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Nat Biomed Eng. 2019 Apr 1. doi: 10.1038/s41551-019-0376-5. [Epub ahead of print]

High-throughput, label-free, single-cell photoacoustic microscopy of intratumoral metabolic heterogeneity.

Hai P1,2, Imai T1,2, Xu S3, Zhang R1, Aft RL4,5, Zou J6, Wang LV7,8.

Author information

1
Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, MO, USA.
2
Caltech Optical Imaging Laboratory, Andrew and Peggy Cherng Department of Medical Engineering, California Institute of Technology, Pasadena, CA, USA.
3
Department of Electrical and Computer Engineering, Texas A&M University, College Station, TX, USA.
4
Department of Surgery, School of Medicine, Washington University, St. Louis, MO, USA.
5
John Cochran Veterans Hospital, St. Louis, MO, USA.
6
Department of Electrical and Computer Engineering, Texas A&M University, College Station, TX, USA. junzou@ece.tamu.edu.
7
Caltech Optical Imaging Laboratory, Andrew and Peggy Cherng Department of Medical Engineering, California Institute of Technology, Pasadena, CA, USA. LVW@caltech.edu.
8
Caltech Optical Imaging Laboratory, Department of Electrical Engineering, California Institute of Technology, Pasadena, CA, USA. LVW@caltech.edu.

Abstract

Intratumoral heterogeneity, which is manifested in almost all of the hallmarks of cancer, including the significantly altered metabolic profiles of cancer cells, represents a challenge to effective cancer therapy. High-throughput measurements of the metabolism of individual cancer cells would allow direct visualization and quantification of intratumoral metabolic heterogeneity, yet the throughputs of current measurement techniques are limited to about 120 cells per hour. Here, we show that single-cell photoacoustic microscopy can reach throughputs of approximately 12,000 cells per hour by trapping single cells with blood in an oxygen-diffusion-limited high-density microwell array and by using photoacoustic imaging to measure the haemoglobin oxygen change (that is, the oxygen consumption rate) in the microwells. We demonstrate the capability of this label-free technique by performing high-throughput single-cell oxygen-consumption-rate measurements of cultured cells and by imaging intratumoral metabolic heterogeneity in specimens from patients with breast cancer. High-throughput single-cell photoacoustic microscopy of oxygen consumption rates should enable the faster characterization of intratumoral metabolic heterogeneity.

PMID:
30936431
DOI:
10.1038/s41551-019-0376-5

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