High‐Fidelity Solution Decomposition Fluorescence Tomography in the Presence of Background Interference

Abstract Fluorescence imaging is a cornerstone of preclinical research, yet its utility is hindered by semi‐quantitative limitations due to light scattering. Fluorescence molecular tomography (FMT) aims to overcome these constraints by generating 3D fluorophore maps through model‐based reconstruction. However, background fluorescence, resulting from non‐specific probe binding and autofluorescence, significantly compromises FMT image quality with severe artifacts. Solution decomposition FMT (SD‐FMT) is introduced, an innovative reconstruction method that employs an advanced prior model to decompose the solution into multiple stochastic components. The reformulated inverse problem is resolved using a hybrid projection method (HPM), ensuring robustness and efficiency. Validated through exhaustive phantom and in vivo proof‐of‐concept studies, SD‐FMT represents a paradigm shift in FMT reconstruction, with significant implications for expanding applications in preclinical research and advancing fluorescence‐guided surgical navigation.