Cell-resolution Optical Microscopy for Clinical Translation

Abstract

Optical microscopy remains a cornerstone of medical diagnostics, most notably in histopathology, where cell-resolution imaging of biopsied tissue defines the diagnostic gold standard. Digital pathology and AI-enabled analysis have modernized slide-based workflows, while in vivo confocal and related technologies have demonstrated the feasibility of cellular imaging in fields such as dermatology and ophthalmology. Nonetheless, widespread clinical adoption of high-resolution optical microscopy has been limited by various factors, including limited contrast mechanisms, trade-offs among field of view and resolution, imaging depth, sensitivity to motion, etc. To clarify the landscape of technologies capable of delivering clinically actionable cellular information, this review organizes optical microscopy by underlying contrast mechanisms, including intrinsic contrast (reflection, absorption, refraction/phase, autofluorescence, and Raman scattering) and extrinsic contrast generated by untargeted or targeted molecular probes, and evaluates how these mechanisms are implemented across emerging platforms such as slide-free histopathology, in vivo transmission-based microscopy, and fluorescence-based in situ microscopy. For each modality, we summarize representative system architectures and key preclinical or clinical validation studies. Looking ahead, advances in computational imaging and AI-assisted interpretation are expected to address current limitations and support the selective incorporation of cell-resolution optical microscopy into future diagnostic and surgical workflows.