Improved sensitivity to fluorescence for cancer detection in wide-field image-guided neurosurgery

Abstract

In glioma surgery, Protoporphyrin IX (PpIX) fluorescence may identify residual tumor that could be resected while minimizing damage to normal brain. We demonstrate that improved sensitivity for wide-field spectroscopic fluorescence imaging is achieved with minimal disruption to the neurosurgical workflow using an electron-multiplying charge-coupled device (EMCCD) relative to a state-of-the-art CMOS system. In phantom experiments the EMCCD system can detect at least two orders-of-magnitude lower PpIX. Ex vivo tissue imaging on a rat glioma model demonstrates improved fluorescence contrast compared with neurosurgical fluorescence microscope technology, and the fluorescence detection is confirmed with measurements from a clinically-validated spectroscopic probe. Greater PpIX sensitivity in wide-field fluorescence imaging may improve the residual tumor detection during surgery with consequent impact on survival.

Widefield fluorescence lifetime imaging of protoporphyrin IX for fluorescence‐guided neurosurgery: An ex vivo feasibility study

“…In fact, the food coloring consists of two dyes, namely tartrazine and allura red, which are known to be strong quenchers . We consider this an important observation as these phantoms are widely used for the calibration in spectroscopic imaging of PpIX in brain tumors and quenching might generate false estimations of PpIX concentration values. To still use these phantoms to calibrate spectrometric PpIX imaging devices the influence of the quenching needs to be predicted.…”

“…Tissue phantoms composed of PpIX dimethly ester (CAS:5522‐66‐7; Sigma‐Aldrich, St. Louis, Missouri) dissolved in dimethyl sulfoxide (DMSO), lipid emulsion (Intralipid 20%), distilled water and yellow food coloring (McCormick) were generated based on the study of Jermyn et al These phantoms are state of the art for the calibration of spectroscopic and hyperspectral PpIX imaging devices . The lipid emulsion simulated tissue scattering with μ s [cm −1 ] = {30, 35, 40, 45} while the yellow food color acted as absorber with μ a [cm −1 ] = {18, 30, 42, 50, 60} at 405 nm.…”

“…Fluorescence‐guided surgery, based on 5‐aminolevulinic acid (5‐ALA) induced protoporphyrin IX (PpIX) , has shown to help the surgeon achieve more complete resections and prolonged progression‐free survival in malignant glioma patients . To detect even lower concentrations of PpIX which cannot yet be resolved by the surgeon using commercially available surgical microscopes, spectroscopic measurements or hyperspectral imaging was proposed with promising results for the visualization of even low‐grade gliomas. In general, the measurement of fluorescence intensity is affected by the optical properties of the tissue which pose a major problem in PpIX quantification as these need to be characterized beforehand.…”

Preclinical evaluation of spatial frequency domain-enabled wide-field quantitative imaging for enhanced glioma resection

“…6 We have developed several different platforms for quantitative PpIX FGR, i.e., to measure and map the absolute PpIX concentration, [PpIX], in tissue. [7][8][9] There are two main approaches: semiempirical correction for tissue attenuation, typically using a form of multiple-wavelength ratiometry, and rigorous correction based on independent measurements of the tissue absorption and scattering coefficients at the relevant wavelengths. This study is an extension of two previous developments.…”

“…This study is an extension of two previous developments. The first was the use of hyperspectral fluorescence imaging together with semiempirical correction algorithms 8,9 in which the use of a high-sensitivity electron-multiplying charge-coupled detector (EMCCD) enabled PpIX detection down to 10 ng∕ml in a glioma model. 9 The second development was based on an intraoperative quantitative point-contact fiber-optic spectroscopy probe 7 that has been shown in clinical trials to significantly improve the sensitivity and specificity of residual tumor tissue detection in high-grade glioma and to make FGR of a low-grade tumor feasible in patients.…”