OSA's Digital Library

Biomedical Optics Express

Biomedical Optics Express

  • Editor: Joseph A. Izatt
  • Vol. 4, Iss. 4 — Apr. 1, 2013
  • pp: 596–613

Investigation of depth-resolved nanoscale structural changes in regulated cell proliferation and chromatin decondensation

Shikhar Uttam, Rajan K. Bista, Kevin Staton, Sergey Alexandrov, Serah Choi, Christopher J. Bakkenist, Douglas J. Hartman, Randall E. Brand, and Yang Liu  »View Author Affiliations

Biomedical Optics Express, Vol. 4, Issue 4, pp. 596-613 (2013)

View Full Text Article

Enhanced HTML    Acrobat PDF (1527 KB)

Browse Journals / Lookup Meetings

Browse by Journal and Year


Lookup Conference Papers

Close Browse Journals / Lookup Meetings

Article Tools



We present depth-resolved spatial-domain low-coherence quantitative phase microscopy, a simple approach that utilizes coherence gating to construct a depth-resolved structural feature vector quantifying sub-resolution axial structural changes at different optical depths within the sample. We show that this feature vector is independent of sample thickness variation, and identifies nanoscale structural changes in clinically prepared samples. We present numerical simulations and experimental validation to demonstrate the feasibility of the approach. We also perform experiments using unstained cells to investigate the nanoscale structural changes in regulated cell proliferation through cell cycle and chromatin decondensation induced by histone acetylation.

© 2013 OSA

OCIS Codes
(170.1610) Medical optics and biotechnology : Clinical applications
(170.4730) Medical optics and biotechnology : Optical pathology
(180.3170) Microscopy : Interference microscopy
(300.6300) Spectroscopy : Spectroscopy, Fourier transforms

ToC Category:
Cell Studies

Original Manuscript: January 9, 2013
Revised Manuscript: February 21, 2013
Manuscript Accepted: March 11, 2013
Published: March 22, 2013

Shikhar Uttam, Rajan K. Bista, Kevin Staton, Sergey Alexandrov, Serah Choi, Christopher J. Bakkenist, Douglas J. Hartman, Randall E. Brand, and Yang Liu, "Investigation of depth-resolved nanoscale structural changes in regulated cell proliferation and chromatin decondensation," Biomed. Opt. Express 4, 596-613 (2013)

Sort:  Author  |  Year  |  Journal  |  Reset  


  1. S. Iyer, R. M. Gaikwad, V. Subba-Rao, C. D. Woodworth, and I. Sokolov, “Atomic force microscopy detects differences in the surface brush of normal and cancerous cells,” Nat. Nanotechnol.4(6), 389–393 (2009). [CrossRef] [PubMed]
  2. H. Knecht and S. Mai, “3D imaging of telomeres and nuclear architecture: an emerging tool of 3D nano-morphology-based diagnosis,” J. Cell. Physiol.226(4), 859–867 (2011). [CrossRef] [PubMed]
  3. H. Subramanian, P. Pradhan, Y. Liu, I. R. Capoglu, X. Li, J. D. Rogers, A. Heifetz, D. Kunte, H. K. Roy, A. Taflove, and V. Backman, “Optical methodology for detecting histologically unapparent nanoscale consequences of genetic alterations in biological cells,” Proc. Natl. Acad. Sci. U.S.A.105(51), 20118–20123 (2008). [CrossRef] [PubMed]
  4. H. Subramanian, H. K. Roy, P. Pradhan, M. J. Goldberg, J. Muldoon, R. E. Brand, C. Sturgis, T. Hensing, D. Ray, A. Bogojevic, J. Mohammed, J. S. Chang, and V. Backman, “Nanoscale cellular changes in field carcinogenesis detected by partial wave spectroscopy,” Cancer Res.69(13), 5357–5363 (2009). [CrossRef] [PubMed]
  5. R. K. Bista, T. A. Brentnall, M. P. Bronner, C. J. Langmead, R. E. Brand, and Y. Liu, “Using optical markers of nondysplastic rectal epithelial cells to identify patients with ulcerative colitis-associated neoplasia,” Inflamm. Bowel Dis.17(12), 2427–2435 (2011). [CrossRef] [PubMed]
  6. K. J. Chalut, J. H. Ostrander, M. G. Giacomelli, and A. Wax, “Light scattering measurements of subcellular structure provide noninvasive early detection of chemotherapy-induced apoptosis,” Cancer Res.69(3), 1199–1204 (2009). [CrossRef] [PubMed]
  7. I. Itzkan, L. Qiu, H. Fang, M. M. Zaman, E. Vitkin, I. C. Ghiran, S. Salahuddin, M. Modell, C. Andersson, L. M. Kimerer, P. B. Cipolloni, K. H. Lim, S. D. Freedman, I. Bigio, B. P. Sachs, E. B. Hanlon, and L. T. Perelman, “Confocal light absorption and scattering spectroscopic microscopy monitors organelles in live cells with no exogenous labels,” Proc. Natl. Acad. Sci. U.S.A.104(44), 17255–17260 (2007). [CrossRef] [PubMed]
  8. Z. Wang, K. Tangella, A. Balla, and G. Popescu, “Tissue refractive index as marker of disease,” J. Biomed. Opt.16(11), 116017 (2011). [CrossRef] [PubMed]
  9. G. Popescu, Quantitative Phase Imaging of Cells and Tissues, McGraw-Hill biophotonics (McGraw-Hill, 2011), pp. xx, 362 p.
  10. N. N. Boustany, S. A. Boppart, and V. Backman, “Microscopic imaging and spectroscopy with scattered light,” Annu. Rev. Biomed. Eng.12(1), 285–314 (2010). [CrossRef] [PubMed]
  11. H. K. Roy, H. Subramanian, D. Damania, T. A. Hensing, W. N. Rom, H. I. Pass, D. Ray, J. D. Rogers, A. Bogojevic, M. Shah, T. Kuzniar, P. Pradhan, and V. Backman, “Optical detection of buccal epithelial nanoarchitectural alterations in patients harboring lung cancer: implications for screening,” Cancer Res.70(20), 7748–7754 (2010). [CrossRef] [PubMed]
  12. P. Wang, R. Bista, R. Bhargava, R. E. Brand, and Y. Liu, “Spatial-domain low-coherence quantitative phase microscopy for cancer diagnosis,” Opt. Lett.35(17), 2840–2842 (2010). [CrossRef] [PubMed]
  13. P. Wang, R. K. Bista, W. E. Khalbuss, W. Qiu, S. Uttam, K. Staton, L. Zhang, T. A. Brentnall, R. E. Brand, and Y. Liu, “Nanoscale nuclear architecture for cancer diagnosis beyond pathology via spatial-domain low-coherence quantitative phase microscopy,” J. Biomed. Opt.15(6), 066028 (2010). [CrossRef] [PubMed]
  14. R. K. Bista, S. Uttam, D. J. Hartman, W. Qiu, J. Yu, L. Zhang, R. E. Brand, and Y. Liu, “Investigation of nuclear nano-morphology marker as a biomarker for cancer risk assessment using a mouse model,” J. Biomed. Opt.17(6), 066014 (2012). [CrossRef] [PubMed]
  15. R. K. Bista, P. Wang, R. Bhargava, S. Uttam, D. J. Hartman, R. E. Brand, and Y. Liu, “Nuclear nano-morphology markers of histologically normal cells detect the “field effect” of breast cancer,” Breast Cancer Res. Treat.135(1), 115–124 (2012). [CrossRef] [PubMed]
  16. T. Akkin, C. Joo, and J. F. de Boer, “Depth-resolved measurement of transient structural changes during action potential propagation,” Biophys. J.93(4), 1347–1353 (2007). [CrossRef] [PubMed]
  17. C. Joo and J. F. de Boer, “Spectral-domain optical coherence reflectometric sensor for highly sensitive molecular detection,” Opt. Lett.32(16), 2426–2428 (2007). [CrossRef] [PubMed]
  18. M. A. Choma, A. K. Ellerbee, C. Yang, T. L. Creazzo, and J. A. Izatt, “Spectral-domain phase microscopy,” Opt. Lett.30(10), 1162–1164 (2005). [CrossRef] [PubMed]
  19. A. K. Ellerbee, T. L. Creazzo, and J. A. Izatt, “Investigating nanoscale cellular dynamics with cross-sectional spectral domain phase microscopy,” Opt. Express15(13), 8115–8124 (2007). [CrossRef] [PubMed]
  20. 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(3), 2858–2871 (2010). [CrossRef] [PubMed]
  21. Y. Liu, X. Li, Y. L. Kim, and V. Backman, “Elastic backscattering spectroscopic microscopy,” Opt. Lett.30(18), 2445–2447 (2005). [CrossRef] [PubMed]
  22. A. F. Fercher, C. K. Hitzenberger, G. Kamp, and S. Y. Elzaiat, “Measurement of intraocular distances by backscattering spectral interferometry,” Opt. Commun.117(1-2), 43–48 (1995). [CrossRef]
  23. M. Born and E. Wolf, Principles of Optics: Electromagnetic Theory of Propagation, Interference and Diffraction of Light, 7th (expanded) ed. (Cambridge University Press, 1999).
  24. X. J. Liang, A. Q. Liu, C. S. Lim, T. C. Ayi, and P. H. Yap, “Determining refractive index of single living cell using an integrated microchip,” Sens. Actuators A Phys.133(2), 349–354 (2007). [CrossRef]
  25. L. Cherkezyan, H. Subramanian, V. Stoyneva, J. D. Rogers, S. Yang, D. Damania, A. Taflove, and V. Backman, “Targeted alteration of real and imaginary refractive index of biological cells by histological staining,” Opt. Lett.37(10), 1601–1603 (2012). [CrossRef] [PubMed]
  26. D. J. Cook, Cellular Pathology: Introduction to Techniques and Applications, 2nd ed. (Scion, 2006), pp. xxxii, 384 p.
  27. G. C. Crossmon, “Mounting media for phase microscope specimens,” Stain Technol.24(4), 241–247 (1949). [PubMed]
  28. X. Li, A. Taflove, and V. Backman, “Recent progress in exact and reduced-order modeling of light-scattering properties of complex structures,” IEEE J. Sel. Top. Quantum Electron.11(4), 759–765 (2005). [CrossRef]
  29. B. E. A. Saleh and M. C. Teich, Fundamentals of Photonics, 2nd ed., Wiley series in pure and applied optics (Wiley-Interscience, 2007), pp. xix, 1177 p.
  30. D. Marchion and P. Münster, “Development of histone deacetylase inhibitors for cancer treatment,” Expert Rev. Anticancer Ther.7(4), 583–598 (2007). [CrossRef] [PubMed]
  31. K. F. Tóth, T. A. Knoch, M. Wachsmuth, M. Frank-Stöhr, M. Stöhr, C. P. Bacher, G. Müller, and K. Rippe, “Trichostatin A-induced histone acetylation causes decondensation of interphase chromatin,” J. Cell Sci.117(18), 4277–4287 (2004). [CrossRef] [PubMed]
  32. R. K. Bista, S. Uttam, P. Wang, K. Staton, S. Choi, C. J. Bakkenist, D. J. Hartman, R. E. Brand, and Y. Liu, “Quantification of nanoscale nuclear refractive index changes during the cell cycle,” J. Biomed. Opt.16(7), 070503 (2011). [CrossRef] [PubMed]
  33. O. Momčilović, S. Choi, S. Varum, C. Bakkenist, G. Schatten, and C. Navara, “Ionizing radiation induces ataxia telangiectasia mutated-dependent checkpoint signaling and G(2) but not G(1) cell cycle arrest in pluripotent human embryonic stem cells,” Stem Cells27(8), 1822–1835 (2009). [CrossRef] [PubMed]

Cited By

Alert me when this paper is cited

OSA is able to provide readers links to articles that cite this paper by participating in CrossRef's Cited-By Linking service. CrossRef includes content from more than 3000 publishers and societies. In addition to listing OSA journal articles that cite this paper, citing articles from other participating publishers will also be listed.

« Previous Article  |  Next Article »

OSA is a member of CrossRef.

CrossCheck Deposited