Proper treatment of deep seated brain tumors requires correct histological diagnosis which unambiguously necessitates biopsy sampling. Stereotactically guided sampling of biopsies is widely used but bears the danger of incorrect sampling locations and damage to intracerebral blood vessels. Here, we present a minimally invasive contact endoscopic probe that can be inserted into the tissue inside a standard biopsy needle and allows for fluorescence detection of both tumorous tissue and intracerebral blood vessels. Outer diameter of our contact probe is smaller than 1.5 mm, field-of-view in the range of several hundred microns; the optical design allows for simultaneous detection and visualization of tissue autofluorescence and selective fluorescence signals from deep seated brain tumors and vasculature as shown on in vivo animal models. We demonstrate the tumor detection capability during stereotactic needle insertion in a clinical pilot trial. Using our probe, we expect stereotactic interventions to become safer and more precise and the technology might ultimately be used also for various other kinds of applications.

© 2012 OSA

1. Brain Tumor Primer - a comprehensive introduction to brain tumors (American Brain Tumor Association, 2010).
2. D. Kondziolka, A. D. Firlik, and L. D. Lunsford, “Complications of stereotactic brain surgery,” Neurol. Clin.16(1), 35–54 (1998). [CrossRef] [PubMed]
3. B. A. Flusberg, E. D. Cocker, W. Piyawattanametha, J. C. Jung, E. L. Cheung, and M. J. Schnitzer, “Fiber-optic fluorescence imaging,” Nat. Methods2(12), 941–950 (2005). [CrossRef] [PubMed]
4. F. Helmchen, “Miniaturization of fluorescence microscopes using fibre optics,” Exp. Physiol.87(6), 737–745 (2002). [CrossRef] [PubMed]
5. B. A. Flusberg, A. Nimmerjahn, E. D. Cocker, E. A. Mukamel, R. P. Barretto, T. H. Ko, L. D. Burns, J. C. Jung, and M. J. Schnitzer, “High-speed, miniaturized fluorescence microscopy in freely moving mice,” Nat. Methods5(11), 935–938 (2008). [CrossRef] [PubMed]
6. R. P. Barretto, T. H. Ko, J. C. Jung, T. J. Wang, G. Capps, A. C. Waters, Y. Ziv, A. Attardo, L. Recht, and M. J. Schnitzer, “Time-lapse imaging of disease progression in deep brain areas using fluorescence microendoscopy,” Nat. Med.17(2), 223–228 (2011). [CrossRef] [PubMed]
7. T. J. Muldoon, S. Anandasabapathy, D. Maru, and R. Richards-Kortum, “High-resolution imaging in Barrett’s esophagus: a novel, low-cost endoscopic microscope,” Gastrointest. Endosc.68(4), 737–744 (2008). [CrossRef] [PubMed]
8. K. J. Rosbach, D. Shin, T. J. Muldoon, M. A. Quraishi, L. P. Middleton, K. K. Hunt, F. Meric-Bernstam, T. K. Yu, R. R. Richards-Kortum, and W. Yang, “High-resolution fiber optic microscopy with fluorescent contrast enhancement for the identification of axillary lymph node metastases in breast cancer: a pilot study,” Biomed. Opt. Express1(3), 911–922 (2010). [CrossRef] [PubMed]
9. W. Stummer, H. Stepp, G. Möller, A. Ehrhardt, M. Leonhard, and H. J. Reulen, “Technical principles for protoporphyrin-IX-fluorescence guided microsurgical resection of malignant glioma tissue,” Acta Neurochir. (Wien)140(10), 995–1000 (1998). [CrossRef] [PubMed]
10. R. Ritz, G. C. Feigl, M. U. Schuhmann, A. Ehrhardt, S. Danz, S. Noell, A. Bornemann, and M. S. Tatagiba, “Use of 5-ALA fluorescence guided endoscopic biopsy of a deep-seated primary malignant brain tumor,” J. Neurosurg.114(5), 1410–1413 (2011). [PubMed]
11. K. S. Samkoe, S. L. Gibbs-Strauss, H. H. Yang, S. Khan Hekmatyar, P. Jack Hoopes, J. A. O’Hara, R. A. Kauppinen, and B. W. Pogue, “Protoporphyrin IX fluorescence contrast in invasive glioblastomas is linearly correlated with Gd enhanced magnetic resonance image contrast but has higher diagnostic accuracy,” J. Biomed. Opt.16(9), 096008 (2011). [CrossRef] [PubMed]
12. S. Moriuchi, K. Yamada, M. Dehara, Y. Teramoto, T. Soda, M. Imakita, and M. Taneda, “Use of 5-aminolevulinic acid for the confirmation of deep-seated brain tumors during stereotactic biopsy,” J. Neurosurg.115(2), 278–280 (2011). [CrossRef] [PubMed]
13. G. Widhalm, G. Minchev, A. Woehrer, M. Preusser, B. Kiesel, J. Furtner, A. Mert, A. Ieva, B. Tomanek, D. Prayer, C. Marosi, J. A. Hainfellner, E. Knosp, and S. Wolfsberger, “Strong 5-aminolevulinic acid-induced fluorescence is a novel intraoperative marker for representative tissue samples in stereotactic brain tumor biopsies,” Neurosurg. Rev.35(3), 381–391, discussion 391 (2012). [CrossRef] [PubMed]
14. T. Kuroiwa, Y. Kajimoto, and T. Ohta, “Development and clinical application of near-infrared surgical microscope: preliminary report,” Minim. Invasive Neurosurg.44(4), 240–242 (2001). [CrossRef] [PubMed]
15. A. Raabe, J. Beck, R. Gerlach, M. Zimmermann, and V. Seifert, “Near-infrared indocyanine green video angiography: a new method for intraoperative assessment of vascular flow,” Neurosurgery52(1), 132–139, discussion 139 (2003). [PubMed]
16. T. J. Muldoon, M. C. Pierce, D. L. Nida, M. D. Williams, A. Gillenwater, and R. Richards-Kortum, “Subcellular-resolution molecular imaging within living tissue by fiber microendoscopy,” Opt. Express15(25), 16413–16423 (2007). [CrossRef] [PubMed]
17. K. Irion, “US 7,662,095 (B2) - Endoscope provided with a lighting system and a combined image transmission,” (2010).
18. A. Ehrhardt, H. Stepp, K. M. Irion, W. Stummer, D. Zaak, R. Baumgartner, and A. Hofstetter, “Fluorescence detection of human malignancies using incoherent light systems,” Med. Laser Appl.18(1), 27–35 (2003). [CrossRef]
19. G. A. Wagnières, W. M. Star, and B. C. Wilson, “In vivo fluorescence spectroscopy and imaging for oncological applications,” Photochem. Photobiol.68(5), 603–632 (1998). [PubMed]
20. Y. Kienast, L. von Baumgarten, M. Fuhrmann, W. E. Klinkert, R. Goldbrunner, J. Herms, and F. Winkler, “Real-time imaging reveals the single steps of brain metastasis formation,” Nat. Med.16(1), 116–122 (2010). [CrossRef] [PubMed]
21. F. Winkler, Y. Kienast, M. Fuhrmann, L. Von Baumgarten, S. Burgold, G. Mitteregger, H. Kretzschmar, and J. Herms, “Imaging glioma cell invasion in vivo reveals mechanisms of dissemination and peritumoral angiogenesis,” Glia57(12), 1306–1315 (2009). [CrossRef] [PubMed]
22. S. L. Gibbs-Strauss, J. A. O’Hara, P. J. Hoopes, T. Hasan, and B. W. Pogue, “Noninvasive measurement of aminolevulinic acid-induced protoporphyrin IX fluorescence allowing detection of murine glioma in vivo,” J. Biomed. Opt.14(1), 014007 (2009). [CrossRef] [PubMed]
23. Y. Kang, M. Choi, J. Lee, G. Y. Koh, K. Kwon, and C. Choi, “Quantitative analysis of peripheral tissue perfusion using spatiotemporal molecular dynamics,” PLoS ONE4(1), e4275 (2009). [CrossRef] [PubMed]
24. D. N. Louis, H. Ohgaki, O. D. Wiestler, W. K. Cavenee, P. C. Burger, A. Jouvet, B. W. Scheithauer, and P. Kleihues, “The 2007 WHO classification of tumours of the central nervous system,” Acta Neuropathol.114(2), 97–109 (2007). [CrossRef] [PubMed]
25. S. Eigenbrod, Department of Neuropathology, Ludwig-Maximilians-University Munich, R. Trabold, D. Brucker, C. Erös, B. Suchorska, R. Egensperger, G. Pöpperl, A. Rühm, W. Göbel, H. Kretzschmar, J. C. Tonn, J. Herms, A. Giese, and F. W. Kreth are preparing a manuscript to be called “Molecular stereotactic biopsy technique improves tumor classification in glioma patients.”
26. S. M. Landau, C. Liang, R. T. Kester, T. S. Tkaczyk, and M. R. Descour, “Design and evaluation of an ultra-slim objective for in-vivo deep optical biopsy,” Opt. Express18(5), 4758–4775 (2010). [CrossRef] [PubMed]
27. T. J. Muldoon, D. Roblyer, M. D. Williams, V. M. Stepanek, R. Richards-Kortum, and A. M. Gillenwater, “Noninvasive imaging of oral neoplasia with a high-resolution fiber-optic microendoscope,” Head Neck34(3), 305–312 (2012). [CrossRef] [PubMed]
28. A. Roggan, J. P. Ritz, V. Knappe, C. T. Germer, C. Isbert, D. Schädel, and G. Müller, “Radiation planning for thermal laser treatment,” Med. Laser Appl.16(2), 65–72 (2001). [CrossRef]
29. A. Rühm, Laser-Research-Laboratory, Ludwig-Maximilians-University Munich, W. Göbel, and H. Stepp are preparing a manuscript to be called “Fiber baser fluorescence diagnosis based on PpIX and ICG – Excitation power limitations due to thermal effects in human brain tissue.”
30. W. Göbel, J. N. Kerr, A. Nimmerjahn, and F. Helmchen, “Miniaturized two-photon microscope based on a flexible coherent fiber bundle and a gradient-index lens objective,” Opt. Lett.29(21), 2521–2523 (2004). [CrossRef] [PubMed]
31. A. Johansson, G. Palte, O. Schnell, J. C. Tonn, J. Herms, and H. Stepp, “5-Aminolevulinic acid-induced protoporphyrin IX levels in tissue of human malignant brain tumors,” Photochem. Photobiol.86(6), 1373–1378 (2010). [CrossRef] [PubMed]

Acta Neurochir. (Wien)

• W. Stummer, H. Stepp, G. Möller, A. Ehrhardt, M. Leonhard, and H. J. Reulen, “Technical principles for protoporphyrin-IX-fluorescence guided microsurgical resection of malignant glioma tissue,” Acta Neurochir. (Wien)140(10), 995–1000 (1998). [CrossRef] [PubMed]

Acta Neuropathol.

• D. N. Louis, H. Ohgaki, O. D. Wiestler, W. K. Cavenee, P. C. Burger, A. Jouvet, B. W. Scheithauer, and P. Kleihues, “The 2007 WHO classification of tumours of the central nervous system,” Acta Neuropathol.114(2), 97–109 (2007). [CrossRef] [PubMed]

Biomed. Opt. Express

• K. J. Rosbach, D. Shin, T. J. Muldoon, M. A. Quraishi, L. P. Middleton, K. K. Hunt, F. Meric-Bernstam, T. K. Yu, R. R. Richards-Kortum, and W. Yang, “High-resolution fiber optic microscopy with fluorescent contrast enhancement for the identification of axillary lymph node metastases in breast cancer: a pilot study,” Biomed. Opt. Express1(3), 911–922 (2010). [CrossRef] [PubMed]

Exp. Physiol.

• F. Helmchen, “Miniaturization of fluorescence microscopes using fibre optics,” Exp. Physiol.87(6), 737–745 (2002). [CrossRef] [PubMed]

Gastrointest. Endosc.

• T. J. Muldoon, S. Anandasabapathy, D. Maru, and R. Richards-Kortum, “High-resolution imaging in Barrett’s esophagus: a novel, low-cost endoscopic microscope,” Gastrointest. Endosc.68(4), 737–744 (2008). [CrossRef] [PubMed]

Glia

• F. Winkler, Y. Kienast, M. Fuhrmann, L. Von Baumgarten, S. Burgold, G. Mitteregger, H. Kretzschmar, and J. Herms, “Imaging glioma cell invasion in vivo reveals mechanisms of dissemination and peritumoral angiogenesis,” Glia57(12), 1306–1315 (2009). [CrossRef] [PubMed]

Head Neck

• T. J. Muldoon, D. Roblyer, M. D. Williams, V. M. Stepanek, R. Richards-Kortum, and A. M. Gillenwater, “Noninvasive imaging of oral neoplasia with a high-resolution fiber-optic microendoscope,” Head Neck34(3), 305–312 (2012). [CrossRef] [PubMed]

J. Biomed. Opt.

• S. L. Gibbs-Strauss, J. A. O’Hara, P. J. Hoopes, T. Hasan, and B. W. Pogue, “Noninvasive measurement of aminolevulinic acid-induced protoporphyrin IX fluorescence allowing detection of murine glioma in vivo,” J. Biomed. Opt.14(1), 014007 (2009). [CrossRef] [PubMed]
• K. S. Samkoe, S. L. Gibbs-Strauss, H. H. Yang, S. Khan Hekmatyar, P. Jack Hoopes, J. A. O’Hara, R. A. Kauppinen, and B. W. Pogue, “Protoporphyrin IX fluorescence contrast in invasive glioblastomas is linearly correlated with Gd enhanced magnetic resonance image contrast but has higher diagnostic accuracy,” J. Biomed. Opt.16(9), 096008 (2011). [CrossRef] [PubMed]

J. Neurosurg.

• S. Moriuchi, K. Yamada, M. Dehara, Y. Teramoto, T. Soda, M. Imakita, and M. Taneda, “Use of 5-aminolevulinic acid for the confirmation of deep-seated brain tumors during stereotactic biopsy,” J. Neurosurg.115(2), 278–280 (2011). [CrossRef] [PubMed]
• R. Ritz, G. C. Feigl, M. U. Schuhmann, A. Ehrhardt, S. Danz, S. Noell, A. Bornemann, and M. S. Tatagiba, “Use of 5-ALA fluorescence guided endoscopic biopsy of a deep-seated primary malignant brain tumor,” J. Neurosurg.114(5), 1410–1413 (2011). [PubMed]

Med. Laser Appl.

• A. Ehrhardt, H. Stepp, K. M. Irion, W. Stummer, D. Zaak, R. Baumgartner, and A. Hofstetter, “Fluorescence detection of human malignancies using incoherent light systems,” Med. Laser Appl.18(1), 27–35 (2003). [CrossRef]
• A. Roggan, J. P. Ritz, V. Knappe, C. T. Germer, C. Isbert, D. Schädel, and G. Müller, “Radiation planning for thermal laser treatment,” Med. Laser Appl.16(2), 65–72 (2001). [CrossRef]

Minim. Invasive Neurosurg.

• T. Kuroiwa, Y. Kajimoto, and T. Ohta, “Development and clinical application of near-infrared surgical microscope: preliminary report,” Minim. Invasive Neurosurg.44(4), 240–242 (2001). [CrossRef] [PubMed]

Nat. Med.

• R. P. Barretto, T. H. Ko, J. C. Jung, T. J. Wang, G. Capps, A. C. Waters, Y. Ziv, A. Attardo, L. Recht, and M. J. Schnitzer, “Time-lapse imaging of disease progression in deep brain areas using fluorescence microendoscopy,” Nat. Med.17(2), 223–228 (2011). [CrossRef] [PubMed]
• Y. Kienast, L. von Baumgarten, M. Fuhrmann, W. E. Klinkert, R. Goldbrunner, J. Herms, and F. Winkler, “Real-time imaging reveals the single steps of brain metastasis formation,” Nat. Med.16(1), 116–122 (2010). [CrossRef] [PubMed]

Nat. Methods

• B. A. Flusberg, E. D. Cocker, W. Piyawattanametha, J. C. Jung, E. L. Cheung, and M. J. Schnitzer, “Fiber-optic fluorescence imaging,” Nat. Methods2(12), 941–950 (2005). [CrossRef] [PubMed]
• B. A. Flusberg, A. Nimmerjahn, E. D. Cocker, E. A. Mukamel, R. P. Barretto, T. H. Ko, L. D. Burns, J. C. Jung, and M. J. Schnitzer, “High-speed, miniaturized fluorescence microscopy in freely moving mice,” Nat. Methods5(11), 935–938 (2008). [CrossRef] [PubMed]

Neurol. Clin.

• D. Kondziolka, A. D. Firlik, and L. D. Lunsford, “Complications of stereotactic brain surgery,” Neurol. Clin.16(1), 35–54 (1998). [CrossRef] [PubMed]

Neurosurg. Rev.

• G. Widhalm, G. Minchev, A. Woehrer, M. Preusser, B. Kiesel, J. Furtner, A. Mert, A. Ieva, B. Tomanek, D. Prayer, C. Marosi, J. A. Hainfellner, E. Knosp, and S. Wolfsberger, “Strong 5-aminolevulinic acid-induced fluorescence is a novel intraoperative marker for representative tissue samples in stereotactic brain tumor biopsies,” Neurosurg. Rev.35(3), 381–391, discussion 391 (2012). [CrossRef] [PubMed]

Neurosurgery

• A. Raabe, J. Beck, R. Gerlach, M. Zimmermann, and V. Seifert, “Near-infrared indocyanine green video angiography: a new method for intraoperative assessment of vascular flow,” Neurosurgery52(1), 132–139, discussion 139 (2003). [PubMed]

Opt. Express

• T. J. Muldoon, M. C. Pierce, D. L. Nida, M. D. Williams, A. Gillenwater, and R. Richards-Kortum, “Subcellular-resolution molecular imaging within living tissue by fiber microendoscopy,” Opt. Express15(25), 16413–16423 (2007). [CrossRef] [PubMed]
• S. M. Landau, C. Liang, R. T. Kester, T. S. Tkaczyk, and M. R. Descour, “Design and evaluation of an ultra-slim objective for in-vivo deep optical biopsy,” Opt. Express18(5), 4758–4775 (2010). [CrossRef] [PubMed]

Opt. Lett.

• W. Göbel, J. N. Kerr, A. Nimmerjahn, and F. Helmchen, “Miniaturized two-photon microscope based on a flexible coherent fiber bundle and a gradient-index lens objective,” Opt. Lett.29(21), 2521–2523 (2004). [CrossRef] [PubMed]

Photochem. Photobiol.

• A. Johansson, G. Palte, O. Schnell, J. C. Tonn, J. Herms, and H. Stepp, “5-Aminolevulinic acid-induced protoporphyrin IX levels in tissue of human malignant brain tumors,” Photochem. Photobiol.86(6), 1373–1378 (2010). [CrossRef] [PubMed]
• G. A. Wagnières, W. M. Star, and B. C. Wilson, “In vivo fluorescence spectroscopy and imaging for oncological applications,” Photochem. Photobiol.68(5), 603–632 (1998). [PubMed]

PLoS ONE

• Y. Kang, M. Choi, J. Lee, G. Y. Koh, K. Kwon, and C. Choi, “Quantitative analysis of peripheral tissue perfusion using spatiotemporal molecular dynamics,” PLoS ONE4(1), e4275 (2009). [CrossRef] [PubMed]

Other

• S. Eigenbrod, Department of Neuropathology, Ludwig-Maximilians-University Munich, R. Trabold, D. Brucker, C. Erös, B. Suchorska, R. Egensperger, G. Pöpperl, A. Rühm, W. Göbel, H. Kretzschmar, J. C. Tonn, J. Herms, A. Giese, and F. W. Kreth are preparing a manuscript to be called “Molecular stereotactic biopsy technique improves tumor classification in glioma patients.”
• A. Rühm, Laser-Research-Laboratory, Ludwig-Maximilians-University Munich, W. Göbel, and H. Stepp are preparing a manuscript to be called “Fiber baser fluorescence diagnosis based on PpIX and ICG – Excitation power limitations due to thermal effects in human brain tissue.”
• K. Irion, “US 7,662,095 (B2) - Endoscope provided with a lighting system and a combined image transmission,” (2010).
• Brain Tumor Primer - a comprehensive introduction to brain tumors (American Brain Tumor Association, 2010).

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