We introduce photothermal optical lock-in Optical Coherence Microscopy (poli-OCM), a volumetric imaging technique, which combines the depth sectioning of OCM with the high sensitivity of photothermal microscopy while maintaining the fast acquisition speed inherent to OCM. We report on the detection of single 40 nm gold particles with a 0.5 μm lateral and 2 μm axial resolution over a 50 μm depth of field and the three-dimensional localization of gold colloids within living cells. In combination with intrinsic sample contrast measured with dark-field OCM, poli-OCM offers a versatile platform for functional cell imaging.

© 2012 OSA

1. R. Weissleder and U. Mahmood, “Molecular imaging,” Radiology219, 316–333 (2001). [PubMed]
2. J. Vogelsang, R. Kasper, C. Steinhauer, B. Person, M. Heilemann, M. Sauer, and P. Tinnefeld, “A reducing and oxidizing system minimizes photobleaching and blinking of fluorescent dyes,” Angew. Chem. Int. Ed.47, 5465–5469 (2008). [CrossRef]
3. C. J. Murphy, A. M. Gole, J. W. Stone, P. N. Sisco, A. M. Alkilany, E. C. Goldsmith, and S. C. Baxter, “Gold nanoparticles in biology: beyond toxicity to cellular imaging,” Accounts Chem. Res.41, 1721–1730 (2008). [CrossRef]
4. M. Celebrano, P. Kukura, A. Renn, and V. Sandoghdar, “Single-molecule imaging by optical absorption,” Nat. Photonics5, 95–98 (2011). [CrossRef]
5. U. Resch-Genger, M. Grabolle, S. Cavaliere-Jaricot, R. Nitschke, and T. Nann, “Quantum dots versus organic dyes as fluorescent labels,” Nat. Methods5, 763–775 (2008). [CrossRef] [PubMed]
6. D. Boyer, P. Tamarat, A. Maali, B. Lounis, and M. Orrit, “Photothermal imaging of nanometer-sized metal particles among scatterers,” Science297, 1160–1163 (2002). [CrossRef] [PubMed]
7. S. Berciaud, L. Cognet, G. Blab, and B. Lounis, “Photothermal heterodyne imaging of individual nonfluorescent nanoclusters and nanocrystals,” Phys. Rev. Lett.93, 257402 (2004). [CrossRef]
8. L. Novotny and B. Hecht, Principles of Nano-Optics (Cambridge University Press, 2012).
9. J. Kim, J. Oh, H. W. Kang, M. D. Feldman, and T. E. Milner, “Photothermal response of superparamagnetic iron oxide nanoparticles,” Laser Surg. Med.40, 415–421 (2008). [CrossRef]
10. D. Lasne, G. A. Blab, F. De Giorgi, F. Ichas, B. Lounis, and L. Cognet, “Label-free optical imaging of mitochondria in live cells,” Opt. Express15, 14184–14193 (2007). [CrossRef] [PubMed]
11. S. Lu, W. Min, S. Chong, G. R. Holtom, and X. S. Xie, “Label-free imaging of heme proteins with two-photon excited photothermal lens microscopy,” Appl. Phys. Lett.96, 113701 (2010). [CrossRef]
12. A. Gaiduk, P. V. Ruijgrok, M. Yorulmaz, and M. Orrit, “Detection limits in photothermal microscopy,” Chem. Sci.1, 343–350 (2010). [CrossRef]
13. A. Fercher, W. Drexler, C. Hitzenberger, and T. Lasser, “Optical coherence tomography - principles and applications,” Rep. Prog. Phys.66, 239–303 (2003). [CrossRef]
14. J. Izatt, M. Hee, G. Owen, E. Swanson, and J. Fujimoto, “Optical coherence microscopy in scattering media,” Opt. Lett.19, 590–592 (1994). [CrossRef] [PubMed]
15. A. K. Ellerbee, T. L. Creazzo, and J. A. Izatt, “Investigating nanoscale cellular dynamics with cross-sectional spectral domain phase microscopy,” Opt. Express15, 8115–8124 (2007). [CrossRef] [PubMed]
16. C. Joo, C. L. Evans, T. Stepinac, T. Hasan, and J. F. de Boer, “Diffusive and directional intracellular dynamics measured by field-based dynamic light scattering,” Opt. Express18, 2858–2871 (2010). [CrossRef] [PubMed]
17. M. Villiger, C. Pache, and T. Lasser, “Dark-field optical coherence microscopy,” Opt. Lett.35, 3489–3491 (2010). [CrossRef] [PubMed]
18. J.-A. Conchello and J. W. Lichtman, “Optical sectioning microscopy,” Nat. Meth.2, 920–931 (2005). [CrossRef]
19. A. S. Paranjape, R. Kuranov, S. Baranov, L. L. Ma, J. W. Villard, T. Wang, K. V. Sokolov, M. D. Feldman, K. P. Johnston, and T. E. Milner, “Depth resolved photothermal OCT detection of macrophages in tissue using nanorose,” Biomed. Opt. Express1, 2–16 (2010). [CrossRef]
20. M. C. Skala, M. J. Crow, A. Wax, and J. A. Izatt, “Photothermal Optical coherence tomography of epidermal growth factor receptor in live cells using immunotargeted gold nanospheres,” Nano Lett.8, 3461–3467 (2008). [CrossRef] [PubMed]
21. C. Zhou, T.-H. Tsai, D. C. Adler, H.-C. Lee, D. W. Cohen, A. Mondelblatt, Y. Wang, J. L. Connolly, and J. G. Fujimoto, “Photothermal optical coherence tomography in ex vivo human breast tissues using gold nanoshells,” Opt. Lett.35, 700–702 (2010). [CrossRef] [PubMed]
22. Y. Jung, R. Reif, Y. Zeng, and R. K. Wang, “Three-dimensional high-resolution imaging of gold nanorods uptake in sentinel lymph nodes,” Nano Lett.11, 2938–2943 (2011). [CrossRef] [PubMed]
23. E. Absil, G. Tessier, M. Gross, M. Atlan, N. Warnasooriya, S. Suck, M. Coppey-Moisan, and D. Fournier, “Photothermal heterodyne holography of gold nanoparticles,” Opt. Express18, 780–786 (2010). [CrossRef] [PubMed]
24. D. C. Adler, S.-W. Huang, R. Huber, and J. G. Fujimoto, “Photothermal detection of gold nanoparticles using phase-sensitive optical coherence tomography,” Opt. Express16, 4376–4393 (2008). [CrossRef] [PubMed]
25. J. Izatt and M. Choma, “Theory of optical coherence tomography,” in Optical coherence tomography, W. Drexler, ed. (Springer Verlag, 2008), pp. 47–72. [CrossRef]
26. R. Leitgeb, C. Hitzenberger, and A. Fercher, “Performance of Fourier domain vs. time domain optical coherence tomography,” Opt. Express11, 889–894 (2003). [CrossRef] [PubMed]
27. R. A. Leitgeb, M. Villiger, A. H. Bachmann, L. Steinmann, and T. Lasser, “Extended focus depth for Fourier domain optical coherence microscopy,” Opt. Lett.31, 2450–2452 (2006). [CrossRef] [PubMed]
28. M. Villiger and T. Lasser, “Image formation and tomogram reconstruction in optical coherence microscopy,” J. Opt. Soc. Am. A27, 2216–2228 (2010). [CrossRef]
29. V. Kodach, N. Bosschaart, and J. Kalkman, “Concentration dependent scattering coefficients of intralipid measured with OCT,” in “Biomedical Optics,”, OSA Technical Digest (CD) (Optical Society of America, 2010), paper BSuD11. [PubMed]
30. M. Leutenegger, R. Rao, R. A. Leitgeb, and T. Lasser, “Fast focus field calculations,” Opt. Express14, 11277–11291 (2006). [CrossRef] [PubMed]
31. R. Herman and T. Wiggins, “Production and uses of diffractionless beams,” J. Opt. Soc. Am. A8, 932–942 (1991). [CrossRef]
32. D. McGloin and K. Dholakia, “Bessel beams: diffraction in a new light,” Contemp. Phys.46, 15–28 (2005). [CrossRef]
33. S. Boppart, A. Oldenburg, C. Xu, and D. Marks, “Optical probes and techniques for molecular contrast enhancement in coherence imaging,” J. Biomed. Opt.10, 041208 (2005). [CrossRef]
34. A. Oldenburg, F. Toublan, K. Suslick, A. Wei, and S. Boppart, “Magnetomotive contrast for in vivo optical coherence tomography,” Opt. Express13, 6597–6614 (2005). [CrossRef] [PubMed]
35. V. Crecea, A. L. Oldenburg, X. Liang, T. S. Ralston, and S. A. Boppart, “Magnetomotive nanoparticle transducers for optical rheology of viscoelastic materials,” Opt. Express17, 23114–23122 (2009). [CrossRef]
36. M. Wagner, P. Weber, T. Bruns, W. S. L. Strauss, R. Wittig, and H. Schneckenburger, “Light dose is a limiting factor to maintain cell viability in fluorescence microscopy and single molecule detection,” Int. J. Mol. Sci.11, 956–966 (2010). [CrossRef] [PubMed]

Accounts Chem. Res.

• C. J. Murphy, A. M. Gole, J. W. Stone, P. N. Sisco, A. M. Alkilany, E. C. Goldsmith, and S. C. Baxter, “Gold nanoparticles in biology: beyond toxicity to cellular imaging,” Accounts Chem. Res.41, 1721–1730 (2008). [CrossRef]

Angew. Chem. Int. Ed.

• J. Vogelsang, R. Kasper, C. Steinhauer, B. Person, M. Heilemann, M. Sauer, and P. Tinnefeld, “A reducing and oxidizing system minimizes photobleaching and blinking of fluorescent dyes,” Angew. Chem. Int. Ed.47, 5465–5469 (2008). [CrossRef]

Appl. Phys. Lett.

• S. Lu, W. Min, S. Chong, G. R. Holtom, and X. S. Xie, “Label-free imaging of heme proteins with two-photon excited photothermal lens microscopy,” Appl. Phys. Lett.96, 113701 (2010). [CrossRef]

Biomed. Opt. Express

• A. S. Paranjape, R. Kuranov, S. Baranov, L. L. Ma, J. W. Villard, T. Wang, K. V. Sokolov, M. D. Feldman, K. P. Johnston, and T. E. Milner, “Depth resolved photothermal OCT detection of macrophages in tissue using nanorose,” Biomed. Opt. Express1, 2–16 (2010). [CrossRef]

Chem. Sci.

• A. Gaiduk, P. V. Ruijgrok, M. Yorulmaz, and M. Orrit, “Detection limits in photothermal microscopy,” Chem. Sci.1, 343–350 (2010). [CrossRef]

Contemp. Phys.

• D. McGloin and K. Dholakia, “Bessel beams: diffraction in a new light,” Contemp. Phys.46, 15–28 (2005). [CrossRef]

Int. J. Mol. Sci.

• M. Wagner, P. Weber, T. Bruns, W. S. L. Strauss, R. Wittig, and H. Schneckenburger, “Light dose is a limiting factor to maintain cell viability in fluorescence microscopy and single molecule detection,” Int. J. Mol. Sci.11, 956–966 (2010). [CrossRef] [PubMed]

J. Biomed. Opt.

• S. Boppart, A. Oldenburg, C. Xu, and D. Marks, “Optical probes and techniques for molecular contrast enhancement in coherence imaging,” J. Biomed. Opt.10, 041208 (2005). [CrossRef]

J. Opt. Soc. Am. A

• M. Villiger and T. Lasser, “Image formation and tomogram reconstruction in optical coherence microscopy,” J. Opt. Soc. Am. A27, 2216–2228 (2010). [CrossRef]
• R. Herman and T. Wiggins, “Production and uses of diffractionless beams,” J. Opt. Soc. Am. A8, 932–942 (1991). [CrossRef]

Laser Surg. Med.

• J. Kim, J. Oh, H. W. Kang, M. D. Feldman, and T. E. Milner, “Photothermal response of superparamagnetic iron oxide nanoparticles,” Laser Surg. Med.40, 415–421 (2008). [CrossRef]

Nano Lett.

• M. C. Skala, M. J. Crow, A. Wax, and J. A. Izatt, “Photothermal Optical coherence tomography of epidermal growth factor receptor in live cells using immunotargeted gold nanospheres,” Nano Lett.8, 3461–3467 (2008). [CrossRef] [PubMed]
• Y. Jung, R. Reif, Y. Zeng, and R. K. Wang, “Three-dimensional high-resolution imaging of gold nanorods uptake in sentinel lymph nodes,” Nano Lett.11, 2938–2943 (2011). [CrossRef] [PubMed]

Nat. Meth.

• J.-A. Conchello and J. W. Lichtman, “Optical sectioning microscopy,” Nat. Meth.2, 920–931 (2005). [CrossRef]

Nat. Methods

• U. Resch-Genger, M. Grabolle, S. Cavaliere-Jaricot, R. Nitschke, and T. Nann, “Quantum dots versus organic dyes as fluorescent labels,” Nat. Methods5, 763–775 (2008). [CrossRef] [PubMed]

Nat. Photonics

• M. Celebrano, P. Kukura, A. Renn, and V. Sandoghdar, “Single-molecule imaging by optical absorption,” Nat. Photonics5, 95–98 (2011). [CrossRef]

Opt. Express

• A. K. Ellerbee, T. L. Creazzo, and J. A. Izatt, “Investigating nanoscale cellular dynamics with cross-sectional spectral domain phase microscopy,” Opt. Express15, 8115–8124 (2007). [CrossRef] [PubMed]
• C. Joo, C. L. Evans, T. Stepinac, T. Hasan, and J. F. de Boer, “Diffusive and directional intracellular dynamics measured by field-based dynamic light scattering,” Opt. Express18, 2858–2871 (2010). [CrossRef] [PubMed]
• D. Lasne, G. A. Blab, F. De Giorgi, F. Ichas, B. Lounis, and L. Cognet, “Label-free optical imaging of mitochondria in live cells,” Opt. Express15, 14184–14193 (2007). [CrossRef] [PubMed]
• E. Absil, G. Tessier, M. Gross, M. Atlan, N. Warnasooriya, S. Suck, M. Coppey-Moisan, and D. Fournier, “Photothermal heterodyne holography of gold nanoparticles,” Opt. Express18, 780–786 (2010). [CrossRef] [PubMed]
• D. C. Adler, S.-W. Huang, R. Huber, and J. G. Fujimoto, “Photothermal detection of gold nanoparticles using phase-sensitive optical coherence tomography,” Opt. Express16, 4376–4393 (2008). [CrossRef] [PubMed]
• R. Leitgeb, C. Hitzenberger, and A. Fercher, “Performance of Fourier domain vs. time domain optical coherence tomography,” Opt. Express11, 889–894 (2003). [CrossRef] [PubMed]
• M. Leutenegger, R. Rao, R. A. Leitgeb, and T. Lasser, “Fast focus field calculations,” Opt. Express14, 11277–11291 (2006). [CrossRef] [PubMed]
• A. Oldenburg, F. Toublan, K. Suslick, A. Wei, and S. Boppart, “Magnetomotive contrast for in vivo optical coherence tomography,” Opt. Express13, 6597–6614 (2005). [CrossRef] [PubMed]
• V. Crecea, A. L. Oldenburg, X. Liang, T. S. Ralston, and S. A. Boppart, “Magnetomotive nanoparticle transducers for optical rheology of viscoelastic materials,” Opt. Express17, 23114–23122 (2009). [CrossRef]

Opt. Lett.

• R. A. Leitgeb, M. Villiger, A. H. Bachmann, L. Steinmann, and T. Lasser, “Extended focus depth for Fourier domain optical coherence microscopy,” Opt. Lett.31, 2450–2452 (2006). [CrossRef] [PubMed]
• C. Zhou, T.-H. Tsai, D. C. Adler, H.-C. Lee, D. W. Cohen, A. Mondelblatt, Y. Wang, J. L. Connolly, and J. G. Fujimoto, “Photothermal optical coherence tomography in ex vivo human breast tissues using gold nanoshells,” Opt. Lett.35, 700–702 (2010). [CrossRef] [PubMed]
• M. Villiger, C. Pache, and T. Lasser, “Dark-field optical coherence microscopy,” Opt. Lett.35, 3489–3491 (2010). [CrossRef] [PubMed]
• J. Izatt, M. Hee, G. Owen, E. Swanson, and J. Fujimoto, “Optical coherence microscopy in scattering media,” Opt. Lett.19, 590–592 (1994). [CrossRef] [PubMed]

Phys. Rev. Lett.

• S. Berciaud, L. Cognet, G. Blab, and B. Lounis, “Photothermal heterodyne imaging of individual nonfluorescent nanoclusters and nanocrystals,” Phys. Rev. Lett.93, 257402 (2004). [CrossRef]

Radiology

• R. Weissleder and U. Mahmood, “Molecular imaging,” Radiology219, 316–333 (2001). [PubMed]

Rep. Prog. Phys.

• A. Fercher, W. Drexler, C. Hitzenberger, and T. Lasser, “Optical coherence tomography - principles and applications,” Rep. Prog. Phys.66, 239–303 (2003). [CrossRef]

Science

• D. Boyer, P. Tamarat, A. Maali, B. Lounis, and M. Orrit, “Photothermal imaging of nanometer-sized metal particles among scatterers,” Science297, 1160–1163 (2002). [CrossRef] [PubMed]

Other

• L. Novotny and B. Hecht, Principles of Nano-Optics (Cambridge University Press, 2012).
• J. Izatt and M. Choma, “Theory of optical coherence tomography,” in Optical coherence tomography, W. Drexler, ed. (Springer Verlag, 2008), pp. 47–72. [CrossRef]
• V. Kodach, N. Bosschaart, and J. Kalkman, “Concentration dependent scattering coefficients of intralipid measured with OCT,” in “Biomedical Optics,”, OSA Technical Digest (CD) (Optical Society of America, 2010), paper BSuD11. [PubMed]

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