Analytical devices having dichroic prism arrays

• US 9,945,781 B2
• Filed: 01/17/2017
• Issued: 04/17/2018
• Est. Priority Date: 05/31/2013
• Status: Active Grant

• Current Assignee: Pacific Bioscience of California Incorporated (L'Oreal SA)
• Original Assignee: Pacific Bioscience of California Incorporated (L'Oreal SA)
• Inventors: Rulison, Aaron, McDonald, Mark, Lundquist, Paul
• Primary Examiner(s): DECENZO, SHAWN H
• Application Number:
  US15/407,443
• Publication Number:
  US 20170167979A1
• Time in Patent Office: 455 Days
• Field of Search: None
• CPC Class Codes: C12Q 1/6874 involving nucleic acid arrays, e.g. sequencing by hybridisation
• CPC Class Codes: G01J 3/2803 using photoelectric array detector
• CPC Class Codes: G01J 3/36 Investigating two or more bands of a spectrum by separate detectors
• CPC Class Codes: G01N 2021/6471 Special filters, filter wheel
• CPC Class Codes: G01N 2021/6478 Special lenses
• 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 21/6452 Individual samples arranged in a regular 2D-array, e.g. multiwell plates
• CPC Class Codes: G01N 21/75 Systems in which material is subjected to a chemical reaction, the progress or the result of the reaction being investigated systems in which material is burnt in a flame or plasma G01N21/72, G01N21/73
• CPC Class Codes: G01N 2201/0633 Directed, collimated illumination
• CPC Class Codes: G02B 13/006 at least one element being a compound optical element, e.g. cemented elements
• CPC Class Codes: G02B 13/0065 having a beam-folding prism or mirror
• CPC Class Codes: G02B 13/0085 employing wafer level optics
• CPC Class Codes: G02B 27/1013 for colour or multispectral image sensors, e.g. splitting an image into monochromatic image components on respective sensors spectral imaging systems G01J
• CPC Class Codes: G02B 3/0056 arranged along two different directions in a plane, e.g. honeycomb arrangement of lenses G02B3/0043 takes precedence; miniaturised objectives for electronic devices employing wafer level optics G02B13/0085
• CPC Class Codes: G02B 3/0062 Stacked lens arrays, i.e. refractive surfaces arranged in at least two planes, without structurally separate optical elements in-between
• CPC Class Codes: G02B 5/045 Prism arrays

Abstract

Apparatus, systems and methods for use in analyzing discrete reactions are provided. The analytical devices of the invention use an array of nanoscale regions (a chip) that has discrete patches, for example, patches of nanoscale regions. In some embodiments an analytical system is provided that has an analysis chip with an array of patches, each of the patches comprising nanoscale regions that emit fluorescent light when illuminated. The system has a two-dimensional (x, y) array of dichroic prisms, each prism comprising a dichroic element that diverts illumination light up in the z dimension of the array to a patch on the analysis chip above it. Each dichroic element transmits fluorescent light emitted by the patch that it illuminates, whereby the emitted light from each patch passes down through each dichroic prism. The analytical system also has a detector below the array of dichroic prisms that detects the transmitted fluorescent light. Such systems are useful for monitoring many analytical reactions at one time including single molecule sequencing reactions.

Claims

1. An analytical system comprising:

an analysis chip comprising an array of patches, each of the patches comprising nanoscale regions that emit fluorescent light when illuminated;

a two-dimensional (x, y) array of dichroic prisms, each prism comprising a dichroic element that diverts illumination light up in the z dimension of the array to a patch on the analysis chip above it, wherein each dichroic element transmits fluorescent light emitted by the patch that it illuminates, whereby the emitted light from each patch passes down through each dichroic prism; and

a detector below the array of dichroic prisms that detects the transmitted fluorescent light.

2. The analytical system of claim 1 wherein the array of dichroic prisms comprises an array of prisms with N rows by M rows, the array of prisms further comprising a row of M beam splitting elements along an edge of the array of prisms, wherein illumination light is sent through the row of M beam splitting elements, and wherein each of the M beam splitting elements diverts a portion of the illumination light into a row of N dichroic elements, and each of the N dichroic elements in the row of N dichroic elements diverts a portion of light to the patch above it.

3. The analytical system of claim 1 wherein the number of dichroic prisms in the array is from about 10 to about 1,000.

4. The analytical system of claim 1 wherein the number of dichroic prisms in the array is from about 50 to about 200.

5. The analytical system of claim 1 wherein each patch of nanoscale regions comprises from about 1,000 to about 50,000 nanoscale regions.

6. The analytical system of claim 1 wherein the chip is in contact with a fluid sample comprising at least a first fluorescent species and a second fluorescent species, wherein the first fluorescent species can act as a first emitter when within or proximal to a nanoscale region, and the second fluorescent species can act as a second emitter when within or proximal to a nanoscale region.

7. The analytical system of claim 6 wherein the first and second fluorescent species comprise labeled nucleotide analogs.

8. The analytical system of claim 1 further comprising an array of color separating elements, the array comprising one color separating element for each dichroic prism.

9. The analytical system of claim 8 wherein the color separating element comprises a grating, a prism, or a grating prism.

10. A method for providing excitation illumination to an array of patches on a chip, wherein the patches emit fluorescent light, comprising:

providing, below the chip, a two-dimensional (x, y) array of dichroic prisms, each prism comprising a dichroic element;

sending excitation illumination light into the array of dichroic prisms such that each dichroic prism diverts illumination light up in the z dimension to a patch on the chip above it, stimulating fluorescent emission from the patches;

whereby the emitted light from each patch passes down through the dichroic prism that illuminated that patch to a detector.

11. The method of claim 10 wherein the array of dichroic prisms comprises an array of prisms with N rows by M rows, further comprising a row of M beam splitting elements along an edge of the array of dichroic prisms, wherein illumination light is sent through the M beam splitting elements, wherein each of the M beam splitting elements diverts a portion of the illumination light into a row of N dichroic elements, and each of the N dichroic elements in the row of N dichroic elements diverts a portion of light to the patch above it.

12. The method of claim 10 wherein the number of dichroic prisms in the array is from about 10 to about 1,000.

13. The method of claim 10 wherein the number of dichroic prisms in the array is from about 50 to about 200.

14. The method of claim 10 wherein the chip is in contact with a fluid sample comprising at least a first fluorescent species and a second fluorescent species, wherein the first fluorescent species can act as a first emitter when within or proximal to a nanoscale region, and the second fluorescent species can act as a second emitter when within or proximal to a nanoscale region.

15. The method of claim 14 wherein the first and second fluorescent species comprise labeled nucleotide analogs.

16. The method of claim 10 further comprising an array of color separating elements, the array comprising one color separating element for each dichroic prism.

17. The method of claim 16 wherein the color separating element comprises a grating, a prism, or a grating prism.

18. The method of claim 10 wherein each patch comprises from about 1,000 to about 50,000 nanoscale regions.