Abstract
Bone regeneration is a complex biological process that involves the coordinated action of osteoblasts, osteoclasts, and mesenchymal stem cells (MSCs). While bone possesses an intrinsic ability to heal, large defects, delayed unions, and non-unions require advanced therapeutic interventions. Electrical stimulation (ES) has emerged as a promising strategy to enhance bone healing by modulating cellular activity, promoting osteogenic differentiation, and accelerating vascularization. This review explores the mechanistic role of bioelectrical cues in bone regeneration, emphasizing the influence of voltage-gated ion channels, particularly voltage-gated calcium channels (VGCCs), in transducing electrical signals into biochemical responses. Various types of ES modalities, including direct current (DC), capacitive coupling (CC), Pulsed Electromagnetic Field (PEMF), and piezoelectric stimulation, are evaluated for their effectiveness in clinical and preclinical applications. Additionally, the synergistic potential of ES when combined with biomaterials, stem cells, and growth factors is discussed. Despite promising results, challenges remain in translating preclinical findings to clinical applications, with key hurdles including standardization of treatment protocols, variability in patient responses, and regulatory constraints. Large-animal models have provided insights into the efficacy of ES-based therapies, but limitations in field penetration and treatment reproducibility hinder widespread adoption. Future advancements in bioelectronic medicine, smart scaffolds, and artificial intelligence (AI)-driven personalized therapies hold potential to optimize ES-based bone regeneration. Addressing current limitations through interdisciplinary research will be critical in establishing ES as a mainstream therapeutic approach in orthopedic and maxillofacial regenerative medicine.