DOES TRAUMATIC BRAIN INJURY ENHANCE THE HEALING OF BONE FRACTURE? A “BEDSIDE TO BENCH TO BEDSIDE” INVESTIGATION

Traumatic brain injury (TBI) patients often show enhanced fracture healing that show robust callus formation(RCF) in the early stages and accelerated fracture union. Although orthopedic community continue to encounter its presence in daily practice, to date, the mechanisms that underlie the enhanced callus formation after TBI remain poorly understood. Peripheral sensory nerves orchestrate bone homeostasis and fracture healing through the release of neuropeptides, such as CGRP. We attempted to investigate whether peripheral sensory nerves and CGRP release in bone were altered and facilate fracture healing after TBI. A five-year retrospective study at a single center investigated the prevalence and TBI-specific risk factors for enhanced callus formation. Machine learning models were developed using TBI variables for accurate patient prediction. The prevalence of robust callus formation was 40.67% (61/150) with significantly wider callus index (1.91±0.62 vs 1.17±0.12, P<0.05) and acceleration in time to callus formation (22.92±11.98 days vs 90.18±34.52 days, P <0.05). Brain contusions (OR 5.914, 95%CI:2.479-14.108), greater TBI severity levels evaluated using Glasgow Coma Scale (OR 3.074, 95% CI:1.149-8.222) and Marshall CT classifications (OR 2.845, 95%CI:1.095-7.390) were identified as independent risk factors for RCF occurrence. The GBDT algorithm showed the best predictive performance using TBI-specific variables with the AUROC 0.86±0.03. The SHAP analysis showed that brain contusions, and GCS scores and Marshall CT classification scores were top three features. In a murine model, TBI severity-dependent and laterality-independent fracture healing responses were observed, with moderate-severe TBI inducing RCF compared to mild TBI. Histological analysis demonstrated rapid periosteum stem cell proliferation and callus ossification post-TBI, leading to increased callus and bone volume. CGRP expression was significantly upregulated in the dorsal root ganglion and fracture callus early in the healing process post-TBI. Peripheral sensory nerve denervation through capsaicin injections attenuated enhanced fracture healing post-TBI, highlighting the role of sensory nerves in this process. Ongoing studies aim to validate these findings using clinical samples and explore injured- brain-derived factors contributing to enhanced sensory nerve sensitization and CGRP release, further elucidating the mechanisms behind accelerated fracture healing after TBI.