Label-Free, Real-Time, In Vivo Optical Biopsy with a Handheld Quantitative Phase Microscope

In this work we develop and demonstrate the utility of a compact, handheld quantitative phase imaging microscope that enables label-free, in vivo optical imaging of bulk tissues with clear cellular and subcellular histological detail in real-time. The proposed device overcomes significant challenges in optical imaging for in vivo applications, particularly for clinical human use. The approach uses quantitative oblique back illumination microscopy (qOBM) to obtain quantitative phase information of opaque samples using epi-illumination. The compact handheld probe achieves 0.8 µm lateral resolution, 5 µm axial resolution, 300 µm X 300 µm field of view, and operates at 25Hz in a wide-field (non-scanning) configuration, enabling real-time imaging. The probe is also inexpensive and has no moving components, making it robust. The utility of the probe is demonstrated in (1) human skin in vivo, (2) brain tumor tissue ex vivo from a murine tumor model and from discarded human tissue from neurosurgery, and (3) in vivo using healthy brain tissue from a large animal model (swine), simulating neurosurgical conditions. Given the clear cellular and subcellular histological detail (i.e., "optical biopsy") obtained in real-time, combined with the ease-of-use and low-cost of the system, the proposed device has significant implications for a broad range of clinical applications.