Customized Scattering‐Robust 3D Speckle Correlation for Improved Resolution and Imaging Depth in Scattering Tissue

Seeing deep and clear in thick scattering tissues using fluorescence imaging is vital for exploring biological phenomena. Although various speckle illumination techniques have been developed to customize speckles to improve imaging resolution and depth in scattering tissues, the lack of a guiding physical model and well‐defined mechanisms for maintaining customized speckle statistics during propagation in scattering media limits their ability to guarantee quality improvement throughout the scattering volume. Here, the speckle with the generalized stationary distribution that can maintain the customized intensity correlation in 3D space is discovered through the derivation and analysis of speckle correlation in Fresnel propagation. The illumination system's correlation transmission model mapping the phase field to speckle intensity correlation is established, enabling the customization of speckles with consistent and expected intensity correlation in 3D space over a depth range of several thousand micrometers. With the enhanced anti‐scattering fluorescence imaging ability of the customized speckle, a more than twofold improvement in 3D average resolution and a twofold improvement in imaging depth have been achieved compared to random speckle under strong optical scattering conditions like those in mouse brain tissue. Fluorescence imaging through millimeter‐thick scattering layers has also been achieved, demonstrating the advantages of high‐resolution volumetric scattering imaging.