Abstract

Fluorescence guided neurosurgery based on 5-aminolevulinic acid (5-ALA) has significantly increased maximal safe resections. Fluorescence lifetime imaging (FLIM) of 5-ALA could further boost this development by its increased sensitivity. However, neurosurgeons require real-time visual feedback which was so far limited in dual-tap CMOS camera based FLIM. By optimizing the number of phase frames required for reconstruction, we here demonstrate real-time 5-ALA FLIM of human high- and low-grade glioma with up to 12 Hz imaging rate over a wide field of view (11.0 x 11.0 mm). Compared to conventional fluorescence imaging, real-time FLIM offers enhanced contrast of weakly fluorescent tissue.

© 2020 Optical Society of America under the terms of the OSA Open Access Publishing Agreement

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2019 (4)

G. Widhalm, J. Olson, J. Weller, J. Bravo, S. J. Han, J. Phillips, S. L. Hervey-Jumper, S. M. Chang, D. W. Roberts, and M. S. Berger, “The value of visible 5-ala fluorescence and quantitative protoporphyrin ix analysis for improved surgery of suspected low-grade gliomas,” J. Neurosurg. 1, 1–10 (2019).
[Crossref]

M. T. Erkkilä, B. Bauer, N. Hecker-Denschlag, M. J. Madera Medina, R. A. Leitgeb, A. Unterhuber, J. Gesperger, T. Roetzer, C. Hauger, W. Drexler, G. Widhalm, and M. Andreana, “Widefield fluorescence lifetime imaging of protoporphyrin ix for fluorescence-guided neurosurgery: An ex vivo feasibility study,” J. Biophotonics 12(6), e201800378 (2019).
[Crossref]

B. K. Hendricks, N. Sanai, and W. Stummer, “Fluorescence-guided surgery with aminolevulinic acid for low-grade gliomas,” J. Neuro-Oncol. 141(1), 13–18 (2019).
[Crossref]

F. Rosique, P. J. Navarro, C. Fernández, and A. Padilla, “A systematic review of perception system and simulators for autonomous vehicles research,” Sensors 19(3), 648 (2019).
[Crossref]

2018 (3)

M.-W. Seo, Y. Shirakawa, Y. Kawata, K. Kagawa, K. Yasutomi, and S. Kawahito, “A time-resolved four-tap lock-in pixel cmos image sensor for real-time fluorescence lifetime imaging microscopy,” IEEE J. Solid-State Circuits 53(8), 2319–2330 (2018).
[Crossref]

V. I. Shcheslavskiy, M. V. Shirmanova, V. V. Dudenkova, K. A. Lukyanov, A. I. Gavrina, A. V. Shumilova, E. Zagaynova, and W. Becker, “Fluorescence time-resolved macroimaging,” Opt. Lett. 43(13), 3152–3155 (2018).
[Crossref]

L. Alston, D. Rousseau, M. Hebert, L. Mahieu-Williame, and B. Montcel, “Nonlinear relation between concentration and fluorescence emission of protoporphyrin ix in calibrated phantoms,” J. Biomed. Opt. 23(09), 1 (2018).
[Crossref]

2017 (2)

J. Bravo, J. Olson, S. Davis, D. Roberts, K. Paulsen, and S. Kanick, “Hyperspectral data processing improves ppix contrast during fluorescence guided surgery of human brain tumors,” Sci. Rep. 7(1), 9455 (2017).
[Crossref]

B. E. Sherlock, J. E. Phipps, J. Bec, and L. Marcu, “Simultaneous, label-free, multispectral fluorescence lifetime imaging and optical coherence tomography using a double-clad fiber,” Opt. Lett. 42(19), 3753–3756 (2017).
[Crossref]

2016 (3)

S. R. Kantelhardt, D. Kalasauskas, K. König, E. Kim, M. Weinigel, A. Uchugonova, and A. Giese, “In vivo multiphoton tomography and fluorescence lifetime imaging of human brain tumor tissue,” J. Neuro-Oncol. 127(3), 473–482 (2016).
[Crossref]

N. A. Markwardt, N. Haj-Hosseini, B. Hollnburger, H. Stepp, P. Zelenkov, and A. Rühm, “405 nm versus 633 nm for protoporphyrin ix excitation in fluorescence-guided stereotactic biopsy of brain tumors,” J. Biophotonics 9(9), 901–912 (2016).
[Crossref]

M. Marois, J. J. Bravo, S. C. Davis, and S. C. Kanick, “Characterization and standardization of tissue-simulating protoporphyrin ix optical phantoms,” J. Biomed. Opt. 21(3), 035003 (2016).
[Crossref]

2015 (4)

P. A. Valdés, V. Jacobs, B. T. Harris, B. C. Wilson, F. Leblond, K. D. Paulsen, and D. W. Roberts, “Quantitative fluorescence using 5-aminolevulinic acid-induced protoporphyrin ix biomarker as a surgical adjunct in low-grade glioma surgery,” J. Neurosurg. 123(3), 771–780 (2015).
[Crossref]

C. G. Hadjipanayis, G. Widhalm, and W. Stummer, “What is the surgical benefit of utilizing 5-aminolevulinic acid for fluorescence-guided surgery of malignant gliomas?” Neurosurgery 77(5), 663–673 (2015).
[Crossref]

H. Chen, G. Holst, and E. Gratton, “Modulated cmos camera for fluorescence lifetime microscopy,” Microsc. Res. Tech. 78(12), 1075–1081 (2015).
[Crossref]

M. Jermyn, K. Mok, J. Mercier, J. Desroches, J. Pichette, K. Saint-Arnaud, L. Bernstein, M.-C. Guiot, K. Petrecca, and F. Leblond, “Intraoperative brain cancer detection with raman spectroscopy in humans,” Sci. Transl. Med. 7(274), 274ra19 (2015).
[Crossref]

2013 (2)

2012 (3)

P. A. Valdés, F. Leblond, V. L. Jacobs, B. C. Wilson, K. D. Paulsen, and D. W. Roberts, “Quantitative, spectrally-resolved intraoperative fluorescence imaging,” Sci. Rep. 2(1), 798 (2012).
[Crossref]

L. Marcu and B. A. Hartl, “Fluorescence lifetime spectroscopy and imaging in neurosurgery,” IEEE J. Sel. Top. Quantum Electron. 18(4), 1465–1477 (2012).
[Crossref]

W. Becker, “Fluorescence lifetime imaging–techniques and applications,” J. Microsc. 247(2), 119–136 (2012).
[Crossref]

2011 (1)

N. Sanai, L. A. Snyder, N. J. Honea, S. W. Coons, J. M. Eschbacher, K. A. Smith, and R. F. Spetzler, “Intraoperative confocal microscopy in the visualization of 5-aminolevulinic acid fluorescence in low-grade gliomas,” J. Neurosurg. 115(4), 740–748 (2011).
[Crossref]

2010 (5)

A. Johansson, G. Palte, O. Schnell, J.-C. Tonn, J. Herms, and H. Stepp, “5-aminolevulinic acid-induced protoporphyrin ix levels in tissue of human malignant brain tumors,” Photochem. Photobiol. 86(6), 1373–1378 (2010).
[Crossref]

Y. H. Sun, N. Hatami, M. Yee, J. E. Phipps, D. S. Elson, F. Gorin, R. J. Schrot, and L. Marcu, “Fluorescence lifetime imaging microscopy for brain tumor image-guided surgery,” J. Biomed. Opt. 15(5), 056022 (2010).
[Crossref]

G. Widhalm, S. Wolfsberger, G. Minchev, A. Woehrer, M. Krssak, T. Czech, D. Prayer, S. Asenbaum, J. A. Hainfellner, and E. Knosp, “5-aminolevulinic acid is a promising marker for detection of anaplastic foci in diffusely infiltrating gliomas with nonsignificant contrast enhancement,” Cancer 116(6), 1545–1552 (2010).
[Crossref]

A. Kim, M. Khurana, Y. Moriyama, and B. C. Wilson, “Quantification of in vivo fluorescence decoupled from the effects of tissue optical properties using fiber-optic spectroscopy measurements,” J. Biomed. Opt. 15(6), 067006 (2010).
[Crossref]

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. French, and G. W. Stamp, “Wide-field fluorescence lifetime imaging of cancer,” Biomed. Opt. Express 1(2), 627–640 (2010).
[Crossref]

2008 (2)

S. R. Kantelhardt, H. Diddens, J. Leppert, V. Rohde, G. Hüttmann, and A. Giese, “Multiphoton excitation fluorescence microscopy of 5-aminolevulinic acid induced fluorescence in experimental gliomas,” Lasers Surg. Med. 40(4), 273–281 (2008).
[Crossref]

J. A. Russell, K. R. Diamond, T. J. Collins, H. F. Tiedje, J. E. Hayward, T. J. Farrell, M. S. Patterson, and Q. Fang, “Characterization of fluorescence lifetime of photofrin and delta-aminolevulinic acid induced protoporphyrin ix in living cells using single-and two-photon excitation,” IEEE J. Sel. Top. Quantum Electron. 14(1), 158–166 (2008).
[Crossref]

2007 (1)

J. Y. Chen and J. E. Thropp, “Review of low frame rate effects on human performance,” IEEE Trans. Syst., Man, Cybern. A 37(6), 1063–1076 (2007).
[Crossref]

2006 (1)

W. Stummer, U. Pichlmeier, T. Meinel, O. D. Wiestler, F. Zanella, and H.-J. ReulenA.-G. S. Group, “Fluorescence-guided surgery with 5-aminolevulinic acid for resection of malignant glioma: a randomised controlled multicentre phase iii trial,” Lancet Oncol. 7(5), 392–401 (2006).
[Crossref]

1998 (1)

S. Walter, S. Susanne, W. Simon, S. Herbert, F. Clemens, G. Claudia, E. G. Alwin, K. Rainer, and J. R. Hans, “Intraoperative detection of malignant gliomas by 5-aminolevulinic acid-induced porphyrin fluorescence,” Neurosurgery 42(3), 518–526 (1998).
[Crossref]

1989 (1)

R. M. Ballew and J. Demas, “An error analysis of the rapid lifetime determination method for the evaluation of single exponential decays,” Anal. Chem. 61(1), 30–33 (1989).
[Crossref]

Ahmad, R.

Alston, L.

L. Alston, D. Rousseau, M. Hebert, L. Mahieu-Williame, and B. Montcel, “Nonlinear relation between concentration and fluorescence emission of protoporphyrin ix in calibrated phantoms,” J. Biomed. Opt. 23(09), 1 (2018).
[Crossref]

Alwin, E. G.

S. Walter, S. Susanne, W. Simon, S. Herbert, F. Clemens, G. Claudia, E. G. Alwin, K. Rainer, and J. R. Hans, “Intraoperative detection of malignant gliomas by 5-aminolevulinic acid-induced porphyrin fluorescence,” Neurosurgery 42(3), 518–526 (1998).
[Crossref]

Andreana, M.

M. T. Erkkilä, B. Bauer, N. Hecker-Denschlag, M. J. Madera Medina, R. A. Leitgeb, A. Unterhuber, J. Gesperger, T. Roetzer, C. Hauger, W. Drexler, G. Widhalm, and M. Andreana, “Widefield fluorescence lifetime imaging of protoporphyrin ix for fluorescence-guided neurosurgery: An ex vivo feasibility study,” J. Biophotonics 12(6), e201800378 (2019).
[Crossref]

Armoiry, X.

Asenbaum, S.

G. Widhalm, S. Wolfsberger, G. Minchev, A. Woehrer, M. Krssak, T. Czech, D. Prayer, S. Asenbaum, J. A. Hainfellner, and E. Knosp, “5-aminolevulinic acid is a promising marker for detection of anaplastic foci in diffusely infiltrating gliomas with nonsignificant contrast enhancement,” Cancer 116(6), 1545–1552 (2010).
[Crossref]

Ballew, R. M.

R. M. Ballew and J. Demas, “An error analysis of the rapid lifetime determination method for the evaluation of single exponential decays,” Anal. Chem. 61(1), 30–33 (1989).
[Crossref]

Bauer, B.

M. T. Erkkilä, B. Bauer, N. Hecker-Denschlag, M. J. Madera Medina, R. A. Leitgeb, A. Unterhuber, J. Gesperger, T. Roetzer, C. Hauger, W. Drexler, G. Widhalm, and M. Andreana, “Widefield fluorescence lifetime imaging of protoporphyrin ix for fluorescence-guided neurosurgery: An ex vivo feasibility study,” J. Biophotonics 12(6), e201800378 (2019).
[Crossref]

Bec, J.

Becker, W.

V. I. Shcheslavskiy, M. V. Shirmanova, V. V. Dudenkova, K. A. Lukyanov, A. I. Gavrina, A. V. Shumilova, E. Zagaynova, and W. Becker, “Fluorescence time-resolved macroimaging,” Opt. Lett. 43(13), 3152–3155 (2018).
[Crossref]

W. Becker, “Fluorescence lifetime imaging–techniques and applications,” J. Microsc. 247(2), 119–136 (2012).
[Crossref]

M. V. Shirmanova, M. Lukina, E. B. Kisileva, V. V. Fedoseeva, V. V. Dudenkova, E. V. Zagaynova, W. Becker, and V. I. Shcheslavskiy, “Interrogation of glioma metabolism on macroscale by flim,” in Multiphoton Microscopy in the Biomedical Sciences XIX, vol. 10882 (International Society for Optics and Photonics, 2019), p. 1088209.

Berger, M. S.

G. Widhalm, J. Olson, J. Weller, J. Bravo, S. J. Han, J. Phillips, S. L. Hervey-Jumper, S. M. Chang, D. W. Roberts, and M. S. Berger, “The value of visible 5-ala fluorescence and quantitative protoporphyrin ix analysis for improved surgery of suspected low-grade gliomas,” J. Neurosurg. 1, 1–10 (2019).
[Crossref]

Bernstein, L.

M. Jermyn, K. Mok, J. Mercier, J. Desroches, J. Pichette, K. Saint-Arnaud, L. Bernstein, M.-C. Guiot, K. Petrecca, and F. Leblond, “Intraoperative brain cancer detection with raman spectroscopy in humans,” Sci. Transl. Med. 7(274), 274ra19 (2015).
[Crossref]

Bravo, J.

G. Widhalm, J. Olson, J. Weller, J. Bravo, S. J. Han, J. Phillips, S. L. Hervey-Jumper, S. M. Chang, D. W. Roberts, and M. S. Berger, “The value of visible 5-ala fluorescence and quantitative protoporphyrin ix analysis for improved surgery of suspected low-grade gliomas,” J. Neurosurg. 1, 1–10 (2019).
[Crossref]

J. Bravo, J. Olson, S. Davis, D. Roberts, K. Paulsen, and S. Kanick, “Hyperspectral data processing improves ppix contrast during fluorescence guided surgery of human brain tumors,” Sci. Rep. 7(1), 9455 (2017).
[Crossref]

Bravo, J. J.

M. Marois, J. J. Bravo, S. C. Davis, and S. C. Kanick, “Characterization and standardization of tissue-simulating protoporphyrin ix optical phantoms,” J. Biomed. Opt. 21(3), 035003 (2016).
[Crossref]

Chang, S. M.

G. Widhalm, J. Olson, J. Weller, J. Bravo, S. J. Han, J. Phillips, S. L. Hervey-Jumper, S. M. Chang, D. W. Roberts, and M. S. Berger, “The value of visible 5-ala fluorescence and quantitative protoporphyrin ix analysis for improved surgery of suspected low-grade gliomas,” J. Neurosurg. 1, 1–10 (2019).
[Crossref]

Chen, H.

H. Chen, G. Holst, and E. Gratton, “Modulated cmos camera for fluorescence lifetime microscopy,” Microsc. Res. Tech. 78(12), 1075–1081 (2015).
[Crossref]

Chen, J. Y.

J. Y. Chen and J. E. Thropp, “Review of low frame rate effects on human performance,” IEEE Trans. Syst., Man, Cybern. A 37(6), 1063–1076 (2007).
[Crossref]

Claudia, G.

S. Walter, S. Susanne, W. Simon, S. Herbert, F. Clemens, G. Claudia, E. G. Alwin, K. Rainer, and J. R. Hans, “Intraoperative detection of malignant gliomas by 5-aminolevulinic acid-induced porphyrin fluorescence,” Neurosurgery 42(3), 518–526 (1998).
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G. Widhalm, J. Olson, J. Weller, J. Bravo, S. J. Han, J. Phillips, S. L. Hervey-Jumper, S. M. Chang, D. W. Roberts, and M. S. Berger, “The value of visible 5-ala fluorescence and quantitative protoporphyrin ix analysis for improved surgery of suspected low-grade gliomas,” J. Neurosurg. 1, 1–10 (2019).
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R. Franke and G. A. Holst, “Frequency-domain fluorescence lifetime imaging system (pco. flim) based on a in-pixel dual tap control cmos image sensor,” in Imaging, Manipulation, and Analysis of Biomolecules, Cells, and Tissues XIII, vol. 9328 (International Society for Optics and Photonics, 2015), p. 93281K.

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N. Sanai, L. A. Snyder, N. J. Honea, S. W. Coons, J. M. Eschbacher, K. A. Smith, and R. F. Spetzler, “Intraoperative confocal microscopy in the visualization of 5-aminolevulinic acid fluorescence in low-grade gliomas,” J. Neurosurg. 115(4), 740–748 (2011).
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J. Bravo, J. Olson, S. Davis, D. Roberts, K. Paulsen, and S. Kanick, “Hyperspectral data processing improves ppix contrast during fluorescence guided surgery of human brain tumors,” Sci. Rep. 7(1), 9455 (2017).
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M. Marois, J. J. Bravo, S. C. Davis, and S. C. Kanick, “Characterization and standardization of tissue-simulating protoporphyrin ix optical phantoms,” J. Biomed. Opt. 21(3), 035003 (2016).
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G. Widhalm, S. Wolfsberger, G. Minchev, A. Woehrer, M. Krssak, T. Czech, D. Prayer, S. Asenbaum, J. A. Hainfellner, and E. Knosp, “5-aminolevulinic acid is a promising marker for detection of anaplastic foci in diffusely infiltrating gliomas with nonsignificant contrast enhancement,” Cancer 116(6), 1545–1552 (2010).
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M. T. Erkkilä, B. Bauer, N. Hecker-Denschlag, M. J. Madera Medina, R. A. Leitgeb, A. Unterhuber, J. Gesperger, T. Roetzer, C. Hauger, W. Drexler, G. Widhalm, and M. Andreana, “Widefield fluorescence lifetime imaging of protoporphyrin ix for fluorescence-guided neurosurgery: An ex vivo feasibility study,” J. Biophotonics 12(6), e201800378 (2019).
[Crossref]

Leppert, J.

S. R. Kantelhardt, H. Diddens, J. Leppert, V. Rohde, G. Hüttmann, and A. Giese, “Multiphoton excitation fluorescence microscopy of 5-aminolevulinic acid induced fluorescence in experimental gliomas,” Lasers Surg. Med. 40(4), 273–281 (2008).
[Crossref]

Lukina, M.

M. V. Shirmanova, M. Lukina, E. B. Kisileva, V. V. Fedoseeva, V. V. Dudenkova, E. V. Zagaynova, W. Becker, and V. I. Shcheslavskiy, “Interrogation of glioma metabolism on macroscale by flim,” in Multiphoton Microscopy in the Biomedical Sciences XIX, vol. 10882 (International Society for Optics and Photonics, 2019), p. 1088209.

Lukyanov, K. A.

Madera Medina, M. J.

M. T. Erkkilä, B. Bauer, N. Hecker-Denschlag, M. J. Madera Medina, R. A. Leitgeb, A. Unterhuber, J. Gesperger, T. Roetzer, C. Hauger, W. Drexler, G. Widhalm, and M. Andreana, “Widefield fluorescence lifetime imaging of protoporphyrin ix for fluorescence-guided neurosurgery: An ex vivo feasibility study,” J. Biophotonics 12(6), e201800378 (2019).
[Crossref]

Mahieu-Williame, L.

L. Alston, D. Rousseau, M. Hebert, L. Mahieu-Williame, and B. Montcel, “Nonlinear relation between concentration and fluorescence emission of protoporphyrin ix in calibrated phantoms,” J. Biomed. Opt. 23(09), 1 (2018).
[Crossref]

B. Montcel, L. Mahieu-Williame, X. Armoiry, D. Meyronet, and J. Guyotat, “Two-peaked 5-ala-induced ppix fluorescence emission spectrum distinguishes glioblastomas from low grade gliomas and infiltrative component of glioblastomas,” Biomed. Opt. Express 4(4), 548–558 (2013).
[Crossref]

Marcu, L.

B. E. Sherlock, J. E. Phipps, J. Bec, and L. Marcu, “Simultaneous, label-free, multispectral fluorescence lifetime imaging and optical coherence tomography using a double-clad fiber,” Opt. Lett. 42(19), 3753–3756 (2017).
[Crossref]

L. Marcu and B. A. Hartl, “Fluorescence lifetime spectroscopy and imaging in neurosurgery,” IEEE J. Sel. Top. Quantum Electron. 18(4), 1465–1477 (2012).
[Crossref]

Y. H. Sun, N. Hatami, M. Yee, J. E. Phipps, D. S. Elson, F. Gorin, R. J. Schrot, and L. Marcu, “Fluorescence lifetime imaging microscopy for brain tumor image-guided surgery,” J. Biomed. Opt. 15(5), 056022 (2010).
[Crossref]

Markwardt, N. A.

N. A. Markwardt, N. Haj-Hosseini, B. Hollnburger, H. Stepp, P. Zelenkov, and A. Rühm, “405 nm versus 633 nm for protoporphyrin ix excitation in fluorescence-guided stereotactic biopsy of brain tumors,” J. Biophotonics 9(9), 901–912 (2016).
[Crossref]

Marois, M.

M. Marois, J. J. Bravo, S. C. Davis, and S. C. Kanick, “Characterization and standardization of tissue-simulating protoporphyrin ix optical phantoms,” J. Biomed. Opt. 21(3), 035003 (2016).
[Crossref]

McGinty, J.

Meinel, T.

W. Stummer, U. Pichlmeier, T. Meinel, O. D. Wiestler, F. Zanella, and H.-J. ReulenA.-G. S. Group, “Fluorescence-guided surgery with 5-aminolevulinic acid for resection of malignant glioma: a randomised controlled multicentre phase iii trial,” Lancet Oncol. 7(5), 392–401 (2006).
[Crossref]

Mercier, J.

M. Jermyn, K. Mok, J. Mercier, J. Desroches, J. Pichette, K. Saint-Arnaud, L. Bernstein, M.-C. Guiot, K. Petrecca, and F. Leblond, “Intraoperative brain cancer detection with raman spectroscopy in humans,” Sci. Transl. Med. 7(274), 274ra19 (2015).
[Crossref]

Meyronet, D.

Minchev, G.

G. Widhalm, S. Wolfsberger, G. Minchev, A. Woehrer, M. Krssak, T. Czech, D. Prayer, S. Asenbaum, J. A. Hainfellner, and E. Knosp, “5-aminolevulinic acid is a promising marker for detection of anaplastic foci in diffusely infiltrating gliomas with nonsignificant contrast enhancement,” Cancer 116(6), 1545–1552 (2010).
[Crossref]

Mok, K.

M. Jermyn, K. Mok, J. Mercier, J. Desroches, J. Pichette, K. Saint-Arnaud, L. Bernstein, M.-C. Guiot, K. Petrecca, and F. Leblond, “Intraoperative brain cancer detection with raman spectroscopy in humans,” Sci. Transl. Med. 7(274), 274ra19 (2015).
[Crossref]

Montcel, B.

L. Alston, D. Rousseau, M. Hebert, L. Mahieu-Williame, and B. Montcel, “Nonlinear relation between concentration and fluorescence emission of protoporphyrin ix in calibrated phantoms,” J. Biomed. Opt. 23(09), 1 (2018).
[Crossref]

B. Montcel, L. Mahieu-Williame, X. Armoiry, D. Meyronet, and J. Guyotat, “Two-peaked 5-ala-induced ppix fluorescence emission spectrum distinguishes glioblastomas from low grade gliomas and infiltrative component of glioblastomas,” Biomed. Opt. Express 4(4), 548–558 (2013).
[Crossref]

Moriyama, Y.

A. Kim, M. Khurana, Y. Moriyama, and B. C. Wilson, “Quantification of in vivo fluorescence decoupled from the effects of tissue optical properties using fiber-optic spectroscopy measurements,” J. Biomed. Opt. 15(6), 067006 (2010).
[Crossref]

Munro, I.

Navarro, P. J.

F. Rosique, P. J. Navarro, C. Fernández, and A. Padilla, “A systematic review of perception system and simulators for autonomous vehicles research,” Sensors 19(3), 648 (2019).
[Crossref]

Neil, M. A.

Olson, J.

G. Widhalm, J. Olson, J. Weller, J. Bravo, S. J. Han, J. Phillips, S. L. Hervey-Jumper, S. M. Chang, D. W. Roberts, and M. S. Berger, “The value of visible 5-ala fluorescence and quantitative protoporphyrin ix analysis for improved surgery of suspected low-grade gliomas,” J. Neurosurg. 1, 1–10 (2019).
[Crossref]

J. Bravo, J. Olson, S. Davis, D. Roberts, K. Paulsen, and S. Kanick, “Hyperspectral data processing improves ppix contrast during fluorescence guided surgery of human brain tumors,” Sci. Rep. 7(1), 9455 (2017).
[Crossref]

Padilla, A.

F. Rosique, P. J. Navarro, C. Fernández, and A. Padilla, “A systematic review of perception system and simulators for autonomous vehicles research,” Sensors 19(3), 648 (2019).
[Crossref]

Palte, G.

A. Johansson, G. Palte, O. Schnell, J.-C. Tonn, J. Herms, and H. Stepp, “5-aminolevulinic acid-induced protoporphyrin ix levels in tissue of human malignant brain tumors,” Photochem. Photobiol. 86(6), 1373–1378 (2010).
[Crossref]

Patterson, M. S.

J. A. Russell, K. R. Diamond, T. J. Collins, H. F. Tiedje, J. E. Hayward, T. J. Farrell, M. S. Patterson, and Q. Fang, “Characterization of fluorescence lifetime of photofrin and delta-aminolevulinic acid induced protoporphyrin ix in living cells using single-and two-photon excitation,” IEEE J. Sel. Top. Quantum Electron. 14(1), 158–166 (2008).
[Crossref]

Paulsen, K.

J. Bravo, J. Olson, S. Davis, D. Roberts, K. Paulsen, and S. Kanick, “Hyperspectral data processing improves ppix contrast during fluorescence guided surgery of human brain tumors,” Sci. Rep. 7(1), 9455 (2017).
[Crossref]

Paulsen, K. D.

P. A. Valdés, V. Jacobs, B. T. Harris, B. C. Wilson, F. Leblond, K. D. Paulsen, and D. W. Roberts, “Quantitative fluorescence using 5-aminolevulinic acid-induced protoporphyrin ix biomarker as a surgical adjunct in low-grade glioma surgery,” J. Neurosurg. 123(3), 771–780 (2015).
[Crossref]

P. A. Valdes, V. L. Jacobs, B. C. Wilson, F. Leblond, D. W. Roberts, and K. D. Paulsen, “System and methods for wide-field quantitative fluorescence imaging during neurosurgery,” Opt. Lett. 38(15), 2786–2788 (2013).
[Crossref]

P. A. Valdés, F. Leblond, V. L. Jacobs, B. C. Wilson, K. D. Paulsen, and D. W. Roberts, “Quantitative, spectrally-resolved intraoperative fluorescence imaging,” Sci. Rep. 2(1), 798 (2012).
[Crossref]

Petrecca, K.

M. Jermyn, K. Mok, J. Mercier, J. Desroches, J. Pichette, K. Saint-Arnaud, L. Bernstein, M.-C. Guiot, K. Petrecca, and F. Leblond, “Intraoperative brain cancer detection with raman spectroscopy in humans,” Sci. Transl. Med. 7(274), 274ra19 (2015).
[Crossref]

Phillips, J.

G. Widhalm, J. Olson, J. Weller, J. Bravo, S. J. Han, J. Phillips, S. L. Hervey-Jumper, S. M. Chang, D. W. Roberts, and M. S. Berger, “The value of visible 5-ala fluorescence and quantitative protoporphyrin ix analysis for improved surgery of suspected low-grade gliomas,” J. Neurosurg. 1, 1–10 (2019).
[Crossref]

Phipps, J. E.

B. E. Sherlock, J. E. Phipps, J. Bec, and L. Marcu, “Simultaneous, label-free, multispectral fluorescence lifetime imaging and optical coherence tomography using a double-clad fiber,” Opt. Lett. 42(19), 3753–3756 (2017).
[Crossref]

Y. H. Sun, N. Hatami, M. Yee, J. E. Phipps, D. S. Elson, F. Gorin, R. J. Schrot, and L. Marcu, “Fluorescence lifetime imaging microscopy for brain tumor image-guided surgery,” J. Biomed. Opt. 15(5), 056022 (2010).
[Crossref]

Pichette, J.

M. Jermyn, K. Mok, J. Mercier, J. Desroches, J. Pichette, K. Saint-Arnaud, L. Bernstein, M.-C. Guiot, K. Petrecca, and F. Leblond, “Intraoperative brain cancer detection with raman spectroscopy in humans,” Sci. Transl. Med. 7(274), 274ra19 (2015).
[Crossref]

Pichlmeier, U.

W. Stummer, U. Pichlmeier, T. Meinel, O. D. Wiestler, F. Zanella, and H.-J. ReulenA.-G. S. Group, “Fluorescence-guided surgery with 5-aminolevulinic acid for resection of malignant glioma: a randomised controlled multicentre phase iii trial,” Lancet Oncol. 7(5), 392–401 (2006).
[Crossref]

Prayer, D.

G. Widhalm, S. Wolfsberger, G. Minchev, A. Woehrer, M. Krssak, T. Czech, D. Prayer, S. Asenbaum, J. A. Hainfellner, and E. Knosp, “5-aminolevulinic acid is a promising marker for detection of anaplastic foci in diffusely infiltrating gliomas with nonsignificant contrast enhancement,” Cancer 116(6), 1545–1552 (2010).
[Crossref]

Rainer, K.

S. Walter, S. Susanne, W. Simon, S. Herbert, F. Clemens, G. Claudia, E. G. Alwin, K. Rainer, and J. R. Hans, “Intraoperative detection of malignant gliomas by 5-aminolevulinic acid-induced porphyrin fluorescence,” Neurosurgery 42(3), 518–526 (1998).
[Crossref]

Requejo-Isidro, J.

Reulen, H.-J.

W. Stummer, U. Pichlmeier, T. Meinel, O. D. Wiestler, F. Zanella, and H.-J. ReulenA.-G. S. Group, “Fluorescence-guided surgery with 5-aminolevulinic acid for resection of malignant glioma: a randomised controlled multicentre phase iii trial,” Lancet Oncol. 7(5), 392–401 (2006).
[Crossref]

Roberts, D.

J. Bravo, J. Olson, S. Davis, D. Roberts, K. Paulsen, and S. Kanick, “Hyperspectral data processing improves ppix contrast during fluorescence guided surgery of human brain tumors,” Sci. Rep. 7(1), 9455 (2017).
[Crossref]

Roberts, D. W.

G. Widhalm, J. Olson, J. Weller, J. Bravo, S. J. Han, J. Phillips, S. L. Hervey-Jumper, S. M. Chang, D. W. Roberts, and M. S. Berger, “The value of visible 5-ala fluorescence and quantitative protoporphyrin ix analysis for improved surgery of suspected low-grade gliomas,” J. Neurosurg. 1, 1–10 (2019).
[Crossref]

P. A. Valdés, V. Jacobs, B. T. Harris, B. C. Wilson, F. Leblond, K. D. Paulsen, and D. W. Roberts, “Quantitative fluorescence using 5-aminolevulinic acid-induced protoporphyrin ix biomarker as a surgical adjunct in low-grade glioma surgery,” J. Neurosurg. 123(3), 771–780 (2015).
[Crossref]

P. A. Valdes, V. L. Jacobs, B. C. Wilson, F. Leblond, D. W. Roberts, and K. D. Paulsen, “System and methods for wide-field quantitative fluorescence imaging during neurosurgery,” Opt. Lett. 38(15), 2786–2788 (2013).
[Crossref]

P. A. Valdés, F. Leblond, V. L. Jacobs, B. C. Wilson, K. D. Paulsen, and D. W. Roberts, “Quantitative, spectrally-resolved intraoperative fluorescence imaging,” Sci. Rep. 2(1), 798 (2012).
[Crossref]

Roetzer, T.

M. T. Erkkilä, B. Bauer, N. Hecker-Denschlag, M. J. Madera Medina, R. A. Leitgeb, A. Unterhuber, J. Gesperger, T. Roetzer, C. Hauger, W. Drexler, G. Widhalm, and M. Andreana, “Widefield fluorescence lifetime imaging of protoporphyrin ix for fluorescence-guided neurosurgery: An ex vivo feasibility study,” J. Biophotonics 12(6), e201800378 (2019).
[Crossref]

Rohde, V.

S. R. Kantelhardt, H. Diddens, J. Leppert, V. Rohde, G. Hüttmann, and A. Giese, “Multiphoton excitation fluorescence microscopy of 5-aminolevulinic acid induced fluorescence in experimental gliomas,” Lasers Surg. Med. 40(4), 273–281 (2008).
[Crossref]

Rosique, F.

F. Rosique, P. J. Navarro, C. Fernández, and A. Padilla, “A systematic review of perception system and simulators for autonomous vehicles research,” Sensors 19(3), 648 (2019).
[Crossref]

Rousseau, D.

L. Alston, D. Rousseau, M. Hebert, L. Mahieu-Williame, and B. Montcel, “Nonlinear relation between concentration and fluorescence emission of protoporphyrin ix in calibrated phantoms,” J. Biomed. Opt. 23(09), 1 (2018).
[Crossref]

Rühm, A.

N. A. Markwardt, N. Haj-Hosseini, B. Hollnburger, H. Stepp, P. Zelenkov, and A. Rühm, “405 nm versus 633 nm for protoporphyrin ix excitation in fluorescence-guided stereotactic biopsy of brain tumors,” J. Biophotonics 9(9), 901–912 (2016).
[Crossref]

Russell, J. A.

J. A. Russell, K. R. Diamond, T. J. Collins, H. F. Tiedje, J. E. Hayward, T. J. Farrell, M. S. Patterson, and Q. Fang, “Characterization of fluorescence lifetime of photofrin and delta-aminolevulinic acid induced protoporphyrin ix in living cells using single-and two-photon excitation,” IEEE J. Sel. Top. Quantum Electron. 14(1), 158–166 (2008).
[Crossref]

Saint-Arnaud, K.

M. Jermyn, K. Mok, J. Mercier, J. Desroches, J. Pichette, K. Saint-Arnaud, L. Bernstein, M.-C. Guiot, K. Petrecca, and F. Leblond, “Intraoperative brain cancer detection with raman spectroscopy in humans,” Sci. Transl. Med. 7(274), 274ra19 (2015).
[Crossref]

Sanai, N.

B. K. Hendricks, N. Sanai, and W. Stummer, “Fluorescence-guided surgery with aminolevulinic acid for low-grade gliomas,” J. Neuro-Oncol. 141(1), 13–18 (2019).
[Crossref]

N. Sanai, L. A. Snyder, N. J. Honea, S. W. Coons, J. M. Eschbacher, K. A. Smith, and R. F. Spetzler, “Intraoperative confocal microscopy in the visualization of 5-aminolevulinic acid fluorescence in low-grade gliomas,” J. Neurosurg. 115(4), 740–748 (2011).
[Crossref]

Schnell, O.

A. Johansson, G. Palte, O. Schnell, J.-C. Tonn, J. Herms, and H. Stepp, “5-aminolevulinic acid-induced protoporphyrin ix levels in tissue of human malignant brain tumors,” Photochem. Photobiol. 86(6), 1373–1378 (2010).
[Crossref]

Schrot, R. J.

Y. H. Sun, N. Hatami, M. Yee, J. E. Phipps, D. S. Elson, F. Gorin, R. J. Schrot, and L. Marcu, “Fluorescence lifetime imaging microscopy for brain tumor image-guided surgery,” J. Biomed. Opt. 15(5), 056022 (2010).
[Crossref]

Seo, M.-W.

M.-W. Seo, Y. Shirakawa, Y. Kawata, K. Kagawa, K. Yasutomi, and S. Kawahito, “A time-resolved four-tap lock-in pixel cmos image sensor for real-time fluorescence lifetime imaging microscopy,” IEEE J. Solid-State Circuits 53(8), 2319–2330 (2018).
[Crossref]

Shcheslavskiy, V. I.

V. I. Shcheslavskiy, M. V. Shirmanova, V. V. Dudenkova, K. A. Lukyanov, A. I. Gavrina, A. V. Shumilova, E. Zagaynova, and W. Becker, “Fluorescence time-resolved macroimaging,” Opt. Lett. 43(13), 3152–3155 (2018).
[Crossref]

M. V. Shirmanova, M. Lukina, E. B. Kisileva, V. V. Fedoseeva, V. V. Dudenkova, E. V. Zagaynova, W. Becker, and V. I. Shcheslavskiy, “Interrogation of glioma metabolism on macroscale by flim,” in Multiphoton Microscopy in the Biomedical Sciences XIX, vol. 10882 (International Society for Optics and Photonics, 2019), p. 1088209.

Sherlock, B. E.

Shirakawa, Y.

M.-W. Seo, Y. Shirakawa, Y. Kawata, K. Kagawa, K. Yasutomi, and S. Kawahito, “A time-resolved four-tap lock-in pixel cmos image sensor for real-time fluorescence lifetime imaging microscopy,” IEEE J. Solid-State Circuits 53(8), 2319–2330 (2018).
[Crossref]

Shirmanova, M. V.

V. I. Shcheslavskiy, M. V. Shirmanova, V. V. Dudenkova, K. A. Lukyanov, A. I. Gavrina, A. V. Shumilova, E. Zagaynova, and W. Becker, “Fluorescence time-resolved macroimaging,” Opt. Lett. 43(13), 3152–3155 (2018).
[Crossref]

M. V. Shirmanova, M. Lukina, E. B. Kisileva, V. V. Fedoseeva, V. V. Dudenkova, E. V. Zagaynova, W. Becker, and V. I. Shcheslavskiy, “Interrogation of glioma metabolism on macroscale by flim,” in Multiphoton Microscopy in the Biomedical Sciences XIX, vol. 10882 (International Society for Optics and Photonics, 2019), p. 1088209.

Shumilova, A. V.

Simon, W.

S. Walter, S. Susanne, W. Simon, S. Herbert, F. Clemens, G. Claudia, E. G. Alwin, K. Rainer, and J. R. Hans, “Intraoperative detection of malignant gliomas by 5-aminolevulinic acid-induced porphyrin fluorescence,” Neurosurgery 42(3), 518–526 (1998).
[Crossref]

Smith, K. A.

N. Sanai, L. A. Snyder, N. J. Honea, S. W. Coons, J. M. Eschbacher, K. A. Smith, and R. F. Spetzler, “Intraoperative confocal microscopy in the visualization of 5-aminolevulinic acid fluorescence in low-grade gliomas,” J. Neurosurg. 115(4), 740–748 (2011).
[Crossref]

Snyder, L. A.

N. Sanai, L. A. Snyder, N. J. Honea, S. W. Coons, J. M. Eschbacher, K. A. Smith, and R. F. Spetzler, “Intraoperative confocal microscopy in the visualization of 5-aminolevulinic acid fluorescence in low-grade gliomas,” J. Neurosurg. 115(4), 740–748 (2011).
[Crossref]

Spetzler, R. F.

N. Sanai, L. A. Snyder, N. J. Honea, S. W. Coons, J. M. Eschbacher, K. A. Smith, and R. F. Spetzler, “Intraoperative confocal microscopy in the visualization of 5-aminolevulinic acid fluorescence in low-grade gliomas,” J. Neurosurg. 115(4), 740–748 (2011).
[Crossref]

Stamp, G. W.

Stepp, H.

N. A. Markwardt, N. Haj-Hosseini, B. Hollnburger, H. Stepp, P. Zelenkov, and A. Rühm, “405 nm versus 633 nm for protoporphyrin ix excitation in fluorescence-guided stereotactic biopsy of brain tumors,” J. Biophotonics 9(9), 901–912 (2016).
[Crossref]

A. Johansson, G. Palte, O. Schnell, J.-C. Tonn, J. Herms, and H. Stepp, “5-aminolevulinic acid-induced protoporphyrin ix levels in tissue of human malignant brain tumors,” Photochem. Photobiol. 86(6), 1373–1378 (2010).
[Crossref]

Stummer, W.

B. K. Hendricks, N. Sanai, and W. Stummer, “Fluorescence-guided surgery with aminolevulinic acid for low-grade gliomas,” J. Neuro-Oncol. 141(1), 13–18 (2019).
[Crossref]

C. G. Hadjipanayis, G. Widhalm, and W. Stummer, “What is the surgical benefit of utilizing 5-aminolevulinic acid for fluorescence-guided surgery of malignant gliomas?” Neurosurgery 77(5), 663–673 (2015).
[Crossref]

W. Stummer, U. Pichlmeier, T. Meinel, O. D. Wiestler, F. Zanella, and H.-J. ReulenA.-G. S. Group, “Fluorescence-guided surgery with 5-aminolevulinic acid for resection of malignant glioma: a randomised controlled multicentre phase iii trial,” Lancet Oncol. 7(5), 392–401 (2006).
[Crossref]

Sun, Y. H.

Y. H. Sun, N. Hatami, M. Yee, J. E. Phipps, D. S. Elson, F. Gorin, R. J. Schrot, and L. Marcu, “Fluorescence lifetime imaging microscopy for brain tumor image-guided surgery,” J. Biomed. Opt. 15(5), 056022 (2010).
[Crossref]

Susanne, S.

S. Walter, S. Susanne, W. Simon, S. Herbert, F. Clemens, G. Claudia, E. G. Alwin, K. Rainer, and J. R. Hans, “Intraoperative detection of malignant gliomas by 5-aminolevulinic acid-induced porphyrin fluorescence,” Neurosurgery 42(3), 518–526 (1998).
[Crossref]

Thillainayagam, A. V.

Thropp, J. E.

J. Y. Chen and J. E. Thropp, “Review of low frame rate effects on human performance,” IEEE Trans. Syst., Man, Cybern. A 37(6), 1063–1076 (2007).
[Crossref]

Tiedje, H. F.

J. A. Russell, K. R. Diamond, T. J. Collins, H. F. Tiedje, J. E. Hayward, T. J. Farrell, M. S. Patterson, and Q. Fang, “Characterization of fluorescence lifetime of photofrin and delta-aminolevulinic acid induced protoporphyrin ix in living cells using single-and two-photon excitation,” IEEE J. Sel. Top. Quantum Electron. 14(1), 158–166 (2008).
[Crossref]

Tonn, J.-C.

A. Johansson, G. Palte, O. Schnell, J.-C. Tonn, J. Herms, and H. Stepp, “5-aminolevulinic acid-induced protoporphyrin ix levels in tissue of human malignant brain tumors,” Photochem. Photobiol. 86(6), 1373–1378 (2010).
[Crossref]

Uchugonova, A.

S. R. Kantelhardt, D. Kalasauskas, K. König, E. Kim, M. Weinigel, A. Uchugonova, and A. Giese, “In vivo multiphoton tomography and fluorescence lifetime imaging of human brain tumor tissue,” J. Neuro-Oncol. 127(3), 473–482 (2016).
[Crossref]

Unterhuber, A.

M. T. Erkkilä, B. Bauer, N. Hecker-Denschlag, M. J. Madera Medina, R. A. Leitgeb, A. Unterhuber, J. Gesperger, T. Roetzer, C. Hauger, W. Drexler, G. Widhalm, and M. Andreana, “Widefield fluorescence lifetime imaging of protoporphyrin ix for fluorescence-guided neurosurgery: An ex vivo feasibility study,” J. Biophotonics 12(6), e201800378 (2019).
[Crossref]

Valdes, P. A.

Valdés, P. A.

P. A. Valdés, V. Jacobs, B. T. Harris, B. C. Wilson, F. Leblond, K. D. Paulsen, and D. W. Roberts, “Quantitative fluorescence using 5-aminolevulinic acid-induced protoporphyrin ix biomarker as a surgical adjunct in low-grade glioma surgery,” J. Neurosurg. 123(3), 771–780 (2015).
[Crossref]

P. A. Valdés, F. Leblond, V. L. Jacobs, B. C. Wilson, K. D. Paulsen, and D. W. Roberts, “Quantitative, spectrally-resolved intraoperative fluorescence imaging,” Sci. Rep. 2(1), 798 (2012).
[Crossref]

Walter, S.

S. Walter, S. Susanne, W. Simon, S. Herbert, F. Clemens, G. Claudia, E. G. Alwin, K. Rainer, and J. R. Hans, “Intraoperative detection of malignant gliomas by 5-aminolevulinic acid-induced porphyrin fluorescence,” Neurosurgery 42(3), 518–526 (1998).
[Crossref]

Weinigel, M.

S. R. Kantelhardt, D. Kalasauskas, K. König, E. Kim, M. Weinigel, A. Uchugonova, and A. Giese, “In vivo multiphoton tomography and fluorescence lifetime imaging of human brain tumor tissue,” J. Neuro-Oncol. 127(3), 473–482 (2016).
[Crossref]

Weller, J.

G. Widhalm, J. Olson, J. Weller, J. Bravo, S. J. Han, J. Phillips, S. L. Hervey-Jumper, S. M. Chang, D. W. Roberts, and M. S. Berger, “The value of visible 5-ala fluorescence and quantitative protoporphyrin ix analysis for improved surgery of suspected low-grade gliomas,” J. Neurosurg. 1, 1–10 (2019).
[Crossref]

Widhalm, G.

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Supplementary Material (1)

NameDescription
» Visualization 1       Simulation of a cytoreductive surgery on a piece of parboiled pork sausage. A 1µg/ml PpIX solution was injected under the surface of the sample and is not visible in the beginning of the video. Incision of the surface revealed elevated lifetimes of 8

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Figures (8)

Fig. 1.
Fig. 1. General working principle of the dual-tap fluorescence lifetime imaging method. While tap A integrates over the first half period of the fluorescence signal, tap B integrates over the complementary other half. This process is repeated until the set exposure time is reached. One sensor readout generates an image pair, corresponding to sampling points at 0$^\circ$ and 180$^\circ$. By introducing an additional phase shift of 90$^\circ$ to the integration windows, the fluorescence signal is sampled at 4 points.
Fig. 2.
Fig. 2. (a) Maximum imaging rates of our setup in dependence of the exposure time for the normalized difference method and the acquisition of 4, 8 and 16 phase frames. (b) Standard deviation of the fluorescence lifetime in dependence of the relative fluorescence intensity for sampling with 4, 8 and 16 phase frames. Imaging was performed on a cuvette containing 1 $\mu$g$/$ml PpIX solution in DMSO. The shot noise limited fluorescence lifetime standard deviation was simulated according to Eq. (6).
Fig. 3.
Fig. 3. Dark noise (mean relative intensity) as a function of the exposure time averaged over all pixels.
Fig. 4.
Fig. 4. (a) Relative fluorescence intensity of a HGG exhibiting strong PpIX fluorescence. (b) - (d) Fluorescence lifetime maps acquired with 16, 8 and 4 phase frames. Exposure time was set to 20 ms. Standard deviation of the lifetime increased towards lower sampling densities, but stayed $< 1.5$ ns. The lower part of the sample (ROI C) was slightly out of focus, leading to very low relative fluorescence intensities. Yet, fluorescence lifetime was still sensitive enough to contrast this part of the sample. (e) - (f) Reducing exposure time increased lifetime standard deviation for ROI A and B, respectively. For higher exposure times, a slight decrease of the standard deviation could be observed.
Fig. 5.
Fig. 5. (a) Relative intensity of the autofluorescence of a sample which was confirmed to be reactive brain parenchyma. (b) - (d) Fluorescence lifetime maps acquired with 16, 8 and 4 phase frames. Exposure time was set to 200 ms. Mean fluorescence lifetimes of the sample were in the range of 2 ns and below.
Fig. 6.
Fig. 6. (a) Relative fluorescence intensity of a LGG sample exhibiting weak PpIX fluorescence. (b) - (d) Fluorescence lifetime maps acquired with 16, 8 and 4 phase frames. Exposure time was set to 100 ms. Areas with increased fluorescence lifetime were found, where no fluorescence could be observed visually.
Fig. 7.
Fig. 7. Normalized difference imaging of the HGG, LGG, and the non-pathological sample. The samples correspond to Fig. 4, Fig. 6, and Fig. 5 respectively. (a,c,e) Optimal working point for normalized difference imaging. Lifetime contrast is maximized. (b,d,f) 90$^{\circ }$ shifted least favorable working point. Lifetime contrast is blurred.
Fig. 8.
Fig. 8. Snapshot taken from a video simulating cytoreductive surgery on a piece of parboiled pork sausage. While the elevated lifetime clearly delineates PpIX on the right-hand side, the intensity image on the left-hand side doesn’t show any contrast between PpIX and surrounding tissue. Imaging was performed at 12 Hz (see Visualization 1).

Tables (2)

Tables Icon

Table 1. Overview of the fluorescence lifetimes τ for the HGG, LGG and non-pathological sample. Imaging was performed using 16, 8 and 4 phase frames. Lifetimes were averaged over the ROI A and B of the respective samples (see Fig. 4 to 6).

Tables Icon

Table 2. Overview of the normalized difference for the HGG, LGG and the non-pathological sample at the optimal and the least favorable working point (WP). Imaging was performed using one sensor readout. The normalized difference was averaged over ROI A and B of the respective samples (see Fig. 7).

Equations (16)

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I ( t ) = I f ( 1 2 + 1 2 cos ( 2 π f mod t + Φ τ ) ) + I s
tan Φ τ = 2 π f mod τ .
Φ τ = arg t 1 t 2 I ( t ) e i t 2 π f mod d t arg k = 0 N 1 I ( k ) e i 2 π k / N
Φ τ arg k = 0 N 1 ( I f ( 1 2 + 1 2 cos ( 2 π k N + Φ τ ) ) + I s ) e i 2 π k / N arg ( k = 0 N 1 ( I f ( 1 2 + 1 2 cos ( 2 π k N + Φ τ ) ) e i 2 π k / N + k = 0 N 1 I s e i 2 π k / N )
I tap = 0 T I ( t ) sign [ cos ( 2 π f mod t + α ) ] d t
Δ Φ τ 1 S N R 1 I S i g n a l 2
Δ τ Δ Φ τ 2 π f m o d 1 I S i g n a l 2 1 2 π f m o d
η = I A I B I A + I B = I tap ( α = β ) I tap ( α = β + π ) I tap ( α = β ) + I tap ( α = β + π ) .
η I f I f + 2 I s sin ( Φ τ + β ) .
β = arctan ( π f mod τ f l ) k π , k Z .
η = I A I B I A + I B
I A = 0 T / 2 I f ( 1 2 + 1 2 cos ( 2 π T t + Φ τ + β ) ) + I s d t
I B = T / 2 T I f ( 1 2 + 1 2 cos ( 2 π T t + Φ τ + β ) ) + I s d t
I A = T 4 ( I f + 2 I s ) T I f 2 π sin ( Φ τ + β )
I B = T 4 ( I f + 2 I s ) + T I f 2 π sin ( Φ τ + β )
η = 2 π I f I f + 2 I s sin ( Φ τ + β ) I f I f + 2 I s sin ( Φ τ + β )

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