Accelerated fracture healing accompanied with traumatic brain injury: A review of clinical studies, animal models and potential mechanisms

The orthopaedic community frequently encounters polytrauma individuals with concomitant traumatic brain injury (TBI) and their fractures demonstrate accelerated fracture union, but the mechanisms remain far from clear. Animal and clinical studies demonstrate robust callus formation at the early healing process and expedited radiographical union. In humans, robust callus formation in TBI occurs independently of fracture fixation methods across multiple fracture sites. Animal studies of TBI replicate clinically relevant enlarged fracture callus as characterized by increased tissue volume and bone volume at the early stages. However, refinement and standardization of the TBI models requires further research. The quest for its underlying mechanisms began with the finding of increased osteogenesis in vitro using the serum and cerebral spinal fluid (CSF) from TBI individuals. This has led to the investigation of myriads of brain-derived factors including humoral factors, cytokines, exosomes, and mi-RNAs. Further, the emerging information of interplay between the skeletal system and central nervous system, the roles of peripheral nerves and their neuropeptides in regulating bone regeneration, offers valuable insights for future research. This review consolidates the findings from both experimental and clinical studies, elucidating the potential mechanisms underlying enhanced fracture healing in concurrent TBI scenarios that may lay down a foundation to develop innovative therapies for fracture healing enhancement and conquer fracture non-union. The translational potential of this article. This review comprehensively summarizes the observations of accelerated fracture healing in the presence of traumatic brain injury from both preclinical and clinical studies. In addition, it also delineates potential cellular and molecular mechanisms. Further detailed investigation into its underlying mechanisms may reveal innovative orthopaedic intervention strategies to improve fracture healing and thus offering promising avenues for future translational applications.