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(A) The TBI only group included TBI without tibia fracture, the ipsilateral polytrauma group included TBI with ipsilateral tibia fracture, the contralateral polytrauma group included TBI with contralateral tibia fracture, and the fracture only group included tibia fracture without TBI.All assessments were performed at three time points, 5, 10 and 14 days post-injury (n = 5–6/group). (C) The representative radiographic image of closed transverse tibia shaft fracture.The aim of this study is to evaluate mechanisms that may influence healing in a pre-clinical murine model of combined fracture and TBI compared to each injury alone.When considered alone, mechanical damage from a TBI causes an immediate and direct loss of neural tissue.To effectively understand how these complex longitudinal factors work together to drive overall healing response we then integrated all outcome measures into a multidimensional principal component analysis (PCA).This preclinical study is the first to specifically investigate the relative influence of systemic versus neuronal factors in driving bone healing outcomes following TBI and fracture polytrauma and suggests that tracking these factors in a clinical environment are important towards delineating differential healing patterns.

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Following fracture, a hematoma forms immediately to stop the bleeding, contain debris, and activate a pro-inflammatory response that initiates repair; in the mouse this process occurs from roughly days 3–5 post-fracture.

A data-driven multivariate analysis integrating all outcome measures showed a distinct pathological state of polytrauma and co-variations between fracture, TBI and systemic markers.

Taken together, our results suggest that a contralateral bone fracture and TBI alter the local neuroinflammatory state to accelerate early fracture healing.

Fracture callus volume and composition were quantified by blinded reviewers using the Olympus CAST system and Visopharm software to enable an unbiased stereological evaluation of soft and hard tissues within the fracture callus.

Fracture alone was compared to the effect of polytrauma.

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