Network Trauma Research series: Modeling Trauma Complexity: Rodent Platforms for Studying Bone Healing and Hemorrhagic Shock

Polytrauma, defined as severe injury to multiple body regions often accompanied by physiological instability, remains a major global health burden with high morbidity and mortality. Among the most clinically relevant two-injury combinations, long-bone fractures and hemorrhagic shock are particularly important, as both critically influence systemic inflammation, remote organ dysfunction such as lung or kidney damage, and tissue regeneration itself. To improve translational understanding of these complex interactions, robust small-animal models, particularly murine systems, have been developed to experimentally dissect the biological mechanisms underlying fracture healing, hypovolemic shock, and their combined effects. This review provides a comprehensive overview of current rodent models for isolated fracture, hemorrhagic shock, and combination trauma. Key methodological variables, such as fracture induction methods, fixation strategies, hemorrhage protocols, anesthesia and analgesia, and the influence of age, sex, and comorbidities are outlined to support informed model selection. Additionally, this manuscript highlights the challenges and opportunities in designing clinically relevant "double-hit" models that mimic real-world trauma patterns while maintaining high reproducibility and animal welfare standards. Collectively, the summarized evidence underscores the importance of standardized, physiologically meaningful preclinical trauma models to advance mechanistic insights and foster the development of effective therapeutic interventions.