US-12619058-B2 - High-throughput spatial imaging system for biological samples

Abstract

An imaging system for capturing spatial images of biological tissue samples may include an imaging chamber configured to hold a biological tissue sample placed in the imaging system; a light source configured to illuminate the biological tissue sample to activate a plurality of fluorophores in the biological tissue sample; and a plurality of Time Delay and Integration (TDI) imagers configured to simultaneously scan the biological tissue sample, where the plurality of TDI imagers may be configured to separately receive light from different ones of the plurality of fluorophores.

Inventors

• Ang Li
• Joseph R. Johnson
• Jean Marc Fan Chung Tsang Min Ching
• Dan Xie
• Stephen Hsiang
• Yun-Ching CHANG

Assignees

• APPLIED MATERIALS, INC.

Dates

Publication Date

20260505

Application Date

20230804

Claims (20)

1. 1 . An imaging system for capturing spatial images of biological tissue samples, the imaging system comprising: an imaging chamber configured to hold a biological tissue sample placed in the imaging system; a light source configured to illuminate the biological tissue sample to activate a plurality of fluorophores in the biological tissue sample; and a plurality of Time Delay and Integration (TDI) imagers configured to simultaneously scan the biological tissue sample, wherein the plurality of TDI imagers are configured to separately receive light from different ones of the plurality of fluorophores.
2. 2 . The imaging system of claim 1 , wherein the imaging system is configured to illuminate the biological tissue sample with light that is shaped similar to a shape one of the plurality of TDI imagers.
3. 3 . The imaging system of claim 1 , further comprising a plurality of filters, each of which correspond to one of the plurality of fluorophores.
4. 4 . The imaging system of claim 1 , further comprising a filter wheel, wherein a first filter on the filter wheel covers a first TDI imager in the plurality of TDI imagers, and a second filter on the filter wheel covers a second TDI imager in the plurality of TDI imagers.
5. 5 . The imaging system of claim 1 , wherein the imaging system is configured to scan a strip of the biological tissue sample in a first direction, then scan an adjacent strip of the biological tissue sample in a second direction that is opposite of the first direction.
6. 6 . The imaging system of claim 5 , wherein the imaging system is configured to focus the imaging system on the biological tissue sample at a beginning of each strip being scanned.
7. 7 . The imaging system of claim 5 , wherein the imaging system is configured to focus the imaging system continually during operation based on a surface mapping of the biological tissue sample.
8. 8 . The imaging system of claim 1 , further comprising a doublet and a cylindrical lens configured to provide Critical-Kholer illumination of the biological tissue sample.
9. 9 . The imaging system of claim 1 , further comprising a Powell lens and a collimator to illuminate the biological tissue sample.
10. 10 . The imaging system of claim 1 , wherein a motion of the biological tissue sample is synchronized with an image capture of the plurality of TDI imagers using a trigger signal that is derived by dividing a main clock signal.
11. 11 . A method of capturing spatial images of biological tissue samples, the method comprising: mounting a biological tissue sample in an imaging chamber of an imaging system; directing light from a light source to illuminate an area on the biological tissue sample to activate a plurality of fluorophores in the biological tissue sample; and scanning the biological tissue sample with a plurality of Time Delay and Integration (TDI) imagers configured to simultaneously scan the biological tissue sample, wherein the plurality of TDI imagers are configured to separately receive light from different ones of the plurality of fluorophores.
12. 12 . The method of claim 11 , further comprising directing a light signal through a first filter onto a first TDI imager in the plurality of TDI imagers using a multiband dichroic mirror.
13. 13 . The method of claim 11 , wherein a first fluorophore in the plurality of fluorophores is received by a first TDI imager in the plurality of TDI imagers, a second fluorophore in the plurality of fluorophores is received by a second TDI imager in the plurality of TDI emitters, and the first fluorophore and the second fluorophore have non-adjacent wavelength ranges in the plurality of fluorophores.
14. 14 . The method of claim 11 , further comprising directing a light signal received from the biological tissue sample into a prism to separate the light signal into separate light signals corresponding to different fluorophores in the plurality of fluorophores.
15. 15 . The method of claim 11 , further comprising processing first raw image data from a first strip received from the plurality of TDI imagers while second raw image data is being scanned by the plurality of TDI imagers.
16. 16 . An imaging system comprising: a plurality of Time Delay and Integration (TDI) imagers configured to simultaneously scan a biological tissue sample, wherein the plurality of TDI imagers are configured to separately receive light from different ones of a plurality of fluorophores.
17. 17 . The imaging system of claim 16 , further comprising a plurality of filters, each of which correspond to one of the plurality of fluorophores.
18. 18 . The imaging system of claim 16 , further comprising a filter wheel, wherein a first filter on the filter wheel covers a first TDI imager in the plurality of TDI imagers, and a second filter on the filter wheel covers a second TDI imager in the plurality of TDI imagers.
19. 19 . The imaging system of claim 16 , wherein the imaging system is configured to scan a strip of the biological tissue sample in a first direction, then scan an adjacent strip of the biological tissue sample in a second direction that is opposite of the first direction.
20. 20 . The imaging system of claim 19 , wherein the imaging system is configured to focus the imaging system on the biological tissue sample at a beginning of each strip being scanned.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to Provisional U.S. Patent Application No. 63/395,261 filed Aug. 4, 2022 entitled “HIGH-THROUGHPUT SPATIAL IMAGING SYSTEM FOR BIOLOGICAL SAMPLES,” the entire disclosure of which is hereby incorporated by reference, for all purposes, as if fully set forth herein. TECHNICAL FIELD This disclosure generally describes capturing spatial images of biological tissue samples. More specifically, this disclosure describes an imaging system using Time Delay Integration (TDI) imagers and other techniques to improve the throughput when capturing spatial images of tissue samples. BACKGROUND Spatial biology is the study of the cellular and sub-cellular environment across multiple dimensions. Spatial biology tools may be used to determine which cells are present in a tissue sample, where they are located in the tissue sample, their biomarker co-expression patterns, and how these cells organize interact within the tissue sample. A sample slide may be prepared with a tissue sample in various imaging workflows may be executed to generate a comprehensive image of the tissue at the cellular and sub-cellular level, producing a single-cell resolution to visualize and quantify biomarker expression. The resulting images may expose how cells interact and organize within the tissue sample. Capturing these complex images of the cell environment may be referred to as spatial omics. High-resolution, highly multiplexed spatial omics is rapidly becoming an essential tool in understanding diseases and other biological conditions. Typically, this type of analysis involves hundreds of complex factors, variables, and processes. An integrated solution may combine imaging and process control methods into a single machine for performing spatial omics. However, generating full spatial images of a tissue sample that accurately represent the volume of the sample requires many individual imaging scans of the sample. This large number of scans required for a full imaging analysis severely limits the throughput of the system. Therefore, improvements in the art are needed. SUMMARY In some embodiments, an imaging system for capturing spatial images of biological tissue samples may include an imaging chamber configured to hold a biological tissue sample placed in the imaging system; a light source configured to illuminate the biological tissue sample to activate a plurality of fluorophores in the biological tissue sample; and a plurality of Time Delay and Integration (TDI) imagers configured to simultaneously scan the biological tissue sample, where the plurality of TDI imagers may be configured to separately receive light from different ones of the plurality of fluorophores. In some embodiments, a method of capturing spatial images of biological tissue samples may include mounting a biological tissue sample in an imaging chamber of an imaging system; directing light from a light source to illuminate an area on the biological tissue sample to activate a plurality of fluorophores in the biological tissue sample; and scanning the biological tissue sample with a plurality of Time Delay and Integration (TDI) imagers configured to simultaneously scan the biological tissue sample, where the plurality of TDI imagers may be configured to separately receive light from different ones of the plurality of fluorophores. In some embodiments, an imaging system may include a plurality of Time Delay and Integration (TDI) imagers configured to simultaneously scan a biological tissue sample, where the plurality of TDI imagers may be configured to separately receive light from different ones of a plurality of fluorophores. In any embodiments, one or more of the following features may be implemented in any combination and without limitation. The imaging system may be configured to illuminate the biological tissue sample with light that is shaped similar to a shape one of the plurality of TDI imagers. The system may include a plurality of filters, each of which correspond to one of the plurality of fluorophores. The system may include a filter wheel, where a first filter on the filter wheel may cover a first TDI imager in the plurality of TDI imagers, and a second filter on the filter wheel may cover a second TDI imager in the plurality of TDI imagers. The imaging system may be configured to scan a strip of the biological tissue sample in a first direction, then scan an adjacent strip of the biological tissue sample in a second direction that is opposite of the first direction. The imaging system may be configured to focus the imaging system on the biological tissue sample at a beginning of each strip being scanned. The imaging system may be configured to focus the imaging system continually during operation based on a surface mapping of the biological tissue sample. The imaging system may include a doublet and a cylindrical lens configured to provide Critical-Kholer illumination of the biological tissue