This protocol delineates a methodological framework for the quantitative analysis of collagen architecture during the processes of skin regeneration and fibrosis. The protocol integrates skin regeneration modeling with advanced computational tools. The splinted wound model facilitates the observation of wound regeneration in mice and the evaluation of therapeutic interventions. The xenografting of human skin allows in vivo investigations of human skin regeneration and the monitoring of dynamic changes following therapy application. To objectively quantify these changes, we employ curvelet transform-based algorithms (CurveAlign and CT-FIRE), which allow clear fiber visualization at brightfield and fluorescent images and extraction of individual fiber parameters. We suggest an algorithm for standardizing data collection and analysis using open-access software for collagen fiber structure examination.