Portable diffraction-based imaging and diagnostic systems and methods

Patent metadata

Field	Value
Publication number	US-10724948-B2
Application number	US-201816025615-A
Country	US
Kind code	B2
Filing date	Jul 2, 2018
Priority date	Aug 16, 2013
Publication date	Jul 28, 2020
Grant date	Jul 28, 2020

Abstract

The disclosure features systems and methods for measuring and diagnosing target constituents bound to labeling particles in a sample. The systems include a radiation source, a sample holder, a detector configured to obtain one or more diffraction patterns of the sample each including information corresponding to optical properties of sample constituents, and an electronic processor configured to, for each of the one or more diffraction patterns: (a) analyze the diffraction pattern to obtain amplitude information and phase information corresponding to the sample constituents; (b) identify one or more particle-bound target sample constituents based on at least one of the amplitude information and the phase information; and (c) determine an amount of at least one of the particle-bound target sample constituents in the sample based on at least one of the amplitude information and the phase information.

First claim

What is claimed is:

1. A diagnostic system comprising:
a radiation source configured to generate illumination radiation;
a sample holder configured to support a sample so that the sample is exposed to the illumination radiation;
a detector configured to obtain one or more diffraction images of the sample, wherein each of the diffraction images comprises information corresponding to optical properties of sample constituents; and
an electronic processor configured to, for each of the one or more diffraction images:
(a) for each sample constituent in the diffraction image, identify a corresponding diffraction pattern;
(b) analyze the diffraction pattern for each sample constituent to obtain spatial amplitude distribution information and spatial phase distribution information corresponding to the sample constituent;
(c) determine whether each sample constituent comprises a target analyte conjugated to a particle based on at least one of the spatial amplitude distribution information and the spatial phase distribution information corresponding to the constituent; and
(d) determine an amount of at least one of the conjugated target analytes in the sample based on at least one of the spatial amplitude distribution information and the spatial phase distribution information.

2. The system of claim 1 , further comprising an aperture configured to spatially filter the illumination radiation to generate partially coherent illumination radiation that is incident on the sample.

3. The system of claim 1 , wherein the electronic processor is configured to:
(d) generating a reconstructed image of the sample;
(e) analyzing the reconstructed image of the sample to obtain phase information corresponding to the diffraction of the illumination radiation by the sample;
(f) analyzing the combined phase information and the diffraction image to obtain an improved reconstructed diffraction image; and
(g) analyzing the improved reconstructed diffraction image to determine whether each sample constituent comprises a target analyte conjugated to a particle.

4. The system of claim 1 , wherein the detector comprises at least one of a charge-coupled device (CCD) and a complementary metal-oxide semiconductor (CMOS) device.

5. The system of claim 1 , wherein the detector comprises a camera of a mobile telephone or tablet.

6. The system of claim 5 , wherein the electronic processor is a graphical processing unit of the mobile telephone or tablet.

7. The system of claim 1 , wherein the sample holder comprises a fluid chamber, an inlet port connected to the fluid chamber, and an outlet port connected to the fluid chamber.

8. The system of claim 1 , further comprising a display unit, wherein the electronic processor is configured to display the at least one of the target analytes on the display unit.

9. The system of claim 8 , wherein the display unit is a screen of a mobile telephone or tablet.

10. The system of claim 8 , wherein the electronic processor is configured to display the one or more target analytes in a first color, and to display other sample constituents in a second color different from the first color.

11. The system of claim 1 , wherein the one or more diffraction images comprises multiple diffraction images, and wherein the electronic processor is configured to identify one or more target analytes common to each of the improved reconstructed diffraction images.

12. The system of claim 1 , wherein the system is configured to identify target analytes comprising cells.

13. The system of claim 12 , wherein the electronic processor is configured to determine, for each cell one or more of the cells, a number of beads bound to the cell.

14. The system of claim 1 , wherein the system is configured to identify target analytes comprising viruses.

15. The system of claim 1 , wherein the system is configured to identify target analytes comprising nucleic acids.

16. The system of claim 1 , wherein the system is configured to identify target analytes comprising bacteria.

17. The system of claim 13 , wherein the electronic processor is configured to display a histogram of the number of beads bound to the one or more of the cells.

18. The system of claim 2 , wherein each of the reconstructed images corresponds to a portion of the sample flowing through the sample holder.

19. The system of claim 2 , wherein the aperture is separated from the radiation source by a distance of 1 mm or less.

20. The system of claim 1 , wherein the sample holder comprises a stage configured to support a substrate bearing the sample.

21. A diagnostic system, comprising:
a radiation source configured to generate illumination radiation;
a sample holder configured to support a sample so that the sample is exposed to the illumination radiation;
a detector configured to obtain one or more diffraction images of the sample, wherein each of the diffraction images comprises information corresponding to optical properties of sample constituents; and
an electronic processor configured to, for each of the one or more diffraction images:
(a) analyze the diffraction image to obtain amplitude information and phase information corresponding to the sample constituents;
(b) identify one or more bead-conjugated cells among the sample constituents based on at least one of the amplitude information and the phase information;
(c) determine, for each bead-conjugated cell, a number of beads conjugated to the cell; and
(d) determine an amount of at least one of the bead-conjugated cells in the sample based on at least one of the amplitude information and the phase information.

Assignees

• Massachusetts Gen Hospital

Inventors

• Weissleder Ralph
• Lee Hakho
• Im Hyungsoon
• Castro Cesar

Classifications

• G01N33/57557

  of other specific parts of the body, e.g. brain · CPC title

• G01N33/5755

  of the uterine cervix, uterine corpus or endometrium · CPC title

• G03H2001/0447

  In-line recording arrangement · CPC title

• G01N33/56972

  White blood cells · CPC title

• G01N2015/1486

  Counting the particles · CPC title