Significance  Live-cell imaging provides an analytical platform for studying cellular structures and functions, leading to great significance for the exploration of disease mechanisms and drug development. Label-free observation of living cells in their natural states presents a grand challenge due to the subnanometer-scale deformations during subcellular dynamics. Additionally, to meet the trend of next-generation atomic manufacturing, nondestructive and accurate in-line characterization is crucial for ensuring high yields in large-scale manufacturing. However, the widely used metrology tools, such as scanning electron microscopy (SEM) and atomic force microscopy (AFM), suffer from extremely low measurement throughput and may introduce invasiveness to the samples. Interferometric Quantitative Phase Microscopy (iQPM), a label-free wide-field imaging technique, has been widely employed to quantitatively obtain morphology distributions and dynamic changes of samples. To satisfy the application demands, the development of high-sensitivity iQPM is of great significance and importance.

Progress  To derive the phase sensitivity theory, noise sources in the phase measurement process are introduced, such as camera noise (including photon shot noise, dark noise, readout noise), 1/f noise, instability of light source, mechanical vibrations, and air disturbances. Then, the key constraint factors that impact the phase sensitivity of iQPM systems can be analyzed, which provides a solid theoretical basis for developing strategies to improve the phase sensitivity. In terms of environmental noise, the interference signal is susceptible to mechanical vibrations and air disturbances. The noise can be effectively alleviated by using common-path interferometry-based iQPM techniques, where noise effects from the sample beam and reference beam propagating along essentially the same path can be eliminated, thus improving the temporal phase sensitivity. Meanwhile, the noise caused by mechanical vibrations can be further reduced through the optimized spatiotemporal filtering method. To reduce the impact of camera noise on phase sensitivity, the methods by increasing the effective well capacity and expanding the dynamic range have been proposed, which can also enable the measurement of subtle phase changes. From the perspective of speckle noise suppression, the proposed strategies aim to superpose images with uncorrelated speckle patterns, which can be achieved by reducing the temporal coherence of the illumination source or modulating the spatial spectrum of the illumination. The high-sensitivity iQPM techniques have been applied in cutting-edge fields such as blood cell analysis, neuroscience, atomic-scale material metrology, and wafer defect detection.

Conclusions and Prospects  This review summarizes critical strategies that have driven substantial advancements in the phase sensitivity of iQPM. By employing these methods, the temporal phase sensitivity of iQPM has been pushed to an impressive 2 pm level. The primary objective of this work is to provide an important reference for further improvement of phase sensitivity. Notably, current noise suppression-based sensitivity enhancement strategies are constrained by the inherent photon shot noise, sensitivity improvement methods based on signal amplification may offer a path to break through the current limitations and achieve higher phase sensitivity.