Abstract

Two photon fluorescent lifetime imaging is a modality that enables depth-sectioned, molecularly-specific imaging of cells and tissue using intrinsic contrast. However, clinical applications have not been well explored due to low imaging speed and limited field of view, which make evaluating large pathology samples extremely challenging. To address these limitations, we have developed direct temporal sampling two photon fluorescent lifetime imaging (DTS-FLIM), a method which enables a several order of magnitude increase in imaging speed by capturing an entire lifetime decay in a single fluorescent excitation. We use this greatly increased speed to perform a preliminary study using gigapixel-scale imaging of human breast pathology surgical specimens.

© 2015 Optical Society of America

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References

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2015 (1)

2014 (1)

Y. K. Tao, D. Shen, Y. Sheikine, O. O. Ahsen, H. H. Wang, D. B. Schmolze, N. B. Johnson, J. S. Brooker, A. E. Cable, J. L. Connolly, and J. G. Fujimoto, “Assessment of breast pathologies using nonlinear microscopy,” Proc. Natl. Acad. Sci. U.S.A. 111(43), 15304–15309 (2014).
[Crossref] [PubMed]

2012 (4)

K. Okabe, N. Inada, C. Gota, Y. Harada, T. Funatsu, and S. Uchiyama, “Intracellular temperature mapping with a fluorescent polymeric thermometer and fluorescence lifetime imaging microscopy,” Nat. Commun. 3, 705 (2012).
[Crossref] [PubMed]

K. Esbona, Z. Li, and L. G. Wilke, “Intraoperative Imprint Cytology and Frozen Section Pathology for Margin Assessment in Breast Conservation Surgery: A Systematic Review,” Ann. Surg. Oncol. 19(10), 3236–3245 (2012).
[Crossref] [PubMed]

R. Patalay, C. Talbot, Y. Alexandrov, M. O. Lenz, S. Kumar, S. Warren, I. Munro, M. A. Neil, K. König, P. M. W. French, A. Chu, G. W. H. Stamp, and C. Dunsby, “Multiphoton multispectral fluorescence lifetime tomography for the evaluation of basal cell carcinomas,” PLoS One 7(9), e43460 (2012).
[Crossref] [PubMed]

M. J. Koehler, A. Preller, P. Elsner, K. König, U. C. Hipler, and M. Kaatz, “Non-invasive evaluation of dermal elastosis by in vivo multiphoton tomography with autofluorescence lifetime measurements,” Exp. Dermatol. 21(1), 48–51 (2012).
[Crossref] [PubMed]

2011 (3)

D. D. U. Li, J. Arlt, D. Tyndall, R. Walker, J. Richardson, D. Stoppa, E. Charbon, and R. K. Henderson, “Video-rate fluorescence lifetime imaging camera with CMOS single-photon avalanche diode arrays and high-speed imaging algorithm,” J. Biomed. Opt. 16(9), 096012 (2011).
[Crossref] [PubMed]

R. Patalay, C. Talbot, Y. Alexandrov, I. Munro, M. A. Neil, K. König, P. M. French, A. Chu, G. W. Stamp, and C. Dunsby, “Quantification of cellular autofluorescence of human skin using multiphoton tomography and fluorescence lifetime imaging in two spectral detection channels,” Biomed. Opt. Express 2(12), 3295–3308 (2011).
[Crossref] [PubMed]

J. M. Uecker, E. H. Bui, K. H. Foulkrod, and J. P. Sabra, “Intraoperative assessment of breast cancer specimens decreases cost and number of reoperations,” Am. Surg. 77(3), 342–344 (2011).
[PubMed]

2010 (1)

2009 (1)

M. W. Conklin, P. P. Provenzano, K. W. Eliceiri, R. Sullivan, and P. J. Keely, “Fluorescence lifetime imaging of endogenous fluorophores in histopathology sections reveals differences between normal and tumor epithelium in carcinoma in situ of the breast,” Cell Biochem. Biophys. 53(3), 145–157 (2009).
[Crossref] [PubMed]

2008 (1)

P. P. Provenzano, C. T. Rueden, S. M. Trier, L. Yan, S. M. Ponik, D. R. Inman, P. J. Keely, and K. W. Eliceiri, “Nonlinear optical imaging and spectral-lifetime computational analysis of endogenous and exogenous fluorophores in breast cancer,” J. Biomed. Opt. 13(3), 031220 (2008).
[Crossref] [PubMed]

2007 (1)

M. C. Skala, K. M. Riching, D. K. Bird, A. Gendron-Fitzpatrick, J. Eickhoff, K. W. Eliceiri, P. J. Keely, and N. Ramanujam, “In vivo multiphoton fluorescence lifetime imaging of protein-bound and free nicotinamide adenine dinucleotide in normal and precancerous epithelia,” J. Biomed. Opt. 12(2), 024014 (2007).
[Crossref] [PubMed]

2006 (2)

P. P. Provenzano, K. W. Eliceiri, J. M. Campbell, D. R. Inman, J. G. White, and P. J. Keely, “Collagen reorganization at the tumor-stromal interface facilitates local invasion,” BMC Med. 4(1), 38 (2006).
[Crossref] [PubMed]

D. L. Price, S. K. Chow, N. A. B. Maclean, H. Hakozaki, S. Peltier, M. E. Martone, and M. H. Ellisman, “High-resolution large-scale mosaic imaging using multiphoton microscopy to characterize transgenic mouse models of human neurological disorders,” Neuroinformatics 4, 65–80 (2006).

2005 (3)

M. Hammer, D. Schweitzer, S. Richter, and E. Königsdörffer, “Sodium fluorescein as a retinal pH indicator?” Physiol. Meas. 26(4), N9–N12 (2005).
[Crossref] [PubMed]

V. K. Ramanujan, J.-H. Zhang, E. Biener, and B. Herman, “Multiphoton fluorescence lifetime contrast in deep tissue imaging: prospects in redox imaging and disease diagnosis,” J. Biomed. Opt. 10(5), 051407 (2005).
[Crossref] [PubMed]

F. Helmchen and W. Denk, “Deep tissue two-photon microscopy,” Nat. Methods 2(12), 932–940 (2005).
[Crossref] [PubMed]

2004 (2)

J. Engel, J. Kerr, A. Schlesinger-Raab, H. Sauer, and D. Hölzel, “Quality of life following breast-conserving therapy or mastectomy: results of a 5-year prospective study,” Breast J. 10(3), 223–231 (2004).
[Crossref] [PubMed]

F. J. Fleming, A. D. Hill, E. W. Mc Dermott, A. O’Doherty, N. J. O’Higgins, and C. M. Quinn, “Intraoperative margin assessment and re-excision rate in breast conserving surgery,” Eur. J. Surg. Oncol. 30(3), 233–237 (2004).
[Crossref] [PubMed]

2003 (4)

W. R. Zipfel, R. M. Williams, R. Christie, A. Y. Nikitin, B. T. Hyman, and W. W. Webb, “Live tissue intrinsic emission microscopy using multiphoton-excited native fluorescence and second harmonic generation,” Proc. Natl. Acad. Sci. U.S.A. 100(12), 7075–7080 (2003).
[Crossref] [PubMed]

S. J. Schnitt, “The diagnosis and management of pre-invasive breast disease: flat epithelial atypia--classification, pathologic features and clinical significance,” Breast Cancer Res. 5(5), 263–268 (2003).
[Crossref] [PubMed]

P. J. Tadrous, J. Siegel, P. M. W. French, S. Shousha, N. Lalani, and G. W. H. Stamp, “Fluorescence lifetime imaging of unstained tissues: early results in human breast cancer,” J. Pathol. 199(3), 309–317 (2003).
[Crossref] [PubMed]

H.-J. Lin, P. Herman, and J. R. Lakowicz, “Fluorescence lifetime-resolved pH imaging of living cells,” Cytometry A 52(2), 77–89 (2003).
[Crossref] [PubMed]

2002 (1)

G. P. Swanson, K. Rynearson, and R. Symmonds, “Significance of margins of excision on breast cancer recurrence,” Am. J. Clin. Oncol. 25(5), 438–441 (2002).
[Crossref] [PubMed]

2000 (1)

J. A. van Dongen, A. C. Voogd, I. S. Fentiman, C. Legrand, R. J. Sylvester, D. Tong, E. van der Schueren, P. A. Helle, K. van Zijl, and H. Bartelink, “Long-term results of a randomized trial comparing breast-conserving therapy with mastectomy: European Organization for Research and Treatment of Cancer 10801 trial,” J. Natl. Cancer Inst. 92(14), 1143–1150 (2000).
[Crossref] [PubMed]

1998 (1)

1995 (1)

P. T. C. So, T. French, W. M. Yu, K. M. Berland, C. Y. Dong, and E. Gratton, “Time-resolved fluorescence microscopy using two-photon excitation,” Bioimaging 3(2), 49–63 (1995).
[Crossref]

1990 (1)

W. Denk, J. H. Strickler, and W. W. Webb, “Two-photon laser scanning fluorescence microscopy,” Science 248(4951), 73–76 (1990).
[Crossref] [PubMed]

Ahmad, R.

Ahsen, O. O.

Y. K. Tao, D. Shen, Y. Sheikine, O. O. Ahsen, H. H. Wang, D. B. Schmolze, N. B. Johnson, J. S. Brooker, A. E. Cable, J. L. Connolly, and J. G. Fujimoto, “Assessment of breast pathologies using nonlinear microscopy,” Proc. Natl. Acad. Sci. U.S.A. 111(43), 15304–15309 (2014).
[Crossref] [PubMed]

Alexandrov, Y.

R. Patalay, C. Talbot, Y. Alexandrov, M. O. Lenz, S. Kumar, S. Warren, I. Munro, M. A. Neil, K. König, P. M. W. French, A. Chu, G. W. H. Stamp, and C. Dunsby, “Multiphoton multispectral fluorescence lifetime tomography for the evaluation of basal cell carcinomas,” PLoS One 7(9), e43460 (2012).
[Crossref] [PubMed]

R. Patalay, C. Talbot, Y. Alexandrov, I. Munro, M. A. Neil, K. König, P. M. French, A. Chu, G. W. Stamp, and C. Dunsby, “Quantification of cellular autofluorescence of human skin using multiphoton tomography and fluorescence lifetime imaging in two spectral detection channels,” Biomed. Opt. Express 2(12), 3295–3308 (2011).
[Crossref] [PubMed]

Arlt, J.

D. D. U. Li, J. Arlt, D. Tyndall, R. Walker, J. Richardson, D. Stoppa, E. Charbon, and R. K. Henderson, “Video-rate fluorescence lifetime imaging camera with CMOS single-photon avalanche diode arrays and high-speed imaging algorithm,” J. Biomed. Opt. 16(9), 096012 (2011).
[Crossref] [PubMed]

Bartelink, H.

J. A. van Dongen, A. C. Voogd, I. S. Fentiman, C. Legrand, R. J. Sylvester, D. Tong, E. van der Schueren, P. A. Helle, K. van Zijl, and H. Bartelink, “Long-term results of a randomized trial comparing breast-conserving therapy with mastectomy: European Organization for Research and Treatment of Cancer 10801 trial,” J. Natl. Cancer Inst. 92(14), 1143–1150 (2000).
[Crossref] [PubMed]

Berland, K. M.

P. T. C. So, T. French, W. M. Yu, K. M. Berland, C. Y. Dong, and E. Gratton, “Time-resolved fluorescence microscopy using two-photon excitation,” Bioimaging 3(2), 49–63 (1995).
[Crossref]

Biener, E.

V. K. Ramanujan, J.-H. Zhang, E. Biener, and B. Herman, “Multiphoton fluorescence lifetime contrast in deep tissue imaging: prospects in redox imaging and disease diagnosis,” J. Biomed. Opt. 10(5), 051407 (2005).
[Crossref] [PubMed]

Bird, D. K.

M. C. Skala, K. M. Riching, D. K. Bird, A. Gendron-Fitzpatrick, J. Eickhoff, K. W. Eliceiri, P. J. Keely, and N. Ramanujam, “In vivo multiphoton fluorescence lifetime imaging of protein-bound and free nicotinamide adenine dinucleotide in normal and precancerous epithelia,” J. Biomed. Opt. 12(2), 024014 (2007).
[Crossref] [PubMed]

Brooker, J. S.

Y. K. Tao, D. Shen, Y. Sheikine, O. O. Ahsen, H. H. Wang, D. B. Schmolze, N. B. Johnson, J. S. Brooker, A. E. Cable, J. L. Connolly, and J. G. Fujimoto, “Assessment of breast pathologies using nonlinear microscopy,” Proc. Natl. Acad. Sci. U.S.A. 111(43), 15304–15309 (2014).
[Crossref] [PubMed]

Bui, E. H.

J. M. Uecker, E. H. Bui, K. H. Foulkrod, and J. P. Sabra, “Intraoperative assessment of breast cancer specimens decreases cost and number of reoperations,” Am. Surg. 77(3), 342–344 (2011).
[PubMed]

Cable, A. E.

Y. K. Tao, D. Shen, Y. Sheikine, O. O. Ahsen, H. H. Wang, D. B. Schmolze, N. B. Johnson, J. S. Brooker, A. E. Cable, J. L. Connolly, and J. G. Fujimoto, “Assessment of breast pathologies using nonlinear microscopy,” Proc. Natl. Acad. Sci. U.S.A. 111(43), 15304–15309 (2014).
[Crossref] [PubMed]

Campbell, J. M.

P. P. Provenzano, K. W. Eliceiri, J. M. Campbell, D. R. Inman, J. G. White, and P. J. Keely, “Collagen reorganization at the tumor-stromal interface facilitates local invasion,” BMC Med. 4(1), 38 (2006).
[Crossref] [PubMed]

Charbon, E.

D. D. U. Li, J. Arlt, D. Tyndall, R. Walker, J. Richardson, D. Stoppa, E. Charbon, and R. K. Henderson, “Video-rate fluorescence lifetime imaging camera with CMOS single-photon avalanche diode arrays and high-speed imaging algorithm,” J. Biomed. Opt. 16(9), 096012 (2011).
[Crossref] [PubMed]

Chow, S. K.

D. L. Price, S. K. Chow, N. A. B. Maclean, H. Hakozaki, S. Peltier, M. E. Martone, and M. H. Ellisman, “High-resolution large-scale mosaic imaging using multiphoton microscopy to characterize transgenic mouse models of human neurological disorders,” Neuroinformatics 4, 65–80 (2006).

Christie, R.

W. R. Zipfel, R. M. Williams, R. Christie, A. Y. Nikitin, B. T. Hyman, and W. W. Webb, “Live tissue intrinsic emission microscopy using multiphoton-excited native fluorescence and second harmonic generation,” Proc. Natl. Acad. Sci. U.S.A. 100(12), 7075–7080 (2003).
[Crossref] [PubMed]

Chu, A.

R. Patalay, C. Talbot, Y. Alexandrov, M. O. Lenz, S. Kumar, S. Warren, I. Munro, M. A. Neil, K. König, P. M. W. French, A. Chu, G. W. H. Stamp, and C. Dunsby, “Multiphoton multispectral fluorescence lifetime tomography for the evaluation of basal cell carcinomas,” PLoS One 7(9), e43460 (2012).
[Crossref] [PubMed]

R. Patalay, C. Talbot, Y. Alexandrov, I. Munro, M. A. Neil, K. König, P. M. French, A. Chu, G. W. Stamp, and C. Dunsby, “Quantification of cellular autofluorescence of human skin using multiphoton tomography and fluorescence lifetime imaging in two spectral detection channels,” Biomed. Opt. Express 2(12), 3295–3308 (2011).
[Crossref] [PubMed]

Cohen, P.

Conklin, M. W.

M. W. Conklin, P. P. Provenzano, K. W. Eliceiri, R. Sullivan, and P. J. Keely, “Fluorescence lifetime imaging of endogenous fluorophores in histopathology sections reveals differences between normal and tumor epithelium in carcinoma in situ of the breast,” Cell Biochem. Biophys. 53(3), 145–157 (2009).
[Crossref] [PubMed]

Connolly, J. L.

Y. K. Tao, D. Shen, Y. Sheikine, O. O. Ahsen, H. H. Wang, D. B. Schmolze, N. B. Johnson, J. S. Brooker, A. E. Cable, J. L. Connolly, and J. G. Fujimoto, “Assessment of breast pathologies using nonlinear microscopy,” Proc. Natl. Acad. Sci. U.S.A. 111(43), 15304–15309 (2014).
[Crossref] [PubMed]

Dayel, M. J.

Denk, W.

F. Helmchen and W. Denk, “Deep tissue two-photon microscopy,” Nat. Methods 2(12), 932–940 (2005).
[Crossref] [PubMed]

W. Denk, J. H. Strickler, and W. W. Webb, “Two-photon laser scanning fluorescence microscopy,” Science 248(4951), 73–76 (1990).
[Crossref] [PubMed]

Dong, C. Y.

P. T. C. So, T. French, W. M. Yu, K. M. Berland, C. Y. Dong, and E. Gratton, “Time-resolved fluorescence microscopy using two-photon excitation,” Bioimaging 3(2), 49–63 (1995).
[Crossref]

Dow, X. Y.

Dowling, K.

Dunsby, C.

Dymoke-Bradshaw, A. K.

Eickhoff, J.

M. C. Skala, K. M. Riching, D. K. Bird, A. Gendron-Fitzpatrick, J. Eickhoff, K. W. Eliceiri, P. J. Keely, and N. Ramanujam, “In vivo multiphoton fluorescence lifetime imaging of protein-bound and free nicotinamide adenine dinucleotide in normal and precancerous epithelia,” J. Biomed. Opt. 12(2), 024014 (2007).
[Crossref] [PubMed]

Eliceiri, K. W.

M. W. Conklin, P. P. Provenzano, K. W. Eliceiri, R. Sullivan, and P. J. Keely, “Fluorescence lifetime imaging of endogenous fluorophores in histopathology sections reveals differences between normal and tumor epithelium in carcinoma in situ of the breast,” Cell Biochem. Biophys. 53(3), 145–157 (2009).
[Crossref] [PubMed]

P. P. Provenzano, C. T. Rueden, S. M. Trier, L. Yan, S. M. Ponik, D. R. Inman, P. J. Keely, and K. W. Eliceiri, “Nonlinear optical imaging and spectral-lifetime computational analysis of endogenous and exogenous fluorophores in breast cancer,” J. Biomed. Opt. 13(3), 031220 (2008).
[Crossref] [PubMed]

M. C. Skala, K. M. Riching, D. K. Bird, A. Gendron-Fitzpatrick, J. Eickhoff, K. W. Eliceiri, P. J. Keely, and N. Ramanujam, “In vivo multiphoton fluorescence lifetime imaging of protein-bound and free nicotinamide adenine dinucleotide in normal and precancerous epithelia,” J. Biomed. Opt. 12(2), 024014 (2007).
[Crossref] [PubMed]

P. P. Provenzano, K. W. Eliceiri, J. M. Campbell, D. R. Inman, J. G. White, and P. J. Keely, “Collagen reorganization at the tumor-stromal interface facilitates local invasion,” BMC Med. 4(1), 38 (2006).
[Crossref] [PubMed]

Ellisman, M. H.

D. L. Price, S. K. Chow, N. A. B. Maclean, H. Hakozaki, S. Peltier, M. E. Martone, and M. H. Ellisman, “High-resolution large-scale mosaic imaging using multiphoton microscopy to characterize transgenic mouse models of human neurological disorders,” Neuroinformatics 4, 65–80 (2006).

Elsner, P.

M. J. Koehler, A. Preller, P. Elsner, K. König, U. C. Hipler, and M. Kaatz, “Non-invasive evaluation of dermal elastosis by in vivo multiphoton tomography with autofluorescence lifetime measurements,” Exp. Dermatol. 21(1), 48–51 (2012).
[Crossref] [PubMed]

Elson, D. S.

Engel, J.

J. Engel, J. Kerr, A. Schlesinger-Raab, H. Sauer, and D. Hölzel, “Quality of life following breast-conserving therapy or mastectomy: results of a 5-year prospective study,” Breast J. 10(3), 223–231 (2004).
[Crossref] [PubMed]

Esbona, K.

K. Esbona, Z. Li, and L. G. Wilke, “Intraoperative Imprint Cytology and Frozen Section Pathology for Margin Assessment in Breast Conservation Surgery: A Systematic Review,” Ann. Surg. Oncol. 19(10), 3236–3245 (2012).
[Crossref] [PubMed]

Fentiman, I. S.

J. A. van Dongen, A. C. Voogd, I. S. Fentiman, C. Legrand, R. J. Sylvester, D. Tong, E. van der Schueren, P. A. Helle, K. van Zijl, and H. Bartelink, “Long-term results of a randomized trial comparing breast-conserving therapy with mastectomy: European Organization for Research and Treatment of Cancer 10801 trial,” J. Natl. Cancer Inst. 92(14), 1143–1150 (2000).
[Crossref] [PubMed]

Fleming, F. J.

F. J. Fleming, A. D. Hill, E. W. Mc Dermott, A. O’Doherty, N. J. O’Higgins, and C. M. Quinn, “Intraoperative margin assessment and re-excision rate in breast conserving surgery,” Eur. J. Surg. Oncol. 30(3), 233–237 (2004).
[Crossref] [PubMed]

Forsyth, A.

Foulkrod, K. H.

J. M. Uecker, E. H. Bui, K. H. Foulkrod, and J. P. Sabra, “Intraoperative assessment of breast cancer specimens decreases cost and number of reoperations,” Am. Surg. 77(3), 342–344 (2011).
[PubMed]

French, P. M.

French, P. M. W.

R. Patalay, C. Talbot, Y. Alexandrov, M. O. Lenz, S. Kumar, S. Warren, I. Munro, M. A. Neil, K. König, P. M. W. French, A. Chu, G. W. H. Stamp, and C. Dunsby, “Multiphoton multispectral fluorescence lifetime tomography for the evaluation of basal cell carcinomas,” PLoS One 7(9), e43460 (2012).
[Crossref] [PubMed]

J. McGinty, N. P. Galletly, C. Dunsby, I. Munro, D. S. Elson, J. Requejo-Isidro, P. Cohen, R. Ahmad, A. Forsyth, A. V. Thillainayagam, M. A. Neil, P. M. W. French, and G. W. Stamp, “Wide-field fluorescence lifetime imaging of cancer,” Biomed. Opt. Express 1(2), 627–640 (2010).
[Crossref] [PubMed]

P. J. Tadrous, J. Siegel, P. M. W. French, S. Shousha, N. Lalani, and G. W. H. Stamp, “Fluorescence lifetime imaging of unstained tissues: early results in human breast cancer,” J. Pathol. 199(3), 309–317 (2003).
[Crossref] [PubMed]

K. Dowling, M. J. Dayel, M. J. Lever, P. M. W. French, J. D. Hares, and A. K. Dymoke-Bradshaw, “Fluorescence lifetime imaging with picosecond resolution for biomedical applications,” Opt. Lett. 23(10), 810–812 (1998).
[Crossref] [PubMed]

French, T.

P. T. C. So, T. French, W. M. Yu, K. M. Berland, C. Y. Dong, and E. Gratton, “Time-resolved fluorescence microscopy using two-photon excitation,” Bioimaging 3(2), 49–63 (1995).
[Crossref]

Fujimoto, J. G.

Y. K. Tao, D. Shen, Y. Sheikine, O. O. Ahsen, H. H. Wang, D. B. Schmolze, N. B. Johnson, J. S. Brooker, A. E. Cable, J. L. Connolly, and J. G. Fujimoto, “Assessment of breast pathologies using nonlinear microscopy,” Proc. Natl. Acad. Sci. U.S.A. 111(43), 15304–15309 (2014).
[Crossref] [PubMed]

Funatsu, T.

K. Okabe, N. Inada, C. Gota, Y. Harada, T. Funatsu, and S. Uchiyama, “Intracellular temperature mapping with a fluorescent polymeric thermometer and fluorescence lifetime imaging microscopy,” Nat. Commun. 3, 705 (2012).
[Crossref] [PubMed]

Galletly, N. P.

Gendron-Fitzpatrick, A.

M. C. Skala, K. M. Riching, D. K. Bird, A. Gendron-Fitzpatrick, J. Eickhoff, K. W. Eliceiri, P. J. Keely, and N. Ramanujam, “In vivo multiphoton fluorescence lifetime imaging of protein-bound and free nicotinamide adenine dinucleotide in normal and precancerous epithelia,” J. Biomed. Opt. 12(2), 024014 (2007).
[Crossref] [PubMed]

Gota, C.

K. Okabe, N. Inada, C. Gota, Y. Harada, T. Funatsu, and S. Uchiyama, “Intracellular temperature mapping with a fluorescent polymeric thermometer and fluorescence lifetime imaging microscopy,” Nat. Commun. 3, 705 (2012).
[Crossref] [PubMed]

Gratton, E.

P. T. C. So, T. French, W. M. Yu, K. M. Berland, C. Y. Dong, and E. Gratton, “Time-resolved fluorescence microscopy using two-photon excitation,” Bioimaging 3(2), 49–63 (1995).
[Crossref]

Hakozaki, H.

D. L. Price, S. K. Chow, N. A. B. Maclean, H. Hakozaki, S. Peltier, M. E. Martone, and M. H. Ellisman, “High-resolution large-scale mosaic imaging using multiphoton microscopy to characterize transgenic mouse models of human neurological disorders,” Neuroinformatics 4, 65–80 (2006).

Hammer, M.

M. Hammer, D. Schweitzer, S. Richter, and E. Königsdörffer, “Sodium fluorescein as a retinal pH indicator?” Physiol. Meas. 26(4), N9–N12 (2005).
[Crossref] [PubMed]

Harada, Y.

K. Okabe, N. Inada, C. Gota, Y. Harada, T. Funatsu, and S. Uchiyama, “Intracellular temperature mapping with a fluorescent polymeric thermometer and fluorescence lifetime imaging microscopy,” Nat. Commun. 3, 705 (2012).
[Crossref] [PubMed]

Hares, J. D.

Helle, P. A.

J. A. van Dongen, A. C. Voogd, I. S. Fentiman, C. Legrand, R. J. Sylvester, D. Tong, E. van der Schueren, P. A. Helle, K. van Zijl, and H. Bartelink, “Long-term results of a randomized trial comparing breast-conserving therapy with mastectomy: European Organization for Research and Treatment of Cancer 10801 trial,” J. Natl. Cancer Inst. 92(14), 1143–1150 (2000).
[Crossref] [PubMed]

Helmchen, F.

F. Helmchen and W. Denk, “Deep tissue two-photon microscopy,” Nat. Methods 2(12), 932–940 (2005).
[Crossref] [PubMed]

Henderson, R. K.

D. D. U. Li, J. Arlt, D. Tyndall, R. Walker, J. Richardson, D. Stoppa, E. Charbon, and R. K. Henderson, “Video-rate fluorescence lifetime imaging camera with CMOS single-photon avalanche diode arrays and high-speed imaging algorithm,” J. Biomed. Opt. 16(9), 096012 (2011).
[Crossref] [PubMed]

Herman, B.

V. K. Ramanujan, J.-H. Zhang, E. Biener, and B. Herman, “Multiphoton fluorescence lifetime contrast in deep tissue imaging: prospects in redox imaging and disease diagnosis,” J. Biomed. Opt. 10(5), 051407 (2005).
[Crossref] [PubMed]

Herman, P.

H.-J. Lin, P. Herman, and J. R. Lakowicz, “Fluorescence lifetime-resolved pH imaging of living cells,” Cytometry A 52(2), 77–89 (2003).
[Crossref] [PubMed]

Hill, A. D.

F. J. Fleming, A. D. Hill, E. W. Mc Dermott, A. O’Doherty, N. J. O’Higgins, and C. M. Quinn, “Intraoperative margin assessment and re-excision rate in breast conserving surgery,” Eur. J. Surg. Oncol. 30(3), 233–237 (2004).
[Crossref] [PubMed]

Hipler, U. C.

M. J. Koehler, A. Preller, P. Elsner, K. König, U. C. Hipler, and M. Kaatz, “Non-invasive evaluation of dermal elastosis by in vivo multiphoton tomography with autofluorescence lifetime measurements,” Exp. Dermatol. 21(1), 48–51 (2012).
[Crossref] [PubMed]

Hölzel, D.

J. Engel, J. Kerr, A. Schlesinger-Raab, H. Sauer, and D. Hölzel, “Quality of life following breast-conserving therapy or mastectomy: results of a 5-year prospective study,” Breast J. 10(3), 223–231 (2004).
[Crossref] [PubMed]

Hyman, B. T.

W. R. Zipfel, R. M. Williams, R. Christie, A. Y. Nikitin, B. T. Hyman, and W. W. Webb, “Live tissue intrinsic emission microscopy using multiphoton-excited native fluorescence and second harmonic generation,” Proc. Natl. Acad. Sci. U.S.A. 100(12), 7075–7080 (2003).
[Crossref] [PubMed]

Inada, N.

K. Okabe, N. Inada, C. Gota, Y. Harada, T. Funatsu, and S. Uchiyama, “Intracellular temperature mapping with a fluorescent polymeric thermometer and fluorescence lifetime imaging microscopy,” Nat. Commun. 3, 705 (2012).
[Crossref] [PubMed]

Inman, D. R.

P. P. Provenzano, C. T. Rueden, S. M. Trier, L. Yan, S. M. Ponik, D. R. Inman, P. J. Keely, and K. W. Eliceiri, “Nonlinear optical imaging and spectral-lifetime computational analysis of endogenous and exogenous fluorophores in breast cancer,” J. Biomed. Opt. 13(3), 031220 (2008).
[Crossref] [PubMed]

P. P. Provenzano, K. W. Eliceiri, J. M. Campbell, D. R. Inman, J. G. White, and P. J. Keely, “Collagen reorganization at the tumor-stromal interface facilitates local invasion,” BMC Med. 4(1), 38 (2006).
[Crossref] [PubMed]

Johnson, N. B.

Y. K. Tao, D. Shen, Y. Sheikine, O. O. Ahsen, H. H. Wang, D. B. Schmolze, N. B. Johnson, J. S. Brooker, A. E. Cable, J. L. Connolly, and J. G. Fujimoto, “Assessment of breast pathologies using nonlinear microscopy,” Proc. Natl. Acad. Sci. U.S.A. 111(43), 15304–15309 (2014).
[Crossref] [PubMed]

Kaatz, M.

M. J. Koehler, A. Preller, P. Elsner, K. König, U. C. Hipler, and M. Kaatz, “Non-invasive evaluation of dermal elastosis by in vivo multiphoton tomography with autofluorescence lifetime measurements,” Exp. Dermatol. 21(1), 48–51 (2012).
[Crossref] [PubMed]

Keely, P. J.

M. W. Conklin, P. P. Provenzano, K. W. Eliceiri, R. Sullivan, and P. J. Keely, “Fluorescence lifetime imaging of endogenous fluorophores in histopathology sections reveals differences between normal and tumor epithelium in carcinoma in situ of the breast,” Cell Biochem. Biophys. 53(3), 145–157 (2009).
[Crossref] [PubMed]

P. P. Provenzano, C. T. Rueden, S. M. Trier, L. Yan, S. M. Ponik, D. R. Inman, P. J. Keely, and K. W. Eliceiri, “Nonlinear optical imaging and spectral-lifetime computational analysis of endogenous and exogenous fluorophores in breast cancer,” J. Biomed. Opt. 13(3), 031220 (2008).
[Crossref] [PubMed]

M. C. Skala, K. M. Riching, D. K. Bird, A. Gendron-Fitzpatrick, J. Eickhoff, K. W. Eliceiri, P. J. Keely, and N. Ramanujam, “In vivo multiphoton fluorescence lifetime imaging of protein-bound and free nicotinamide adenine dinucleotide in normal and precancerous epithelia,” J. Biomed. Opt. 12(2), 024014 (2007).
[Crossref] [PubMed]

P. P. Provenzano, K. W. Eliceiri, J. M. Campbell, D. R. Inman, J. G. White, and P. J. Keely, “Collagen reorganization at the tumor-stromal interface facilitates local invasion,” BMC Med. 4(1), 38 (2006).
[Crossref] [PubMed]

Kerr, J.

J. Engel, J. Kerr, A. Schlesinger-Raab, H. Sauer, and D. Hölzel, “Quality of life following breast-conserving therapy or mastectomy: results of a 5-year prospective study,” Breast J. 10(3), 223–231 (2004).
[Crossref] [PubMed]

Koehler, M. J.

M. J. Koehler, A. Preller, P. Elsner, K. König, U. C. Hipler, and M. Kaatz, “Non-invasive evaluation of dermal elastosis by in vivo multiphoton tomography with autofluorescence lifetime measurements,” Exp. Dermatol. 21(1), 48–51 (2012).
[Crossref] [PubMed]

König, K.

M. J. Koehler, A. Preller, P. Elsner, K. König, U. C. Hipler, and M. Kaatz, “Non-invasive evaluation of dermal elastosis by in vivo multiphoton tomography with autofluorescence lifetime measurements,” Exp. Dermatol. 21(1), 48–51 (2012).
[Crossref] [PubMed]

R. Patalay, C. Talbot, Y. Alexandrov, M. O. Lenz, S. Kumar, S. Warren, I. Munro, M. A. Neil, K. König, P. M. W. French, A. Chu, G. W. H. Stamp, and C. Dunsby, “Multiphoton multispectral fluorescence lifetime tomography for the evaluation of basal cell carcinomas,” PLoS One 7(9), e43460 (2012).
[Crossref] [PubMed]

R. Patalay, C. Talbot, Y. Alexandrov, I. Munro, M. A. Neil, K. König, P. M. French, A. Chu, G. W. Stamp, and C. Dunsby, “Quantification of cellular autofluorescence of human skin using multiphoton tomography and fluorescence lifetime imaging in two spectral detection channels,” Biomed. Opt. Express 2(12), 3295–3308 (2011).
[Crossref] [PubMed]

Königsdörffer, E.

M. Hammer, D. Schweitzer, S. Richter, and E. Königsdörffer, “Sodium fluorescein as a retinal pH indicator?” Physiol. Meas. 26(4), N9–N12 (2005).
[Crossref] [PubMed]

Kumar, S.

R. Patalay, C. Talbot, Y. Alexandrov, M. O. Lenz, S. Kumar, S. Warren, I. Munro, M. A. Neil, K. König, P. M. W. French, A. Chu, G. W. H. Stamp, and C. Dunsby, “Multiphoton multispectral fluorescence lifetime tomography for the evaluation of basal cell carcinomas,” PLoS One 7(9), e43460 (2012).
[Crossref] [PubMed]

Lakowicz, J. R.

H.-J. Lin, P. Herman, and J. R. Lakowicz, “Fluorescence lifetime-resolved pH imaging of living cells,” Cytometry A 52(2), 77–89 (2003).
[Crossref] [PubMed]

Lalani, N.

P. J. Tadrous, J. Siegel, P. M. W. French, S. Shousha, N. Lalani, and G. W. H. Stamp, “Fluorescence lifetime imaging of unstained tissues: early results in human breast cancer,” J. Pathol. 199(3), 309–317 (2003).
[Crossref] [PubMed]

Legrand, C.

J. A. van Dongen, A. C. Voogd, I. S. Fentiman, C. Legrand, R. J. Sylvester, D. Tong, E. van der Schueren, P. A. Helle, K. van Zijl, and H. Bartelink, “Long-term results of a randomized trial comparing breast-conserving therapy with mastectomy: European Organization for Research and Treatment of Cancer 10801 trial,” J. Natl. Cancer Inst. 92(14), 1143–1150 (2000).
[Crossref] [PubMed]

Lenz, M. O.

R. Patalay, C. Talbot, Y. Alexandrov, M. O. Lenz, S. Kumar, S. Warren, I. Munro, M. A. Neil, K. König, P. M. W. French, A. Chu, G. W. H. Stamp, and C. Dunsby, “Multiphoton multispectral fluorescence lifetime tomography for the evaluation of basal cell carcinomas,” PLoS One 7(9), e43460 (2012).
[Crossref] [PubMed]

Lever, M. J.

Li, D. D. U.

D. D. U. Li, J. Arlt, D. Tyndall, R. Walker, J. Richardson, D. Stoppa, E. Charbon, and R. K. Henderson, “Video-rate fluorescence lifetime imaging camera with CMOS single-photon avalanche diode arrays and high-speed imaging algorithm,” J. Biomed. Opt. 16(9), 096012 (2011).
[Crossref] [PubMed]

Li, Z.

K. Esbona, Z. Li, and L. G. Wilke, “Intraoperative Imprint Cytology and Frozen Section Pathology for Margin Assessment in Breast Conservation Surgery: A Systematic Review,” Ann. Surg. Oncol. 19(10), 3236–3245 (2012).
[Crossref] [PubMed]

Lin, H.-J.

H.-J. Lin, P. Herman, and J. R. Lakowicz, “Fluorescence lifetime-resolved pH imaging of living cells,” Cytometry A 52(2), 77–89 (2003).
[Crossref] [PubMed]

Maclean, N. A. B.

D. L. Price, S. K. Chow, N. A. B. Maclean, H. Hakozaki, S. Peltier, M. E. Martone, and M. H. Ellisman, “High-resolution large-scale mosaic imaging using multiphoton microscopy to characterize transgenic mouse models of human neurological disorders,” Neuroinformatics 4, 65–80 (2006).

Martone, M. E.

D. L. Price, S. K. Chow, N. A. B. Maclean, H. Hakozaki, S. Peltier, M. E. Martone, and M. H. Ellisman, “High-resolution large-scale mosaic imaging using multiphoton microscopy to characterize transgenic mouse models of human neurological disorders,” Neuroinformatics 4, 65–80 (2006).

Mc Dermott, E. W.

F. J. Fleming, A. D. Hill, E. W. Mc Dermott, A. O’Doherty, N. J. O’Higgins, and C. M. Quinn, “Intraoperative margin assessment and re-excision rate in breast conserving surgery,” Eur. J. Surg. Oncol. 30(3), 233–237 (2004).
[Crossref] [PubMed]

McGinty, J.

Muir, R. D.

Munro, I.

Neil, M. A.

Nikitin, A. Y.

W. R. Zipfel, R. M. Williams, R. Christie, A. Y. Nikitin, B. T. Hyman, and W. W. Webb, “Live tissue intrinsic emission microscopy using multiphoton-excited native fluorescence and second harmonic generation,” Proc. Natl. Acad. Sci. U.S.A. 100(12), 7075–7080 (2003).
[Crossref] [PubMed]

O’Doherty, A.

F. J. Fleming, A. D. Hill, E. W. Mc Dermott, A. O’Doherty, N. J. O’Higgins, and C. M. Quinn, “Intraoperative margin assessment and re-excision rate in breast conserving surgery,” Eur. J. Surg. Oncol. 30(3), 233–237 (2004).
[Crossref] [PubMed]

O’Higgins, N. J.

F. J. Fleming, A. D. Hill, E. W. Mc Dermott, A. O’Doherty, N. J. O’Higgins, and C. M. Quinn, “Intraoperative margin assessment and re-excision rate in breast conserving surgery,” Eur. J. Surg. Oncol. 30(3), 233–237 (2004).
[Crossref] [PubMed]

Okabe, K.

K. Okabe, N. Inada, C. Gota, Y. Harada, T. Funatsu, and S. Uchiyama, “Intracellular temperature mapping with a fluorescent polymeric thermometer and fluorescence lifetime imaging microscopy,” Nat. Commun. 3, 705 (2012).
[Crossref] [PubMed]

Patalay, R.

R. Patalay, C. Talbot, Y. Alexandrov, M. O. Lenz, S. Kumar, S. Warren, I. Munro, M. A. Neil, K. König, P. M. W. French, A. Chu, G. W. H. Stamp, and C. Dunsby, “Multiphoton multispectral fluorescence lifetime tomography for the evaluation of basal cell carcinomas,” PLoS One 7(9), e43460 (2012).
[Crossref] [PubMed]

R. Patalay, C. Talbot, Y. Alexandrov, I. Munro, M. A. Neil, K. König, P. M. French, A. Chu, G. W. Stamp, and C. Dunsby, “Quantification of cellular autofluorescence of human skin using multiphoton tomography and fluorescence lifetime imaging in two spectral detection channels,” Biomed. Opt. Express 2(12), 3295–3308 (2011).
[Crossref] [PubMed]

Peltier, S.

D. L. Price, S. K. Chow, N. A. B. Maclean, H. Hakozaki, S. Peltier, M. E. Martone, and M. H. Ellisman, “High-resolution large-scale mosaic imaging using multiphoton microscopy to characterize transgenic mouse models of human neurological disorders,” Neuroinformatics 4, 65–80 (2006).

Ponik, S. M.

P. P. Provenzano, C. T. Rueden, S. M. Trier, L. Yan, S. M. Ponik, D. R. Inman, P. J. Keely, and K. W. Eliceiri, “Nonlinear optical imaging and spectral-lifetime computational analysis of endogenous and exogenous fluorophores in breast cancer,” J. Biomed. Opt. 13(3), 031220 (2008).
[Crossref] [PubMed]

Preller, A.

M. J. Koehler, A. Preller, P. Elsner, K. König, U. C. Hipler, and M. Kaatz, “Non-invasive evaluation of dermal elastosis by in vivo multiphoton tomography with autofluorescence lifetime measurements,” Exp. Dermatol. 21(1), 48–51 (2012).
[Crossref] [PubMed]

Price, D. L.

D. L. Price, S. K. Chow, N. A. B. Maclean, H. Hakozaki, S. Peltier, M. E. Martone, and M. H. Ellisman, “High-resolution large-scale mosaic imaging using multiphoton microscopy to characterize transgenic mouse models of human neurological disorders,” Neuroinformatics 4, 65–80 (2006).

Provenzano, P. P.

M. W. Conklin, P. P. Provenzano, K. W. Eliceiri, R. Sullivan, and P. J. Keely, “Fluorescence lifetime imaging of endogenous fluorophores in histopathology sections reveals differences between normal and tumor epithelium in carcinoma in situ of the breast,” Cell Biochem. Biophys. 53(3), 145–157 (2009).
[Crossref] [PubMed]

P. P. Provenzano, C. T. Rueden, S. M. Trier, L. Yan, S. M. Ponik, D. R. Inman, P. J. Keely, and K. W. Eliceiri, “Nonlinear optical imaging and spectral-lifetime computational analysis of endogenous and exogenous fluorophores in breast cancer,” J. Biomed. Opt. 13(3), 031220 (2008).
[Crossref] [PubMed]

P. P. Provenzano, K. W. Eliceiri, J. M. Campbell, D. R. Inman, J. G. White, and P. J. Keely, “Collagen reorganization at the tumor-stromal interface facilitates local invasion,” BMC Med. 4(1), 38 (2006).
[Crossref] [PubMed]

Quinn, C. M.

F. J. Fleming, A. D. Hill, E. W. Mc Dermott, A. O’Doherty, N. J. O’Higgins, and C. M. Quinn, “Intraoperative margin assessment and re-excision rate in breast conserving surgery,” Eur. J. Surg. Oncol. 30(3), 233–237 (2004).
[Crossref] [PubMed]

Ramanujam, N.

M. C. Skala, K. M. Riching, D. K. Bird, A. Gendron-Fitzpatrick, J. Eickhoff, K. W. Eliceiri, P. J. Keely, and N. Ramanujam, “In vivo multiphoton fluorescence lifetime imaging of protein-bound and free nicotinamide adenine dinucleotide in normal and precancerous epithelia,” J. Biomed. Opt. 12(2), 024014 (2007).
[Crossref] [PubMed]

Ramanujan, V. K.

V. K. Ramanujan, J.-H. Zhang, E. Biener, and B. Herman, “Multiphoton fluorescence lifetime contrast in deep tissue imaging: prospects in redox imaging and disease diagnosis,” J. Biomed. Opt. 10(5), 051407 (2005).
[Crossref] [PubMed]

Requejo-Isidro, J.

Richardson, J.

D. D. U. Li, J. Arlt, D. Tyndall, R. Walker, J. Richardson, D. Stoppa, E. Charbon, and R. K. Henderson, “Video-rate fluorescence lifetime imaging camera with CMOS single-photon avalanche diode arrays and high-speed imaging algorithm,” J. Biomed. Opt. 16(9), 096012 (2011).
[Crossref] [PubMed]

Riching, K. M.

M. C. Skala, K. M. Riching, D. K. Bird, A. Gendron-Fitzpatrick, J. Eickhoff, K. W. Eliceiri, P. J. Keely, and N. Ramanujam, “In vivo multiphoton fluorescence lifetime imaging of protein-bound and free nicotinamide adenine dinucleotide in normal and precancerous epithelia,” J. Biomed. Opt. 12(2), 024014 (2007).
[Crossref] [PubMed]

Richter, S.

M. Hammer, D. Schweitzer, S. Richter, and E. Königsdörffer, “Sodium fluorescein as a retinal pH indicator?” Physiol. Meas. 26(4), N9–N12 (2005).
[Crossref] [PubMed]

Rueden, C. T.

P. P. Provenzano, C. T. Rueden, S. M. Trier, L. Yan, S. M. Ponik, D. R. Inman, P. J. Keely, and K. W. Eliceiri, “Nonlinear optical imaging and spectral-lifetime computational analysis of endogenous and exogenous fluorophores in breast cancer,” J. Biomed. Opt. 13(3), 031220 (2008).
[Crossref] [PubMed]

Rynearson, K.

G. P. Swanson, K. Rynearson, and R. Symmonds, “Significance of margins of excision on breast cancer recurrence,” Am. J. Clin. Oncol. 25(5), 438–441 (2002).
[Crossref] [PubMed]

Sabra, J. P.

J. M. Uecker, E. H. Bui, K. H. Foulkrod, and J. P. Sabra, “Intraoperative assessment of breast cancer specimens decreases cost and number of reoperations,” Am. Surg. 77(3), 342–344 (2011).
[PubMed]

Sauer, H.

J. Engel, J. Kerr, A. Schlesinger-Raab, H. Sauer, and D. Hölzel, “Quality of life following breast-conserving therapy or mastectomy: results of a 5-year prospective study,” Breast J. 10(3), 223–231 (2004).
[Crossref] [PubMed]

Schlesinger-Raab, A.

J. Engel, J. Kerr, A. Schlesinger-Raab, H. Sauer, and D. Hölzel, “Quality of life following breast-conserving therapy or mastectomy: results of a 5-year prospective study,” Breast J. 10(3), 223–231 (2004).
[Crossref] [PubMed]

Schmolze, D. B.

Y. K. Tao, D. Shen, Y. Sheikine, O. O. Ahsen, H. H. Wang, D. B. Schmolze, N. B. Johnson, J. S. Brooker, A. E. Cable, J. L. Connolly, and J. G. Fujimoto, “Assessment of breast pathologies using nonlinear microscopy,” Proc. Natl. Acad. Sci. U.S.A. 111(43), 15304–15309 (2014).
[Crossref] [PubMed]

Schnitt, S. J.

S. J. Schnitt, “The diagnosis and management of pre-invasive breast disease: flat epithelial atypia--classification, pathologic features and clinical significance,” Breast Cancer Res. 5(5), 263–268 (2003).
[Crossref] [PubMed]

Schweitzer, D.

M. Hammer, D. Schweitzer, S. Richter, and E. Königsdörffer, “Sodium fluorescein as a retinal pH indicator?” Physiol. Meas. 26(4), N9–N12 (2005).
[Crossref] [PubMed]

Sheikine, Y.

Y. K. Tao, D. Shen, Y. Sheikine, O. O. Ahsen, H. H. Wang, D. B. Schmolze, N. B. Johnson, J. S. Brooker, A. E. Cable, J. L. Connolly, and J. G. Fujimoto, “Assessment of breast pathologies using nonlinear microscopy,” Proc. Natl. Acad. Sci. U.S.A. 111(43), 15304–15309 (2014).
[Crossref] [PubMed]

Shen, D.

Y. K. Tao, D. Shen, Y. Sheikine, O. O. Ahsen, H. H. Wang, D. B. Schmolze, N. B. Johnson, J. S. Brooker, A. E. Cable, J. L. Connolly, and J. G. Fujimoto, “Assessment of breast pathologies using nonlinear microscopy,” Proc. Natl. Acad. Sci. U.S.A. 111(43), 15304–15309 (2014).
[Crossref] [PubMed]

Shousha, S.

P. J. Tadrous, J. Siegel, P. M. W. French, S. Shousha, N. Lalani, and G. W. H. Stamp, “Fluorescence lifetime imaging of unstained tissues: early results in human breast cancer,” J. Pathol. 199(3), 309–317 (2003).
[Crossref] [PubMed]

Siegel, J.

P. J. Tadrous, J. Siegel, P. M. W. French, S. Shousha, N. Lalani, and G. W. H. Stamp, “Fluorescence lifetime imaging of unstained tissues: early results in human breast cancer,” J. Pathol. 199(3), 309–317 (2003).
[Crossref] [PubMed]

Simpson, G. J.

Skala, M. C.

M. C. Skala, K. M. Riching, D. K. Bird, A. Gendron-Fitzpatrick, J. Eickhoff, K. W. Eliceiri, P. J. Keely, and N. Ramanujam, “In vivo multiphoton fluorescence lifetime imaging of protein-bound and free nicotinamide adenine dinucleotide in normal and precancerous epithelia,” J. Biomed. Opt. 12(2), 024014 (2007).
[Crossref] [PubMed]

So, P. T. C.

P. T. C. So, T. French, W. M. Yu, K. M. Berland, C. Y. Dong, and E. Gratton, “Time-resolved fluorescence microscopy using two-photon excitation,” Bioimaging 3(2), 49–63 (1995).
[Crossref]

Stamp, G. W.

Stamp, G. W. H.

R. Patalay, C. Talbot, Y. Alexandrov, M. O. Lenz, S. Kumar, S. Warren, I. Munro, M. A. Neil, K. König, P. M. W. French, A. Chu, G. W. H. Stamp, and C. Dunsby, “Multiphoton multispectral fluorescence lifetime tomography for the evaluation of basal cell carcinomas,” PLoS One 7(9), e43460 (2012).
[Crossref] [PubMed]

P. J. Tadrous, J. Siegel, P. M. W. French, S. Shousha, N. Lalani, and G. W. H. Stamp, “Fluorescence lifetime imaging of unstained tissues: early results in human breast cancer,” J. Pathol. 199(3), 309–317 (2003).
[Crossref] [PubMed]

Stoppa, D.

D. D. U. Li, J. Arlt, D. Tyndall, R. Walker, J. Richardson, D. Stoppa, E. Charbon, and R. K. Henderson, “Video-rate fluorescence lifetime imaging camera with CMOS single-photon avalanche diode arrays and high-speed imaging algorithm,” J. Biomed. Opt. 16(9), 096012 (2011).
[Crossref] [PubMed]

Strickler, J. H.

W. Denk, J. H. Strickler, and W. W. Webb, “Two-photon laser scanning fluorescence microscopy,” Science 248(4951), 73–76 (1990).
[Crossref] [PubMed]

Sullivan, R.

M. W. Conklin, P. P. Provenzano, K. W. Eliceiri, R. Sullivan, and P. J. Keely, “Fluorescence lifetime imaging of endogenous fluorophores in histopathology sections reveals differences between normal and tumor epithelium in carcinoma in situ of the breast,” Cell Biochem. Biophys. 53(3), 145–157 (2009).
[Crossref] [PubMed]

Sullivan, S. Z.

Swanson, G. P.

G. P. Swanson, K. Rynearson, and R. Symmonds, “Significance of margins of excision on breast cancer recurrence,” Am. J. Clin. Oncol. 25(5), 438–441 (2002).
[Crossref] [PubMed]

Sylvester, R. J.

J. A. van Dongen, A. C. Voogd, I. S. Fentiman, C. Legrand, R. J. Sylvester, D. Tong, E. van der Schueren, P. A. Helle, K. van Zijl, and H. Bartelink, “Long-term results of a randomized trial comparing breast-conserving therapy with mastectomy: European Organization for Research and Treatment of Cancer 10801 trial,” J. Natl. Cancer Inst. 92(14), 1143–1150 (2000).
[Crossref] [PubMed]

Symmonds, R.

G. P. Swanson, K. Rynearson, and R. Symmonds, “Significance of margins of excision on breast cancer recurrence,” Am. J. Clin. Oncol. 25(5), 438–441 (2002).
[Crossref] [PubMed]

Tadrous, P. J.

P. J. Tadrous, J. Siegel, P. M. W. French, S. Shousha, N. Lalani, and G. W. H. Stamp, “Fluorescence lifetime imaging of unstained tissues: early results in human breast cancer,” J. Pathol. 199(3), 309–317 (2003).
[Crossref] [PubMed]

Talbot, C.

R. Patalay, C. Talbot, Y. Alexandrov, M. O. Lenz, S. Kumar, S. Warren, I. Munro, M. A. Neil, K. König, P. M. W. French, A. Chu, G. W. H. Stamp, and C. Dunsby, “Multiphoton multispectral fluorescence lifetime tomography for the evaluation of basal cell carcinomas,” PLoS One 7(9), e43460 (2012).
[Crossref] [PubMed]

R. Patalay, C. Talbot, Y. Alexandrov, I. Munro, M. A. Neil, K. König, P. M. French, A. Chu, G. W. Stamp, and C. Dunsby, “Quantification of cellular autofluorescence of human skin using multiphoton tomography and fluorescence lifetime imaging in two spectral detection channels,” Biomed. Opt. Express 2(12), 3295–3308 (2011).
[Crossref] [PubMed]

Tao, Y. K.

Y. K. Tao, D. Shen, Y. Sheikine, O. O. Ahsen, H. H. Wang, D. B. Schmolze, N. B. Johnson, J. S. Brooker, A. E. Cable, J. L. Connolly, and J. G. Fujimoto, “Assessment of breast pathologies using nonlinear microscopy,” Proc. Natl. Acad. Sci. U.S.A. 111(43), 15304–15309 (2014).
[Crossref] [PubMed]

Thillainayagam, A. V.

Tong, D.

J. A. van Dongen, A. C. Voogd, I. S. Fentiman, C. Legrand, R. J. Sylvester, D. Tong, E. van der Schueren, P. A. Helle, K. van Zijl, and H. Bartelink, “Long-term results of a randomized trial comparing breast-conserving therapy with mastectomy: European Organization for Research and Treatment of Cancer 10801 trial,” J. Natl. Cancer Inst. 92(14), 1143–1150 (2000).
[Crossref] [PubMed]

Trier, S. M.

P. P. Provenzano, C. T. Rueden, S. M. Trier, L. Yan, S. M. Ponik, D. R. Inman, P. J. Keely, and K. W. Eliceiri, “Nonlinear optical imaging and spectral-lifetime computational analysis of endogenous and exogenous fluorophores in breast cancer,” J. Biomed. Opt. 13(3), 031220 (2008).
[Crossref] [PubMed]

Tyndall, D.

D. D. U. Li, J. Arlt, D. Tyndall, R. Walker, J. Richardson, D. Stoppa, E. Charbon, and R. K. Henderson, “Video-rate fluorescence lifetime imaging camera with CMOS single-photon avalanche diode arrays and high-speed imaging algorithm,” J. Biomed. Opt. 16(9), 096012 (2011).
[Crossref] [PubMed]

Uchiyama, S.

K. Okabe, N. Inada, C. Gota, Y. Harada, T. Funatsu, and S. Uchiyama, “Intracellular temperature mapping with a fluorescent polymeric thermometer and fluorescence lifetime imaging microscopy,” Nat. Commun. 3, 705 (2012).
[Crossref] [PubMed]

Uecker, J. M.

J. M. Uecker, E. H. Bui, K. H. Foulkrod, and J. P. Sabra, “Intraoperative assessment of breast cancer specimens decreases cost and number of reoperations,” Am. Surg. 77(3), 342–344 (2011).
[PubMed]

van der Schueren, E.

J. A. van Dongen, A. C. Voogd, I. S. Fentiman, C. Legrand, R. J. Sylvester, D. Tong, E. van der Schueren, P. A. Helle, K. van Zijl, and H. Bartelink, “Long-term results of a randomized trial comparing breast-conserving therapy with mastectomy: European Organization for Research and Treatment of Cancer 10801 trial,” J. Natl. Cancer Inst. 92(14), 1143–1150 (2000).
[Crossref] [PubMed]

van Dongen, J. A.

J. A. van Dongen, A. C. Voogd, I. S. Fentiman, C. Legrand, R. J. Sylvester, D. Tong, E. van der Schueren, P. A. Helle, K. van Zijl, and H. Bartelink, “Long-term results of a randomized trial comparing breast-conserving therapy with mastectomy: European Organization for Research and Treatment of Cancer 10801 trial,” J. Natl. Cancer Inst. 92(14), 1143–1150 (2000).
[Crossref] [PubMed]

van Zijl, K.

J. A. van Dongen, A. C. Voogd, I. S. Fentiman, C. Legrand, R. J. Sylvester, D. Tong, E. van der Schueren, P. A. Helle, K. van Zijl, and H. Bartelink, “Long-term results of a randomized trial comparing breast-conserving therapy with mastectomy: European Organization for Research and Treatment of Cancer 10801 trial,” J. Natl. Cancer Inst. 92(14), 1143–1150 (2000).
[Crossref] [PubMed]

Voogd, A. C.

J. A. van Dongen, A. C. Voogd, I. S. Fentiman, C. Legrand, R. J. Sylvester, D. Tong, E. van der Schueren, P. A. Helle, K. van Zijl, and H. Bartelink, “Long-term results of a randomized trial comparing breast-conserving therapy with mastectomy: European Organization for Research and Treatment of Cancer 10801 trial,” J. Natl. Cancer Inst. 92(14), 1143–1150 (2000).
[Crossref] [PubMed]

Walker, R.

D. D. U. Li, J. Arlt, D. Tyndall, R. Walker, J. Richardson, D. Stoppa, E. Charbon, and R. K. Henderson, “Video-rate fluorescence lifetime imaging camera with CMOS single-photon avalanche diode arrays and high-speed imaging algorithm,” J. Biomed. Opt. 16(9), 096012 (2011).
[Crossref] [PubMed]

Wang, H. H.

Y. K. Tao, D. Shen, Y. Sheikine, O. O. Ahsen, H. H. Wang, D. B. Schmolze, N. B. Johnson, J. S. Brooker, A. E. Cable, J. L. Connolly, and J. G. Fujimoto, “Assessment of breast pathologies using nonlinear microscopy,” Proc. Natl. Acad. Sci. U.S.A. 111(43), 15304–15309 (2014).
[Crossref] [PubMed]

Warren, S.

R. Patalay, C. Talbot, Y. Alexandrov, M. O. Lenz, S. Kumar, S. Warren, I. Munro, M. A. Neil, K. König, P. M. W. French, A. Chu, G. W. H. Stamp, and C. Dunsby, “Multiphoton multispectral fluorescence lifetime tomography for the evaluation of basal cell carcinomas,” PLoS One 7(9), e43460 (2012).
[Crossref] [PubMed]

Webb, W. W.

W. R. Zipfel, R. M. Williams, R. Christie, A. Y. Nikitin, B. T. Hyman, and W. W. Webb, “Live tissue intrinsic emission microscopy using multiphoton-excited native fluorescence and second harmonic generation,” Proc. Natl. Acad. Sci. U.S.A. 100(12), 7075–7080 (2003).
[Crossref] [PubMed]

W. Denk, J. H. Strickler, and W. W. Webb, “Two-photon laser scanning fluorescence microscopy,” Science 248(4951), 73–76 (1990).
[Crossref] [PubMed]

White, J. G.

P. P. Provenzano, K. W. Eliceiri, J. M. Campbell, D. R. Inman, J. G. White, and P. J. Keely, “Collagen reorganization at the tumor-stromal interface facilitates local invasion,” BMC Med. 4(1), 38 (2006).
[Crossref] [PubMed]

Wilke, L. G.

K. Esbona, Z. Li, and L. G. Wilke, “Intraoperative Imprint Cytology and Frozen Section Pathology for Margin Assessment in Breast Conservation Surgery: A Systematic Review,” Ann. Surg. Oncol. 19(10), 3236–3245 (2012).
[Crossref] [PubMed]

Williams, R. M.

W. R. Zipfel, R. M. Williams, R. Christie, A. Y. Nikitin, B. T. Hyman, and W. W. Webb, “Live tissue intrinsic emission microscopy using multiphoton-excited native fluorescence and second harmonic generation,” Proc. Natl. Acad. Sci. U.S.A. 100(12), 7075–7080 (2003).
[Crossref] [PubMed]

Yan, L.

P. P. Provenzano, C. T. Rueden, S. M. Trier, L. Yan, S. M. Ponik, D. R. Inman, P. J. Keely, and K. W. Eliceiri, “Nonlinear optical imaging and spectral-lifetime computational analysis of endogenous and exogenous fluorophores in breast cancer,” J. Biomed. Opt. 13(3), 031220 (2008).
[Crossref] [PubMed]

Yu, W. M.

P. T. C. So, T. French, W. M. Yu, K. M. Berland, C. Y. Dong, and E. Gratton, “Time-resolved fluorescence microscopy using two-photon excitation,” Bioimaging 3(2), 49–63 (1995).
[Crossref]

Zhang, J.-H.

V. K. Ramanujan, J.-H. Zhang, E. Biener, and B. Herman, “Multiphoton fluorescence lifetime contrast in deep tissue imaging: prospects in redox imaging and disease diagnosis,” J. Biomed. Opt. 10(5), 051407 (2005).
[Crossref] [PubMed]

Zipfel, W. R.

W. R. Zipfel, R. M. Williams, R. Christie, A. Y. Nikitin, B. T. Hyman, and W. W. Webb, “Live tissue intrinsic emission microscopy using multiphoton-excited native fluorescence and second harmonic generation,” Proc. Natl. Acad. Sci. U.S.A. 100(12), 7075–7080 (2003).
[Crossref] [PubMed]

Am. J. Clin. Oncol. (1)

G. P. Swanson, K. Rynearson, and R. Symmonds, “Significance of margins of excision on breast cancer recurrence,” Am. J. Clin. Oncol. 25(5), 438–441 (2002).
[Crossref] [PubMed]

Am. Surg. (1)

J. M. Uecker, E. H. Bui, K. H. Foulkrod, and J. P. Sabra, “Intraoperative assessment of breast cancer specimens decreases cost and number of reoperations,” Am. Surg. 77(3), 342–344 (2011).
[PubMed]

Ann. Surg. Oncol. (1)

K. Esbona, Z. Li, and L. G. Wilke, “Intraoperative Imprint Cytology and Frozen Section Pathology for Margin Assessment in Breast Conservation Surgery: A Systematic Review,” Ann. Surg. Oncol. 19(10), 3236–3245 (2012).
[Crossref] [PubMed]

Bioimaging (1)

P. T. C. So, T. French, W. M. Yu, K. M. Berland, C. Y. Dong, and E. Gratton, “Time-resolved fluorescence microscopy using two-photon excitation,” Bioimaging 3(2), 49–63 (1995).
[Crossref]

Biomed. Opt. Express (2)

BMC Med. (1)

P. P. Provenzano, K. W. Eliceiri, J. M. Campbell, D. R. Inman, J. G. White, and P. J. Keely, “Collagen reorganization at the tumor-stromal interface facilitates local invasion,” BMC Med. 4(1), 38 (2006).
[Crossref] [PubMed]

Breast Cancer Res. (1)

S. J. Schnitt, “The diagnosis and management of pre-invasive breast disease: flat epithelial atypia--classification, pathologic features and clinical significance,” Breast Cancer Res. 5(5), 263–268 (2003).
[Crossref] [PubMed]

Breast J. (1)

J. Engel, J. Kerr, A. Schlesinger-Raab, H. Sauer, and D. Hölzel, “Quality of life following breast-conserving therapy or mastectomy: results of a 5-year prospective study,” Breast J. 10(3), 223–231 (2004).
[Crossref] [PubMed]

Cell Biochem. Biophys. (1)

M. W. Conklin, P. P. Provenzano, K. W. Eliceiri, R. Sullivan, and P. J. Keely, “Fluorescence lifetime imaging of endogenous fluorophores in histopathology sections reveals differences between normal and tumor epithelium in carcinoma in situ of the breast,” Cell Biochem. Biophys. 53(3), 145–157 (2009).
[Crossref] [PubMed]

Cytometry A (1)

H.-J. Lin, P. Herman, and J. R. Lakowicz, “Fluorescence lifetime-resolved pH imaging of living cells,” Cytometry A 52(2), 77–89 (2003).
[Crossref] [PubMed]

Eur. J. Surg. Oncol. (1)

F. J. Fleming, A. D. Hill, E. W. Mc Dermott, A. O’Doherty, N. J. O’Higgins, and C. M. Quinn, “Intraoperative margin assessment and re-excision rate in breast conserving surgery,” Eur. J. Surg. Oncol. 30(3), 233–237 (2004).
[Crossref] [PubMed]

Exp. Dermatol. (1)

M. J. Koehler, A. Preller, P. Elsner, K. König, U. C. Hipler, and M. Kaatz, “Non-invasive evaluation of dermal elastosis by in vivo multiphoton tomography with autofluorescence lifetime measurements,” Exp. Dermatol. 21(1), 48–51 (2012).
[Crossref] [PubMed]

J. Biomed. Opt. (4)

P. P. Provenzano, C. T. Rueden, S. M. Trier, L. Yan, S. M. Ponik, D. R. Inman, P. J. Keely, and K. W. Eliceiri, “Nonlinear optical imaging and spectral-lifetime computational analysis of endogenous and exogenous fluorophores in breast cancer,” J. Biomed. Opt. 13(3), 031220 (2008).
[Crossref] [PubMed]

V. K. Ramanujan, J.-H. Zhang, E. Biener, and B. Herman, “Multiphoton fluorescence lifetime contrast in deep tissue imaging: prospects in redox imaging and disease diagnosis,” J. Biomed. Opt. 10(5), 051407 (2005).
[Crossref] [PubMed]

D. D. U. Li, J. Arlt, D. Tyndall, R. Walker, J. Richardson, D. Stoppa, E. Charbon, and R. K. Henderson, “Video-rate fluorescence lifetime imaging camera with CMOS single-photon avalanche diode arrays and high-speed imaging algorithm,” J. Biomed. Opt. 16(9), 096012 (2011).
[Crossref] [PubMed]

M. C. Skala, K. M. Riching, D. K. Bird, A. Gendron-Fitzpatrick, J. Eickhoff, K. W. Eliceiri, P. J. Keely, and N. Ramanujam, “In vivo multiphoton fluorescence lifetime imaging of protein-bound and free nicotinamide adenine dinucleotide in normal and precancerous epithelia,” J. Biomed. Opt. 12(2), 024014 (2007).
[Crossref] [PubMed]

J. Natl. Cancer Inst. (1)

J. A. van Dongen, A. C. Voogd, I. S. Fentiman, C. Legrand, R. J. Sylvester, D. Tong, E. van der Schueren, P. A. Helle, K. van Zijl, and H. Bartelink, “Long-term results of a randomized trial comparing breast-conserving therapy with mastectomy: European Organization for Research and Treatment of Cancer 10801 trial,” J. Natl. Cancer Inst. 92(14), 1143–1150 (2000).
[Crossref] [PubMed]

J. Pathol. (1)

P. J. Tadrous, J. Siegel, P. M. W. French, S. Shousha, N. Lalani, and G. W. H. Stamp, “Fluorescence lifetime imaging of unstained tissues: early results in human breast cancer,” J. Pathol. 199(3), 309–317 (2003).
[Crossref] [PubMed]

Nat. Commun. (1)

K. Okabe, N. Inada, C. Gota, Y. Harada, T. Funatsu, and S. Uchiyama, “Intracellular temperature mapping with a fluorescent polymeric thermometer and fluorescence lifetime imaging microscopy,” Nat. Commun. 3, 705 (2012).
[Crossref] [PubMed]

Nat. Methods (1)

F. Helmchen and W. Denk, “Deep tissue two-photon microscopy,” Nat. Methods 2(12), 932–940 (2005).
[Crossref] [PubMed]

Neuroinformatics (1)

D. L. Price, S. K. Chow, N. A. B. Maclean, H. Hakozaki, S. Peltier, M. E. Martone, and M. H. Ellisman, “High-resolution large-scale mosaic imaging using multiphoton microscopy to characterize transgenic mouse models of human neurological disorders,” Neuroinformatics 4, 65–80 (2006).

Opt. Lett. (2)

Physiol. Meas. (1)

M. Hammer, D. Schweitzer, S. Richter, and E. Königsdörffer, “Sodium fluorescein as a retinal pH indicator?” Physiol. Meas. 26(4), N9–N12 (2005).
[Crossref] [PubMed]

PLoS One (1)

R. Patalay, C. Talbot, Y. Alexandrov, M. O. Lenz, S. Kumar, S. Warren, I. Munro, M. A. Neil, K. König, P. M. W. French, A. Chu, G. W. H. Stamp, and C. Dunsby, “Multiphoton multispectral fluorescence lifetime tomography for the evaluation of basal cell carcinomas,” PLoS One 7(9), e43460 (2012).
[Crossref] [PubMed]

Proc. Natl. Acad. Sci. U.S.A. (2)

W. R. Zipfel, R. M. Williams, R. Christie, A. Y. Nikitin, B. T. Hyman, and W. W. Webb, “Live tissue intrinsic emission microscopy using multiphoton-excited native fluorescence and second harmonic generation,” Proc. Natl. Acad. Sci. U.S.A. 100(12), 7075–7080 (2003).
[Crossref] [PubMed]

Y. K. Tao, D. Shen, Y. Sheikine, O. O. Ahsen, H. H. Wang, D. B. Schmolze, N. B. Johnson, J. S. Brooker, A. E. Cable, J. L. Connolly, and J. G. Fujimoto, “Assessment of breast pathologies using nonlinear microscopy,” Proc. Natl. Acad. Sci. U.S.A. 111(43), 15304–15309 (2014).
[Crossref] [PubMed]

Science (1)

W. Denk, J. H. Strickler, and W. W. Webb, “Two-photon laser scanning fluorescence microscopy,” Science 248(4951), 73–76 (1990).
[Crossref] [PubMed]

Other (2)

“Cancer Facts and Figures,” (American Cancer Society, 2014).

J. D. Bancroft and A. Stevens, Theory and Practice of Histological Techniques, 6th ed. (Churchill Livingstone, Edinburgh; New York, 2008), pp. xiv, 726.

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Figures (4)

Fig. 1
Fig. 1 DTS-FLIM system diagram. Femtosecond pulses are divided into sample (upper left) and reference arms (lower right). In the reference arm, a photodiode generates an electrical pulse train which is frequency multiplied 22-fold to 1.76 GHz and used as the sampling clock. In the sample arm, a resonant scanner and galvanometer image the tissue surface using a high NA objective. Fluorescent emission from the sample is split from the excitation via a 650 nm longpass dichroic filter and detected using a PMT with a further 650 nm short pass filter. Finally, direct time sampling (DTS) with 22 temporal bins per pixel is performed via the A/D.
Fig. 2
Fig. 2 Validation of the absolute accuracy of the direct temporal sampling TPM-FLIM system. a) System instrument response function. b) The deconvolved lifetime curve for sodium flouroscein in PBS together with the best single exponential fit.
Fig. 3
Fig. 3 a) 200 megapixel TPM-FLIM mosaic of an 4.0 x 6.8 mm field of view generated from 1 billion individual lifetime measurements in approximately 3 minutes. Differences in intrinsic lifetime clearly delineate adipocytes (green) from surrounding normal stroma (blue). Scale bar: 1 mm. b) Enlarged view of a branching blood vessel with epithelial cell lining. Scale bar: 100 um. c) Enlarged view of adipocytes and adjacent blood vessel (lower left). Scale bar: 100 um.
Fig. 4
Fig. 4 a) TPM-FLIM mosaic of the region surrounding a breast duct. Scale bar: 1 mm. b) Enlarged view of the cellular region of a breast duct showing enhanced long lifetime component relative to surrounding stroma. Prominent nuclear shadows can be observed in the ductal region (arrows). Scale bar: 100 microns.

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