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Histological imaging is essential for fields such as oncology, and biological research. However, capturing histological images requires tissue to be prepared in thin sections, then stained with dyes such as hematoxylin and eosin (H&E) to capture tissue morphology. This requires intensive processing, which fundamentally alters tissue structure and chemistry. Presented here is the second generation of photoacoustic remote sensing (SG-PARS) histology microscopes, which aim to circumvent current limitations, providing histological visualizations label-free directly within bulk unprocessed tissues. As photons interact with tissues, they may be scattered or absorbed, where absorption will cause the emission of photons (radiative relaxation) or the generation of heat and pressure (non-radiative relaxation). The SG-PARS features a refined architecture providing simultaneous sensitivity to optical scattering, non-radiative relaxation, and radiative relaxation. Leveraging these contrasts, the SG-PARS may provide visualizations in unstained specimens which directly emulate H&E staining. Combined with deep-learning based (cycleGAN) colorization, the SG-PARS rapidly generates emulated H&E images nearly equivalent to traditional H&E preparations. In addition, the SG-PARS may provide novel chromophore specific properties proposed as the total absorption (the combined radiative and non-radiative absorption magnitude) and the quantum efficiency ratio (QER) (the proportional radiative and non-radiative absorption response). These characteristics may enable visualizations with chromophore specificity beyond that provided by traditional H&E staining. In addition, the SG-PARS features extensive architecture innovations, such as a new 2.7 MHz excitation with a hybrid optomechanical scanning architecture, and a novel visible wavelength detection with a circulator-based pathway and an avalanche photodetector. Applied directly in unprocessed human tissues, the SG-PARS provides marked improvements in contrast, sensitivity, resolution, and scanning speed representing a vital milestone in the development of a microscope ready for clinical adoption.
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