifying, based on the measured quantum tunneling current, the measured voltage, or the measured impedance, the part of the linear biomolecule introduced into the gap.

10. A method of making a device for sequencing a linear biomolecule using quantum tunneling, the method comprising:

providing a substrate having a top surface;

depositing a first electrode onto a first portion of the top surface of the substrate;

depositing a first dielectric layer onto a second portion of the top surface of the substrate;

depositing a sacrificial layer onto a top surface of the first electrode;

depositing a second electrode onto the sacrificial layer and onto a top surface of the first dielectric layer; and

removing the sacrificial layer, thereby forming a gap defined by the top surface of the first electrode and a bottom surface of the second electrode, wherein a width of the gap corresponds to a size of the linear biomolecule such that a quantum tunneling current is transmitted between the first electrode and the second electrode when;

a voltage is applied across the first electrode and the second electrode; and

a part of the linear biomolecule is present in the gap.

11. The method of claim 10, wherein the sacrificial layer is further deposited onto the top surface of the first dielectric layer, and wherein the gap is further defined by the top surface of the first dielectric layer and a side surface of the second electrode.

12. The method of claim 10, wherein the first electrode and the second electrode are oriented orthogonally to one another.

13. The method of claim 10, wherein the sacrificial layer is deposited using an atomic layer deposition process.

14. The method of claim 10, wherein the sacrificial layer is removed using an etching process, and wherein the etching process includes exposing the sacrificial layer to an etchant.