Analytical devices having compact lens train arrays

• US 9,581,550 B2
• Filed: 05/29/2014
• Issued: 02/28/2017
• 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): Flinders, Jeremy C
• Application Number:
  US14/289,905
• Publication Number:
  US 20150024968A1
• Time in Patent Office: 1,006 Days
• US Class Current: 1/1
• 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 of nanoscale regions. The chip mates with a collection device comprising an array of compact lens trains (CLTs) where each of the CLTs corresponds to a single patch of nanoscale regions. Each CLT collects the emitted light from a patch on the chip, collimates the light, performs color separation on the collimated emitted light, and focuses the separated light onto a portion of pixels on the detector below the CLT. Such systems are useful for monitoring many analytical reactions at one time including single molecule sequencing reactions.

Claims

1. A detection system for measuring the emitted light from an array of patches of nanoscale regions comprising:

a chip having an array of patches of nanoscale regions, each patch of nanoscale regions having an array of nanoscale regions;

wherein light is emitted from the nanoscale regions from at least a first emitter and a second emitter, each emitting a different spectral range of light;

an emitted light collection system comprising an array of compact lens trains (CLT'"'"'s), each CLT corresponding to a patch of nanoscale regions,

wherein each CLT comprises;

a collimating lens for collimating light from the emission sources;

a color separating element for spectrally separating light; and

a focusing lens for focusing light from the color separating element; and

a detector comprising an array of pixels onto which the focusing lens focuses light;

whereby images of the nanoscale regions are focused onto the detector such that some pixels on the detector detect signal corresponding to the first spectral range, and some pixels on the detector detect signal corresponding to the second spectral range, thereby separately detecting light corresponding to the first emitter and the second emitter over time.

2. The detection system of claim 1 wherein the nanoscale regions comprise zero mode waveguides.

3. The detection system of claim 1 wherein the chip comprises waveguides which provide excitation light to the nanoscale regions.

4. The detection system of claim 1 wherein the chip comprises an array of microlenses below the nanoscale regions wherein each nanoscale region has a microlens.

5. The detection system of claim 4 wherein the CLT further comprises a rejection filter for selectively rejecting excitation light.

6. The detection system of claim 1 wherein each patch of nanoscale regions comprises 1,000 to 50,000 nanoscale regions.

7. The detection system of claim 1 wherein the array of CLT'"'"'s has from 9 to 400 CLTs.

8. The detection system of claim 1 wherein the array of CLT'"'"'s has from 25 to 100 CLTs.

9. The detection system of claim 1 wherein the array of CLT'"'"'s comprises an array of plates, each plate comprising an array of optical elements.

10. The detection system of claim 9 wherein the array of CLTs comprises a collimating lens plate comprising an array of collimating lenses, a color separating element plate comprising an array of color separating elements, and a focusing lens plate comprising an array of color separating elements.

11. The detection system of claim 1 wherein two or more sets of images of nanoscale regions are formed on the detector, wherein one set of images is formed with light corresponding to the first emitter, and one set of images is formed with light corresponding to the second emitter.

12. The detection system of claim 1 wherein the CLT comprises a non-telecentric lens system, and the chip comprises an array of microlenses below the nanoscale regions wherein each nanoscale region has a microlens.

13. The detection system of claim 1 wherein the CLT further comprises a field flattening lens between the focusing lens and the detector.

14. The detection system of claim 1 wherein the area taken up by a patch of nanoscale regions on the chip is within a factor of 3 of the area of the portion of the detector onto which the patch of nanoscale regions is focused.

15. The detection system of claim 1 wherein the distance between the chip and the detector is less than two times the largest lateral dimension of the detector or the chip.

16. The detection system of claim 1 wherein the distance between the chip and the detector is less than about 30 mm.

17. The detection system of claim 1 wherein the detector comprises a plurality of sensors.

18. The detection system of claim 17 wherein the plurality of sensors comprises 2 to 9 sensors.

19. A method for measuring the emitted light from an array of patches of nanoscale regions comprising:

providing a chip having an array of patches of nanoscale regions, each patch of nanoscale regions having an array of nanoscale regions;

wherein light is emitted from the nanoscale regions from at least a first emitter and a second emitter, each emitting a different spectral range of light;

passing the emitted light through an emitted light collection system comprising an array of compact lens trains (CLTs), each CLT corresponding to a patch of nanoscale regions,

wherein within each CLT;

light from the emission sources is collimated with a collimating lens;

the light is spectrally separated by a color separating element; and

light from the color separating element is focused onto a detector with a focusing lens; and

detecting light corresponding to the first emitter and second emitter over time on a detector comprising an array of pixels;

whereby images of the nanoscale regions are focused onto the detector such that some pixels on the detector detect signal corresponding to the first spectral range, and some pixels on the detector detect signal corresponding to the second spectral range.

20. An analysis system for measuring emitted fluorescent light from an array of patches of nanoscale regions comprising:

(a) a holder for receiving a chip, the chip having an array of patches of nanoscale regions in contact with a reaction fluid, each patch of nanoscale regions having an array of nanoscale regions;

wherein fluorescent light is emitted from the nanoscale regions from at least a first emitter and a second emitter, each emitting a different spectral range of light;

(b) an illumination system providing excitation illumination to the nanoscale regions on the analysis chip,

(c) an emitted light collection system comprising an array of compact lens trains (CLTs), each CLT corresponding to a patch of nanoscale regions,

wherein each CLT comprises;

(i) a collimating lens for collimating light from the emission sources;

(ii) a color separating element for spectrally separating the light; and

(iii) a focusing lens for focusing light from the color separating element; and

(d) a detector comprising an array of pixels onto which the focusing lens focuses light;

whereby images of the nanoscale regions are focused onto the detector such that some pixels on the detector detect signal corresponding to the first spectral range, and some pixels on the detector detect signal corresponding to the second spectral range, thereby separately detecting light corresponding to the first emitter and the second emitter over time.