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We report both sub-diffraction-limited quantum metrology and quantum enhanced spatial resolution for the first time in a biological context. Nanoparticles are tracked with quantum correlated light as they diffuse through an extended region of a living cell in a quantum enhanced photonic force microscope. This allows spatial structure within the cell to be mapped at length scales down to 10 nm. Control experiments in water show a 14% resolution enhancement compared to experiments with coherent light. Our results confirm the longstanding prediction that quantum correlated light can enhance spatial resolution at the nanoscale and in biology. Combined with state-of-the-art quantum light sources, this technique provides a path towards an order of magnitude improvement in resolution over similar classical imaging techniques.
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Oblique plane microscopy (OPM) enables high speed, volumetric fluorescence imaging through a single-objective geometry. While these advantages have positioned OPM as a valuable tool to probe biological questions in animal models, its potential for in vivo human imaging is largely unexplored due to its typical use with exogenous fluorescent dyes. Here we introduce a scattering-contrast oblique plane microscope (sOPM) and demonstrate label-free imaging of blood cells flowing through human capillaries in vivo. The sOPM illuminates a capillary bed in the ventral tongue with an oblique light sheet, and images side- and back- scattered signal from blood cells. By synchronizing sOPM with a conventional capillaroscope, we acquire paired widefield and axial images of blood cells flowing through a capillary loop. The widefield capillaroscope image provides absorption contrast and confirms the presence of red blood cells (RBCs), while the sOPM image may aid in determining whether optical absorption gaps (OAGs) between RBCs have cellular or acellular composition. Further, we demonstrate consequential differences between fluorescence and scatteri
Thick biological tissues give rise to not only the scattering of incoming light waves, but also aberrations of the remaining unscattered waves. Due to the inability of existing optical imaging methodologies to overcome both of these problems simultaneously, imaging depth at the sub- micron spatial resolution has remained extremely shallow. Here we present an experimental approach for identifying and eliminating aberrations even in the presence of strong multiple light scattering. For time-gated complex-field maps of reflected waves taken over various illumination channels, we identify two sets of aberration correction maps, one for the illumination path and one for the reflection path, that can preferentially accumulate the unscattered signal waves over the multiple-scattered waves. By performing closed-loop optimization for forward and phase- conjugation processes, we demonstrated a spatial resolution of 600 nm up to the unprecedented imaging depth of 7 scattering mean free paths.
In a previous paper [M. Tsang, Phys. Rev. A 99, 012305 (2019)], I proposed a quantum limit to the estimation of object moments in subdiffraction incoherent optical imaging. In this sequel, I prove the quantum limit rigorously by infinite-dimensional analysis. A key to the proof is the choice of an unfavorable parametric submodel to give a bound for the semiparametric problem. By generalizing the quantum limit for a larger class of moments, I also prove that the measurement method of spatial-mode demultiplexing (SPADE) with just one or two modes is able to achieve the quantum limit. For comparison, I derive a classical bound for direct imaging using the parametric-submodel approach, which suggests that direct imaging is substantially inferior.
Magnetic resonance imaging (MRI) is a non-invasive and label-free technique widely used in medical diagnosis and life science research, and its success has benefited greatly from continuing efforts on enhancing contrast and resolution. Here we reported nanoscale MRI in a single cell using an atomic-size quantum sensor. With nitrogen-vacancy center in diamond, the intracellular protein ferritin has been imaged with a spatial resolution of ~ 10 nanometers, and ferritin-containing organelles were co-localized by correlative MRI and electron microscopy. Comparing to the current micrometer resolution in current state-of-art conventional MRI, our approach represents a 100-fold enhancement, and paves the way for MRI of intracellular proteins.
Fluorescence microscopy is a powerful tool to measure molecular specific information in biological samples. However, most biological tissues are highly heterogeneous because of refractive index (RI) differences and thus degrade the signal-to-noise ratio of fluorescence images. At the same time, RI is an intrinsic optical property of label free biological tissues that quantitatively relates to cell morphology, mass, and stiffness. Conventional imaging techniques measure fluorescence and RI of biological samples separately. Here, we develop a new computational hybrid imaging method based on a multi-slice model of multiple scattering that reconstructs 3D fluorescence and 3D RI from the same dataset of fluorescence images. Our method not only bridges the gap between fluorescence and RI imaging and provides a panoramic view of the biological samples, but also can digitally correct multiple scattering effect of fluorescence images from the reconstructed 3D RI. Computational hybrid imaging opens a unique avenue beyond conventional imaging techniques.
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