Label-free, real-time optical biopsy with a handheld quantitative phase microscope

We present a compact, handheld quantitative phase imaging microscope that enables label-free, real-time optical imaging of bulk tissues with clear cellular and subcellular histological detail, effectively providing an “optical biopsy.” The approach uses quantitative oblique back-illumination microscopy (qOBM) to obtain quantitative phase information of opaque samples using epi-illumination. The probe has a wide-field, non-scanning architecture that achieves 0.8 µm lateral and 5 µm axial resolution across a 300 µm × 300 µm field of view at 25 frames per second. The probe is also low-cost, contains no moving components, is easy to use and can operate through a sterile sheath, addressing key barriers to clinical implementation. To demonstrate its utility, we image (1) human skin in vivo, (2) murine and human brain tumors ex vivo, and (3) swine brain in vivo under typical neurosurgical conditions. By providing real-time, label-free histological information in a robust and accessible handheld format, this technology creates broad opportunities for future clinical translation, including intraoperative and point-of-care histological tissue assessment. This study presents a compact handheld quantitative phase microscope that provides real time, label-free images of living tissues with sub-cellular detail, offering a potential tool for rapid intraoperative and point of-care histological in situ tissue assessment.