Systemic versus local delivery of mesenchymal stem cells to improve the early stages of fracture healing in a polytrauma model.

Fracture healing complications, including nonunion, are common in polytrauma patients partly due to systemic inflammatory dysregulation. Although mesenchymal stem cells (MSCs) have been widely explored for their regenerative properties, their therapeutic potential in polytrauma patients remains uncertain. Given the clinical interest in both systemic and localized stem cell therapies, understanding how delivery route influences MSCs biodistribution, inflammatory modulation, and therapeutic efficacy is critical for optimizing treatment strategies in polytrauma. Hence, we compared systemic versus local MSCs delivery in a polytrauma model. We evaluated inflammatory responses and bone formation in a C57BL/6J murine model across four groups: (1) isolated fracture, (2) polytrauma (femur fracture + chest trauma), (3) polytrauma + systemic MSC delivery, and (4) polytrauma + local MSC delivery in hyaluronic acid-based hydrogels at the fracture site. Polytrauma induced a prolonged inflammatory response characterized by elevated interleukin 1 alpha and beta (IL-1α & β), tumor necrosis factor-alpha (TNF-α), interferon-gamma (IFN-γ), and monocyte chemoattractant protein-1 and - 5 (MCP-1 & MCP-5). Both delivery methods significantly reduced inflammation and proinflammatory cytokines, though local delivery yielded more consistent effects. IVIS imaging confirmed MSC retention at the fracture site in the local delivery group, while systemic administration of MSCs resulted in pulmonary entrapment. Although systemic MSCs failed to enhance fracture healing significantly, local MSC delivery promoted bone formation evidenced by CT and histological characterizations. These findings demonstrate that local MSC delivery in a hydrogel scaffold represents a superior strategy for improving fracture healing in polytrauma patients compared to systemic delivery.