Abstract

Interleukin-12 (IL-12) is a pro-inflammatory cytokine known for its role in immunity, and previous studies have shown that IL-12 provides mitigation of radiation injury. In this study, we utilize a multimodal microscopy system equipped with second harmonic generation (SHG) and fluorescence lifetime imaging microscopy (FLIM) to examine the effect of IL-12 on collagen structure and cellular metabolic activity in vivo during skin wound healing. This preliminary study illustrates the highly dynamic and heterogeneous in vivo microenvironment of the wounded skin. In addition, results suggest that IL-12 triggers a significantly more rapid and greater cellular metabolic response in the wounded animals. These results can elucidate insights into the response mechanism of IL-12 in both wound healing and acute radiation syndrome.

© 2015 Optical Society of America

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    [Crossref] [PubMed]
  2. S. A. Gerber, R. J. Cummings, J. L. Judge, M. L. Barlow, J. Nanduri, D. E. Johnson, J. Palis, A. P. Pentland, E. M. Lord, and J. L. Ryan, “Interleukin-12 preserves the cutaneous physical and immunological barrier after radiation exposure,” Radiat. Res. 183(1), 72–81 (2015).
    [Crossref] [PubMed]
  3. M. B. Witte and A. Barbul, “General principles of wound healing,” Surg. Clin. North Am. 77(3), 509–528 (1997).
    [Crossref] [PubMed]
  4. Z. Gluzman-Poltorak, V. Vainstein, and L. A. Basile, “Recombinant interleukin-12, but not granulocyte-colony stimulating factor, improves survival in lethally irradiated nonhuman primates in the absence of supportive care: evidence for the development of a frontline radiation medical countermeasure,” Am. J. Hematol. 89(9), 868–873 (2014).
    [Crossref] [PubMed]
  5. F. H. Epstein, A. J. Singer, and R. A. F. Clark, “Cutaneous wound healing,” N. Engl. J. Med. 341(10), 738–746 (1999).
    [Crossref] [PubMed]
  6. P. Martin, “Wound healing--aiming for perfect skin regeneration,” Science 276(5309), 75–81 (1997).
    [Crossref] [PubMed]
  7. J. Li, J. Chen, and R. Kirsner, “Pathophysiology of acute wound healing,” Clin. Dermatol. 25(1), 9–18 (2007).
    [Crossref] [PubMed]
  8. B. W. Graf, E. J. Chaney, M. Marjanovic, S. G. Adie, M. De Lisio, M. C. Valero, M. D. Boppart, and S. A. Boppart, “Long-term time-lapse multimodal intravital imaging of regeneration and bone-marrow-derived cell dynamics in skin,” Technology 1(1), 8–19 (2013).
    [PubMed]
  9. M. C. Skala, K. M. Riching, A. Gendron-Fitzpatrick, J. Eickhoff, K. W. Eliceiri, J. G. White, and N. Ramanujam, “In vivo multiphoton microscopy of NADH and FAD redox states, fluorescence lifetimes, and cellular morphology in precancerous epithelia,” Proc. Natl. Acad. Sci. U.S.A. 104(49), 19494–19499 (2007).
    [Crossref] [PubMed]
  10. A. J. Walsh and M. C. Skala, “Optical metabolic imaging quantifies heterogeneous cell populations,” Biomed. Opt. Express 6(2), 559–573 (2015).
    [Crossref] [PubMed]
  11. M. Balu, K. M. Kelly, C. B. Zachary, R. M. Harris, T. B. Krasieva, K. König, A. J. Durkin, and B. J. Tromberg, “Distinguishing between benign and malignant melanocytic nevi by in vivo multiphoton microscopy,” Cancer Res. 74(10), 2688–2697 (2014).
    [Crossref] [PubMed]
  12. P. J. Campagnola and L. M. Loew, “Second-harmonic imaging microscopy for visualizing biomolecular arrays in cells, tissues and organisms,” Nat. Biotechnol. 21(11), 1356–1360 (2003).
    [Crossref] [PubMed]
  13. J. R. Lakowicz, H. Szmacinski, K. Nowaczyk, and M. L. Johnson, “Fluorescence lifetime imaging of free and protein-bound NADH,” Proc. Natl. Acad. Sci. U.S.A. 89(4), 1271–1275 (1992).
    [Crossref] [PubMed]
  14. B. W. Graf, A. J. Bower, E. J. Chaney, M. Marjanovic, S. G. Adie, M. De Lisio, M. C. Valero, M. D. Boppart, and S. A. Boppart, “In vivo multimodal microscopy for detecting bone-marrow-derived cell contribution to skin regeneration,” J. Biophotonics 7(1-2), 96–102 (2014).
    [Crossref] [PubMed]
  15. S. Wu, H. Li, H. Yang, X. Zhang, Z. Li, and S. Xu, “Quantitative analysis on collagen morphology in aging skin based on multiphoton microscopy,” J. Biomed. Opt. 16(4), 040502 (2011).
    [Crossref] [PubMed]
  16. R. A. Rao, M. R. Mehta, and K. C. Toussaint., “Fourier transform-second-harmonic generation imaging of biological tissues,” Opt. Express 17(17), 14534–14542 (2009).
    [Crossref] [PubMed]
  17. P. D. Dale, J. A. Sherratt, and P. K. Maini, “A mathematical model for collagen fibre formation during foetal and adult dermal wound healing,” Proc. Biol. Sci. 263(1370), 653–660 (1996).
    [Crossref] [PubMed]
  18. D. K. Bird, L. Yan, K. M. Vrotsos, K. W. Eliceiri, E. M. Vaughan, P. J. Keely, J. G. White, and N. Ramanujam, “Metabolic mapping of MCF10A human breast cells via multiphoton fluorescence lifetime imaging of the coenzyme NADH,” Cancer Res. 65(19), 8766–8773 (2005).
    [Crossref] [PubMed]
  19. M. Balu, A. Mazhar, C. K. Hayakawa, R. Mittal, T. B. Krasieva, K. König, V. Venugopalan, and B. J. Tromberg, “In vivo multiphoton NADH fluorescence reveals depth-dependent keratinocyte metabolism in human skin,” Biophys. J. 104(1), 258–267 (2013).
    [Crossref] [PubMed]
  20. M. S. Roberts, Y. Dancik, T. W. Prow, C. A. Thorling, L. L. Lin, J. E. Grice, T. A. Robertson, K. König, and W. Becker, “Non-invasive imaging of skin physiology and percutaneous penetration using fluorescence spectral and lifetime imaging with multiphoton and confocal microscopy,” Eur. J. Pharm. Biopharm. 77(3), 469–488 (2011).
    [Crossref] [PubMed]
  21. R. Niesner, B. Peker, P. Schlüsche, and K. H. Gericke, “Noniterative biexponential fluorescence lifetime imaging in the investigation of cellular metabolism by means of NAD(P)H autofluorescence,” ChemPhysChem 5(8), 1141–1149 (2004).
    [Crossref] [PubMed]
  22. M. J. Im and J. E. Hoopes, “Energy metabolism in healing skin wounds,” J. Surg. Res. 10(10), 459–464 (1970).
    [Crossref] [PubMed]
  23. K. Blinova, S. Carroll, S. Bose, A. V. Smirnov, J. J. Harvey, J. R. Knutson, and R. S. Balaban, “Distribution of mitochondrial NADH fluorescence lifetimes: steady-state kinetics of matrix NADH interactions,” Biochemistry 44(7), 2585–2594 (2005).
    [Crossref] [PubMed]
  24. A. Mayevsky, “Mitochondrial function and energy metabolism in cancer cells: past overview and future perspectives,” Mitochondrion 9(3), 165–179 (2009).
    [Crossref] [PubMed]
  25. M. Saraste, “Oxidative phosphorylation at the fin de siècle,” Science 283(5407), 1488–1493 (1999).
    [Crossref] [PubMed]

2015 (2)

S. A. Gerber, R. J. Cummings, J. L. Judge, M. L. Barlow, J. Nanduri, D. E. Johnson, J. Palis, A. P. Pentland, E. M. Lord, and J. L. Ryan, “Interleukin-12 preserves the cutaneous physical and immunological barrier after radiation exposure,” Radiat. Res. 183(1), 72–81 (2015).
[Crossref] [PubMed]

A. J. Walsh and M. C. Skala, “Optical metabolic imaging quantifies heterogeneous cell populations,” Biomed. Opt. Express 6(2), 559–573 (2015).
[Crossref] [PubMed]

2014 (3)

M. Balu, K. M. Kelly, C. B. Zachary, R. M. Harris, T. B. Krasieva, K. König, A. J. Durkin, and B. J. Tromberg, “Distinguishing between benign and malignant melanocytic nevi by in vivo multiphoton microscopy,” Cancer Res. 74(10), 2688–2697 (2014).
[Crossref] [PubMed]

B. W. Graf, A. J. Bower, E. J. Chaney, M. Marjanovic, S. G. Adie, M. De Lisio, M. C. Valero, M. D. Boppart, and S. A. Boppart, “In vivo multimodal microscopy for detecting bone-marrow-derived cell contribution to skin regeneration,” J. Biophotonics 7(1-2), 96–102 (2014).
[Crossref] [PubMed]

Z. Gluzman-Poltorak, V. Vainstein, and L. A. Basile, “Recombinant interleukin-12, but not granulocyte-colony stimulating factor, improves survival in lethally irradiated nonhuman primates in the absence of supportive care: evidence for the development of a frontline radiation medical countermeasure,” Am. J. Hematol. 89(9), 868–873 (2014).
[Crossref] [PubMed]

2013 (2)

B. W. Graf, E. J. Chaney, M. Marjanovic, S. G. Adie, M. De Lisio, M. C. Valero, M. D. Boppart, and S. A. Boppart, “Long-term time-lapse multimodal intravital imaging of regeneration and bone-marrow-derived cell dynamics in skin,” Technology 1(1), 8–19 (2013).
[PubMed]

M. Balu, A. Mazhar, C. K. Hayakawa, R. Mittal, T. B. Krasieva, K. König, V. Venugopalan, and B. J. Tromberg, “In vivo multiphoton NADH fluorescence reveals depth-dependent keratinocyte metabolism in human skin,” Biophys. J. 104(1), 258–267 (2013).
[Crossref] [PubMed]

2011 (2)

M. S. Roberts, Y. Dancik, T. W. Prow, C. A. Thorling, L. L. Lin, J. E. Grice, T. A. Robertson, K. König, and W. Becker, “Non-invasive imaging of skin physiology and percutaneous penetration using fluorescence spectral and lifetime imaging with multiphoton and confocal microscopy,” Eur. J. Pharm. Biopharm. 77(3), 469–488 (2011).
[Crossref] [PubMed]

S. Wu, H. Li, H. Yang, X. Zhang, Z. Li, and S. Xu, “Quantitative analysis on collagen morphology in aging skin based on multiphoton microscopy,” J. Biomed. Opt. 16(4), 040502 (2011).
[Crossref] [PubMed]

2009 (2)

R. A. Rao, M. R. Mehta, and K. C. Toussaint., “Fourier transform-second-harmonic generation imaging of biological tissues,” Opt. Express 17(17), 14534–14542 (2009).
[Crossref] [PubMed]

A. Mayevsky, “Mitochondrial function and energy metabolism in cancer cells: past overview and future perspectives,” Mitochondrion 9(3), 165–179 (2009).
[Crossref] [PubMed]

2007 (2)

M. C. Skala, K. M. Riching, A. Gendron-Fitzpatrick, J. Eickhoff, K. W. Eliceiri, J. G. White, and N. Ramanujam, “In vivo multiphoton microscopy of NADH and FAD redox states, fluorescence lifetimes, and cellular morphology in precancerous epithelia,” Proc. Natl. Acad. Sci. U.S.A. 104(49), 19494–19499 (2007).
[Crossref] [PubMed]

J. Li, J. Chen, and R. Kirsner, “Pathophysiology of acute wound healing,” Clin. Dermatol. 25(1), 9–18 (2007).
[Crossref] [PubMed]

2005 (2)

D. K. Bird, L. Yan, K. M. Vrotsos, K. W. Eliceiri, E. M. Vaughan, P. J. Keely, J. G. White, and N. Ramanujam, “Metabolic mapping of MCF10A human breast cells via multiphoton fluorescence lifetime imaging of the coenzyme NADH,” Cancer Res. 65(19), 8766–8773 (2005).
[Crossref] [PubMed]

K. Blinova, S. Carroll, S. Bose, A. V. Smirnov, J. J. Harvey, J. R. Knutson, and R. S. Balaban, “Distribution of mitochondrial NADH fluorescence lifetimes: steady-state kinetics of matrix NADH interactions,” Biochemistry 44(7), 2585–2594 (2005).
[Crossref] [PubMed]

2004 (1)

R. Niesner, B. Peker, P. Schlüsche, and K. H. Gericke, “Noniterative biexponential fluorescence lifetime imaging in the investigation of cellular metabolism by means of NAD(P)H autofluorescence,” ChemPhysChem 5(8), 1141–1149 (2004).
[Crossref] [PubMed]

2003 (2)

G. Trinchieri, “Interleukin-12 and the regulation of innate resistance and adaptive immunity,” Nat. Rev. Immunol. 3(2), 133–146 (2003).
[Crossref] [PubMed]

P. J. Campagnola and L. M. Loew, “Second-harmonic imaging microscopy for visualizing biomolecular arrays in cells, tissues and organisms,” Nat. Biotechnol. 21(11), 1356–1360 (2003).
[Crossref] [PubMed]

1999 (2)

F. H. Epstein, A. J. Singer, and R. A. F. Clark, “Cutaneous wound healing,” N. Engl. J. Med. 341(10), 738–746 (1999).
[Crossref] [PubMed]

M. Saraste, “Oxidative phosphorylation at the fin de siècle,” Science 283(5407), 1488–1493 (1999).
[Crossref] [PubMed]

1997 (2)

P. Martin, “Wound healing--aiming for perfect skin regeneration,” Science 276(5309), 75–81 (1997).
[Crossref] [PubMed]

M. B. Witte and A. Barbul, “General principles of wound healing,” Surg. Clin. North Am. 77(3), 509–528 (1997).
[Crossref] [PubMed]

1996 (1)

P. D. Dale, J. A. Sherratt, and P. K. Maini, “A mathematical model for collagen fibre formation during foetal and adult dermal wound healing,” Proc. Biol. Sci. 263(1370), 653–660 (1996).
[Crossref] [PubMed]

1992 (1)

J. R. Lakowicz, H. Szmacinski, K. Nowaczyk, and M. L. Johnson, “Fluorescence lifetime imaging of free and protein-bound NADH,” Proc. Natl. Acad. Sci. U.S.A. 89(4), 1271–1275 (1992).
[Crossref] [PubMed]

1970 (1)

M. J. Im and J. E. Hoopes, “Energy metabolism in healing skin wounds,” J. Surg. Res. 10(10), 459–464 (1970).
[Crossref] [PubMed]

Adie, S. G.

B. W. Graf, A. J. Bower, E. J. Chaney, M. Marjanovic, S. G. Adie, M. De Lisio, M. C. Valero, M. D. Boppart, and S. A. Boppart, “In vivo multimodal microscopy for detecting bone-marrow-derived cell contribution to skin regeneration,” J. Biophotonics 7(1-2), 96–102 (2014).
[Crossref] [PubMed]

B. W. Graf, E. J. Chaney, M. Marjanovic, S. G. Adie, M. De Lisio, M. C. Valero, M. D. Boppart, and S. A. Boppart, “Long-term time-lapse multimodal intravital imaging of regeneration and bone-marrow-derived cell dynamics in skin,” Technology 1(1), 8–19 (2013).
[PubMed]

Balaban, R. S.

K. Blinova, S. Carroll, S. Bose, A. V. Smirnov, J. J. Harvey, J. R. Knutson, and R. S. Balaban, “Distribution of mitochondrial NADH fluorescence lifetimes: steady-state kinetics of matrix NADH interactions,” Biochemistry 44(7), 2585–2594 (2005).
[Crossref] [PubMed]

Balu, M.

M. Balu, K. M. Kelly, C. B. Zachary, R. M. Harris, T. B. Krasieva, K. König, A. J. Durkin, and B. J. Tromberg, “Distinguishing between benign and malignant melanocytic nevi by in vivo multiphoton microscopy,” Cancer Res. 74(10), 2688–2697 (2014).
[Crossref] [PubMed]

M. Balu, A. Mazhar, C. K. Hayakawa, R. Mittal, T. B. Krasieva, K. König, V. Venugopalan, and B. J. Tromberg, “In vivo multiphoton NADH fluorescence reveals depth-dependent keratinocyte metabolism in human skin,” Biophys. J. 104(1), 258–267 (2013).
[Crossref] [PubMed]

Barbul, A.

M. B. Witte and A. Barbul, “General principles of wound healing,” Surg. Clin. North Am. 77(3), 509–528 (1997).
[Crossref] [PubMed]

Barlow, M. L.

S. A. Gerber, R. J. Cummings, J. L. Judge, M. L. Barlow, J. Nanduri, D. E. Johnson, J. Palis, A. P. Pentland, E. M. Lord, and J. L. Ryan, “Interleukin-12 preserves the cutaneous physical and immunological barrier after radiation exposure,” Radiat. Res. 183(1), 72–81 (2015).
[Crossref] [PubMed]

Basile, L. A.

Z. Gluzman-Poltorak, V. Vainstein, and L. A. Basile, “Recombinant interleukin-12, but not granulocyte-colony stimulating factor, improves survival in lethally irradiated nonhuman primates in the absence of supportive care: evidence for the development of a frontline radiation medical countermeasure,” Am. J. Hematol. 89(9), 868–873 (2014).
[Crossref] [PubMed]

Becker, W.

M. S. Roberts, Y. Dancik, T. W. Prow, C. A. Thorling, L. L. Lin, J. E. Grice, T. A. Robertson, K. König, and W. Becker, “Non-invasive imaging of skin physiology and percutaneous penetration using fluorescence spectral and lifetime imaging with multiphoton and confocal microscopy,” Eur. J. Pharm. Biopharm. 77(3), 469–488 (2011).
[Crossref] [PubMed]

Bird, D. K.

D. K. Bird, L. Yan, K. M. Vrotsos, K. W. Eliceiri, E. M. Vaughan, P. J. Keely, J. G. White, and N. Ramanujam, “Metabolic mapping of MCF10A human breast cells via multiphoton fluorescence lifetime imaging of the coenzyme NADH,” Cancer Res. 65(19), 8766–8773 (2005).
[Crossref] [PubMed]

Blinova, K.

K. Blinova, S. Carroll, S. Bose, A. V. Smirnov, J. J. Harvey, J. R. Knutson, and R. S. Balaban, “Distribution of mitochondrial NADH fluorescence lifetimes: steady-state kinetics of matrix NADH interactions,” Biochemistry 44(7), 2585–2594 (2005).
[Crossref] [PubMed]

Boppart, M. D.

B. W. Graf, A. J. Bower, E. J. Chaney, M. Marjanovic, S. G. Adie, M. De Lisio, M. C. Valero, M. D. Boppart, and S. A. Boppart, “In vivo multimodal microscopy for detecting bone-marrow-derived cell contribution to skin regeneration,” J. Biophotonics 7(1-2), 96–102 (2014).
[Crossref] [PubMed]

B. W. Graf, E. J. Chaney, M. Marjanovic, S. G. Adie, M. De Lisio, M. C. Valero, M. D. Boppart, and S. A. Boppart, “Long-term time-lapse multimodal intravital imaging of regeneration and bone-marrow-derived cell dynamics in skin,” Technology 1(1), 8–19 (2013).
[PubMed]

Boppart, S. A.

B. W. Graf, A. J. Bower, E. J. Chaney, M. Marjanovic, S. G. Adie, M. De Lisio, M. C. Valero, M. D. Boppart, and S. A. Boppart, “In vivo multimodal microscopy for detecting bone-marrow-derived cell contribution to skin regeneration,” J. Biophotonics 7(1-2), 96–102 (2014).
[Crossref] [PubMed]

B. W. Graf, E. J. Chaney, M. Marjanovic, S. G. Adie, M. De Lisio, M. C. Valero, M. D. Boppart, and S. A. Boppart, “Long-term time-lapse multimodal intravital imaging of regeneration and bone-marrow-derived cell dynamics in skin,” Technology 1(1), 8–19 (2013).
[PubMed]

Bose, S.

K. Blinova, S. Carroll, S. Bose, A. V. Smirnov, J. J. Harvey, J. R. Knutson, and R. S. Balaban, “Distribution of mitochondrial NADH fluorescence lifetimes: steady-state kinetics of matrix NADH interactions,” Biochemistry 44(7), 2585–2594 (2005).
[Crossref] [PubMed]

Bower, A. J.

B. W. Graf, A. J. Bower, E. J. Chaney, M. Marjanovic, S. G. Adie, M. De Lisio, M. C. Valero, M. D. Boppart, and S. A. Boppart, “In vivo multimodal microscopy for detecting bone-marrow-derived cell contribution to skin regeneration,” J. Biophotonics 7(1-2), 96–102 (2014).
[Crossref] [PubMed]

Campagnola, P. J.

P. J. Campagnola and L. M. Loew, “Second-harmonic imaging microscopy for visualizing biomolecular arrays in cells, tissues and organisms,” Nat. Biotechnol. 21(11), 1356–1360 (2003).
[Crossref] [PubMed]

Carroll, S.

K. Blinova, S. Carroll, S. Bose, A. V. Smirnov, J. J. Harvey, J. R. Knutson, and R. S. Balaban, “Distribution of mitochondrial NADH fluorescence lifetimes: steady-state kinetics of matrix NADH interactions,” Biochemistry 44(7), 2585–2594 (2005).
[Crossref] [PubMed]

Chaney, E. J.

B. W. Graf, A. J. Bower, E. J. Chaney, M. Marjanovic, S. G. Adie, M. De Lisio, M. C. Valero, M. D. Boppart, and S. A. Boppart, “In vivo multimodal microscopy for detecting bone-marrow-derived cell contribution to skin regeneration,” J. Biophotonics 7(1-2), 96–102 (2014).
[Crossref] [PubMed]

B. W. Graf, E. J. Chaney, M. Marjanovic, S. G. Adie, M. De Lisio, M. C. Valero, M. D. Boppart, and S. A. Boppart, “Long-term time-lapse multimodal intravital imaging of regeneration and bone-marrow-derived cell dynamics in skin,” Technology 1(1), 8–19 (2013).
[PubMed]

Chen, J.

J. Li, J. Chen, and R. Kirsner, “Pathophysiology of acute wound healing,” Clin. Dermatol. 25(1), 9–18 (2007).
[Crossref] [PubMed]

Clark, R. A. F.

F. H. Epstein, A. J. Singer, and R. A. F. Clark, “Cutaneous wound healing,” N. Engl. J. Med. 341(10), 738–746 (1999).
[Crossref] [PubMed]

Cummings, R. J.

S. A. Gerber, R. J. Cummings, J. L. Judge, M. L. Barlow, J. Nanduri, D. E. Johnson, J. Palis, A. P. Pentland, E. M. Lord, and J. L. Ryan, “Interleukin-12 preserves the cutaneous physical and immunological barrier after radiation exposure,” Radiat. Res. 183(1), 72–81 (2015).
[Crossref] [PubMed]

Dale, P. D.

P. D. Dale, J. A. Sherratt, and P. K. Maini, “A mathematical model for collagen fibre formation during foetal and adult dermal wound healing,” Proc. Biol. Sci. 263(1370), 653–660 (1996).
[Crossref] [PubMed]

Dancik, Y.

M. S. Roberts, Y. Dancik, T. W. Prow, C. A. Thorling, L. L. Lin, J. E. Grice, T. A. Robertson, K. König, and W. Becker, “Non-invasive imaging of skin physiology and percutaneous penetration using fluorescence spectral and lifetime imaging with multiphoton and confocal microscopy,” Eur. J. Pharm. Biopharm. 77(3), 469–488 (2011).
[Crossref] [PubMed]

De Lisio, M.

B. W. Graf, A. J. Bower, E. J. Chaney, M. Marjanovic, S. G. Adie, M. De Lisio, M. C. Valero, M. D. Boppart, and S. A. Boppart, “In vivo multimodal microscopy for detecting bone-marrow-derived cell contribution to skin regeneration,” J. Biophotonics 7(1-2), 96–102 (2014).
[Crossref] [PubMed]

B. W. Graf, E. J. Chaney, M. Marjanovic, S. G. Adie, M. De Lisio, M. C. Valero, M. D. Boppart, and S. A. Boppart, “Long-term time-lapse multimodal intravital imaging of regeneration and bone-marrow-derived cell dynamics in skin,” Technology 1(1), 8–19 (2013).
[PubMed]

Durkin, A. J.

M. Balu, K. M. Kelly, C. B. Zachary, R. M. Harris, T. B. Krasieva, K. König, A. J. Durkin, and B. J. Tromberg, “Distinguishing between benign and malignant melanocytic nevi by in vivo multiphoton microscopy,” Cancer Res. 74(10), 2688–2697 (2014).
[Crossref] [PubMed]

Eickhoff, J.

M. C. Skala, K. M. Riching, A. Gendron-Fitzpatrick, J. Eickhoff, K. W. Eliceiri, J. G. White, and N. Ramanujam, “In vivo multiphoton microscopy of NADH and FAD redox states, fluorescence lifetimes, and cellular morphology in precancerous epithelia,” Proc. Natl. Acad. Sci. U.S.A. 104(49), 19494–19499 (2007).
[Crossref] [PubMed]

Eliceiri, K. W.

M. C. Skala, K. M. Riching, A. Gendron-Fitzpatrick, J. Eickhoff, K. W. Eliceiri, J. G. White, and N. Ramanujam, “In vivo multiphoton microscopy of NADH and FAD redox states, fluorescence lifetimes, and cellular morphology in precancerous epithelia,” Proc. Natl. Acad. Sci. U.S.A. 104(49), 19494–19499 (2007).
[Crossref] [PubMed]

D. K. Bird, L. Yan, K. M. Vrotsos, K. W. Eliceiri, E. M. Vaughan, P. J. Keely, J. G. White, and N. Ramanujam, “Metabolic mapping of MCF10A human breast cells via multiphoton fluorescence lifetime imaging of the coenzyme NADH,” Cancer Res. 65(19), 8766–8773 (2005).
[Crossref] [PubMed]

Epstein, F. H.

F. H. Epstein, A. J. Singer, and R. A. F. Clark, “Cutaneous wound healing,” N. Engl. J. Med. 341(10), 738–746 (1999).
[Crossref] [PubMed]

Gendron-Fitzpatrick, A.

M. C. Skala, K. M. Riching, A. Gendron-Fitzpatrick, J. Eickhoff, K. W. Eliceiri, J. G. White, and N. Ramanujam, “In vivo multiphoton microscopy of NADH and FAD redox states, fluorescence lifetimes, and cellular morphology in precancerous epithelia,” Proc. Natl. Acad. Sci. U.S.A. 104(49), 19494–19499 (2007).
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R. Niesner, B. Peker, P. Schlüsche, and K. H. Gericke, “Noniterative biexponential fluorescence lifetime imaging in the investigation of cellular metabolism by means of NAD(P)H autofluorescence,” ChemPhysChem 5(8), 1141–1149 (2004).
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Z. Gluzman-Poltorak, V. Vainstein, and L. A. Basile, “Recombinant interleukin-12, but not granulocyte-colony stimulating factor, improves survival in lethally irradiated nonhuman primates in the absence of supportive care: evidence for the development of a frontline radiation medical countermeasure,” Am. J. Hematol. 89(9), 868–873 (2014).
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M. S. Roberts, Y. Dancik, T. W. Prow, C. A. Thorling, L. L. Lin, J. E. Grice, T. A. Robertson, K. König, and W. Becker, “Non-invasive imaging of skin physiology and percutaneous penetration using fluorescence spectral and lifetime imaging with multiphoton and confocal microscopy,” Eur. J. Pharm. Biopharm. 77(3), 469–488 (2011).
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M. Balu, K. M. Kelly, C. B. Zachary, R. M. Harris, T. B. Krasieva, K. König, A. J. Durkin, and B. J. Tromberg, “Distinguishing between benign and malignant melanocytic nevi by in vivo multiphoton microscopy,” Cancer Res. 74(10), 2688–2697 (2014).
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M. Balu, A. Mazhar, C. K. Hayakawa, R. Mittal, T. B. Krasieva, K. König, V. Venugopalan, and B. J. Tromberg, “In vivo multiphoton NADH fluorescence reveals depth-dependent keratinocyte metabolism in human skin,” Biophys. J. 104(1), 258–267 (2013).
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M. Balu, K. M. Kelly, C. B. Zachary, R. M. Harris, T. B. Krasieva, K. König, A. J. Durkin, and B. J. Tromberg, “Distinguishing between benign and malignant melanocytic nevi by in vivo multiphoton microscopy,” Cancer Res. 74(10), 2688–2697 (2014).
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M. Balu, A. Mazhar, C. K. Hayakawa, R. Mittal, T. B. Krasieva, K. König, V. Venugopalan, and B. J. Tromberg, “In vivo multiphoton NADH fluorescence reveals depth-dependent keratinocyte metabolism in human skin,” Biophys. J. 104(1), 258–267 (2013).
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J. R. Lakowicz, H. Szmacinski, K. Nowaczyk, and M. L. Johnson, “Fluorescence lifetime imaging of free and protein-bound NADH,” Proc. Natl. Acad. Sci. U.S.A. 89(4), 1271–1275 (1992).
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S. Wu, H. Li, H. Yang, X. Zhang, Z. Li, and S. Xu, “Quantitative analysis on collagen morphology in aging skin based on multiphoton microscopy,” J. Biomed. Opt. 16(4), 040502 (2011).
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S. Wu, H. Li, H. Yang, X. Zhang, Z. Li, and S. Xu, “Quantitative analysis on collagen morphology in aging skin based on multiphoton microscopy,” J. Biomed. Opt. 16(4), 040502 (2011).
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[Crossref] [PubMed]

B. W. Graf, E. J. Chaney, M. Marjanovic, S. G. Adie, M. De Lisio, M. C. Valero, M. D. Boppart, and S. A. Boppart, “Long-term time-lapse multimodal intravital imaging of regeneration and bone-marrow-derived cell dynamics in skin,” Technology 1(1), 8–19 (2013).
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Mehta, M. R.

Mittal, R.

M. Balu, A. Mazhar, C. K. Hayakawa, R. Mittal, T. B. Krasieva, K. König, V. Venugopalan, and B. J. Tromberg, “In vivo multiphoton NADH fluorescence reveals depth-dependent keratinocyte metabolism in human skin,” Biophys. J. 104(1), 258–267 (2013).
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S. A. Gerber, R. J. Cummings, J. L. Judge, M. L. Barlow, J. Nanduri, D. E. Johnson, J. Palis, A. P. Pentland, E. M. Lord, and J. L. Ryan, “Interleukin-12 preserves the cutaneous physical and immunological barrier after radiation exposure,” Radiat. Res. 183(1), 72–81 (2015).
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J. R. Lakowicz, H. Szmacinski, K. Nowaczyk, and M. L. Johnson, “Fluorescence lifetime imaging of free and protein-bound NADH,” Proc. Natl. Acad. Sci. U.S.A. 89(4), 1271–1275 (1992).
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S. A. Gerber, R. J. Cummings, J. L. Judge, M. L. Barlow, J. Nanduri, D. E. Johnson, J. Palis, A. P. Pentland, E. M. Lord, and J. L. Ryan, “Interleukin-12 preserves the cutaneous physical and immunological barrier after radiation exposure,” Radiat. Res. 183(1), 72–81 (2015).
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R. Niesner, B. Peker, P. Schlüsche, and K. H. Gericke, “Noniterative biexponential fluorescence lifetime imaging in the investigation of cellular metabolism by means of NAD(P)H autofluorescence,” ChemPhysChem 5(8), 1141–1149 (2004).
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S. A. Gerber, R. J. Cummings, J. L. Judge, M. L. Barlow, J. Nanduri, D. E. Johnson, J. Palis, A. P. Pentland, E. M. Lord, and J. L. Ryan, “Interleukin-12 preserves the cutaneous physical and immunological barrier after radiation exposure,” Radiat. Res. 183(1), 72–81 (2015).
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M. S. Roberts, Y. Dancik, T. W. Prow, C. A. Thorling, L. L. Lin, J. E. Grice, T. A. Robertson, K. König, and W. Becker, “Non-invasive imaging of skin physiology and percutaneous penetration using fluorescence spectral and lifetime imaging with multiphoton and confocal microscopy,” Eur. J. Pharm. Biopharm. 77(3), 469–488 (2011).
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M. C. Skala, K. M. Riching, A. Gendron-Fitzpatrick, J. Eickhoff, K. W. Eliceiri, J. G. White, and N. Ramanujam, “In vivo multiphoton microscopy of NADH and FAD redox states, fluorescence lifetimes, and cellular morphology in precancerous epithelia,” Proc. Natl. Acad. Sci. U.S.A. 104(49), 19494–19499 (2007).
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Riching, K. M.

M. C. Skala, K. M. Riching, A. Gendron-Fitzpatrick, J. Eickhoff, K. W. Eliceiri, J. G. White, and N. Ramanujam, “In vivo multiphoton microscopy of NADH and FAD redox states, fluorescence lifetimes, and cellular morphology in precancerous epithelia,” Proc. Natl. Acad. Sci. U.S.A. 104(49), 19494–19499 (2007).
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M. S. Roberts, Y. Dancik, T. W. Prow, C. A. Thorling, L. L. Lin, J. E. Grice, T. A. Robertson, K. König, and W. Becker, “Non-invasive imaging of skin physiology and percutaneous penetration using fluorescence spectral and lifetime imaging with multiphoton and confocal microscopy,” Eur. J. Pharm. Biopharm. 77(3), 469–488 (2011).
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M. S. Roberts, Y. Dancik, T. W. Prow, C. A. Thorling, L. L. Lin, J. E. Grice, T. A. Robertson, K. König, and W. Becker, “Non-invasive imaging of skin physiology and percutaneous penetration using fluorescence spectral and lifetime imaging with multiphoton and confocal microscopy,” Eur. J. Pharm. Biopharm. 77(3), 469–488 (2011).
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S. A. Gerber, R. J. Cummings, J. L. Judge, M. L. Barlow, J. Nanduri, D. E. Johnson, J. Palis, A. P. Pentland, E. M. Lord, and J. L. Ryan, “Interleukin-12 preserves the cutaneous physical and immunological barrier after radiation exposure,” Radiat. Res. 183(1), 72–81 (2015).
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P. D. Dale, J. A. Sherratt, and P. K. Maini, “A mathematical model for collagen fibre formation during foetal and adult dermal wound healing,” Proc. Biol. Sci. 263(1370), 653–660 (1996).
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M. C. Skala, K. M. Riching, A. Gendron-Fitzpatrick, J. Eickhoff, K. W. Eliceiri, J. G. White, and N. Ramanujam, “In vivo multiphoton microscopy of NADH and FAD redox states, fluorescence lifetimes, and cellular morphology in precancerous epithelia,” Proc. Natl. Acad. Sci. U.S.A. 104(49), 19494–19499 (2007).
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K. Blinova, S. Carroll, S. Bose, A. V. Smirnov, J. J. Harvey, J. R. Knutson, and R. S. Balaban, “Distribution of mitochondrial NADH fluorescence lifetimes: steady-state kinetics of matrix NADH interactions,” Biochemistry 44(7), 2585–2594 (2005).
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J. R. Lakowicz, H. Szmacinski, K. Nowaczyk, and M. L. Johnson, “Fluorescence lifetime imaging of free and protein-bound NADH,” Proc. Natl. Acad. Sci. U.S.A. 89(4), 1271–1275 (1992).
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M. S. Roberts, Y. Dancik, T. W. Prow, C. A. Thorling, L. L. Lin, J. E. Grice, T. A. Robertson, K. König, and W. Becker, “Non-invasive imaging of skin physiology and percutaneous penetration using fluorescence spectral and lifetime imaging with multiphoton and confocal microscopy,” Eur. J. Pharm. Biopharm. 77(3), 469–488 (2011).
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[Crossref] [PubMed]

M. Balu, A. Mazhar, C. K. Hayakawa, R. Mittal, T. B. Krasieva, K. König, V. Venugopalan, and B. J. Tromberg, “In vivo multiphoton NADH fluorescence reveals depth-dependent keratinocyte metabolism in human skin,” Biophys. J. 104(1), 258–267 (2013).
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Z. Gluzman-Poltorak, V. Vainstein, and L. A. Basile, “Recombinant interleukin-12, but not granulocyte-colony stimulating factor, improves survival in lethally irradiated nonhuman primates in the absence of supportive care: evidence for the development of a frontline radiation medical countermeasure,” Am. J. Hematol. 89(9), 868–873 (2014).
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B. W. Graf, A. J. Bower, E. J. Chaney, M. Marjanovic, S. G. Adie, M. De Lisio, M. C. Valero, M. D. Boppart, and S. A. Boppart, “In vivo multimodal microscopy for detecting bone-marrow-derived cell contribution to skin regeneration,” J. Biophotonics 7(1-2), 96–102 (2014).
[Crossref] [PubMed]

B. W. Graf, E. J. Chaney, M. Marjanovic, S. G. Adie, M. De Lisio, M. C. Valero, M. D. Boppart, and S. A. Boppart, “Long-term time-lapse multimodal intravital imaging of regeneration and bone-marrow-derived cell dynamics in skin,” Technology 1(1), 8–19 (2013).
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M. Balu, A. Mazhar, C. K. Hayakawa, R. Mittal, T. B. Krasieva, K. König, V. Venugopalan, and B. J. Tromberg, “In vivo multiphoton NADH fluorescence reveals depth-dependent keratinocyte metabolism in human skin,” Biophys. J. 104(1), 258–267 (2013).
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White, J. G.

M. C. Skala, K. M. Riching, A. Gendron-Fitzpatrick, J. Eickhoff, K. W. Eliceiri, J. G. White, and N. Ramanujam, “In vivo multiphoton microscopy of NADH and FAD redox states, fluorescence lifetimes, and cellular morphology in precancerous epithelia,” Proc. Natl. Acad. Sci. U.S.A. 104(49), 19494–19499 (2007).
[Crossref] [PubMed]

D. K. Bird, L. Yan, K. M. Vrotsos, K. W. Eliceiri, E. M. Vaughan, P. J. Keely, J. G. White, and N. Ramanujam, “Metabolic mapping of MCF10A human breast cells via multiphoton fluorescence lifetime imaging of the coenzyme NADH,” Cancer Res. 65(19), 8766–8773 (2005).
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S. Wu, H. Li, H. Yang, X. Zhang, Z. Li, and S. Xu, “Quantitative analysis on collagen morphology in aging skin based on multiphoton microscopy,” J. Biomed. Opt. 16(4), 040502 (2011).
[Crossref] [PubMed]

Xu, S.

S. Wu, H. Li, H. Yang, X. Zhang, Z. Li, and S. Xu, “Quantitative analysis on collagen morphology in aging skin based on multiphoton microscopy,” J. Biomed. Opt. 16(4), 040502 (2011).
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D. K. Bird, L. Yan, K. M. Vrotsos, K. W. Eliceiri, E. M. Vaughan, P. J. Keely, J. G. White, and N. Ramanujam, “Metabolic mapping of MCF10A human breast cells via multiphoton fluorescence lifetime imaging of the coenzyme NADH,” Cancer Res. 65(19), 8766–8773 (2005).
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Yang, H.

S. Wu, H. Li, H. Yang, X. Zhang, Z. Li, and S. Xu, “Quantitative analysis on collagen morphology in aging skin based on multiphoton microscopy,” J. Biomed. Opt. 16(4), 040502 (2011).
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Zachary, C. B.

M. Balu, K. M. Kelly, C. B. Zachary, R. M. Harris, T. B. Krasieva, K. König, A. J. Durkin, and B. J. Tromberg, “Distinguishing between benign and malignant melanocytic nevi by in vivo multiphoton microscopy,” Cancer Res. 74(10), 2688–2697 (2014).
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Zhang, X.

S. Wu, H. Li, H. Yang, X. Zhang, Z. Li, and S. Xu, “Quantitative analysis on collagen morphology in aging skin based on multiphoton microscopy,” J. Biomed. Opt. 16(4), 040502 (2011).
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Am. J. Hematol. (1)

Z. Gluzman-Poltorak, V. Vainstein, and L. A. Basile, “Recombinant interleukin-12, but not granulocyte-colony stimulating factor, improves survival in lethally irradiated nonhuman primates in the absence of supportive care: evidence for the development of a frontline radiation medical countermeasure,” Am. J. Hematol. 89(9), 868–873 (2014).
[Crossref] [PubMed]

Biochemistry (1)

K. Blinova, S. Carroll, S. Bose, A. V. Smirnov, J. J. Harvey, J. R. Knutson, and R. S. Balaban, “Distribution of mitochondrial NADH fluorescence lifetimes: steady-state kinetics of matrix NADH interactions,” Biochemistry 44(7), 2585–2594 (2005).
[Crossref] [PubMed]

Biomed. Opt. Express (1)

Biophys. J. (1)

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Figures (5)

Fig. 1
Fig. 1 Schematic of the multimodal microscope. Abbreviations: M – mirror, SM - scanning mirror, L - lens; DM -dichroic mirror, O - objective lens, PMT - photomultiplier tube, FB - fiber bundle.
Fig. 2
Fig. 2 Representative SHG images of the wounded skin from the wounded group with rMuIL-12 injection showing wound healing progression. Scale bar: 200 μm applies to all.
Fig. 3
Fig. 3 Analysis of collagen alignment using SHG images. An eccentricity value closer to 0 suggests normal collagen structure, and a value closer to 1 suggests collagen fibers with a preferred orientation. Boxed area in the upper image is a representative example illustrating the size of the small SHG images below. FT stands for Fourier transform.
Fig. 4
Fig. 4 2D Fourier transforms show the change in collagen alignment during wound healing. (a) Representative SHG and 2D spatial Fourier transform images from each experimental group on selected imaging days. (b) Longitudinal tracking of collagen alignment/orientation during the one month study period. † Both wounded groups show significantly higher alignment compared to the non-wounded group on day 14 (p < 0.05); * in the wounded group with placebo injection, the level of collagen alignment is significantly higher on day 14 compared to days 2, 7, and 28 (p < 0.05). Scale bar: 30 μm applies to all.
Fig. 5
Fig. 5 Dynamics of the metabolic activity in the wounded skin during healing using FLIM. (a) Representative FLIM images from each experimental group on selected days. (b) Longitudinal tracking of the change in fluorescence lifetime during wound healing. ‡ Wounded with rMuIL-12 group has a significantly longer lifetime compared to the wounded with placebo group on day 2 (p < 0.05); † wounded group with rMuIL-12 injection has a significantly longer lifetime compared to the non-wounded group on day 3 (p < 0.05); * in the wounded with rMuIL-12 group, the lifetimes on days 2 and 3 were significantly longer than day 0 (p < 0.05). Scale bar: 20 μm applies to all.

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