Towards in-vivo label-free detection of brain tumor margins with epi-illumination tomographic quantitative phase imaging

Abstract

Brain tumor surgery involves a delicate balance between maximizing the extent of tumor resection while minimizing damage to healthy brain tissue that is vital for neurological function. However, differentiating between tumor, particularly infiltrative disease, and healthy brain in-vivo remains a significant clinical challenge. Here we demonstrate that quantitative oblique back illumination microscopy (qOBM)—a novel label-free optical imaging technique that achieves tomographic quantitative phase imaging in thick scattering samples—clearly differentiates between healthy brain tissue and tumor, including infiltrative disease. Data from a bulk and infiltrative brain tumor animal model show that qOBM enables quantitative phase imaging of thick fresh brain tissues with remarkable cellular and subcellular detail that closely resembles histopathology using hematoxylin and eosin (H&E) stained fixed tissue sections, the gold standard for cancer detection. Quantitative biophysical features are also extracted from qOBM which yield robust surrogate biomarkers of disease that enable (1) automated tumor and margin detection with high sensitivity and specificity and (2) facile visualization of tumor regions. Finally, we develop a low-cost, flexible, fiber-based handheld qOBM device which brings this technology one step closer to in-vivo clinical use. This work has significant implications for guiding neurosurgery by paving the way for a tool that delivers real-time, label-free, in-vivo brain tumor margin detection.

Quantitative phase imaging through an ultra-thin lensless fiber endoscope

“…Due to the simplicity of the proposed method, digital holography and wavefront shaping are not necessary, which leads to a compact and cost-effective system. In addition, compared to endoscopes implementing micro-lens or printed structures on fiber tips 27 , 29 , 30 , our system is built from a commercially off-the-shelf fiber bundle and common optical components, which is easily replicable for further applications.…”

“…However, the phase information of the sample is lost due to the incoherent illumination. Despite computational methods that have been proposed to recover the 3D information of samples 28 – 30 , precise QPI via MCF with nanoscale sensitivity is still challenging. Coherent imaging is achieved via multi-mode fibers with transmission matrix measurement 31 , 32 or wavefront shaping 33 – 38 , and similar approaches are also applied to MCF-based coherent imaging 39 – 45 .…”

Quantitative Phase Imaging: Recent Advances and Expanding Potential in Biomedicine

“…Another adaptive approach is to use QPI methods developed in an in vitro setting to address issues of light scattering in thick samples and phase unwrapping and then translate them for in vivo imaging through miniaturization. This has led to attempts to miniaturize certain platforms, such as diffraction phase microscopy (DPM), into an endoscope (i.e., eDPM), or to making a fiber optics based qOBM system . Demonstrations of these techniques have so far been limited to ex vivo imaging.…”

Functional imaging with dynamic quantitative oblique back-illumination microscopy

“…7,8 This tomographic label-free, non-invasive, affordable, and real-time quantitative imaging technique has been applied to image the cellular and subcellular structures of samples such as tumors in fresh thick brain tissue, blood cells in collection bags, and thick organoids. [7][8][9][10][11] Here, we propose dynamic-qOBM (DqOBM) to enable functional imaging based on the dynamics of the RI distribution of cellular and subcellular structures. In DqOBM, a sample is imaged over a period of time (e.g., fraction of a minute), and then each pixel is colorized based on the frequency response of its dynamic signal (see Fig.…”