Dynamic hydrogels with repeatable ultrasound-activated microbubble oscillation enable stepwise spatiotemporal growth factor release for tissue regeneration

Effective tissue regeneration requires precise spatiotemporal therapeutic delivery while maintaining scaffold mechanical integrity, which remains a major challenge in regenerative medicine. Here, we present an ultrasound (US)-activated tissue regeneration platform based on engineered osteogenic microbubbles (MMB-BMPs) embedded in a dynamic hyaluronic acid hydrogel (dHA), forming a mechanically robust scaffold (dHAMBH). Upon repeated US stimulation at the resonant frequency, MMB-BMPs underwent stable oscillation within the hydrogel, enabling stepwise, on-demand release of iron oxide nanoparticles (IONPs) and bone morphogenetic protein-2 (BMP-2), while maintaining scaffold integrity after multiple stimulations cycles. This controlled co-delivery enhances osteogenic differentiation of human bone marrow-derived mesenchymal stromal cells (hMSCs). In a mouse critical-sized calvarial defect model, the dHAMBH hydrogel combined with US stimulation accelerated bone regeneration, achieving a 1.7-fold increase in new bone volume compared with the non-US stimulated control. Overall, this work establishes a US-activated platform that enables precise, repeatable therapeutic delivery to enhance tissue regeneration.