Quantum-enhanced nonlinear microscopy.

Publisher: Nature Publishing Group Country of Publication: England NLM ID: 0410462 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1476-4687 (Electronic) Linking ISSN: 00280836 NLM ISO Abbreviation: Nature Subsets: MEDLINE

Publication: Basingstoke : Nature Publishing Group
Original Publication: London, Macmillan Journals ltd.

Lasers*/adverse effects ; Lighting*/adverse effects ; Photons*/adverse effects ; Quantum Theory* ; Spectrum Analysis, Raman*/instrumentation ; Spectrum Analysis, Raman*/methods; Microscopy/*methods; Cells/pathology ; Cells/radiation effects ; Microscopy/instrumentation ; Signal-To-Noise Ratio

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 speed ¹ . 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 processes ^2-4 . Theory predicts that biological imaging may be improved without increasing light intensity by using quantum photon correlations ^1,5 . 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 specimens ^6,7 , but photodamage is a major roadblock for many applications ^8,9 . 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.

Comment in: Nature. 2021 Jun;594(7862):180-181. (PMID: 34108692)
Erratum in: Nature. 2021 Aug;596(7873):E12. (PMID: 34341545)

Taylor, M. A. & Bowen, W. P. Quantum metrology and its application in biology. Phys. Rep. 615, 1–59 (2016). (PMID: 10.1016/j.physrep.2015.12.002)
Li, B., Wu, C., Wang, M., Charan, K. & Xu, C, An adaptive excitation source for high-speed multiphoton microscopy. Nat. Methods 17, 163–166 (2020). (PMID: 10.1038/s41592-019-0663-931792434)
Wäldchen, S., Lehmann, J., Klein, T., Van De Linde, S. & Sauer, M. Light-induced cell damage in live-cell super-resolution microscopy. Sci. Rep. 5, 15348 (2015). (PMID: 26481189461148610.1038/srep15348)
Mauranyapin, N. P., Madsen, L. S., Taylor, M. A., Waleed, M. & Bowen, W. P. Evanescent single-molecule biosensing with quantum-limited precision. Nat. Photon. 11, 477–481 (2017). (PMID: 10.1038/nphoton.2017.99)
Slusher, R. E. Quantum optics in the ’80s. Opt. Photon. News 1, 27–30 (1990). (PMID: 10.1364/OPN.1.12.000027)
Cheng, J.-X. & Sunney Xie, X. Vibrational spectroscopic imaging of living systems: an emerging platform for biology and medicine. Science 350, aaa8870 (2015). (PMID: 10.1126/science.aaa887026612955)
Wei, L. et al. Super-multiplex vibrational imaging. Nature 544, 465–470 (2017). (PMID: 28424513593992510.1038/nature22051)
Camp, C. H. Jr & Cicerone, M. T. Chemically sensitive bioimaging with coherent Raman scattering. Nat. Photon. 9, 295–305 (2015). (PMID: 10.1038/nphoton.2015.60)
Fu, Y., Wang, H., Shi, R. & Cheng, J.-X. Characterization of photodamage in coherent anti-Stokes Raman scattering microscopy. Opt. Express 14, 3942–3951 (2006). (PMID: 10.1364/OE.14.00394219516542)
Sigal, Y. M., Zhou, R. & Zhuang, X. Visualizing and discovering cellular structures with super-resolution microscopy. Science 361, 880–887 (2018). (PMID: 30166485653540010.1126/science.aau1044)
Alex, M. et al. Applying systems-level spectral imaging and analysis to reveal the organelle interactome. Nature 546, 162–167 (2017). (PMID: 10.1038/nature22369)
Adam, Y. et al. Voltage imaging and optogenetics reveal behaviour-dependent changes in hippocampal dynamics. Nature 569, 413–417 (2019). (PMID: 31043747661393810.1038/s41586-019-1166-7)
Schermelleh, L. et al. Super-resolution microscopy demystified. Nat. Cell Biol. 21, 72–84 (2019). (PMID: 10.1038/s41556-018-0251-830602772)
Sewell, R. J., Napolitano, M., Behbood, N., Colangelo, G. & Mitchell, M. W. Certified quantum non-demolition measurement of a macroscopic material system. Nat. Photon. 7, 517–520 (2013). (PMID: 10.1038/nphoton.2013.100)
Aasi, J. et al. Enhanced sensitivity of the LIGO gravitational wave detector by using squeezed states of light. Nat. Photon. 7, 613–619 (2013). (PMID: 10.1038/nphoton.2013.177)
Giovannetti, V., Lloyd, S. & Maccone, L. Advances in quantum metrology. Nat. Photon. 5, 222–229 (2011). (PMID: 10.1038/nphoton.2011.35)
Moreau, P.-A., Toninelli, E., Gregory, T. & Padgett, M. J. Imaging with quantum states of light. Nat. Rev. Phys. 1, 367–380 (2019). (PMID: 10.1038/s42254-019-0056-0)
Brida, G., Genovese, M. & Ruo Berchera, I. Experimental realization of sub-shot-noise quantum imaging. Nat. Photon. 4, 227–230 (2010). (PMID: 10.1038/nphoton.2010.29)
Defienne, H., Reichert, M., Fleischer, J. W. & Faccio, D. Quantum image distillation. Sci. Adv. 5, eaax0307 (2019). (PMID: 31667343679998110.1126/sciadv.aax0307)
Sabines-Chesterking, J. et al. Twin-beam sub-shot-noise raster-scanning microscope. Opt. Express 27, 30810–30818 (2019). (PMID: 10.1364/OE.27.03081031684324)
Samantaray, N., Ruo-Berchera, I., Meda, A. & Genovese, M. Realization of the first sub-shot-noise wide field microscope. Light Sci. Appl. 6, e17005 (2017). (PMID: 30167268606223010.1038/lsa.2017.5)
Gregory, T., Moreau, P.-A., Toninelli, E. & Padgett, M. J. Imaging through noise with quantum illumination. Sci. Adv. 6, eaay2652 (2020). (PMID: 32083179700726310.1126/sciadv.aay2652)
Israel, Y., Rosen, S. & Silberberg, Y. Supersensitive polarization microscopy using NOON states of light. Phys. Rev. Lett. 112, 103604 (2014). (PMID: 10.1103/PhysRevLett.112.10360424679294)
Ono, T., Okamoto, R. & Takeuchi, S. An entanglement-enhanced microscope. Nat. Commun. 4, 2426 (2013). (PMID: 10.1038/ncomms342624026165)
Lemos, G. B. et al. Quantum imaging with undetected photons. Nature 512, 409–412 (2014). (PMID: 10.1038/nature1358625164751)
Kalashnikov, D. A., Paterova, A. V., Kulik, S. P. & Krivitsky, L. A. Infrared spectroscopy with visible light. Nat. Photon. 10, 98–101 (2016). (PMID: 10.1038/nphoton.2015.252)
Paterova, A. V., Yang, H., An, C., Kalashnikov, D. A. & Krivitsky, L. A. Tunable optical coherence tomography in the infrared range using visible photons. Quantum Sci. Technol. 3, 025008 (2018). (PMID: 10.1088/2058-9565/aab567)
Zhang, L. et al. Spectral tracing of deuterium for imaging glucose metabolism. Nat. Biomed. Eng. 3, 402–413 (2019). (PMID: 31036888659968010.1038/s41551-019-0393-4)
Tian, F. et al. Monitoring peripheral nerve degeneration in ALS by label-free stimulated Raman scattering imaging. Nat. Commun. 7, 13283 (2016). (PMID: 27796305509559810.1038/ncomms13283)
Liu, B. et al. Label-free spectroscopic detection of membrane potential using stimulated Raman scattering. Appl. Phys. Lett. 106, 173704 (2015). (PMID: 10.1063/1.4919104)
Konstanze, T. et al. Phenazine production promotes antibiotic tolerance and metabolic heterogeneity in Pseudomonas aeruginosa biofilms. Nat. Commun. 10, 762 (2019). (PMID: 10.1038/s41467-019-08733-w)
Saar, B. G. et al. Video-rate molecular imaging in vivo with stimulated Raman scattering. Science 330, 1368–1370 (2010). (PMID: 21127249346235910.1126/science.1197236)
Freudiger, C. W. et al. Stimulated Raman scattering microscopy with a robust fibre laser source. Nat. Photon. 8, 153–159 (2014). (PMID: 10.1038/nphoton.2013.360)
Freudiger, C. W. et al. Label-free biomedical imaging with high sensitivity by stimulated Raman scattering microscopy. Science 322, 1857–1861 (2008). (PMID: 19095943357603610.1126/science.1165758)
Pooser, R. C. & Lawrie, B. Plasmonic trace sensing below the photon shot noise limit. ACS Photon. 3, 8–13 (2016). (PMID: 10.1021/acsphotonics.5b00501)
Dowran, M., Kumar, A., Lawrie, B. J., Pooser, R. C. & Marino, A. M. Quantum-enhanced plasmonic sensing. Optica 5, 628–633 (2018). (PMID: 10.1364/OPTICA.5.000628)
Michael, A. et al. Biological measurement beyond the quantum limit. Nat. Photon. 7, 229–233 (2013). (PMID: 10.1038/nphoton.2012.346)
Michael, A. et al. Subdiffraction-limited quantum imaging within a living cell. Phys. Rev. X 4, 011017 (2014).
Tenne, R. et al. Super-resolution enhancement by quantum image scanning microscopy. Nat. Photon. 13, 116–122 (2019). (PMID: 10.1038/s41566-018-0324-z)
Phan, N. M., Cheng, M. F., Bessarab, D. A. & Krivitsky, L. A. Interaction of fixed number of photons with retinal rod cells. Phys. Rev. Lett. 112, 213601 (2014). (PMID: 10.1103/PhysRevLett.112.213601)
Choi, Y. et al. Shot-noise-limited two-color stimulated Raman scattering microscopy with a balanced detection scheme. J. Phys. Chem. B 124, 2591–2599 (2020). (PMID: 10.1021/acs.jpcb.0c0106532176510)
de Andrade, R. B. et al. Quantum-enhanced continuous-wave stimulated Raman spectroscopy. Optica 7, 470–475 (2020). (PMID: 10.1364/OPTICA.386584)
Triginer Garces, G. et al. Quantum-enhanced stimulated emission detection for label-free microscopy. Appl. Phys. Lett. 117, 024002 (2020). (PMID: 10.1063/5.0009681)
Okuno, M. et al. Quantitative CARS molecular fingerprinting of single living cells with the use of the maximum entropy method. Angew. Chem. 122, 6925–6929 (2010). (PMID: 10.1002/ange.201001560)
Kochan, K., Peng, H., Wood, B. R. & Haritos, V. S. Single cell assessment of yeast metabolic engineering for enhanced lipid production using Raman and AFM-IR imaging. Biotechnol. Biofuels 11, 106 (2018). (PMID: 29643936589196810.1186/s13068-018-1108-x)
A Roadmap for Quantum Technologies in the UK 16 (UK Quantum Technologies Programme, 2015); https://epsrc.ukri.org/newsevents/pubs/quantumtechroadmap.
Vahlbruch, H., Mehmet, M., Danzmann, K. & Schnabel, R. Detection of 15 dB squeezed states of light and their application for the absolute calibration of photoelectric quantum efficiency. Phys. Rev. Lett. 117, 110801 (2016). (PMID: 2766167310.1103/PhysRevLett.117.110801)
Hoover, E. E. & Squier, J. A. Advances in multiphoton microscopy technology. Nat. Photon. 7, 93–101 (2013). (PMID: 10.1038/nphoton.2012.361)
Zong, C. et al. Plasmon-enhanced stimulated Raman scattering microscopy with single-molecule detection sensitivity. Nat. Commun. 10, 5318 (2019). (PMID: 31754221687256110.1038/s41467-019-13230-1)
Michael, Y., Bello, L., Rosenbluh, M. & Pe’er, A. Squeezing-enhanced Raman spectroscopy. npj Quantum Inf. 5, 81 (2019). (PMID: 10.1038/s41534-019-0197-0)

Date Created: 20210610 Date Completed: 20210802 Latest Revision: 20220419

20231215

10.1038/s41586-021-03528-w

34108694