Systems and methods for genome mapping

Patent metadata

Field	Value
Publication number	US-10866229-B2
Application number	US-201815883183-A
Country	US
Kind code	B2
Filing date	Jan 30, 2018
Priority date	Jan 30, 2017
Publication date	Dec 15, 2020
Grant date	Dec 15, 2020

Abstract

A system for molecular mapping includes a semiconductor substrate defining a reservoir to receive a sample of molecules and a nanofluidic channel in fluid communication with the reservoir. The system also includes a plurality of electrodes, in electrical communication with the nanofluidic channel, to electrophoretically trap the sample of molecules in the nanofluidic channel. At least one avalanche photodiode is fabricated in the semiconductor substrate and disposed within an optical near-field of the nanofluidic channel to detect fluorescence emission from at least one molecule in the sample of molecules.

First claim

The invention claimed is:

1. A system for molecular mapping, the system comprising:
a semiconductor substrate defining a reservoir to receive a sample of molecules and a nanofluidic channel in fluid communication with the reservoir;
a plurality of electrodes, disposed on the semiconductor substrate in electrical communication with the nanofluidic channel, to electrophoretically trap the sample of molecules in the nanofluidic channel; and
at least one avalanche photodiode, fabricated in the semiconductor substrate and disposed within an optical near-field of the nanofluidic channel, to detect fluorescence emission from at least one molecule in the sample of molecules.

2. The system of claim 1 , wherein the nanofluidic channel has a width substantially equal to or less than 100 nm.

3. The system of claim 1 , wherein the nanofluidic channel has a length substantially equal to or greater than 100 μm.

4. The system of claim 1 , wherein the plurality of electrodes is configured to apply an alternate current (AC) voltage to the nanofluidic channel so as to trap the sample of molecules via a dielectrophoretic force.

5. The system of claim 1 , wherein the at least one avalanche photodiode comprises a p-doped region having a front surface toward the nanofluidic channel and a curved back surface opposite the front surface, and the system further comprises:
an n-doped region disposed around the back surface of the p-doped region.

6. The system of claim 5 , further comprising:
an oxide disposed between the p-doped region and the n-doped region.

7. The system of claim 1 , wherein the at least one avalanche photodiode is disposed within about 50 nm to about 200 nm from the nanofluidic channel.

8. The system of claim 1 , wherein the at least one avalanche photodiode comprises a p-n junction defining a plane and is configured to receive the fluorescence emission along a direction substantially parallel to the plane of the p-n junction.

9. The system of claim 1 , wherein the at least one avalanche photodiode comprises a plurality of avalanche photodiodes disposed along the nanofluidic channel.

10. The system of claim 1 , wherein the at least one avalanche photodiode is configured to detect the fluorescence emission with a resolution below a diffraction limit of the fluorescence emission.

11. A method of molecular mapping, the method comprising:
loading a sample of molecules from a reservoir into a nanofluidic channel, the reservoir and the nanofluidic channel being defined within a semiconductor substrate;
trapping the sample of molecules in the nanofluidic channel at least in part with an electrophoretic force generated by a plurality of electrodes in electrical communication with the nanofluidic channel; and
detecting a fluorescence emission from at least one molecule in the sample of molecules using at least one avalanche photodiode fabricated in the semiconductor substrate and disposed within a distance from the nanofluidic channel that is less than a wavelength of the fluorescence emission.

12. The method of claim 11 , wherein loading the sample of molecules comprises loading a protein into the nanofluidic channel.

13. The method of claim 11 , wherein loading the sample of molecules comprises loading deoxyribonucleic acid (DNA) into the nanofluidic channel.

14. The method of claim 11 , wherein trapping the sample comprises applying an alternate current (AC) voltage on the nanofluidic channel so as to trap the sample of molecules via dielectrophoretic force.

15. The method of claim 11 , wherein detecting the fluorescence emission comprises receiving the fluorescence emission along a direction substantially parallel to an interface between a p-doped region and an n-doped region of a p-n junction in the at least one avalanche photodiode.

16. The method of claim 11 , wherein detecting the fluorescence emission comprises detecting the fluorescence emission using an array of avalanche photodiodes disposed along the nanofluidic channel.

17. The method of claim 11 , wherein detecting the fluorescence emission comprises detecting the fluorescence emission with a resolution below a diffraction limit of the fluorescence emission.

18. The method of claim 11 , further comprising:
exciting in the at least one molecule to elicit the fluorescence emission.

19. The method of claim 18 , wherein the exciting further includes exciting the molecule using a laser pulse from a laser source, the method further comprising synchronizing a bias of the avalanche photodiode with timing of the laser pulse to reduce or prevent detection of the laser pulse, by the avalanche photodiode, due to scattering of the laser pulse.

20. The method of claim 19 , wherein the synchronizing includes:
recording timing information for the laser pulse;
estimating a time range for the detecting the fluorescence emission; and
biasing the avalanche photodiode to prevent its operation outside the time range.

21. A system for molecular mapping, the system comprising:
a semiconductor substrate defining a reservoir to receive a sample of molecules and a nanofluidic channel having a width substantially equal to or less than 100 nm and in fluid communication with the reservoir;
a plurality of electrodes, disposed on the semiconductor substrate in electrical communication with the nanofluidic channel, to electrophoretically trap the sample of molecules in the nanofluidic channel; and
at least one avalanche photodiode, fabricated in the semiconductor substrate and disposed within 800 nm of the nanofluidic channel, to detect fluorescence emission from at least one molecule in the sample of molecules, wherein:
the at least one avalanche photodiode comprises a p-doped region and an n-doped region and configured to receive the fluorescence emission along a direction substantially parallel to an interface between the p-doped region and the n-doped region, and
the at least one avalanche photodiode is configured to detect the fluorescence emission with a resolution below a diffraction limit of the fluorescence emission.

Assignees

• Massachusetts Inst Technology

Inventors

• Meng Huaiyu
• Ram Rajeev

Classifications

• H10F77/953

  for devices having potential barriers · CPC title

• H10F77/933

  for devices having potential barriers · CPC title

• H10F55/26

  wherein the radiation-sensitive semiconductor devices have potential barriers · CPC title

• H10F30/225

  the potential barrier working in avalanche mode, e.g. avalanche photodiodes · CPC title

• G01N27/44713

  Particularly adapted electric power supply · CPC title