In recent years, fluorescence image-guided surgery (FIGS) with contrast provided by 5-aminolevulinic acid (5- ALA)-induced PpIX fluorescence has been demonstrated to improve surgical outcomes for glioma patients. However, there are several limitations to these wide-field imaging methods. For example, it is difficult to accurately determine a surgical margin based on subtle variations in fluorescence intensity in glioma tissues, which are diffuse and lack a distinct transition between tumor and normal. Furthermore, wide-field (low- resolution) approaches, such as FIGS and MRI, provide pixel intensities that represent an average value from many cells, resulting in a diminished ability to detect the sparse tumor cell populations at the margins of diffuse gliomas. This problem is exacerbated in low-grade gliomas, where 5-ALA-induced PpIX fluorescence is only generated in rare proliferating cell populations and is undetectable via wide-field FIGS. Recently, Dr. Nader Sanai, a Co-Investigator on this project, has shown that intraoperative cellular-resolution confocal microscopy can be used to visualize the sparse fluorescent cells in low-grade glioma patients treated with 5-ALA. The implications of this finding are highly significant since reported rates of gross-total resection (GTR) have been relatively low for low-grade gliomas (14% to 46%), suggesting a need for improved image-guidance techniques. Here, we propose to optimize a hand-held intraoperative confocal microscope, previously developed by the PI, to visualize low-grade glioma cells that express 5-ALA-induced PpIX, and to demonstrate that this real-time quantitative in vivo imaging technique correlates with MRI and invasive histopathology for margin assessment. This project brings together a proven team of collaborators, including Co-Investigator Olav Solgaard at Stanford University, to develop an optimized optical-sectioning microscope that incorporates a highly robust MicroElectroMechanical System (MEMS) scanner and an achromatic (wavelength-agile) optical design recently published by the PI's lab. Preclinical ex vivo and in vivo imaging will be performed with a highly realistic and infiltrative at model of glioma to demonstrate the ability to correlate the density of cells expressing PpIX fluorescence vs. actual tumor-cell density and histological grade. Clinical studies will leverage the existing expertise of Co-Investigator Nader Sanai, at Barrow Neurological Institute (BNI), with both wide-field FIGS and intraoperative confocal microscopy of PpIX fluorescence in glioma patients. Based on established and approved protocols at BNI, an exploratory clinical study will be performed to correlate the density of PpIX-labeled cells with histopathology, pre-operative MRI (intraoperative neuronavigation), and post- operative MRI. The results of these preliminary studies will justify future clinical investigations to assess patient outcomes such as volumetric extent of resection, overall survival, and neurological morbidity.

Public Health Relevance

We propose to develop a miniature intraoperative confocal microscope to assist with the resection of low-grade gliomas. The aims of this project are translational and seek to develop clinical imaging technologies for improving human health.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
7R01CA175391-02
Application #
8890436
Study Section
Biomedical Imaging Technology Study Section (BMIT)
Program Officer
Zhang, Huiming
Project Start
2014-09-01
Project End
2019-08-31
Budget Start
2014-09-01
Budget End
2015-08-31
Support Year
2
Fiscal Year
2014
Total Cost
$349,403
Indirect Cost
$104,637
Name
University of Washington
Department
Engineering (All Types)
Type
Schools of Engineering
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
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Wei, Linpeng; Chen, Ye; Yin, Chengbo et al. (2017) Optical-sectioning microscopy of protoporphyrin IX fluorescence in human gliomas: standardization and quantitative comparison with histology. J Biomed Opt 22:46005
Chen, Ye; Glaser, Adam; Liu, Jonathan T C (2017) Bessel-beam illumination in dual-axis confocal microscopy mitigates resolution degradation caused by refractive heterogeneities. J Biophotonics 10:68-74
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Wang, Yu; Kang, Soyoung; Doerksen, Josh D et al. (2016) Surgical Guidance via Multiplexed Molecular Imaging of Fresh Tissues Labeled with SERS-Coded Nanoparticles. IEEE J Sel Top Quantum Electron 22:
Liu, Qiang; Sanai, Nader; Jin, Wei-Na et al. (2016) Neural stem cells sustain natural killer cells that dictate recovery from brain inflammation. Nat Neurosci 19:243-52
Glaser, Adam K; Chen, Ye; Liu, Jonathan T C (2016) Fractal propagation method enables realistic optical microscopy simulations in biological tissues. Optica 3:861-869

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