Programmed PTH pulsatility coupled with piezoelectric stimulation via ultrasound-activated scaffolds synergizes deep bone defect regeneration.

Large bone defects in deep anatomical regions continue to pose significant clinical challenges for osteogenic reconstruction. While pulsatile low-dose parathyroid hormone (PTH) administration shows therapeutic potential for bone regeneration, its effective delivery to deep tissue defects remains problematic. To address this limitation, we developed a novel piezoelectric scaffold (KM@PTH) by integrating PTH with potassium sodium niobate (KNN)-mesoporous bioactive glass (MBG) composites. The KM@PTH system achieves synergistic deep bone regeneration by coupling ultrasound-activated piezoelectric stimulation with spatiotemporally programmed PTH pulsatility, where electromechanical microcurrents and biochemical signaling collaboratively enhance osteogenesis. This dual-modality approach initiates electrostatic PTH liberation while ultrasound-induced mechanical vibrations enhance protein release from the scaffold matrix. In a rabbit femoral defect model demonstrating deep tissue penetration capability, ultrasound-triggered pulsatile PTH delivery from KM@PTH significantly enhanced bone regeneration. Transcriptomic profiling identified calcium ion homeostasis as the central regulatory mechanism, elucidating the synergistic interplay between pulsatile PTH kinetics and electromechanical stimulation. The combined modality promoted osteogenesis through coordinated pathways: Enhanced calcium influx stimulating mitochondrial bioenergetics and mineralization; PKA/PKC-mediated upregulation of osteogenic factors; and mitochondrial functional activation coupled with inhibition of efferocytosis to enhance mesenchymal stem cell osteogenic commitment. This innovative integration of ultrasound-responsive piezoelectric systems with programmable drug release establishes a translatable paradigm for reconstructing challenging deep bone defects.