Intracellular microlasers

Journal name:
Nature Photonics
Year published:
Published online

Optical microresonators1, which confine light within a small cavity, are widely exploited for various applications ranging from the realization of lasers2 and nonlinear devices3, 4, 5 to biochemical and optomechanical sensing6, 7, 8, 9, 10, 11. Here we use microresonators and suitable optical gain materials inside biological cells to demonstrate various optical functions in vitro including lasing. We explore two distinct types of microresonator—soft and hard—that support whispering-gallery modes. Soft droplets formed by injecting oil or using natural lipid droplets support intracellular laser action. The laser spectra from oil-droplet microlasers can chart cytoplasmic internal stress (∼500 pN μm–2) and its dynamic fluctuations at a sensitivity of 20 pN μm–2 (20 Pa). In a second form, whispering-gallery modes within phagocytized polystyrene beads of different sizes enable individual tagging of thousands of cells easily and, in principle, a much larger number by multiplexing with different dyes.

At a glance


  1. Injected oil droplet laser.
    Figure 1: Injected oil droplet laser.

    a, Schematic of the injection of oil into the cytoplasm of a cell. b, Confocal fluorescence image of a cell with a PPE droplet doped with Nile red dye (red). The cell nucleus (blue) became kidney-shaped, giving space to the droplet. c, Bright-field (left) and laser-output (right) images of a cell with a droplet (arrows) above the lasing threshold. d, Output light intensity from a droplet as a function of pump pulse energy, showing a distinct laser threshold (arrow). Dashed line: linear fit to the fluorescence output below threshold. e, A typical output spectrum of the lasing modes. All modes are first radial modes, two modes with TE polarization and two with TM. Each mode is split into multiple submodes. From their splitting in these data, the spheroid is determined to be of oblate shape with equatorial and polar semi-axes measuring 8.3 and 8.5 µm, respectively. f, Time-lapse variation of the output spectrum for a live cell (left) and a dead cell fixed with formaldehyde (right). g, Standard deviation of the square of eccentricity and corresponding internal stress for live and fixed (dead) cells. Scale bars (b,c,f), 10 µm.

  2. Adipocyte lasers.
    Figure 2: Adipocyte lasers.

    a, Illustration of a typical mature subcutaneous adipocyte with a lipid droplet. b, Individual adipocytes extracted from subcutaneous porcine fat. c, Confocal image of an adipocyte containing a large lipid droplet (orange), which occupies the majority of the cell volume. The nucleus (blue) is visible next to the droplet. d, Spectrum from a 45 µm adipocyte above lasing threshold, showing typical WGM spectral peaks. Inset: fluorescence image of the cell above lasing threshold. e, Output energy as a function of pump energy. Dashed line: linear fit to the fluorescence output below laser threshold. f, Two-photon confocal image of adipocytes in situ in subcutaneous fat tissue, after intradermal injection of Nile red dye (yellow). g, Generation of cellular laser emission from within tissue. The pump laser is fibre-optically guided into the subcutaneous fat layer after injecting a mixture of collagenase and Nile red dye. h, Spectrum of light collected by the optical fibre from the tissue. Scale bars, 200 µm (b) and 20 µm (c,d,f).

  3. Three different types of solid intracellular microcavity.
    Figure 3: Three different types of solid intracellular microcavity.

    a, Schematic of a bead inside a cell. b, Confocal fluorescence image of a HeLa cell containing a polystyrene bead (green), nucleus (blue) and plasma membrane (red). c, Laser emission from a fluorescent polystyrene bead inside a cell. d, Emission spectra and images (insets) of a fluorescent polystyrene bead below (top) and above (bottom) lasing threshold (3.2 nJ). e, Laser output from a 8.7 µm non-fluorescent BaTiO3 bead embedded in a cell containing CMFDA dye in its cytoplasm. f, Spontaneous emission from a 3.5 µm BaTiO3 bead coated with Alexa 488 dye below laser threshold. Scale bars, 10 µm.

  4. Tagging and sensing applications of solid intracellular microcavities.
    Figure 4: Tagging and sensing applications of solid intracellular microcavities.

    a, Bright-field image of a HeLa cell containing a polystyrene fluorescent bead. b, False-colour image of the cell in a, showing the intensity of the oscillating WGMs. c, A bead diameter map calculated from confocal hyperspectral images of the WGM output. d,e, Multiple HeLa cells containing beads (d) and the corresponding bead diameter map (e). f, Time-lapse measurements of a resonant peak from a glass bead inside a HeLa cell. The addition of 2 g l–1 sodium chloride at t = 0 caused the peak wavelength to shift. Scale bars, 10 µm.

  5. Size of intracellular microlasers.
    Figure 5: Size of intracellular microlasers.

    Q-factors of WGMs are highly dependent on the refractive index and cavity size. The two dashed lines represent theoretical calculations of two Q-factors: 106 and 103, respectively. Circles indicate the measured minimum size of laser achieved inside a cell for a lipid droplet in an adipocyte, a polystyrene bead and a PPE droplet inside a HeLa cell, and BaTiO3 beads in 15 mM pyrromethene solution, as well as InGaP disk lasers in air28.


  1. Vahala, K. J. Optical microcavities. Nature 424, 839846 (2003).
  2. Qian, S. X., Snow, J. B., Tzeng, H. M. & Chang, R. K. Lasing droplets—highlighting the liquid–air interface by laser-emission. Science 231, 486488 (1986).
  3. Hill, M. T. et al. A fast low-power optical memory based on coupled micro-ring lasers. Nature 432, 206209 (2004).
  4. Kippenberg, T. J., Holzwarth, R. & Diddams, S. A. Microresonator-based optical frequency combs. Science 332, 555559 (2011).
  5. Spillane, S. M., Kippenberg, T. J. & Vahala, K. J. Ultralow-threshold Raman laser using a spherical dielectric microcavity. Nature 415, 621623 (2002).
  6. Armani, A. M., Kulkarni, R. P., Fraser, S. E., Flagan, R. C. & Vahala, K. J. Label-free, single-molecule detection with optical microcavities. Science 317, 783787 (2007).
  7. Vollmer, F. & Arnold, S. Whispering-gallery-mode biosensing: label-free detection down to single molecules. Nature Methods 5, 591596 (2008).
  8. Zhu, J. G. et al. On-chip single nanoparticle detection and sizing by mode splitting in an ultrahigh-Q microresonator. Nature Photon. 4, 4649 (2010).
  9. Fan, X. D. & White, I. M. Optofluidic microsystems for chemical and biological analysis. Nature Photon. 5, 591597 (2011).
  10. Baaske, M. D., Foreman, M. R. & Vollmer, F. Single-molecule nucleic acid interactions monitored on a label-free microcavity biosensor platform. Nature Nanotech. 9, 933939 (2014).
  11. Himmelhaus, M. & Francois, A. In-vitro sensing of biomechanical forces in live cells by a whispering gallery mode biosensor. Biosens. Bioelectron. 25, 418427 (2009).
  12. Zhang, J., Campbell, R. E., Ting, A. Y. & Tsien, R. Y. Creating new fluorescent probes for cell biology. Nature Rev. Mol. Cell Biol. 3, 906918 (2002).
  13. Gather, M. C. & Yun, S. H. Single-cell biological lasers. Nature Photon. 5, 406410 (2011).
  14. Jonáš, A. et al. In vitro and in vivo biolasing of fluorescent proteins suspended in liquid microdroplet cavities. Lab. Chip 14, 30933100 (2014).
  15. Shambat, G. et al. Single-cell photonic nanocavity probes. Nano Lett. 13, 49995005 (2013).
  16. Fan, X. & Yun, S.-H. The potential of optofluidic biolasers. Nature Methods 11, 141147 (2014).
  17. Hill, M. T. & Gather, M. C. Advances in small lasers. Nature Photon. 8, 908918 (2014).
  18. Zhang, Y. & Yu, L. C. Microinjection as a tool of mechanical delivery. Curr. Opin. Biotechnol. 19, 506510 (2008).
  19. Campàs, O. et al. Quantifying cell-generated mechanical forces within living embryonic tissues. Nature Methods 11, 183189 (2014).
  20. Gardan, D., Gondret, F. & Louveau, I. Lipid metabolism and secretory function of porcine intramuscular adipocytes compared with subcutaneous and perirenal adipocytes. Am. J. Physiol. Endocrinol. Metab. 291, E372E380 (2006).
  21. Cannon, G. J. & Swanson, J. A. The macrophage capacity for phagocytosis. J. Cell Sci. 101, 907913 (1992).
  22. Kobayashi, S. et al. Artificial induction of autophagy around polystyrene beads in nonphagocytic cells. Autophagy 6, 3645 (2010).
  23. Gorodetsky, M. L. & Fomin, A. E. Geometrical theory of whispering-gallery modes. IEEE J. Sel. Topics Quantum Electron. 12, 3339 (2006).
  24. Livet, J. et al. Transgenic strategies for combinatorial expression of fluorescent proteins in the nervous system. Nature 450, 5662 (2007).
  25. Schultz, S. G. Molecular Biology of Membrane Transport Disorders (Springer, 1996).
  26. Wang, Q. J. et al. Whispering-gallery mode resonators for highly unidirectional laser action. Proc. Natl Acad. Sci. USA 107, 2240722412 (2010).
  27. Nizamoglu, S., Gather, M. C. & Yun, S. H. All-biomaterial laser using vitamin and biopolymers. Adv. Mater. 25, 59435947 (2013).
  28. Zhang, Z. et al. Visible submicron microdisk lasers. Appl. Phys. Lett. 90, 111119 (2007).
  29. Choi, M. et al. A terahertz metamaterial with unnaturally high refractive index. Nature 470, 369373 (2011).
  30. Stockman, M. I. Spasers explained. Nature Photon. 2, 327329 (2008).

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  1. Wellman Center for Photomedicine, Harvard Medical School, Massachusetts General Hospital, 65 Landsdowne Street UP-5, Cambridge, Massachusetts 02139, USA

    • Matjaž Humar &
    • Seok Hyun Yun
  2. Condensed Matter Department, J. Stefan Institute, Jamova 39, Ljubljana SI-1000, Slovenia

    • Matjaž Humar
  3. Harvard–MIT Health Sciences and Technology, 77 Massachusetts Avenue Cambridge, Cambridge, Massachusetts 02139, USA

    • Seok Hyun Yun


M.H. and S.H.Y. designed the study. M.H. carried out the experiments and analysed the data. M.H. and S.H.Y. wrote the manuscript.

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