FluoRa - a System for Combined Fluorescence and Microcirculation Measurements in Brain Tumor Surgery (original) (raw)
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The optical touch pointer (OTP), a fluorescence spectroscopy based system, assists brain surgeons during guided brain tumor resection in patients with glioblastoma multiforme (GBM). After recording and analyzing the autofluorescence spectrum of the tissue, it is possible to distinguish malignant from healthy brain tissue. A challenge during the intraoperative measurements is the interference of blood. If it gets in contact with the laser pointer, the blood blocks the light transmission to and from the tissue. The purposes of the project were to study and categorize patterns of blood interference and to present possible solutions to avoid signal blocking by blood.
Protoporphyrin IX (PpIX) induced by 5-aminolevulinic acid (5-ALA) is increasingly used as a fluorescent marker for fluorescence-guided resection of malignant gliomas. Understanding how the properties of the excitation light source and PpIX fluorescence interact with the surgical microscope is critical for effective use of the fluorescence-guided tumor resection technique. In this study, we performed a detailed assessment of the intensity of the emitted blue light and white light and the light beam profile of clinical grade operating microscopes used for PpIX visualization. These measurements revealed both recognized fluorescence photobleaching limitations and unrecognized limitations that may alter quantitative observations of PpIX fluorescence obtained with the operating microscope with potential impact on research and clinical uses. We also evaluated the optical properties of a photostable fluorescent standard with an excitation-emission profile similar to PpIX. In addition, we measured the time-dependent dynamics of 5-ALA-induced PpIX fluorescence in an animal glioma model. Finally, we developed a ratiometric method for quantification of the PpIX fluorescence that uses the photostable fluorescent standard to normalize PpIX fluorescence intensity. This method increases accuracy and allows reproducible and direct comparability of the measurements from multiple samples. Operating microscopes are commonplace within the neurosurgical operating theater and are a mainstay of surgical procedures for brain tumor removal 1. As the most important visualization tool in daily use for neurosurgery, operating microscopes are gaining advanced functionality by means of innovative illumination modes. To ensure surgical success, the neurosurgeon must fully understand the illumination properties and functionality of the microscope, especially within the context of fluorescence-guided tumor resection. The principle of fluorescence-guided tumor resection relies on the use of targeting agents with fluorescent properties that can be administered to patients before or during surgery. These agents are intended to accumulate within and around the tumor tissue or within the cells of the tumor, depending on the selectivity and actions of the fluorophore. The desired diagnostic result is to augment visual differentiation and detection of the tumor tissue margins during surgery based on fluorescence. The most notable recent example of a fluorescent agent developed for tumor detection in neurosurgery is 5-aminolevulinic acid (5-ALA), which is used to indicate the presence of tumors and the border regions of malignant gliomas 2. 5-ALA was recently designated as the first US Food and Drug Administration-approved agent for fluorescence-guided resection of high-grade gliomas 3. This prodrug results in fluorescent PpIX accumulation in tumors through a distortion in the metabolic conversion of 5-ALA to heme 4. Understanding both the nuances of its fluorescent properties and the effects that occur with changes in excitation intensity and duration of light
Novel Optical Instrumentation for Biomedical Applications III, 2007
The highly malignant brain tumor, glioblastoma multiforme, is difficult to totally resect without aid due to its infiltrative way of growing and its morphological similarities to surrounding functioning brain under direct vision in the operating field. The need for an inexpensive and robust real-time visualizing system for resection guiding in neurosurgery has been formulated by research groups all over the world. The main goal is to develop a system that helps the neurosurgeon to make decisions during the surgical procedure. A compact fiber optic system using fluorescence spectroscopy has been developed for guiding neurosurgical resections. The system is based on a high power light emitting diode at 395 nm and a spectrometer. A fiber bundle arrangement is used to guide the excitation light and fluorescence light between the instrument and the tissue target. The system is controlled through a computer interface and software package especially developed for the application. This robust and simple instrument has been evaluated in vivo both on healthy skin but also during a neurosurgical resection procedure. Before surgery the patient received orally a low dose of 5-aminolevulinic acid, converted to the fluorescence tumor marker protoporphyrin IX in the malignant cells. Preliminary results indicate that PpIX fluorescence and brain tissue autofluorescence can be recorded with the help of the developed system intraoperatively during resection of glioblastoma multiforme.
Scientific reports, 2018
Protoporphyrin IX (PpIX) induced by 5-aminolevulinic acid (5-ALA) is increasingly used as a fluorescent marker for fluorescence-guided resection of malignant gliomas. Understanding how the properties of the excitation light source and PpIX fluorescence interact with the surgical microscope is critical for effective use of the fluorescence-guided tumor resection technique. In this study, we performed a detailed assessment of the intensity of the emitted blue light and white light and the light beam profile of clinical grade operating microscopes used for PpIX visualization. These measurements revealed both recognized fluorescence photobleaching limitations and unrecognized limitations that may alter quantitative observations of PpIX fluorescence obtained with the operating microscope with potential impact on research and clinical uses. We also evaluated the optical properties of a photostable fluorescent standard with an excitation-emission profile similar to PpIX. In addition, we me...
Journal of Biomedical Optics, 2022
Significance: 5-aminolevulinic acid (5-ALA)-induced protoporphyrin IX (PpIX) fluorescence is currently used for image-guided glioma resection. Typically, this widefield imaging method highlights the bulk of high-grade gliomas, but it underperforms at the infiltrating edge where PpIX fluorescence is not visible to the eyes. Fluorescence lifetime imaging (FLIm) has the potential to detect PpIX fluorescence below the visible detection threshold. Moreover, simultaneous acquisition of time-resolved nicotinamide adenine (phosphate) dinucleotide [NAD(P)H] fluorescence may provide metabolic information from the tumor environment to further improve overall tumor detection. Aim: We investigate the ability of pulse sampling, fiber-based FLIm to simultaneously image PpIX and NAD(P)H fluorescence of glioma infiltrative margins in patients. Approach: A mesoscopic fiber-based point-scanning FLIm device (355 nm pulses) was used to simultaneously resolve the fluorescence decay of PpIX (629/53 nm) and NAD(P)H (470/28 nm). The FLIm device enabled data acquisition at room light and rapid (<33 ms) augmentation of FLIm parameters on the surgical field-of-view. FLIm measurements from superficial tumors and tissue areas around the resection margins were performed on three glioblastoma patients in vivo following inspection of PpIX visible fluorescence with a conventional neurosurgical microscope. Microbiopsies were collected from FLIm imaged areas for histopathological evaluation. Results: The average lifetime from PpIX and NAD(P)H fluorescence distinguished between tumor and surrounding tissue. FLIm measurements of resection margins presented a range of PpIX and NAD(P)H lifetime values (τ PpIX ∼ 3 to 14 ns, τ NADðPÞH ¼ 3 to 6 ns) associated with unaffected tissue and areas of low-density tumor infiltration. Conclusions: Intraoperative FLIm could simultaneously detect the emission of PpIX and NAD(P)H from patients in vivo during craniotomy procedures. This approach doubles as a clinical tool to identify tumor areas while performing tissue resection and as a research tool to study tumor microenvironmental changes in vivo. Intraoperative FLIm of 5-ALA-induced PpIX and tissue autofluorescence makes a promising surgical adjunct to guide tumor resection surgery.
Optical Brain Biopsy with a Fluorescence and Vessel Tracing Probe
Operative Neurosurgery, 2021
BACKGROUND: Accurate stereotactic biopsies of brain tumors are imperative for diagnosis and tailoring of the therapy. Repetitive needle insertions enhance risks of brain lesioning, hemorrhage, and complications due to prolonged procedure. OBJECTIVE: To investigate clinical benefits of a combined 5-aminolaevulinic acid (5-ALA) fluorescence and laser Doppler flowmetry system for the detection of malignant brain tumor and blood vessels in stereotactic biopsies. METHODS: Planning of targets and trajectories was followed by optical measurements in 20 patients, using the Leksell Stereotactic System and a manual insertion device. Fluorescence spectra, microvascular blood flow, and tissue grayness were recorded each millimeter along the paths. Biopsies were taken at preplanned positions. The diagnoses were compared with the fluorescence signals. The recordings were plotted against measurement positions and compared. Sites indicating a risk of hemorrhage were counted as well as the time for the procedures. RESULTS: Signals were recorded along 28 trajectories, and 78 biopsies were collected. The final diagnosis showed 17 glioblastomas, 2 lymphomas, and 1 astrocytoma grade III. Fluorescence was seen along 23 of the paths with 4 having the peak of 5-ALA fluorescence 3 mm or more from the precalculated target. There was increased microcirculation in 40 of 905 measured positions. The measurement time for each trajectory was 5 to 10 min. CONCLUSION: The probe provided direct feedback of increased blood flow along the trajectory and of malignant tissue in the vicinity of the target. The method can increase the precision and the safety of the biopsy procedure and reduce time.
IEEE Journal of Selected Topics in Quantum Electronics, 2016
Time-resolved fluorescence (TRF) and diffuse reflectance (DR) spectroscopy are two optical biopsy modalities that have been studied in tumor diagnosis. Combination of TRF and DR spectroscopy allows us to obtain more features such as fluorescence intensity, lifetime, and optical properties, thus potentially improving the tissue diagnostic accuracy. In this article, an integrated TRF-DR spectroscopy instrument was developed to acquire time-resolved fluorescence spectra as well as spatially resolved diffuse reflectance spectra in sequence for intraoperative detection of brain tumor margin. The performance of TRF-DR spectroscopy instrumentation was calibrated and evaluated using endogenous biomolecules, tissue phantoms, and ex vivo brain tumor specimens. The results demonstrated the TRF-DR system is capable to retrieve the fluorescence and optical properties accurately.
2011
Object-Accurate discrimination between tumor and normal tissue is crucial for optimal tumor resection. Qualitative fluorescence of protoporphyrin IX (PpIX), synthesized endogenously following δ-aminolevulinic acid (ALA) administration, has been used for this purpose in highgrade glioma (HGG). The authors show that diagnostically significant but visually imperceptible concentrations of PpIX can be quantitatively measured in vivo and used to discriminate normal from neoplastic brain tissue across a range of tumor histologies. Methods-The authors studied 14 patients with diagnoses of low-grade glioma (LGG), HGG, meningioma, and metastasis under an institutional review board-approved protocol for fluorescence-guided resection. The primary aim of the study was to compare the diagnostic capabilities of a highly sensitive, spectrally resolved quantitative fluorescence approach to conventional fluorescence imaging for detection of neoplastic tissue in vivo. Results-A significant difference in the quantitative measurements of PpIX concentration occurred in all tumor groups compared with normal brain tissue. Receiver operating characteristic (ROC) curve analysis of PpIX concentration as a diagnostic variable for detection of neoplastic tissue yielded a classification efficiency of 87% (AUC = 0.95, specificity = 92%, sensitivity = 84%) compared with 66% (AUC = 0.73, specificity = 100%, sensitivity = 47%) for conventional fluorescence imaging (p < 0.0001). More than 81%