Abstract

We present a non-invasive, label-free method of imaging blood cells flowing through human capillaries in vivo using oblique back-illumination capillaroscopy (OBC). Green light illumination allows simultaneous phase and absorption contrast, enhancing the ability to distinguish red and white blood cells. Single-sided illumination through the objective lens enables 200 Hz imaging with close illumination-detection separation and a simplified setup. Phase contrast is optimized when the illumination axis is offset from the detection axis by approximately 225 µm when imaging ∼80 µm deep in phantoms and human ventral tongue. We demonstrate high-speed imaging of individual red blood cells, white blood cells with sub-cellular detail, and platelets flowing through capillaries and vessels in human tongue. A custom pneumatic cap placed over the objective lens stabilizes the field of view, enabling longitudinal imaging of a single capillary for up to seven minutes. We present high-quality images of blood cells in individuals with Fitzpatrick skin phototypes II, IV, and VI, showing that the technique is robust to high peripheral melanin concentration. The signal quality, speed, simplicity, and robustness of this approach underscores its potential for non-invasive blood cell counting.

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

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References

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    [Crossref]
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    [Crossref]
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    [Crossref]
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    [Crossref]
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    [Crossref]
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    [Crossref]

2019 (2)

P. Ledwig and F. E. Robles, “Epi-mode tomographic quantitative phase imaging in thick scattering samples,” Biomed. Opt. Express 10(7), 3605–3621 (2019).
[Crossref]

M. E. Kandel, C. Hu, G. N. Kouzehgarani, E. Min, K. M. Sullivan, H. Kong, J. M. Li, D. N. Robson, M. U. Gillette, C. Best-Popescu, and G. Popescu, “Epi-illumination gradient light interference microscopy for imaging opaque structures,” Nat. Commun. 10(1), 4691 (2019).
[Crossref]

2018 (3)

D. Carpentras, T. Laforest, M. Künzi, and C. Moser, “Effect of backscattering in phase contrast imaging of the retina,” Biomed. Opt. Express 26(6), 6785–6795 (2018).
[Crossref]

P. Ledwig, M. Sghayyer, J. Kurtzberg, and F. E. Robles, “Dual-wavelength oblique back-illumination microscopy for the non-invasive imaging and quantification of blood in collection and storage bags,” Biomed. Opt. Express 9(6), 2743 (2018).
[Crossref]

A. Bourquard, A. Pablo-Trinidad, I. Butterworth, Á. Sánchez-Ferro, C. Cerrato, K. Humala, M. F. Urdiola, C. D. Rio, B. Valles, J. M. Tucker-Schwartz, E. S. Lee, B. J. Vakoc, T. P. Padera, M. J. Ledesma-Carbayo, Y.-B. Chen, E. P. Hochberg, M. L. Gray, and C. Castro-González, “Non-invasive detection of severe neutropenia in chemotherapy patients by optical imaging of nailfold microcirculation,” Sci. Rep. 8(1), 5301 (2018).
[Crossref]

2017 (3)

M. M. Winer, A. Zeidan, D. Yeheskely-Hayon, L. Golan, L. Minai, E. J. Dann, and D. Yelin, “In vivo noninvasive microscopy of human leucocytes,” Sci. Rep. 7(1), 13031–8 (2017).
[Crossref]

D. Agrawal and R. Sarode, “Complete Blood Count or Complete Blood Count with Differential: What’s the Difference?” The Am. J. Medicine 130(8), 915–916 (2017).
[Crossref]

E. Tai, G. P. Guy Jr., A. Dunbar, and L. C. Richardson, “Cost of Cancer-Related Neutropenia or Fever Hospitalizations, United States 2012,” J. Oncol. Pract. 13(6), e552–e561 (2017).
[Crossref]

2015 (1)

U. Baran, L. Shi, and R. K. Wang, “Capillary blood flow imaging within human finger cuticle using optical microangiography,” J. Biophotonics 8(1-2), 46–51 (2015).
[Crossref]

2014 (1)

L. Feller, A. Masilana, R. A. G. Khammissa, M. Altini, Y. Jadwat, and J. Lemmer, “Melanin: the biophysiology of oral melanocytes and physiological oral pigmentation,” Head & Face Med. 10(1), 8 (2014).
[Crossref]

2013 (3)

2012 (4)

L. Golan, D. Yeheskely-Hayon, L. Minai, and E. J. Dann, “Noninvasive imaging of flowing blood cells using label-free spectrally encoded flow cytometry,” Biomed. Opt. Express 3(6), 1455–1464 (2012).
[Crossref]

C.-K. Chen and T.-M. Liu, “Imaging morphodynamics of human blood cells in vivo with video-rate third harmonic generation microscopy,” Biomed. Opt. Express 3(11), 2860–2865 (2012).
[Crossref]

T. N. Ford, K. K. Chu, and J. Mertz, “Phase-gradient microscopy in thick tissue with oblique back-illumination,” Nat. Methods 9(12), 1195–1197 (2012).
[Crossref]

S. Prestin, S. Rothschild, C. S. Betz, and M. Kraft, “Measurement of epithelial thickness within the oral cavity using optical coherence tomography,” Head and Neck 34(12), 1777–1781 (2012).
[Crossref]

2008 (1)

J. A. Widness, “Pathophysiology of Anaemia during the Neonatal Period, Including Anaemia of Prematurity,” Neoreviews 9(11), e520–e525 (2008).
[Crossref]

2004 (1)

J. Crawford, D. C. Dale, and G. H. Lyman, “Chemotherapy-Induced Neutropenia. Risks, consequences, and new directions for its management,” Cancer 100(2), 228–237 (2004).
[Crossref]

2000 (1)

R. B. Presland and B. A. Dale, “Epithelial Structural Proteins of the Skin and Oral Cavity: Function in Health and Disease,” Critical Rev. Oral Biol. Medicine 11(4), 383–408 (2000).
[Crossref]

1999 (2)

C. E. Curtis, W. G. Iacono, and M. Beiser, “Relationship between Nailfold Plexus Visibility and Clinical, Neuropsychological, and Brain Structural Measures in Schizoprenia,” Soc. Biol. Psychiatry 46(1), 102–109 (1999).
[Crossref]

M. Rajadhyaksha, R. R. Anderson, and R. H. Webb, “Video-rate confocal scanning laser microscope for imaging human tissues in vivo,” Appl. Opt. 38(10), 2105–2115 (1999).
[Crossref]

1997 (2)

I. M. Braverman, “The cutaneous microcirculation: Ultrastructure and microanatomical organization,” Microcirculation 4(3), 329–340 (1997).
[Crossref]

C. H. Chang, R. K. Tsai, W. C. Wu, S. L. Kuo, and H. S. Yu, “Use of Dynamic Capillaroscopy for Studying Cutaneous Microcirculation in Patients with Diabetes Mellitus,” Microvasc. Res. 53(2), 121–127 (1997).
[Crossref]

1994 (1)

A. W. Barrett and C. Scully, “Human oral mucosal melanocytes: a review,” J. Oral Pathol. Med. 23(3), 97–103 (1994).
[Crossref]

1986 (1)

F. Lefford and J. C. W. Edwards, “Nailfold capillary microscopy in connective tissue disease: a quantitative morphological analysis,” Ann. Rheum. Dis. 45(9), 741–749 (1986).
[Crossref]

1925 (1)

G. E. Brown, “The Skin Capillaries in Raynaud’s Disease,” Arch. Intern. Med. 35(1), 56–73 (1925).
[Crossref]

A. van Driel, P. B. A.

Agrawal, D.

D. Agrawal and R. Sarode, “Complete Blood Count or Complete Blood Count with Differential: What’s the Difference?” The Am. J. Medicine 130(8), 915–916 (2017).
[Crossref]

Allen White, G.

P. Tsai, N. Nishimura, E. Yoder, E. Dolnick, G. Allen White, and D. Kleinfeld, Principles, Design,and Construction of a Two-Photon Laser-Scanning Microscope for In Vitro and In Vivo Brain Imaging, May 2014 (2002).

Altini, M.

L. Feller, A. Masilana, R. A. G. Khammissa, M. Altini, Y. Jadwat, and J. Lemmer, “Melanin: the biophysiology of oral melanocytes and physiological oral pigmentation,” Head & Face Med. 10(1), 8 (2014).
[Crossref]

Amelink, A.

Anderson, R. R.

Baran, U.

U. Baran, L. Shi, and R. K. Wang, “Capillary blood flow imaging within human finger cuticle using optical microangiography,” J. Biophotonics 8(1-2), 46–51 (2015).
[Crossref]

Barrett, A. W.

A. W. Barrett and C. Scully, “Human oral mucosal melanocytes: a review,” J. Oral Pathol. Med. 23(3), 97–103 (1994).
[Crossref]

Beiser, M.

C. E. Curtis, W. G. Iacono, and M. Beiser, “Relationship between Nailfold Plexus Visibility and Clinical, Neuropsychological, and Brain Structural Measures in Schizoprenia,” Soc. Biol. Psychiatry 46(1), 102–109 (1999).
[Crossref]

Best-Popescu, C.

M. E. Kandel, C. Hu, G. N. Kouzehgarani, E. Min, K. M. Sullivan, H. Kong, J. M. Li, D. N. Robson, M. U. Gillette, C. Best-Popescu, and G. Popescu, “Epi-illumination gradient light interference microscopy for imaging opaque structures,” Nat. Commun. 10(1), 4691 (2019).
[Crossref]

Betz, C. S.

S. Prestin, S. Rothschild, C. S. Betz, and M. Kraft, “Measurement of epithelial thickness within the oral cavity using optical coherence tomography,” Head and Neck 34(12), 1777–1781 (2012).
[Crossref]

Bourquard, A.

A. Bourquard, A. Pablo-Trinidad, I. Butterworth, Á. Sánchez-Ferro, C. Cerrato, K. Humala, M. F. Urdiola, C. D. Rio, B. Valles, J. M. Tucker-Schwartz, E. S. Lee, B. J. Vakoc, T. P. Padera, M. J. Ledesma-Carbayo, Y.-B. Chen, E. P. Hochberg, M. L. Gray, and C. Castro-González, “Non-invasive detection of severe neutropenia in chemotherapy patients by optical imaging of nailfold microcirculation,” Sci. Rep. 8(1), 5301 (2018).
[Crossref]

Braverman, I. M.

I. M. Braverman, “The cutaneous microcirculation: Ultrastructure and microanatomical organization,” Microcirculation 4(3), 329–340 (1997).
[Crossref]

Brown, G. E.

G. E. Brown, “The Skin Capillaries in Raynaud’s Disease,” Arch. Intern. Med. 35(1), 56–73 (1925).
[Crossref]

Butterworth, I.

A. Bourquard, A. Pablo-Trinidad, I. Butterworth, Á. Sánchez-Ferro, C. Cerrato, K. Humala, M. F. Urdiola, C. D. Rio, B. Valles, J. M. Tucker-Schwartz, E. S. Lee, B. J. Vakoc, T. P. Padera, M. J. Ledesma-Carbayo, Y.-B. Chen, E. P. Hochberg, M. L. Gray, and C. Castro-González, “Non-invasive detection of severe neutropenia in chemotherapy patients by optical imaging of nailfold microcirculation,” Sci. Rep. 8(1), 5301 (2018).
[Crossref]

Carpentras, D.

D. Carpentras, T. Laforest, M. Künzi, and C. Moser, “Effect of backscattering in phase contrast imaging of the retina,” Biomed. Opt. Express 26(6), 6785–6795 (2018).
[Crossref]

Castro-González, C.

A. Bourquard, A. Pablo-Trinidad, I. Butterworth, Á. Sánchez-Ferro, C. Cerrato, K. Humala, M. F. Urdiola, C. D. Rio, B. Valles, J. M. Tucker-Schwartz, E. S. Lee, B. J. Vakoc, T. P. Padera, M. J. Ledesma-Carbayo, Y.-B. Chen, E. P. Hochberg, M. L. Gray, and C. Castro-González, “Non-invasive detection of severe neutropenia in chemotherapy patients by optical imaging of nailfold microcirculation,” Sci. Rep. 8(1), 5301 (2018).
[Crossref]

Cerrato, C.

A. Bourquard, A. Pablo-Trinidad, I. Butterworth, Á. Sánchez-Ferro, C. Cerrato, K. Humala, M. F. Urdiola, C. D. Rio, B. Valles, J. M. Tucker-Schwartz, E. S. Lee, B. J. Vakoc, T. P. Padera, M. J. Ledesma-Carbayo, Y.-B. Chen, E. P. Hochberg, M. L. Gray, and C. Castro-González, “Non-invasive detection of severe neutropenia in chemotherapy patients by optical imaging of nailfold microcirculation,” Sci. Rep. 8(1), 5301 (2018).
[Crossref]

Chang, C. H.

C. H. Chang, R. K. Tsai, W. C. Wu, S. L. Kuo, and H. S. Yu, “Use of Dynamic Capillaroscopy for Studying Cutaneous Microcirculation in Patients with Diabetes Mellitus,” Microvasc. Res. 53(2), 121–127 (1997).
[Crossref]

Chen, C.-K.

Chen, Y.-B.

A. Bourquard, A. Pablo-Trinidad, I. Butterworth, Á. Sánchez-Ferro, C. Cerrato, K. Humala, M. F. Urdiola, C. D. Rio, B. Valles, J. M. Tucker-Schwartz, E. S. Lee, B. J. Vakoc, T. P. Padera, M. J. Ledesma-Carbayo, Y.-B. Chen, E. P. Hochberg, M. L. Gray, and C. Castro-González, “Non-invasive detection of severe neutropenia in chemotherapy patients by optical imaging of nailfold microcirculation,” Sci. Rep. 8(1), 5301 (2018).
[Crossref]

Chu, K. K.

T. N. Ford, K. K. Chu, and J. Mertz, “Phase-gradient microscopy in thick tissue with oblique back-illumination,” Nat. Methods 9(12), 1195–1197 (2012).
[Crossref]

Crawford, J.

J. Crawford, D. C. Dale, and G. H. Lyman, “Chemotherapy-Induced Neutropenia. Risks, consequences, and new directions for its management,” Cancer 100(2), 228–237 (2004).
[Crossref]

Curtis, C. E.

C. E. Curtis, W. G. Iacono, and M. Beiser, “Relationship between Nailfold Plexus Visibility and Clinical, Neuropsychological, and Brain Structural Measures in Schizoprenia,” Soc. Biol. Psychiatry 46(1), 102–109 (1999).
[Crossref]

Dale, B. A.

R. B. Presland and B. A. Dale, “Epithelial Structural Proteins of the Skin and Oral Cavity: Function in Health and Disease,” Critical Rev. Oral Biol. Medicine 11(4), 383–408 (2000).
[Crossref]

Dale, D. C.

J. Crawford, D. C. Dale, and G. H. Lyman, “Chemotherapy-Induced Neutropenia. Risks, consequences, and new directions for its management,” Cancer 100(2), 228–237 (2004).
[Crossref]

Dann, E. J.

M. M. Winer, A. Zeidan, D. Yeheskely-Hayon, L. Golan, L. Minai, E. J. Dann, and D. Yelin, “In vivo noninvasive microscopy of human leucocytes,” Sci. Rep. 7(1), 13031–8 (2017).
[Crossref]

L. Golan, D. Yeheskely-Hayon, L. Minai, and E. J. Dann, “Noninvasive imaging of flowing blood cells using label-free spectrally encoded flow cytometry,” Biomed. Opt. Express 3(6), 1455–1464 (2012).
[Crossref]

de Bruijn, H. S.

Dolnick, E.

P. Tsai, N. Nishimura, E. Yoder, E. Dolnick, G. Allen White, and D. Kleinfeld, Principles, Design,and Construction of a Two-Photon Laser-Scanning Microscope for In Vitro and In Vivo Brain Imaging, May 2014 (2002).

Dunbar, A.

E. Tai, G. P. Guy Jr., A. Dunbar, and L. C. Richardson, “Cost of Cancer-Related Neutropenia or Fever Hospitalizations, United States 2012,” J. Oncol. Pract. 13(6), e552–e561 (2017).
[Crossref]

Edwards, J. C. W.

F. Lefford and J. C. W. Edwards, “Nailfold capillary microscopy in connective tissue disease: a quantitative morphological analysis,” Ann. Rheum. Dis. 45(9), 741–749 (1986).
[Crossref]

Feller, L.

L. Feller, A. Masilana, R. A. G. Khammissa, M. Altini, Y. Jadwat, and J. Lemmer, “Melanin: the biophysiology of oral melanocytes and physiological oral pigmentation,” Head & Face Med. 10(1), 8 (2014).
[Crossref]

Ford, T. N.

T. N. Ford and J. Mertz, “Video-rate imaging of microcirculation with single-exposure oblique back-illumination microscopy,” J. Biomed. Opt. 18(6), 066007 (2013).
[Crossref]

T. N. Ford, K. K. Chu, and J. Mertz, “Phase-gradient microscopy in thick tissue with oblique back-illumination,” Nat. Methods 9(12), 1195–1197 (2012).
[Crossref]

Gamm, U. A.

Gillette, M. U.

M. E. Kandel, C. Hu, G. N. Kouzehgarani, E. Min, K. M. Sullivan, H. Kong, J. M. Li, D. N. Robson, M. U. Gillette, C. Best-Popescu, and G. Popescu, “Epi-illumination gradient light interference microscopy for imaging opaque structures,” Nat. Commun. 10(1), 4691 (2019).
[Crossref]

Golan, L.

M. M. Winer, A. Zeidan, D. Yeheskely-Hayon, L. Golan, L. Minai, E. J. Dann, and D. Yelin, “In vivo noninvasive microscopy of human leucocytes,” Sci. Rep. 7(1), 13031–8 (2017).
[Crossref]

L. Golan, D. Yeheskely-Hayon, L. Minai, and E. J. Dann, “Noninvasive imaging of flowing blood cells using label-free spectrally encoded flow cytometry,” Biomed. Opt. Express 3(6), 1455–1464 (2012).
[Crossref]

Gray, M. L.

A. Bourquard, A. Pablo-Trinidad, I. Butterworth, Á. Sánchez-Ferro, C. Cerrato, K. Humala, M. F. Urdiola, C. D. Rio, B. Valles, J. M. Tucker-Schwartz, E. S. Lee, B. J. Vakoc, T. P. Padera, M. J. Ledesma-Carbayo, Y.-B. Chen, E. P. Hochberg, M. L. Gray, and C. Castro-González, “Non-invasive detection of severe neutropenia in chemotherapy patients by optical imaging of nailfold microcirculation,” Sci. Rep. 8(1), 5301 (2018).
[Crossref]

Guy Jr., G. P.

E. Tai, G. P. Guy Jr., A. Dunbar, and L. C. Richardson, “Cost of Cancer-Related Neutropenia or Fever Hospitalizations, United States 2012,” J. Oncol. Pract. 13(6), e552–e561 (2017).
[Crossref]

Hochberg, E. P.

A. Bourquard, A. Pablo-Trinidad, I. Butterworth, Á. Sánchez-Ferro, C. Cerrato, K. Humala, M. F. Urdiola, C. D. Rio, B. Valles, J. M. Tucker-Schwartz, E. S. Lee, B. J. Vakoc, T. P. Padera, M. J. Ledesma-Carbayo, Y.-B. Chen, E. P. Hochberg, M. L. Gray, and C. Castro-González, “Non-invasive detection of severe neutropenia in chemotherapy patients by optical imaging of nailfold microcirculation,” Sci. Rep. 8(1), 5301 (2018).
[Crossref]

Hu, C.

M. E. Kandel, C. Hu, G. N. Kouzehgarani, E. Min, K. M. Sullivan, H. Kong, J. M. Li, D. N. Robson, M. U. Gillette, C. Best-Popescu, and G. Popescu, “Epi-illumination gradient light interference microscopy for imaging opaque structures,” Nat. Commun. 10(1), 4691 (2019).
[Crossref]

Humala, K.

A. Bourquard, A. Pablo-Trinidad, I. Butterworth, Á. Sánchez-Ferro, C. Cerrato, K. Humala, M. F. Urdiola, C. D. Rio, B. Valles, J. M. Tucker-Schwartz, E. S. Lee, B. J. Vakoc, T. P. Padera, M. J. Ledesma-Carbayo, Y.-B. Chen, E. P. Hochberg, M. L. Gray, and C. Castro-González, “Non-invasive detection of severe neutropenia in chemotherapy patients by optical imaging of nailfold microcirculation,” Sci. Rep. 8(1), 5301 (2018).
[Crossref]

Iacono, W. G.

C. E. Curtis, W. G. Iacono, and M. Beiser, “Relationship between Nailfold Plexus Visibility and Clinical, Neuropsychological, and Brain Structural Measures in Schizoprenia,” Soc. Biol. Psychiatry 46(1), 102–109 (1999).
[Crossref]

Jadwat, Y.

L. Feller, A. Masilana, R. A. G. Khammissa, M. Altini, Y. Jadwat, and J. Lemmer, “Melanin: the biophysiology of oral melanocytes and physiological oral pigmentation,” Head & Face Med. 10(1), 8 (2014).
[Crossref]

Jung, P.

P. Jung and F. Trautinger, “Capillaroscopy,” J. Ger. Soc. Dermatol. 11(8), 731–736 (2013).
[Crossref]

Kandel, M. E.

M. E. Kandel, C. Hu, G. N. Kouzehgarani, E. Min, K. M. Sullivan, H. Kong, J. M. Li, D. N. Robson, M. U. Gillette, C. Best-Popescu, and G. Popescu, “Epi-illumination gradient light interference microscopy for imaging opaque structures,” Nat. Commun. 10(1), 4691 (2019).
[Crossref]

Khammissa, R. A. G.

L. Feller, A. Masilana, R. A. G. Khammissa, M. Altini, Y. Jadwat, and J. Lemmer, “Melanin: the biophysiology of oral melanocytes and physiological oral pigmentation,” Head & Face Med. 10(1), 8 (2014).
[Crossref]

Kleinfeld, D.

P. Tsai, N. Nishimura, E. Yoder, E. Dolnick, G. Allen White, and D. Kleinfeld, Principles, Design,and Construction of a Two-Photon Laser-Scanning Microscope for In Vitro and In Vivo Brain Imaging, May 2014 (2002).

Kong, H.

M. E. Kandel, C. Hu, G. N. Kouzehgarani, E. Min, K. M. Sullivan, H. Kong, J. M. Li, D. N. Robson, M. U. Gillette, C. Best-Popescu, and G. Popescu, “Epi-illumination gradient light interference microscopy for imaging opaque structures,” Nat. Commun. 10(1), 4691 (2019).
[Crossref]

Kouzehgarani, G. N.

M. E. Kandel, C. Hu, G. N. Kouzehgarani, E. Min, K. M. Sullivan, H. Kong, J. M. Li, D. N. Robson, M. U. Gillette, C. Best-Popescu, and G. Popescu, “Epi-illumination gradient light interference microscopy for imaging opaque structures,” Nat. Commun. 10(1), 4691 (2019).
[Crossref]

Kraft, M.

S. Prestin, S. Rothschild, C. S. Betz, and M. Kraft, “Measurement of epithelial thickness within the oral cavity using optical coherence tomography,” Head and Neck 34(12), 1777–1781 (2012).
[Crossref]

Künzi, M.

D. Carpentras, T. Laforest, M. Künzi, and C. Moser, “Effect of backscattering in phase contrast imaging of the retina,” Biomed. Opt. Express 26(6), 6785–6795 (2018).
[Crossref]

Kuo, S. L.

C. H. Chang, R. K. Tsai, W. C. Wu, S. L. Kuo, and H. S. Yu, “Use of Dynamic Capillaroscopy for Studying Cutaneous Microcirculation in Patients with Diabetes Mellitus,” Microvasc. Res. 53(2), 121–127 (1997).
[Crossref]

Kurtzberg, J.

Laforest, T.

D. Carpentras, T. Laforest, M. Künzi, and C. Moser, “Effect of backscattering in phase contrast imaging of the retina,” Biomed. Opt. Express 26(6), 6785–6795 (2018).
[Crossref]

Ledesma-Carbayo, M. J.

A. Bourquard, A. Pablo-Trinidad, I. Butterworth, Á. Sánchez-Ferro, C. Cerrato, K. Humala, M. F. Urdiola, C. D. Rio, B. Valles, J. M. Tucker-Schwartz, E. S. Lee, B. J. Vakoc, T. P. Padera, M. J. Ledesma-Carbayo, Y.-B. Chen, E. P. Hochberg, M. L. Gray, and C. Castro-González, “Non-invasive detection of severe neutropenia in chemotherapy patients by optical imaging of nailfold microcirculation,” Sci. Rep. 8(1), 5301 (2018).
[Crossref]

Ledwig, P.

Lee, E. S.

A. Bourquard, A. Pablo-Trinidad, I. Butterworth, Á. Sánchez-Ferro, C. Cerrato, K. Humala, M. F. Urdiola, C. D. Rio, B. Valles, J. M. Tucker-Schwartz, E. S. Lee, B. J. Vakoc, T. P. Padera, M. J. Ledesma-Carbayo, Y.-B. Chen, E. P. Hochberg, M. L. Gray, and C. Castro-González, “Non-invasive detection of severe neutropenia in chemotherapy patients by optical imaging of nailfold microcirculation,” Sci. Rep. 8(1), 5301 (2018).
[Crossref]

Lefford, F.

F. Lefford and J. C. W. Edwards, “Nailfold capillary microscopy in connective tissue disease: a quantitative morphological analysis,” Ann. Rheum. Dis. 45(9), 741–749 (1986).
[Crossref]

Lemmer, J.

L. Feller, A. Masilana, R. A. G. Khammissa, M. Altini, Y. Jadwat, and J. Lemmer, “Melanin: the biophysiology of oral melanocytes and physiological oral pigmentation,” Head & Face Med. 10(1), 8 (2014).
[Crossref]

Li, J. M.

M. E. Kandel, C. Hu, G. N. Kouzehgarani, E. Min, K. M. Sullivan, H. Kong, J. M. Li, D. N. Robson, M. U. Gillette, C. Best-Popescu, and G. Popescu, “Epi-illumination gradient light interference microscopy for imaging opaque structures,” Nat. Commun. 10(1), 4691 (2019).
[Crossref]

Liu, T.-M.

Lyman, G. H.

J. Crawford, D. C. Dale, and G. H. Lyman, “Chemotherapy-Induced Neutropenia. Risks, consequences, and new directions for its management,” Cancer 100(2), 228–237 (2004).
[Crossref]

M. Lowik, C. W. G.

M. Sterenborg, H. J. C.

Masilana, A.

L. Feller, A. Masilana, R. A. G. Khammissa, M. Altini, Y. Jadwat, and J. Lemmer, “Melanin: the biophysiology of oral melanocytes and physiological oral pigmentation,” Head & Face Med. 10(1), 8 (2014).
[Crossref]

Mertz, J.

T. N. Ford and J. Mertz, “Video-rate imaging of microcirculation with single-exposure oblique back-illumination microscopy,” J. Biomed. Opt. 18(6), 066007 (2013).
[Crossref]

T. N. Ford, K. K. Chu, and J. Mertz, “Phase-gradient microscopy in thick tissue with oblique back-illumination,” Nat. Methods 9(12), 1195–1197 (2012).
[Crossref]

Min, E.

M. E. Kandel, C. Hu, G. N. Kouzehgarani, E. Min, K. M. Sullivan, H. Kong, J. M. Li, D. N. Robson, M. U. Gillette, C. Best-Popescu, and G. Popescu, “Epi-illumination gradient light interference microscopy for imaging opaque structures,” Nat. Commun. 10(1), 4691 (2019).
[Crossref]

Minai, L.

M. M. Winer, A. Zeidan, D. Yeheskely-Hayon, L. Golan, L. Minai, E. J. Dann, and D. Yelin, “In vivo noninvasive microscopy of human leucocytes,” Sci. Rep. 7(1), 13031–8 (2017).
[Crossref]

L. Golan, D. Yeheskely-Hayon, L. Minai, and E. J. Dann, “Noninvasive imaging of flowing blood cells using label-free spectrally encoded flow cytometry,” Biomed. Opt. Express 3(6), 1455–1464 (2012).
[Crossref]

Mol, I. M.

Moser, C.

D. Carpentras, T. Laforest, M. Künzi, and C. Moser, “Effect of backscattering in phase contrast imaging of the retina,” Biomed. Opt. Express 26(6), 6785–6795 (2018).
[Crossref]

Nishimura, N.

P. Tsai, N. Nishimura, E. Yoder, E. Dolnick, G. Allen White, and D. Kleinfeld, Principles, Design,and Construction of a Two-Photon Laser-Scanning Microscope for In Vitro and In Vivo Brain Imaging, May 2014 (2002).

Pablo-Trinidad, A.

A. Bourquard, A. Pablo-Trinidad, I. Butterworth, Á. Sánchez-Ferro, C. Cerrato, K. Humala, M. F. Urdiola, C. D. Rio, B. Valles, J. M. Tucker-Schwartz, E. S. Lee, B. J. Vakoc, T. P. Padera, M. J. Ledesma-Carbayo, Y.-B. Chen, E. P. Hochberg, M. L. Gray, and C. Castro-González, “Non-invasive detection of severe neutropenia in chemotherapy patients by optical imaging of nailfold microcirculation,” Sci. Rep. 8(1), 5301 (2018).
[Crossref]

Padera, T. P.

A. Bourquard, A. Pablo-Trinidad, I. Butterworth, Á. Sánchez-Ferro, C. Cerrato, K. Humala, M. F. Urdiola, C. D. Rio, B. Valles, J. M. Tucker-Schwartz, E. S. Lee, B. J. Vakoc, T. P. Padera, M. J. Ledesma-Carbayo, Y.-B. Chen, E. P. Hochberg, M. L. Gray, and C. Castro-González, “Non-invasive detection of severe neutropenia in chemotherapy patients by optical imaging of nailfold microcirculation,” Sci. Rep. 8(1), 5301 (2018).
[Crossref]

Popescu, G.

M. E. Kandel, C. Hu, G. N. Kouzehgarani, E. Min, K. M. Sullivan, H. Kong, J. M. Li, D. N. Robson, M. U. Gillette, C. Best-Popescu, and G. Popescu, “Epi-illumination gradient light interference microscopy for imaging opaque structures,” Nat. Commun. 10(1), 4691 (2019).
[Crossref]

Presland, R. B.

R. B. Presland and B. A. Dale, “Epithelial Structural Proteins of the Skin and Oral Cavity: Function in Health and Disease,” Critical Rev. Oral Biol. Medicine 11(4), 383–408 (2000).
[Crossref]

Prestin, S.

S. Prestin, S. Rothschild, C. S. Betz, and M. Kraft, “Measurement of epithelial thickness within the oral cavity using optical coherence tomography,” Head and Neck 34(12), 1777–1781 (2012).
[Crossref]

Rajadhyaksha, M.

Richardson, L. C.

E. Tai, G. P. Guy Jr., A. Dunbar, and L. C. Richardson, “Cost of Cancer-Related Neutropenia or Fever Hospitalizations, United States 2012,” J. Oncol. Pract. 13(6), e552–e561 (2017).
[Crossref]

Rio, C. D.

A. Bourquard, A. Pablo-Trinidad, I. Butterworth, Á. Sánchez-Ferro, C. Cerrato, K. Humala, M. F. Urdiola, C. D. Rio, B. Valles, J. M. Tucker-Schwartz, E. S. Lee, B. J. Vakoc, T. P. Padera, M. J. Ledesma-Carbayo, Y.-B. Chen, E. P. Hochberg, M. L. Gray, and C. Castro-González, “Non-invasive detection of severe neutropenia in chemotherapy patients by optical imaging of nailfold microcirculation,” Sci. Rep. 8(1), 5301 (2018).
[Crossref]

Robinson, D. J.

Robles, F. E.

Robson, D. N.

M. E. Kandel, C. Hu, G. N. Kouzehgarani, E. Min, K. M. Sullivan, H. Kong, J. M. Li, D. N. Robson, M. U. Gillette, C. Best-Popescu, and G. Popescu, “Epi-illumination gradient light interference microscopy for imaging opaque structures,” Nat. Commun. 10(1), 4691 (2019).
[Crossref]

Rothschild, S.

S. Prestin, S. Rothschild, C. S. Betz, and M. Kraft, “Measurement of epithelial thickness within the oral cavity using optical coherence tomography,” Head and Neck 34(12), 1777–1781 (2012).
[Crossref]

Sánchez-Ferro, Á.

A. Bourquard, A. Pablo-Trinidad, I. Butterworth, Á. Sánchez-Ferro, C. Cerrato, K. Humala, M. F. Urdiola, C. D. Rio, B. Valles, J. M. Tucker-Schwartz, E. S. Lee, B. J. Vakoc, T. P. Padera, M. J. Ledesma-Carbayo, Y.-B. Chen, E. P. Hochberg, M. L. Gray, and C. Castro-González, “Non-invasive detection of severe neutropenia in chemotherapy patients by optical imaging of nailfold microcirculation,” Sci. Rep. 8(1), 5301 (2018).
[Crossref]

Sarode, R.

D. Agrawal and R. Sarode, “Complete Blood Count or Complete Blood Count with Differential: What’s the Difference?” The Am. J. Medicine 130(8), 915–916 (2017).
[Crossref]

Scully, C.

A. W. Barrett and C. Scully, “Human oral mucosal melanocytes: a review,” J. Oral Pathol. Med. 23(3), 97–103 (1994).
[Crossref]

Sghayyer, M.

Shi, L.

U. Baran, L. Shi, and R. K. Wang, “Capillary blood flow imaging within human finger cuticle using optical microangiography,” J. Biophotonics 8(1-2), 46–51 (2015).
[Crossref]

Snoeks, T. J. A.

Sullivan, K. M.

M. E. Kandel, C. Hu, G. N. Kouzehgarani, E. Min, K. M. Sullivan, H. Kong, J. M. Li, D. N. Robson, M. U. Gillette, C. Best-Popescu, and G. Popescu, “Epi-illumination gradient light interference microscopy for imaging opaque structures,” Nat. Commun. 10(1), 4691 (2019).
[Crossref]

Tai, E.

E. Tai, G. P. Guy Jr., A. Dunbar, and L. C. Richardson, “Cost of Cancer-Related Neutropenia or Fever Hospitalizations, United States 2012,” J. Oncol. Pract. 13(6), e552–e561 (2017).
[Crossref]

Trautinger, F.

P. Jung and F. Trautinger, “Capillaroscopy,” J. Ger. Soc. Dermatol. 11(8), 731–736 (2013).
[Crossref]

Tsai, P.

P. Tsai, N. Nishimura, E. Yoder, E. Dolnick, G. Allen White, and D. Kleinfeld, Principles, Design,and Construction of a Two-Photon Laser-Scanning Microscope for In Vitro and In Vivo Brain Imaging, May 2014 (2002).

Tsai, R. K.

C. H. Chang, R. K. Tsai, W. C. Wu, S. L. Kuo, and H. S. Yu, “Use of Dynamic Capillaroscopy for Studying Cutaneous Microcirculation in Patients with Diabetes Mellitus,” Microvasc. Res. 53(2), 121–127 (1997).
[Crossref]

Tucker-Schwartz, J. M.

A. Bourquard, A. Pablo-Trinidad, I. Butterworth, Á. Sánchez-Ferro, C. Cerrato, K. Humala, M. F. Urdiola, C. D. Rio, B. Valles, J. M. Tucker-Schwartz, E. S. Lee, B. J. Vakoc, T. P. Padera, M. J. Ledesma-Carbayo, Y.-B. Chen, E. P. Hochberg, M. L. Gray, and C. Castro-González, “Non-invasive detection of severe neutropenia in chemotherapy patients by optical imaging of nailfold microcirculation,” Sci. Rep. 8(1), 5301 (2018).
[Crossref]

Urdiola, M. F.

A. Bourquard, A. Pablo-Trinidad, I. Butterworth, Á. Sánchez-Ferro, C. Cerrato, K. Humala, M. F. Urdiola, C. D. Rio, B. Valles, J. M. Tucker-Schwartz, E. S. Lee, B. J. Vakoc, T. P. Padera, M. J. Ledesma-Carbayo, Y.-B. Chen, E. P. Hochberg, M. L. Gray, and C. Castro-González, “Non-invasive detection of severe neutropenia in chemotherapy patients by optical imaging of nailfold microcirculation,” Sci. Rep. 8(1), 5301 (2018).
[Crossref]

Vakoc, B. J.

A. Bourquard, A. Pablo-Trinidad, I. Butterworth, Á. Sánchez-Ferro, C. Cerrato, K. Humala, M. F. Urdiola, C. D. Rio, B. Valles, J. M. Tucker-Schwartz, E. S. Lee, B. J. Vakoc, T. P. Padera, M. J. Ledesma-Carbayo, Y.-B. Chen, E. P. Hochberg, M. L. Gray, and C. Castro-González, “Non-invasive detection of severe neutropenia in chemotherapy patients by optical imaging of nailfold microcirculation,” Sci. Rep. 8(1), 5301 (2018).
[Crossref]

Valles, B.

A. Bourquard, A. Pablo-Trinidad, I. Butterworth, Á. Sánchez-Ferro, C. Cerrato, K. Humala, M. F. Urdiola, C. D. Rio, B. Valles, J. M. Tucker-Schwartz, E. S. Lee, B. J. Vakoc, T. P. Padera, M. J. Ledesma-Carbayo, Y.-B. Chen, E. P. Hochberg, M. L. Gray, and C. Castro-González, “Non-invasive detection of severe neutropenia in chemotherapy patients by optical imaging of nailfold microcirculation,” Sci. Rep. 8(1), 5301 (2018).
[Crossref]

van der Ploeg-van den Heuvel, A.

van Leeuwen-van Zaane, F.

Wang, R. K.

U. Baran, L. Shi, and R. K. Wang, “Capillary blood flow imaging within human finger cuticle using optical microangiography,” J. Biophotonics 8(1-2), 46–51 (2015).
[Crossref]

Webb, R. H.

Widness, J. A.

J. A. Widness, “Pathophysiology of Anaemia during the Neonatal Period, Including Anaemia of Prematurity,” Neoreviews 9(11), e520–e525 (2008).
[Crossref]

Winer, M. M.

M. M. Winer, A. Zeidan, D. Yeheskely-Hayon, L. Golan, L. Minai, E. J. Dann, and D. Yelin, “In vivo noninvasive microscopy of human leucocytes,” Sci. Rep. 7(1), 13031–8 (2017).
[Crossref]

Wu, W. C.

C. H. Chang, R. K. Tsai, W. C. Wu, S. L. Kuo, and H. S. Yu, “Use of Dynamic Capillaroscopy for Studying Cutaneous Microcirculation in Patients with Diabetes Mellitus,” Microvasc. Res. 53(2), 121–127 (1997).
[Crossref]

Yeheskely-Hayon, D.

M. M. Winer, A. Zeidan, D. Yeheskely-Hayon, L. Golan, L. Minai, E. J. Dann, and D. Yelin, “In vivo noninvasive microscopy of human leucocytes,” Sci. Rep. 7(1), 13031–8 (2017).
[Crossref]

L. Golan, D. Yeheskely-Hayon, L. Minai, and E. J. Dann, “Noninvasive imaging of flowing blood cells using label-free spectrally encoded flow cytometry,” Biomed. Opt. Express 3(6), 1455–1464 (2012).
[Crossref]

Yelin, D.

M. M. Winer, A. Zeidan, D. Yeheskely-Hayon, L. Golan, L. Minai, E. J. Dann, and D. Yelin, “In vivo noninvasive microscopy of human leucocytes,” Sci. Rep. 7(1), 13031–8 (2017).
[Crossref]

Yoder, E.

P. Tsai, N. Nishimura, E. Yoder, E. Dolnick, G. Allen White, and D. Kleinfeld, Principles, Design,and Construction of a Two-Photon Laser-Scanning Microscope for In Vitro and In Vivo Brain Imaging, May 2014 (2002).

Yu, H. S.

C. H. Chang, R. K. Tsai, W. C. Wu, S. L. Kuo, and H. S. Yu, “Use of Dynamic Capillaroscopy for Studying Cutaneous Microcirculation in Patients with Diabetes Mellitus,” Microvasc. Res. 53(2), 121–127 (1997).
[Crossref]

Zeidan, A.

M. M. Winer, A. Zeidan, D. Yeheskely-Hayon, L. Golan, L. Minai, E. J. Dann, and D. Yelin, “In vivo noninvasive microscopy of human leucocytes,” Sci. Rep. 7(1), 13031–8 (2017).
[Crossref]

Ann. Rheum. Dis. (1)

F. Lefford and J. C. W. Edwards, “Nailfold capillary microscopy in connective tissue disease: a quantitative morphological analysis,” Ann. Rheum. Dis. 45(9), 741–749 (1986).
[Crossref]

Appl. Opt. (1)

Arch. Intern. Med. (1)

G. E. Brown, “The Skin Capillaries in Raynaud’s Disease,” Arch. Intern. Med. 35(1), 56–73 (1925).
[Crossref]

Biomed. Opt. Express (6)

Cancer (1)

J. Crawford, D. C. Dale, and G. H. Lyman, “Chemotherapy-Induced Neutropenia. Risks, consequences, and new directions for its management,” Cancer 100(2), 228–237 (2004).
[Crossref]

Critical Rev. Oral Biol. Medicine (1)

R. B. Presland and B. A. Dale, “Epithelial Structural Proteins of the Skin and Oral Cavity: Function in Health and Disease,” Critical Rev. Oral Biol. Medicine 11(4), 383–408 (2000).
[Crossref]

Head & Face Med. (1)

L. Feller, A. Masilana, R. A. G. Khammissa, M. Altini, Y. Jadwat, and J. Lemmer, “Melanin: the biophysiology of oral melanocytes and physiological oral pigmentation,” Head & Face Med. 10(1), 8 (2014).
[Crossref]

Head and Neck (1)

S. Prestin, S. Rothschild, C. S. Betz, and M. Kraft, “Measurement of epithelial thickness within the oral cavity using optical coherence tomography,” Head and Neck 34(12), 1777–1781 (2012).
[Crossref]

J. Biomed. Opt. (1)

T. N. Ford and J. Mertz, “Video-rate imaging of microcirculation with single-exposure oblique back-illumination microscopy,” J. Biomed. Opt. 18(6), 066007 (2013).
[Crossref]

J. Biophotonics (1)

U. Baran, L. Shi, and R. K. Wang, “Capillary blood flow imaging within human finger cuticle using optical microangiography,” J. Biophotonics 8(1-2), 46–51 (2015).
[Crossref]

J. Ger. Soc. Dermatol. (1)

P. Jung and F. Trautinger, “Capillaroscopy,” J. Ger. Soc. Dermatol. 11(8), 731–736 (2013).
[Crossref]

J. Oncol. Pract. (1)

E. Tai, G. P. Guy Jr., A. Dunbar, and L. C. Richardson, “Cost of Cancer-Related Neutropenia or Fever Hospitalizations, United States 2012,” J. Oncol. Pract. 13(6), e552–e561 (2017).
[Crossref]

J. Oral Pathol. Med. (1)

A. W. Barrett and C. Scully, “Human oral mucosal melanocytes: a review,” J. Oral Pathol. Med. 23(3), 97–103 (1994).
[Crossref]

Microcirculation (1)

I. M. Braverman, “The cutaneous microcirculation: Ultrastructure and microanatomical organization,” Microcirculation 4(3), 329–340 (1997).
[Crossref]

Microvasc. Res. (1)

C. H. Chang, R. K. Tsai, W. C. Wu, S. L. Kuo, and H. S. Yu, “Use of Dynamic Capillaroscopy for Studying Cutaneous Microcirculation in Patients with Diabetes Mellitus,” Microvasc. Res. 53(2), 121–127 (1997).
[Crossref]

Nat. Commun. (1)

M. E. Kandel, C. Hu, G. N. Kouzehgarani, E. Min, K. M. Sullivan, H. Kong, J. M. Li, D. N. Robson, M. U. Gillette, C. Best-Popescu, and G. Popescu, “Epi-illumination gradient light interference microscopy for imaging opaque structures,” Nat. Commun. 10(1), 4691 (2019).
[Crossref]

Nat. Methods (1)

T. N. Ford, K. K. Chu, and J. Mertz, “Phase-gradient microscopy in thick tissue with oblique back-illumination,” Nat. Methods 9(12), 1195–1197 (2012).
[Crossref]

Neoreviews (1)

J. A. Widness, “Pathophysiology of Anaemia during the Neonatal Period, Including Anaemia of Prematurity,” Neoreviews 9(11), e520–e525 (2008).
[Crossref]

Sci. Rep. (2)

A. Bourquard, A. Pablo-Trinidad, I. Butterworth, Á. Sánchez-Ferro, C. Cerrato, K. Humala, M. F. Urdiola, C. D. Rio, B. Valles, J. M. Tucker-Schwartz, E. S. Lee, B. J. Vakoc, T. P. Padera, M. J. Ledesma-Carbayo, Y.-B. Chen, E. P. Hochberg, M. L. Gray, and C. Castro-González, “Non-invasive detection of severe neutropenia in chemotherapy patients by optical imaging of nailfold microcirculation,” Sci. Rep. 8(1), 5301 (2018).
[Crossref]

M. M. Winer, A. Zeidan, D. Yeheskely-Hayon, L. Golan, L. Minai, E. J. Dann, and D. Yelin, “In vivo noninvasive microscopy of human leucocytes,” Sci. Rep. 7(1), 13031–8 (2017).
[Crossref]

Soc. Biol. Psychiatry (1)

C. E. Curtis, W. G. Iacono, and M. Beiser, “Relationship between Nailfold Plexus Visibility and Clinical, Neuropsychological, and Brain Structural Measures in Schizoprenia,” Soc. Biol. Psychiatry 46(1), 102–109 (1999).
[Crossref]

The Am. J. Medicine (1)

D. Agrawal and R. Sarode, “Complete Blood Count or Complete Blood Count with Differential: What’s the Difference?” The Am. J. Medicine 130(8), 915–916 (2017).
[Crossref]

Other (1)

P. Tsai, N. Nishimura, E. Yoder, E. Dolnick, G. Allen White, and D. Kleinfeld, Principles, Design,and Construction of a Two-Photon Laser-Scanning Microscope for In Vitro and In Vivo Brain Imaging, May 2014 (2002).

Supplementary Material (5)

NameDescription
» Visualization 1       Red blood cells and platelets passing through a human ventral tongue capillary. Scale bar 10µm.
» Visualization 2       A small ~600nm diameter lipid particle is visible passing through a human ventral tongue capillary. Scale bar is 10µm.
» Visualization 3       Red blood and white blood cells passing through a vessel in human ventral tongue. Scale bar is 10µm.
» Visualization 4       Two white blood cells with different granularity passing through a human ventral tongue capillary. Scale bar is 10µm.
» Visualization 5       A granulocyte passes through a vessel in human ventral tongue. Scale bar is 10µm.

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Figures (7)

Fig. 1.
Fig. 1. (a) Oblique back-illumination capillaroscope optical layout. An LED is placed at the focal plane of a collimating lens (CL), and imaged critically into a capillary bed by a 40x objective lens. Scattered light is reflected off a beamsplitter (BS) and focused onto a laterally-displaced sCMOS by a tube lens (TL). (b) Oblique illumination is produced by offsetting the field of view (FOV) from the image of the LED. The camera displacement ($\delta x^{\prime }$) causes a 1/40x displacement in object space ($\delta x$). (c)-(d) An intensity gradient is produced, making the illumination-detection offset vary with distance across the full FOV for a fixed $\delta x$ = 208 $\mu$m.
Fig. 2.
Fig. 2. (a) Image of pneumatic objective cap, and (b) mechanical drawing (mm units).
Fig. 3.
Fig. 3. Imaging a single capillary translated across the full FOV. (a) Full FOV with intensity gradient outlining where 90 x 90 $\mu$m regions of interest were acquired: cyan (b), magenta (c), and yellow (d). (b) Red blood cells close to the intensity peak (left edge of sensor) demonstrate only absorption contrast, (c) phase contrast is maximized near the center of the full FOV, and degrades due to low signal at large displacements, (d). (e) & (f) Enlarged regions of interest (15 x 15 $\mu$m) at locations of minimum and maximum phase contrast, respectively, with example normalized intensity plot profiles shown for each, (g). (h) Overall trend of distance across FOV vs. phase contrast demonstrates highest contrast at approximately 200-250 $\mu$m illumination-detection separation.
Fig. 4.
Fig. 4. Oblique back-illumination capillaroscopy can resolve red blood cells (RBCs), white blood cells (WBCs), platelets, and potentially chylomicrons or other lipid particles within human ventral tongue capillaries. (a)-(d) A superficial capillary within a dermal papilla surrounded by stratum spinosum shows red blood cells (a)-(b), platelets (b)-(c), and lipid particles (d) (see Visualization 1 and Visualization 2). (e)-(h) Thousands of red blood cells pass rapidly through larger vessels with intermittent white blood cells of various size and granularity (see Visualization 3). (i)-(l) Granular and agranular white blood cells of varying size are visible across multiple different capillaries (see Visualization 4 and Visualization 5).
Fig. 5.
Fig. 5. (a)-(c) Imaging of three human subjects demonstrates robustness of ventral tongue imaging to differences in Fitzpatrick skin phototype. (e)-(g) enlarged regions of interest. (d) Plot profiles across two adjacent stacked red blood cells in each image. (h) Enlarged plot profiles across adjacent red blood cell interface (dashed lines).
Fig. 6.
Fig. 6. Images of a stationary 6 $\mu$m phase particle in a back-scattering phantom (a) shows optimal phase contrast at 240 $\mu$m of LED displacement (b). Example images of this particle are shown for (c) on-axis LED imaging and (d) 240 $\mu$m LED displacement. (e), (f) When the illumination is diametrically opposed ($\pm 240 \mu$m displacement), traditionally OBM allows the calculation of (g) absorption-only (addition image), and (h) phase-only (subtraction image) contrast.
Fig. 7.
Fig. 7. (a) Schematic of dual source oblique back-illumination capillaroscope using diametrically opposed red and amber LEDs. The two sources are combined and later separated by two identical dichroic mirrors (DM) and projected onto two identical sensors. (b) Enlarged schematic of illumination technique in sample space where critically imaged, offset LEDs produce net diametrically opposed oblique illumination. (c) Red channel image, (d) amber channel image, (e) absorption-only (addition) image, (f) phase-only (subtraction) image, and (g) plot profile through red blood cell in phase-only image demonstrates characteristic phase contrast from oblique illumination.

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