Abstract

We present a multiphoton microscopy approach with clearing optimized for pathology evaluation producing image quality comparable to traditional histology. Use of benzyl alcohol/benzyl benzoate with 4',6-diamidino-2-phenylindole and eosin in an optimized imaging setup results in optical sections nearly indistinguishable from traditionally-cut sections. Application to human renal tissue demonstrates diagnostic-level image quality can be maintained through 1 millimeter of tissue. Three dimensional perspectives reveal changes of glomerular capsule cells not evident on single sections. Collagen-derived second harmonic generation can be visualized through entire biopsies. Multiphoton microscopy with clearing has potential for increasing the yield of histologic evaluation of biopsy specimens.

© 2016 Optical Society of America

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References

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2014 (2)

R. Torres, S. Vesuna, and M. J. Levene, “High-resolution, 2- and 3-dimensional imaging of uncut, unembedded tissue biopsy samples,” Arch. Pathol. Lab. Med. 138(3), 395–402 (2014).
[Crossref] [PubMed]

S. J. Shankland, B. Smeets, J. W. Pippin, and M. J. Moeller, “The emergence of the glomerular parietal epithelial cell,” Nat. Rev. Nephrol. 10(3), 158–173 (2014).
[Crossref] [PubMed]

2013 (3)

M.-T. Ke, S. Fujimoto, and T. Imai, “SeeDB: a simple and morphology-preserving optical clearing agent for neuronal circuit reconstruction,” Nat. Neurosci. 16(8), 1154–1161 (2013).
[Crossref] [PubMed]

T. Kuwajima, A. A. Sitko, P. Bhansali, C. Jurgens, W. Guido, and C. Mason, “ClearT: a detergent- and solvent-free clearing method for neuronal and non-neuronal tissue,” Development 140(6), 1364–1368 (2013).
[Crossref] [PubMed]

K. Chung and K. Deisseroth, “CLARITY for mapping the nervous system,” Nat. Methods 10(6), 508–513 (2013).
[Crossref] [PubMed]

2012 (2)

A. Ertürk, K. Becker, N. Jährling, C. P. Mauch, C. D. Hojer, J. G. Egen, F. Hellal, F. Bradke, M. Sheng, and H. U. Dodt, “Three-dimensional imaging of solvent-cleared organs using 3DISCO,” Nat. Protoc. 7(11), 1983–1995 (2012).
[Crossref] [PubMed]

X. Chen, O. Nadiarynkh, S. Plotnikov, and P. J. Campagnola, “Second harmonic generation microscopy for quantitative analysis of collagen fibrillar structure,” Nat. Protoc. 7(4), 654–669 (2012).
[Crossref] [PubMed]

2011 (2)

P. A. Young, S. G. Clendenon, J. M. Byars, and K. W. Dunn, “The effects of refractive index heterogeneity within kidney tissue on multiphoton fluorescence excitation microscopy,” J. Microsc. 242(2), 148–156 (2011).
[Crossref] [PubMed]

H. Hama, H. Kurokawa, H. Kawano, R. Ando, T. Shimogori, H. Noda, K. Fukami, A. Sakaue-Sawano, and A. Miyawaki, “Scale: a chemical approach for fluorescence imaging and reconstruction of transparent mouse brain,” Nat. Neurosci. 14(11), 1481–1488 (2011).
[Crossref] [PubMed]

2003 (3)

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]

T. A. Pologruto, B. L. Sabatini, and K. Svoboda, “ScanImage: flexible software for operating laser scanning microscopes,” Biomed. Eng. Online 2(1), 13 (2003).
[Crossref] [PubMed]

W. R. Zipfel, R. M. Williams, and W. W. Webb, “Nonlinear magic: multiphoton microscopy in the biosciences,” Nat. Biotechnol. 21(11), 1369–1377 (2003).
[Crossref] [PubMed]

2001 (1)

Q. T. Nguyen, N. Callamaras, C. Hsieh, and I. Parker, “Construction of a two-photon microscope for video-rate Ca(2+) imaging,” Cell Calcium 30(6), 383–393 (2001).
[Crossref] [PubMed]

1999 (1)

1998 (1)

V. E. Centonze and J. G. White, “Multiphoton excitation provides optical sections from deeper within scattering specimens than confocal imaging,” Biophys. J. 75(4), 2015–2024 (1998).
[Crossref] [PubMed]

1992 (1)

N. Marcussen, “Atubular glomeruli and the structural basis for chronic renal failure,” Lab. Invest. 66(3), 265–284 (1992).
[PubMed]

1989 (1)

J. A. Dent, A. G. Polson, and M. W. Klymkowsky, “A whole-mount immunocytochemical analysis of the expression of the intermediate filament protein vimentin in Xenopus,” Development 105(1), 61–74 (1989).
[PubMed]

Ando, R.

H. Hama, H. Kurokawa, H. Kawano, R. Ando, T. Shimogori, H. Noda, K. Fukami, A. Sakaue-Sawano, and A. Miyawaki, “Scale: a chemical approach for fluorescence imaging and reconstruction of transparent mouse brain,” Nat. Neurosci. 14(11), 1481–1488 (2011).
[Crossref] [PubMed]

Becker, K.

A. Ertürk, K. Becker, N. Jährling, C. P. Mauch, C. D. Hojer, J. G. Egen, F. Hellal, F. Bradke, M. Sheng, and H. U. Dodt, “Three-dimensional imaging of solvent-cleared organs using 3DISCO,” Nat. Protoc. 7(11), 1983–1995 (2012).
[Crossref] [PubMed]

Bhansali, P.

T. Kuwajima, A. A. Sitko, P. Bhansali, C. Jurgens, W. Guido, and C. Mason, “ClearT: a detergent- and solvent-free clearing method for neuronal and non-neuronal tissue,” Development 140(6), 1364–1368 (2013).
[Crossref] [PubMed]

Bradke, F.

A. Ertürk, K. Becker, N. Jährling, C. P. Mauch, C. D. Hojer, J. G. Egen, F. Hellal, F. Bradke, M. Sheng, and H. U. Dodt, “Three-dimensional imaging of solvent-cleared organs using 3DISCO,” Nat. Protoc. 7(11), 1983–1995 (2012).
[Crossref] [PubMed]

Buehler, C.

Byars, J. M.

P. A. Young, S. G. Clendenon, J. M. Byars, and K. W. Dunn, “The effects of refractive index heterogeneity within kidney tissue on multiphoton fluorescence excitation microscopy,” J. Microsc. 242(2), 148–156 (2011).
[Crossref] [PubMed]

Callamaras, N.

Q. T. Nguyen, N. Callamaras, C. Hsieh, and I. Parker, “Construction of a two-photon microscope for video-rate Ca(2+) imaging,” Cell Calcium 30(6), 383–393 (2001).
[Crossref] [PubMed]

Campagnola, P. J.

X. Chen, O. Nadiarynkh, S. Plotnikov, and P. J. Campagnola, “Second harmonic generation microscopy for quantitative analysis of collagen fibrillar structure,” Nat. Protoc. 7(4), 654–669 (2012).
[Crossref] [PubMed]

Centonze, V. E.

V. E. Centonze and J. G. White, “Multiphoton excitation provides optical sections from deeper within scattering specimens than confocal imaging,” Biophys. J. 75(4), 2015–2024 (1998).
[Crossref] [PubMed]

Chen, X.

X. Chen, O. Nadiarynkh, S. Plotnikov, and P. J. Campagnola, “Second harmonic generation microscopy for quantitative analysis of collagen fibrillar structure,” Nat. Protoc. 7(4), 654–669 (2012).
[Crossref] [PubMed]

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]

Chung, K.

K. Chung and K. Deisseroth, “CLARITY for mapping the nervous system,” Nat. Methods 10(6), 508–513 (2013).
[Crossref] [PubMed]

Clendenon, S. G.

P. A. Young, S. G. Clendenon, J. M. Byars, and K. W. Dunn, “The effects of refractive index heterogeneity within kidney tissue on multiphoton fluorescence excitation microscopy,” J. Microsc. 242(2), 148–156 (2011).
[Crossref] [PubMed]

Deisseroth, K.

K. Chung and K. Deisseroth, “CLARITY for mapping the nervous system,” Nat. Methods 10(6), 508–513 (2013).
[Crossref] [PubMed]

Dent, J. A.

J. A. Dent, A. G. Polson, and M. W. Klymkowsky, “A whole-mount immunocytochemical analysis of the expression of the intermediate filament protein vimentin in Xenopus,” Development 105(1), 61–74 (1989).
[PubMed]

Dodt, H. U.

A. Ertürk, K. Becker, N. Jährling, C. P. Mauch, C. D. Hojer, J. G. Egen, F. Hellal, F. Bradke, M. Sheng, and H. U. Dodt, “Three-dimensional imaging of solvent-cleared organs using 3DISCO,” Nat. Protoc. 7(11), 1983–1995 (2012).
[Crossref] [PubMed]

Dunn, K. W.

P. A. Young, S. G. Clendenon, J. M. Byars, and K. W. Dunn, “The effects of refractive index heterogeneity within kidney tissue on multiphoton fluorescence excitation microscopy,” J. Microsc. 242(2), 148–156 (2011).
[Crossref] [PubMed]

Egen, J. G.

A. Ertürk, K. Becker, N. Jährling, C. P. Mauch, C. D. Hojer, J. G. Egen, F. Hellal, F. Bradke, M. Sheng, and H. U. Dodt, “Three-dimensional imaging of solvent-cleared organs using 3DISCO,” Nat. Protoc. 7(11), 1983–1995 (2012).
[Crossref] [PubMed]

Ertürk, A.

A. Ertürk, K. Becker, N. Jährling, C. P. Mauch, C. D. Hojer, J. G. Egen, F. Hellal, F. Bradke, M. Sheng, and H. U. Dodt, “Three-dimensional imaging of solvent-cleared organs using 3DISCO,” Nat. Protoc. 7(11), 1983–1995 (2012).
[Crossref] [PubMed]

Fujimoto, S.

M.-T. Ke, S. Fujimoto, and T. Imai, “SeeDB: a simple and morphology-preserving optical clearing agent for neuronal circuit reconstruction,” Nat. Neurosci. 16(8), 1154–1161 (2013).
[Crossref] [PubMed]

Fukami, K.

H. Hama, H. Kurokawa, H. Kawano, R. Ando, T. Shimogori, H. Noda, K. Fukami, A. Sakaue-Sawano, and A. Miyawaki, “Scale: a chemical approach for fluorescence imaging and reconstruction of transparent mouse brain,” Nat. Neurosci. 14(11), 1481–1488 (2011).
[Crossref] [PubMed]

Guido, W.

T. Kuwajima, A. A. Sitko, P. Bhansali, C. Jurgens, W. Guido, and C. Mason, “ClearT: a detergent- and solvent-free clearing method for neuronal and non-neuronal tissue,” Development 140(6), 1364–1368 (2013).
[Crossref] [PubMed]

Hama, H.

H. Hama, H. Kurokawa, H. Kawano, R. Ando, T. Shimogori, H. Noda, K. Fukami, A. Sakaue-Sawano, and A. Miyawaki, “Scale: a chemical approach for fluorescence imaging and reconstruction of transparent mouse brain,” Nat. Neurosci. 14(11), 1481–1488 (2011).
[Crossref] [PubMed]

Hellal, F.

A. Ertürk, K. Becker, N. Jährling, C. P. Mauch, C. D. Hojer, J. G. Egen, F. Hellal, F. Bradke, M. Sheng, and H. U. Dodt, “Three-dimensional imaging of solvent-cleared organs using 3DISCO,” Nat. Protoc. 7(11), 1983–1995 (2012).
[Crossref] [PubMed]

Hojer, C. D.

A. Ertürk, K. Becker, N. Jährling, C. P. Mauch, C. D. Hojer, J. G. Egen, F. Hellal, F. Bradke, M. Sheng, and H. U. Dodt, “Three-dimensional imaging of solvent-cleared organs using 3DISCO,” Nat. Protoc. 7(11), 1983–1995 (2012).
[Crossref] [PubMed]

Hsieh, C.

Q. T. Nguyen, N. Callamaras, C. Hsieh, and I. Parker, “Construction of a two-photon microscope for video-rate Ca(2+) imaging,” Cell Calcium 30(6), 383–393 (2001).
[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]

Imai, T.

M.-T. Ke, S. Fujimoto, and T. Imai, “SeeDB: a simple and morphology-preserving optical clearing agent for neuronal circuit reconstruction,” Nat. Neurosci. 16(8), 1154–1161 (2013).
[Crossref] [PubMed]

Jährling, N.

A. Ertürk, K. Becker, N. Jährling, C. P. Mauch, C. D. Hojer, J. G. Egen, F. Hellal, F. Bradke, M. Sheng, and H. U. Dodt, “Three-dimensional imaging of solvent-cleared organs using 3DISCO,” Nat. Protoc. 7(11), 1983–1995 (2012).
[Crossref] [PubMed]

Jurgens, C.

T. Kuwajima, A. A. Sitko, P. Bhansali, C. Jurgens, W. Guido, and C. Mason, “ClearT: a detergent- and solvent-free clearing method for neuronal and non-neuronal tissue,” Development 140(6), 1364–1368 (2013).
[Crossref] [PubMed]

Kawano, H.

H. Hama, H. Kurokawa, H. Kawano, R. Ando, T. Shimogori, H. Noda, K. Fukami, A. Sakaue-Sawano, and A. Miyawaki, “Scale: a chemical approach for fluorescence imaging and reconstruction of transparent mouse brain,” Nat. Neurosci. 14(11), 1481–1488 (2011).
[Crossref] [PubMed]

Ke, M.-T.

M.-T. Ke, S. Fujimoto, and T. Imai, “SeeDB: a simple and morphology-preserving optical clearing agent for neuronal circuit reconstruction,” Nat. Neurosci. 16(8), 1154–1161 (2013).
[Crossref] [PubMed]

Kim, K. H.

Klymkowsky, M. W.

J. A. Dent, A. G. Polson, and M. W. Klymkowsky, “A whole-mount immunocytochemical analysis of the expression of the intermediate filament protein vimentin in Xenopus,” Development 105(1), 61–74 (1989).
[PubMed]

Kurokawa, H.

H. Hama, H. Kurokawa, H. Kawano, R. Ando, T. Shimogori, H. Noda, K. Fukami, A. Sakaue-Sawano, and A. Miyawaki, “Scale: a chemical approach for fluorescence imaging and reconstruction of transparent mouse brain,” Nat. Neurosci. 14(11), 1481–1488 (2011).
[Crossref] [PubMed]

Kuwajima, T.

T. Kuwajima, A. A. Sitko, P. Bhansali, C. Jurgens, W. Guido, and C. Mason, “ClearT: a detergent- and solvent-free clearing method for neuronal and non-neuronal tissue,” Development 140(6), 1364–1368 (2013).
[Crossref] [PubMed]

Levene, M. J.

R. Torres, S. Vesuna, and M. J. Levene, “High-resolution, 2- and 3-dimensional imaging of uncut, unembedded tissue biopsy samples,” Arch. Pathol. Lab. Med. 138(3), 395–402 (2014).
[Crossref] [PubMed]

Marcussen, N.

N. Marcussen, “Atubular glomeruli and the structural basis for chronic renal failure,” Lab. Invest. 66(3), 265–284 (1992).
[PubMed]

Mason, C.

T. Kuwajima, A. A. Sitko, P. Bhansali, C. Jurgens, W. Guido, and C. Mason, “ClearT: a detergent- and solvent-free clearing method for neuronal and non-neuronal tissue,” Development 140(6), 1364–1368 (2013).
[Crossref] [PubMed]

Mauch, C. P.

A. Ertürk, K. Becker, N. Jährling, C. P. Mauch, C. D. Hojer, J. G. Egen, F. Hellal, F. Bradke, M. Sheng, and H. U. Dodt, “Three-dimensional imaging of solvent-cleared organs using 3DISCO,” Nat. Protoc. 7(11), 1983–1995 (2012).
[Crossref] [PubMed]

Miyawaki, A.

H. Hama, H. Kurokawa, H. Kawano, R. Ando, T. Shimogori, H. Noda, K. Fukami, A. Sakaue-Sawano, and A. Miyawaki, “Scale: a chemical approach for fluorescence imaging and reconstruction of transparent mouse brain,” Nat. Neurosci. 14(11), 1481–1488 (2011).
[Crossref] [PubMed]

Moeller, M. J.

S. J. Shankland, B. Smeets, J. W. Pippin, and M. J. Moeller, “The emergence of the glomerular parietal epithelial cell,” Nat. Rev. Nephrol. 10(3), 158–173 (2014).
[Crossref] [PubMed]

Nadiarynkh, O.

X. Chen, O. Nadiarynkh, S. Plotnikov, and P. J. Campagnola, “Second harmonic generation microscopy for quantitative analysis of collagen fibrillar structure,” Nat. Protoc. 7(4), 654–669 (2012).
[Crossref] [PubMed]

Nguyen, Q. T.

Q. T. Nguyen, N. Callamaras, C. Hsieh, and I. Parker, “Construction of a two-photon microscope for video-rate Ca(2+) imaging,” Cell Calcium 30(6), 383–393 (2001).
[Crossref] [PubMed]

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]

Noda, H.

H. Hama, H. Kurokawa, H. Kawano, R. Ando, T. Shimogori, H. Noda, K. Fukami, A. Sakaue-Sawano, and A. Miyawaki, “Scale: a chemical approach for fluorescence imaging and reconstruction of transparent mouse brain,” Nat. Neurosci. 14(11), 1481–1488 (2011).
[Crossref] [PubMed]

Parker, I.

Q. T. Nguyen, N. Callamaras, C. Hsieh, and I. Parker, “Construction of a two-photon microscope for video-rate Ca(2+) imaging,” Cell Calcium 30(6), 383–393 (2001).
[Crossref] [PubMed]

Pippin, J. W.

S. J. Shankland, B. Smeets, J. W. Pippin, and M. J. Moeller, “The emergence of the glomerular parietal epithelial cell,” Nat. Rev. Nephrol. 10(3), 158–173 (2014).
[Crossref] [PubMed]

Plotnikov, S.

X. Chen, O. Nadiarynkh, S. Plotnikov, and P. J. Campagnola, “Second harmonic generation microscopy for quantitative analysis of collagen fibrillar structure,” Nat. Protoc. 7(4), 654–669 (2012).
[Crossref] [PubMed]

Pologruto, T. A.

T. A. Pologruto, B. L. Sabatini, and K. Svoboda, “ScanImage: flexible software for operating laser scanning microscopes,” Biomed. Eng. Online 2(1), 13 (2003).
[Crossref] [PubMed]

Polson, A. G.

J. A. Dent, A. G. Polson, and M. W. Klymkowsky, “A whole-mount immunocytochemical analysis of the expression of the intermediate filament protein vimentin in Xenopus,” Development 105(1), 61–74 (1989).
[PubMed]

Sabatini, B. L.

T. A. Pologruto, B. L. Sabatini, and K. Svoboda, “ScanImage: flexible software for operating laser scanning microscopes,” Biomed. Eng. Online 2(1), 13 (2003).
[Crossref] [PubMed]

Sakaue-Sawano, A.

H. Hama, H. Kurokawa, H. Kawano, R. Ando, T. Shimogori, H. Noda, K. Fukami, A. Sakaue-Sawano, and A. Miyawaki, “Scale: a chemical approach for fluorescence imaging and reconstruction of transparent mouse brain,” Nat. Neurosci. 14(11), 1481–1488 (2011).
[Crossref] [PubMed]

Shankland, S. J.

S. J. Shankland, B. Smeets, J. W. Pippin, and M. J. Moeller, “The emergence of the glomerular parietal epithelial cell,” Nat. Rev. Nephrol. 10(3), 158–173 (2014).
[Crossref] [PubMed]

Sheng, M.

A. Ertürk, K. Becker, N. Jährling, C. P. Mauch, C. D. Hojer, J. G. Egen, F. Hellal, F. Bradke, M. Sheng, and H. U. Dodt, “Three-dimensional imaging of solvent-cleared organs using 3DISCO,” Nat. Protoc. 7(11), 1983–1995 (2012).
[Crossref] [PubMed]

Shimogori, T.

H. Hama, H. Kurokawa, H. Kawano, R. Ando, T. Shimogori, H. Noda, K. Fukami, A. Sakaue-Sawano, and A. Miyawaki, “Scale: a chemical approach for fluorescence imaging and reconstruction of transparent mouse brain,” Nat. Neurosci. 14(11), 1481–1488 (2011).
[Crossref] [PubMed]

Sitko, A. A.

T. Kuwajima, A. A. Sitko, P. Bhansali, C. Jurgens, W. Guido, and C. Mason, “ClearT: a detergent- and solvent-free clearing method for neuronal and non-neuronal tissue,” Development 140(6), 1364–1368 (2013).
[Crossref] [PubMed]

Smeets, B.

S. J. Shankland, B. Smeets, J. W. Pippin, and M. J. Moeller, “The emergence of the glomerular parietal epithelial cell,” Nat. Rev. Nephrol. 10(3), 158–173 (2014).
[Crossref] [PubMed]

So, P. T.

Svoboda, K.

T. A. Pologruto, B. L. Sabatini, and K. Svoboda, “ScanImage: flexible software for operating laser scanning microscopes,” Biomed. Eng. Online 2(1), 13 (2003).
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Torres, R.

R. Torres, S. Vesuna, and M. J. Levene, “High-resolution, 2- and 3-dimensional imaging of uncut, unembedded tissue biopsy samples,” Arch. Pathol. Lab. Med. 138(3), 395–402 (2014).
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Vesuna, S.

R. Torres, S. Vesuna, and M. J. Levene, “High-resolution, 2- and 3-dimensional imaging of uncut, unembedded tissue biopsy samples,” Arch. Pathol. Lab. Med. 138(3), 395–402 (2014).
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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).
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W. R. Zipfel, R. M. Williams, and W. W. Webb, “Nonlinear magic: multiphoton microscopy in the biosciences,” Nat. Biotechnol. 21(11), 1369–1377 (2003).
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V. E. Centonze and J. G. White, “Multiphoton excitation provides optical sections from deeper within scattering specimens than confocal imaging,” Biophys. J. 75(4), 2015–2024 (1998).
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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. R. Zipfel, R. M. Williams, and W. W. Webb, “Nonlinear magic: multiphoton microscopy in the biosciences,” Nat. Biotechnol. 21(11), 1369–1377 (2003).
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P. A. Young, S. G. Clendenon, J. M. Byars, and K. W. Dunn, “The effects of refractive index heterogeneity within kidney tissue on multiphoton fluorescence excitation microscopy,” J. Microsc. 242(2), 148–156 (2011).
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W. R. Zipfel, R. M. Williams, and W. W. Webb, “Nonlinear magic: multiphoton microscopy in the biosciences,” Nat. Biotechnol. 21(11), 1369–1377 (2003).
[Crossref] [PubMed]

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).
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Appl. Opt. (1)

Arch. Pathol. Lab. Med. (1)

R. Torres, S. Vesuna, and M. J. Levene, “High-resolution, 2- and 3-dimensional imaging of uncut, unembedded tissue biopsy samples,” Arch. Pathol. Lab. Med. 138(3), 395–402 (2014).
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Biomed. Eng. Online (1)

T. A. Pologruto, B. L. Sabatini, and K. Svoboda, “ScanImage: flexible software for operating laser scanning microscopes,” Biomed. Eng. Online 2(1), 13 (2003).
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V. E. Centonze and J. G. White, “Multiphoton excitation provides optical sections from deeper within scattering specimens than confocal imaging,” Biophys. J. 75(4), 2015–2024 (1998).
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T. Kuwajima, A. A. Sitko, P. Bhansali, C. Jurgens, W. Guido, and C. Mason, “ClearT: a detergent- and solvent-free clearing method for neuronal and non-neuronal tissue,” Development 140(6), 1364–1368 (2013).
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K. Chung and K. Deisseroth, “CLARITY for mapping the nervous system,” Nat. Methods 10(6), 508–513 (2013).
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H. Hama, H. Kurokawa, H. Kawano, R. Ando, T. Shimogori, H. Noda, K. Fukami, A. Sakaue-Sawano, and A. Miyawaki, “Scale: a chemical approach for fluorescence imaging and reconstruction of transparent mouse brain,” Nat. Neurosci. 14(11), 1481–1488 (2011).
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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).
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Figures (6)

Fig. 1
Fig. 1 A) 3D renal biopsy reconstruction using MPM with clearing. Scale bar = 500 µm. B) Corresponding multiphoton image obtained at depth of 400 μm, pseudo-colored to mimic H&E.
Fig. 2
Fig. 2 A) Traditionally processed kidney H&E section using 100x lens. B-D) Pseudo-colored MPM with clearing. Range of fine features recognizable include B) glomerular capillary walls, C) cytoplasmic granules, and D) nuclear membranes and chromatin patterns. Scale bar – 30 µm.
Fig. 3
Fig. 3 Pseudo-colored MPM images on cleared renal tissue show preservation of clarity and contrast throughout entire core renal biopsies. Depths - A) 200 µm, B) 600 µm, C) 1000 µm. Scale bar – 40 µm.
Fig. 4
Fig. 4 A). Renal glomerulus using MPM/clearing at 300 µm depth. Black inset shows capillary loop (black arrow) with luminal RBC. White inset shows visualization of mesangial cell (white arrow) facilitated by thin optical sectioning and high color contrast. B) Atubular glomerulus cross-section using MPM/clearing. Glomerular changes and surrounding connective tissue and edema are noted, but the functional status based on parietal epithelial cells and tubular connection cannot be assessed in a single section. Dimensions – 350 x 350 µm.
Fig. 5
Fig. 5 Reconstructions in 3D of a normal (A) and atubular (B) capsule showing changes in the nuclei of the parietal epithelial cells lining the capsule that are not apparent on two dimensional histologic sections. Glomeruli have been digitally removed. Sections correspond to Fig. 4(a) and 4(b), respectively. Block dimensions are approximately 400x400x150μm. Arrows in (A) indicate proximal tubule connection.
Fig. 6
Fig. 6 A). 3D reconstruction of collagen in human kidney biopsy using MPM/SHG in cleared tissue. B) Single MPM section showing two dimensional collagen arrangement (green) with modified background pseudo H&E coloring. (Scale bar – 500 µm) C) Higher magnification view of B showing sparse collagen SHG around glomerulus. (Scale bar – 50 µm) D) Z-projection over depth of 200 µm within the same glomerulus as in C.

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