Portable diffraction-based imaging and diagnostic systems and methods

Patent metadata

Field	Value
Publication number	US-10012589-B2
Application number	US-201414912038-A
Country	US
Kind code	B2
Filing date	Aug 18, 2014
Priority date	Aug 16, 2013
Publication date	Jul 3, 2018
Grant date	Jul 3, 2018

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 method for analyzing a sample, the method comprising:
obtaining one or more diffraction patterns of the sample by illuminating the sample with spatially filtered, partially coherent radiation;
for each one of the one or more diffraction patterns:
(a) analyzing the diffraction pattern to obtain amplitude information and phase information corresponding to diffraction of the illumination radiation by the sample, wherein analyzing the diffraction pattern comprises:
(i) generating a reconstructed image of the sample;
(ii) analyzing the reconstructed image of the sample to obtain phase information corresponding to the diffraction of the illumination radiation by the sample;
(iii) analyzing the combined phase information and the diffraction pattern to obtain an improved reconstructed image of the sample; and
(iv) analyzing the improved reconstructed image to identify the one or more target sample constituents in the sample;

(b) identifying one or more target sample constituents based on at least one of the amplitude information and the phase information; and
(c) determining an amount of at least one of the target sample constituents in the sample based on at least one of the amplitude information and the phase information;

determining a number of labeled target sample constituents in the sample based on the reconstructed image, wherein the one or more target sample constituents comprise cells and beads bound to the cells; and
for each cell comprising beads, determining a number of beads bound to the cell.

2. The method of claim 1 , further comprising displaying a histogram of the number of beads bound to each of the cells.

3. The method of claim 1 , wherein the sample comprises blood, and wherein the target sample constituents comprise circulating tumor cells.

4. The method of claim 1 , wherein the sample comprises maternal blood, and wherein the target sample constituents comprise fetal cells.

5. The method of claim 1 , further comprising obtaining the one or more diffraction patterns of the sample using a lens-free detector.

6. The method of claim 1 , wherein analyzing the reconstructed image of the sample to obtain phase information comprises identifying a region of support in the reconstructed image for each of one or more target sample constituents in the reconstructed image.

7. The method of claim 1 , wherein determining the number of labeled target sample constituents comprises, for each candidate target sample constituent in the improved reconstructed image, determining whether the candidate target sample constituent is an actual cell based on phase information corresponding to diffraction of the spatially filtered radiation by the candidate target sample constituent.

8. The method of claim 1 , the method further comprising identifying beads conjugated to the cells based on at least one of the phase information and the intensity information corresponding to diffraction of the spatially filtered radiation by the sample.

9. The method of claim 8 , further comprising identifying an object in the reconstructed image as a bead if a magnitude of phase information associated with the object is less than a first selected threshold value and a magnitude of intensity information associated with the object is larger than a second selected threshold value.

10. The method of claim 1 , further comprising labeling the target sample constituents prior to illuminating the sample.

11. The method of claim 10 , wherein labeling the target sample constituents comprises binding the target sample constituents to the beads.

12. The method of claim 11 , wherein optical properties of the labeled target sample constituents are different from optical properties of unlabeled sample constituents.

13. The method of claim 12 , further comprising labeling different types of target sample constituents by binding the different types of target sample constituents to different types of beads.

14. The method of claim 13 , wherein each different type of labeled target sample constituents has optical properties different from other types of labeled target sample constituents.

15. The method of claim 11 , wherein labeling the target sample constituents further comprises binding the target sample constituents to nanoparticles comprising gold.

16. The method of claim 15 , further comprising depositing a coating comprising silver on the labeled target sample constituents.

17. A method for analyzing a sample, the method comprising:
obtaining one or more diffraction patterns of the sample by illuminating the sample with spatially filtered, partially coherent radiation;
for each one of the one or more diffraction patterns:
(a) analyzing the diffraction pattern to obtain amplitude information and phase information corresponding to diffraction of the illumination radiation by the sample, wherein analyzing the diffraction pattern comprises:
(i) generating a reconstructed image of the sample;
(ii) analyzing the reconstructed image of the sample to obtain phase information corresponding to the diffraction of the illumination radiation by the sample;
(iii) analyzing the combined phase information and the diffraction pattern to obtain an improved reconstructed image of the sample; and
(iv) analyzing the improved reconstructed image to identify the one or more target sample constituents in the sample;

(b) identifying one or more target sample constituents based on at least one of the amplitude information and the phase information; and
(c) determining an amount of at least one of the target sample constituents in the sample based on at least one of the amplitude information and the phase information; and

determining a number of labeled target sample constituents in the sample based on the reconstructed image,
wherein the one or more labeled target sample constituents comprise labeled cells; and
wherein determining the number of labeled cells comprises, for each candidate cell in the improved reconstructed image, determining whether the candidate cell is an actual cell based on phase information corresponding to diffraction of the spatially filtered radiation by the candidate cell.

18. The method of claim 17 , wherein the labeled cells comprise at least one of circulating tumor cells and fetal cells.

19. A method for analyzing a sample, the method comprising:
labeling target sample constituents in the sample;
obtaining one or more diffraction patterns of the sample by illuminating the sample with spatially filtered, partially coherent radiation; and
for each one of the one or more diffraction patterns:
(a) analyzing the diffraction pattern to obtain amplitude information and phase information corresponding to diffraction of the illumination radiation by the sample;
(b) identifying one or more of the target sample constituents based on at least one of the amplitude information and the phase information; and
(c) determining an amount of at least one of the target sample constituents in the sample based on at least one of the amplitude information and the phase information,

wherein labeling the target sample constituents comprises binding different types of target sample constituents to different types of particles; and
wherein optical properties of the labeled target sample constituents are different from optical properties of unlabeled sample constituents.

20. The method of claim 19 , wherein each different type of labeled target sample constituents has optical properties different from other types of label

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

• G01N2015/1486

  Counting the particles · CPC title

• G01N33/56972

  White blood cells · CPC title

• G01N15/06

  Investigating concentration of particle suspensions (by weighing G01N5/00; investigating sedimentation of particle suspensions G01N15/04; investigating individual particles G01N15/10) · CPC title