The performance of light microscopes is limited by the stochastic nature of light, which exists in discrete packets of energy known as photons. Randomness in the times that photons are detected introduces shot noise, which fundamentally constrains sensitivity, resolution and speed1. Although the long-established solution to this problem is to increase the intensity of the illumination light, this is not always possible when investigating living systems, because bright lasers can severely disturb biological processes2,3,4. Theory predicts that biological imaging may be improved without increasing light intensity by using quantum photon correlations1,5. Here we experimentally show that quantum correlations allow a signal-to-noise ratio beyond the photodamage limit of conventional microscopy. Our microscope is a coherent Raman microscope that offers subwavelength resolution and incorporates bright quantum correlated illumination. The correlations allow imaging of molecular bonds within a cell with a 35 per cent improved signal-to-noise ratio compared with conventional microscopy, corresponding to a 14 per cent improvement in concentration sensitivity. This enables the observation of biological structures that would not otherwise be resolved. Coherent Raman microscopes allow highly selective biomolecular fingerprinting in unlabelled specimens6,7, but photodamage is a major roadblock for many applications8,9. By showing that the photodamage limit can be overcome, our work will enable order-of-magnitude improvements in the signal-to-noise ratio and the imaging speed.
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The data that support the findings of this study are included in the Supplementary Information. This includes data quantifying the detector design and performance (Supplementary Figs. 3–5); example power spectral densities of the stimulated Raman signal-to-noise ratio with and without squeezing (Supplementary Fig. 6); the raw measured power spectral densities of detector electronic noise, shot-noise and squeezing (Supplementary Fig. 7); experimental measurements of the squeezed variance and classical deamplification of the Stokes field as a function of the optical parametric amplifier pump power (Supplementary Fig. 9); the photocurrent power spectral density used to determine the concentration sensitivity when probing the CH aromatic stretch band in polystyrene (Supplementary Fig. 10); measurements of cell photodamage (Supplementary Fig. 11); and comparative cell images with and without quantum enhancement (Supplementary Fig. 12). Further data are available from the corresponding author upon reasonable request. Source data are provided with this paper.
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We acknowledge W. Wasserman for sourcing the yeast cells in trying circumstances, U. Hoff for contributions to the construction of the apparatus and APE GmbH for support related to the laser system. This work was supported primarily by the Air Force Office of Scientific Research (AFOSR) grant FA2386-14-1-4046. It was also supported by the Australian Research Council Centre of Excellence for Engineered Quantum Systems (EQUS, CE170100009). W.P.B. acknowledges the Australian Research Council Future Fellowship, FT140100650. M.A.T. acknowledges the Australian Research Council Discovery Early Career Research Award, DE190100641.
The authors declare no competing interests.
Peer review information Nature thanks the anonymous reviewers for their contribution to the peer review of this work. Peer reviewer reports are available.
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Casacio, C.A., Madsen, L.S., Terrasson, A. et al. Quantum-enhanced nonlinear microscopy. Nature 594, 201–206 (2021). https://doi.org/10.1038/s41586-021-03528-w