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Bringing brain tumors to glow: Fluorescence lifetime imaging for neurosurgery [Invited]

18 Jun | By Mikael Erkkilä
Bringing brain tumors to glow: Fluorescence lifetime imaging for neurosurgery [Invited]
In fluorescence guided neurosurgery the surgeon often struggles to detect fluorescence by eye. By the use of a modulated laser at 405 nm Protoporphyrin IX fluorescence is induced within 5-aminolevulinic acid tagged brain tumors. This fluorescence is registered through a dual-tap CMOS camera acting as a time-of-flight sensor. The resulting fluorescence lifetime maps allow for a more sensitive and complete visualization of tumor borders and might help surgeons in future to maximize their resections.
Image source: Journal of Biophotonics, WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim (front cover, issue 06/2019)
By: Mikael T. Erkkilä, Marco Andreana and Angelika Unterhuber

Brain tumors make only about 2% of all cancers diagnosed but are often linked to a negative prognosis for the patient. While several cancer entitities are treated by the removal of surrounding tissue or even the full organ, the brain is more sensitive in this regard requiring additional effort not to damage any healthy, functional areas. However, as the overall survival correlates with the extent of resection the surgeon faces the difficult task of removing as much malignant tissue as possible while avoiding to harm healthy areas.


Within the last two decades fluorescence guided surgery has had an immense impact within the neurosurgical routine. By administering the patient dye-inducing drugs (5-Aminolevulinic acid, 5-ALA) or even directly dyes (fluorescein, Indocyanine green) specific parts within the surgical field like the tumor or the vasculature can be highlighted. Especially, the use of 5-ALA induced Protoporphyrin IX (PPIX) fluorescence has helped neurosurgeons to achieve more complete resection, thus, improving the outcome for the patients and enabling them a longer symptom-free lifetime.


However, fluorescence guidance has mainly be limited to very aggresive tumors like glioblastoma multiforme and brain metastases from stage 4 secondary cancers. Low grade gliomas or infiltration zones are often undetected and thereby left untreated. The main reason for that is the low amount of PPIX accumulating in the malignant cells which the surgeon cannot detect anymore solely by using his or her eyes. The use of more sensitive cameras in modern surgical microscopes has improved this problem only marginally as both the PPIX fluorescence and the intrinsic autofluorescence of the tissue are equally amplified.


As an alternative to that researchers from the Medical University of Vienna around Assoc.-Prof. Dr. Angelika Unterhuber in cooperation with the Carl Zeiss Meditec AG in Germany developed an imaging system which measures the time delay of the fluorescence relative to its excitation. Instead of acquiring intensity images the dual-tap CMOS camera (pco.FLIM, PCO AG) enables frequency domain based time-of-flight imaging which is here used for fluorescence lifetime imaging. As the lifetime is independent of the fluorescence yield it allows a better visualization of tumor borders with malignant tissue exhibiting longer decay times compared to the auto-fluorescent background of the healthy tissue. This allows the detection of remaining PPIX fluorescence in minor tumor infiltrated zones where surgeons had not reported any fluorescence and would have overseen this important area.


While the study was only performed on ex vivo tissue samples, the results are promising to advance this method towards clinical trials. In addition, time-of-flight sensors are now in heavy demand due to self-driving cars and autonomous vehicles which pushes the development and cost-effective miniaturization of these devices. It is thereby to expect that in future fluorescence lifetime imaging will not only be restricted to microscopy and molecular biology but evolve into a translational optical technology used for various medical needs.


These findings were published in 2019 in the Journal of Biophotonics and featured on the front cover on this months issue. 


Link to publication


Mikael T. Erkkilä, M.Sc.,  Marco Andreana, Ph.D., and Assoc.-Prof. Dr. Angelika Unterhuber are part of the Drexler Lab at the Center of Medical Physics and Biomedical Engineering at the Medical University of Vienna, Austria. Their research concentrate on the development of advanced microscopy and spectroscopy methods targeting biomedical applications and clinical translation.


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