Cerebrospinal Fluid-Derived extracellular Vesicle-Inspired Multifunctional bone regeneration scaffold for cranial defect repair

• Cerebrospinal fluid immersion in the skull can promote skull repair in mouse model. • CSF EVs could promote macrophage differentiation, bone regeneration and angiogenesis. • CSF EVs were combined with DFO and scaffolds to develop a novel composite scaffold. • Composite scaffold showed great repair effect in a model of cranial bone defects. Extracellular Vesicles (EVs) have emerged as a focal point in research concerning material-related immune responses and osteogenesis. While previous studies have linked EVs in cerebrospinal fluid (CSF) to neurodegenerative diseases, our investigation reveals a novel perspective: CSF EVs possess the potential to stimulate osteogenesis, presenting a significant advancement. Thus, we explored the synergistic effects of cerebrospinal fluid-derived extracellular vesicles (CSF EVs) and deferoxamine (DFO), another osteogenic factor, within a hydrogel scaffold for bone regeneration. The composite scaffolds doped EVs and DFO (EDGP scaffold) exhibited remarkable outcomes, including enhanced differentiation of M2 macrophages, increased angiogenesis, and heightened osteoblast differentiation. We elucidated the underlying mechanism wherein CSF EVs might facilitate mesenchymal stem cells’ osteogenesis via the JAK1/STAT3 pathway. Upon implantation at the bone defect site, the EDGP scaffold demonstrated superior efficacy in fostering new bone formation, evident by elevated levels of osteoblastic differentiation markers and enhanced calcium nodule formation. This personalized treatment model has great potential to be integrated into neurosurgical interventions for individualized skull defect correction, leveraging the unique regenerative potential of EVs derived from the patient’s own cerebrospinal fluid in combination with biomimetically scaffolds to improve bone regeneration by avoiding immune rejection, size differences, and limited bone donors.