Spatial bridges of hierarchical scaffolds orchestrate MSCs/SCs interaction for bone regeneration

The spatiotemporal distribution of multiple cells and their interactions with extracellular matrix in three-dimensional microenvironments play a critical role in regulating cell behaviors and modulating tissue development and regeneration. Preparation of hierarchical structural scaffolds for multicellular crosstalk in tissue engineering holds great significance. Here, inspired conceptually by the idea of "magpie bridge", biomimetic hierarchical multi-channel scaffolds, serving as "spatial bridges" to orchestrate multicellular spatiotemporal interactions have been proposed for innervated bone regeneration. Hierarchical multi-channel structures facilitate the mutual migration and energy metabolism activities of mesenchymal stem cells (MSCs) and Schwann cells (SCs), thereby enhancing their specific differentiation. Transcriptomic analysis revealed that MSCs/SCs cross-talk mediated by cytokine-cytokine receptor interactions, including the activation of multiple neurogenesis/osteogenesis-related signaling pathways. In rabbit bone defect model, SCs-laden hierarchical multi-channel scaffolds constructed a neuro-inductive metabolism-activated microenvironment, thereby achieving 3.24-fold increase in bone regeneration and 2.29-fold increase in neuro-vascular networks reconstruction compared to traditional bioceramic scaffolds in the core defects region at 12-week post-surgery, respectively. Therefore, this study introduces an exceptional concept that biomimetic hierarchical scaffolds serve as "spatial bridges" for accelerating multicellular spatiotemporal interactions of complex tissue and organ regeneration, opening new avenues for designing next-generation regenerative biomaterials.