Noninvasive Terahertz Therapy Promoted Bone Regeneration via Localized Angiogenesis in a Pre-Clinical Tibial Defect Model

<b><i>Objective:</i></b> Bone defects present a significant clinical challenge, often requiring surgical intervention due to delayed healing. Terahertz (THz) radiation, a noninvasive physical energy-based therapy, has shown potential in promoting bone regeneration through biomolecular interactions. This study aims to evaluate the therapeutic efficacy of THz irradiation in enhancing bone repair using a pre-clinical rat tibial fracture defect model. <b><i>Methods:</i></b> A standardized tibial bone defect model was created in rats, with daily THz irradiation (0.1 THz, 20 min/session) administered continuously for 28 days. Micro-computed tomography (CT) evaluations were performed weekly throughout the study period, while histological assessments (hematoxylin and eosin [HE] and Masson staining), vascular endothelial growth factor (VEGF) immunohistochemistry, and serum biomarker analyses were exclusively conducted at the 28-days endpoint. Micro-CT imaging, histopathological staining, and tyramide signal amplification analyses were conducted to assess bone volume fraction, collagen deposition, and angiogenesis. Blood biochemical markers were also evaluated to determine systemic metabolic effects. <b><i>Results:</i></b> By week 4, the THz-treated group demonstrated a higher new bone formation compared with control group. Micro-CT analysis revealed significantly improved cortical continuity and bone volume fraction at weeks 3 and 4 (<i>p</i> < 0.05). HE and Masson staining showed enhanced collagen alignment and trabecular organization. The IF test indicated increased VEGFA expression in local new bone (<i>p</i> < 0.01), suggesting augmented angiogenesis. No significant changes were observed in serum <i>biochemistry</i> markers, indicating localized rather than systemic effects. <b><i>Conclusions:</i></b> THz radiation effectively accelerates bone defect healing by enhancing osteoblast activity and vascularization without systemic metabolic alterations. These findings highlight the potential of THz therapy as a novel, noninvasive approach for bone regeneration, warranting further research for clinical translation.