Improving Richardson--Lucy Deconvolution with Diffusion Priors for Fluorescence Microscopy

Richardson--Lucy (RL) deconvolution improves fluorescence microscopy images by recovering details lost to diffraction. It estimates the original fluorescence signal that most likely produced the measured photon counts under a Poisson imaging model. Although RL incorporates a physical model of fluorescence image formation and can improve contrast, deconvolution remains fundamentally ill-posed, and the measurements alone provide limited evidence for reliably reconstructing fine biological structure. Without additional structural guidance, RL can amplify noise and exhibit unstable convergence in low-photon regimes. Regularizers such as total variation (TV) reduce this instability but often introduce oversmoothing. Here, we investigate learned generative priors as a form of structural guidance for RL by integrating a score-based diffusion prior into a decoupled inverse-problem framework for fluorescence microscopy deconvolution. The diffusion prior is used during the RL optimization iterations, while RL retains Poisson data consistency. We validate the framework across diverse biological samples and cellular morphologies. The results show reduced RL noise amplification with improved preservation of weak filamentous and punctate structures under low photon counts.