3D printed scaffolds regulated by neural-bone metabolic coupling promote bone unit regeneration.

The bone unit (BU) is a multicellular functional unit composed of neuromodulatory networks, bone tissue, and functional blood vessels. As a functional extension of bone regeneration, the BU coordinates neural signal, regeneration of the circulatory network and remodeling of the bone matrix through the neural-bone metabolic coupling mechanism. Currently, effective strategies are lacking to remodel the homeostasis of the neural-bone metabolic coupling, which in turn leads to impaired BU regeneration. Here, we constructed a 3D-printed biomimetic hydrogel scaffold, GGMN-GSE, to synergistically couple nerve-bone metabolism and restore BU regeneration through electrophysiological microenvironment reconstruction and functional cell recruitment. The GGMN layer (Grooved GelMA@MXene@NGF) incorporates conductive MXene to emulate periosteal electrophysiology and features biomimetic microgrooves to guide neural orientation, collectively modulating neural-bone metabolic coupling. The GSE layer (GelMA@SVVYGLR-E7), engineered with a dual-targeting peptide, recruits BMSCs/EPCs to supply functional cells while remodeling the vasculo-osseous regenerative niche, synergistically driving osteogenic regeneration. In vitro, the GGMN-GSE scaffold promoted nerve fiber regeneration and induced secretion of neuropeptides such as CGRP, GHRH, and VIP, and activated