Bioactive ultrasound preserves periosteal vascular architecture during mechanical unloading

Mechanical unloading during spaceflight disrupts skeletal homeostasis through coordinated alterations in bone remodeling, vascular architecture, and local tissue oxygenation. Although low-intensity pulsed ultrasound (LIPUS) exerts osteogenic and angiogenic effects, whether bioactive physical stimulation restores osteovascular adaptation during unloading remains unknown. Here, we investigated the effects of daily LIPUS treatment using a murine hindlimb unloading model. Mechanical unloading induced progressive trabecular and cortical bone deterioration accompanied by disruption of periosteal vascular architecture, increased local hypoxia, and elevated systemic inflammatory cytokines. LIPUS significantly attenuated bone loss by suppressing osteoclast activation, partially preserving mature osteoblasts, and maintaining the periosteal vascular architecture. Preservation of vascular architecture was positively associated with bone mass, whereas tissue hypoxia was inversely associated with cortical thickness. LIPUS also reduced periosteal hypoxia and partially suppressed systemic inflammatory responses. Together, these findings identify preservation of periosteal vascular architecture as a key component of skeletal adaptation to mechanical unloading and highlight bioactive ultrasound as a non-invasive approach for preserving skeletal homeostasis under unloading conditions.