Arrays of integrated analytical devices

• US 9,915,612 B2
• Filed: 03/06/2017
• Issued: 03/13/2018
• Est. Priority Date: 08/27/2014
• Status: Active Grant

• Current Assignee: Pacific Bioscience of California Incorporated (L'Oreal SA)
• Original Assignee: Pacific Bioscience of California Incorporated (L'Oreal SA)
• Inventors: Grot, Annette, Saxena, Ravi, Lundquist, Paul
• Primary Examiner(s): NGUYEN, SANG H
• Application Number:
  US15/451,305
• Publication Number:
  US 20170176335A1
• Time in Patent Office: 372 Days
• CPC Class Codes: G01N 2021/6439 with indicators, stains, dyes, tags, labels, marks
• CPC Class Codes: G01N 2021/6478 Special lenses
• CPC Class Codes: G01N 2021/7756 Sensor type
• CPC Class Codes: G01N 2021/7786 Fluorescence
• CPC Class Codes: G01N 21/6428 Measuring fluorescence of fluorescent products of reactions or of fluorochrome labelled reactive substances, e.g. measuring quenching effects, using measuring "optrodes" in vivo A61B5/00; immunoassay G01N33/53
• CPC Class Codes: G01N 21/6454 using an integrated detector array
• CPC Class Codes: G01N 21/648 using evanescent coupling or surface plasmon coupling for the excitation of fluorescence
• CPC Class Codes: G01N 21/7703 using reagent-clad optical fibres or optical waveguides using measurement of total internal reflection or attenuated total reflection G01N21/552; optical fibres or waveguides per se G02B
• CPC Class Codes: G01N 21/78 producing a change of colour
• CPC Class Codes: G01N 2201/068 Optics, miscellaneous
• CPC Class Codes: G01N 2201/0873 Using optically integrated constructions
• CPC Class Codes: G02B 2006/12102 Lens
• CPC Class Codes: G02B 2006/12109 Filter
• CPC Class Codes: G02B 27/4238 in optical recording or readout devices optical pick-up devices such as for CD, DVD or BD reader or recorder using diffraction optics G11B7/1353
• CPC Class Codes: G02B 27/4244 in wavelength selecting devices spectrometry G01J
• CPC Class Codes: G02B 5/1895 such optical elements having dioptric power
• CPC Class Codes: G02B 5/201 in the form of arrays
• CPC Class Codes: G02B 5/285 comprising deposited thin solid films G02B5/281 - G02B5/289 take precedence; multilayered film filters for fibre optic multiplexing G02B6/29361
• CPC Class Codes: G02B 6/132 by deposition of thin films
• CPC Class Codes: G02B 6/136 by etching
• CPC Class Codes: H01L 27/14621 : Colour filter arrangements
• CPC Class Codes: H01L 27/14627 : Microlenses
• CPC Class Codes: H01L 27/14685 : Process for coatings or optical elements

Abstract

Arrays of integrated analytical devices and their methods for production are provided. The arrays are useful in the analysis of highly multiplexed optical reactions in large numbers at high densities, including biochemical reactions, such as nucleic acid sequencing reactions. The devices allow the highly sensitive discrimination of optical signals using features such as spectra, amplitude, and time resolution, or combinations thereof. The devices include an integrated diffractive beam shaping element that provides for the spatial separation of light emitted from the optical reactions.

Claims

1. A method for producing an array of integrated analytical devices comprising:

providing a substrate layer, wherein the substrate layer is a rigid inorganic material;

depositing a laser rejection filter element layer on the substrate layer;

depositing a color filtration layer on the laser rejection filter element layer, wherein the color filtration layer comprises 2 to 9 color filtration elements per analytical device, each color filtration element specific for a range of light wavelengths;

depositing a lens element layer on the color filtration layer, wherein the lens element layer comprises a diffractive beam shaping element for each analytical device;

depositing an excitation waveguide layer on the lens element layer;

optionally depositing a first aperture layer on the substrate layer, the color filtration layer, or the lens element layer;

depositing a nanowell layer on the excitation waveguide layer; and

patterning and etching the nanowell layer to define a nanowell for each analytical device;

wherein the diffractive beam shaping element is configured to spatially separate light emitted from the nanoscale emission volume into a plurality of beams and to direct the spatially-separated light beams through the color filtration elements.

2. The method of claim 1, wherein there are 2 color filtration elements per integrated analytical device.

3. The method of claim 1, wherein the integrated analytical devices are configured to distinguish four different detectable signal events.

4. The method of claim 1, wherein the diffractive beam shaping element is a hybrid lens.

5. The method of claim 1, wherein the diffractive beam shaping element comprises a Fresnel lens.

6. The method of claim 1, wherein the diffractive beam shaping element comprises amorphous silicon.

7. The method of claim 1, wherein the color filtration elements are dichroic filters.

8. The method of claim 1, wherein the color filtration elements are thin-film interference filters.

9. The method of claim 1, wherein the color filtration elements comprise amorphous silicon and silicon oxide.

10. The method of claim 1, wherein the color filtration elements are absorption filters.

11. The method of claim 1, further comprising:

depositing a second aperture layer on the substrate layer, the color filtration layer, or the lens element layer.

12. The method of claim 11, further comprising:

depositing a third aperture layer on the substrate layer, the color filtration layer, or the lens element layer.

13. The method of claim 1, wherein the first aperture layer comprises titanium nitride.

14. The method of claim 1, wherein the excitation waveguide layer comprises at least one waveguide excitation source, and the nanowell of each analytical device is patterned and etched directly above the waveguide excitation source.

15. The method of claim 1, wherein the substrate layer comprises a plurality of sensing regions per analytical device, the excitation waveguide layer comprises at least one waveguide excitation source, and the sensing regions are collinear with respect to the waveguide excitation source.

16. The method of claim 1, wherein the substrate layer comprises a plurality of sensing regions per analytical device, the excitation waveguide layer comprises at least one waveguide excitation source, and the sensing regions are not collinear with respect to the waveguide excitation source.

17. The method of claim 1, wherein the substrate layer comprises a plurality of sensing regions per analytical device, the excitation waveguide layer comprises at least one waveguide excitation source, and the sensing regions are diagonal with respect to the waveguide excitation source.

18. The method of claim 1, wherein the substrate layer comprises a plurality of sensing regions per analytical device, the excitation waveguide layer comprises at least one waveguide excitation source, and the sensing regions are perpendicular with respect to the waveguide excitation source.

19. The method of claim 1, wherein the excitation waveguide layer comprises a plurality of waveguide excitation sources.

20. The method of claim 19, wherein the waveguide excitation sources are oriented parallel to one another.

21. The method of claim 19, wherein the nanowell of each analytical device is patterned and etched directly above one of the waveguide excitation sources.

22. The method of claim 19, wherein the nanowells in the array of analytical devices are arranged in a regular grid pattern.

23. The method of claim 19, wherein the nanowells in the array of analytical devices are arranged in an offset grid pattern.

24. The method of claim 19, wherein the substrate layer comprises a plurality of sensing regions per analytical device, and the sensing regions are collinear with respect to the waveguide excitation sources.

25. The method of claim 19, wherein the substrate layer comprises a plurality of sensing regions per analytical device, and the sensing regions are not collinear with respect to the waveguide excitation sources.

26. The method of claim 19, wherein the substrate layer comprises a plurality of sensing regions per analytical device, and the sensing regions are diagonal with respect to the waveguide excitation sources.

27. The method of claim 1, wherein the diffractive beam shaping element of each analytical device is configured to collimate light emitted from the nanowell of each analytical device.

28. The method of claim 1, wherein the substrate layer comprises a plurality of rectangular sensing regions per analytical device.

29. The method of claim 1, wherein the substrate layer comprises a plurality of square sensing regions per analytical device.

30. The method of claim 1, wherein the substrate layer comprises a CMOS sensor.

31. The method of claim 1, wherein the method produces an array of at least 1,000, at least 10,000, at least 100,000, at least 1,000,000, or at least 10,000,000 integrated analytical devices.

32. The method of claim 1, wherein the nanowell penetrates into the upper cladding of the excitation waveguide layer.