Bioinspired Engineering of Streamlined Skeletal Interoception: Neural Bioprinted Piezoelectric Scaffolds for Neuro-Vascularized Bone Regeneration.

The skeletal interoception system that orchestrates bone homeostasis and regeneration through a coordinated "afferent-integration-efferent" reflex arc has been overlooked in bone tissue engineering. The dorsal root ganglion (DRG) neurons constitute the hubs of this system. Moreover, beyond their canonical role within the interoceptive pathway, these neurons exert a direct effector role by secreting calcitonin gene-related peptide (CGRP) to promote bone repair. However, current sensory nerve-targeted strategies in bone tissue engineering remain static, bypassing the dynamic reflex arc and failing to establish an autonomous functional system. To address this, a streamlined interoception unit was engineered using neural bioprinting of DRG neurons within piezoelectric scaffolds. Upon sensing ultrasound (US) stimulation, the piezoelectric poly(l-lactide) (PLLA) component mediates mechanoelectrical coupling, triggering a Ca2 + influx-induced effector response in the incorporated DRG neurons that enhances CGRP secretion and expression. The secreted CGRP subsequently promotes osteogenesis and angiogenesis in vitro and accelerates neuro-vascularized bone regeneration in a rat femoral condyle defect model. This study established a bioinspired platform with a self-contained "sensor-effector" circuit, offering a novel engineered strategy for bone regeneration.