Dynamic linking bone ECM-mimic hydrogel for anti-inflammatory therapy of cranial defect

Abstract

Cranial defect repair is frequently hindered by limited intrinsic regenerative capacity, infection risks, and chronic inflammation, whereas conventional grafts and inert implants often suffer from poor host integration. Herein, we report an extracellular matrix–mimicking hydrogel that synchronizes angiogenesis, osteogenesis, and immunomodulation through dynamic thiol–disulfide chemistry and sacrificial prevascularization. Hyaluronic acid functionalized with L-cysteine ethyl ester (HACys) was crosslinked with allicin to yield a viscoadaptive, stress-relaxing network, within which type I collagen was extruded into VEGF-loaded threads to serve as sacrificial templates (HACys-VEGF@Coll-A). Upon enzymatic degradation, these threads generated VEGF-lined microchannels designed to guide rapid vascular ingress. The composite demonstrated excellent cytocompatibility with BMSCs and selectively enhanced HUVEC viability and spreading. Furthermore, VEGF-presenting constructs significantly promoted endothelial tube formation and migration while upregulating VEGF mRNA, confirming preserved bioactivity. In BMSCs, VEGF-containing hydrogels increased alkaline phosphatase activity and mineral deposition, concomitant with the upregulation of osteogenic genes (ALP, COL1, RUNX2, OCN). Notably, macrophages shifted from a CD86high/CD206low toward a CD86low/CD206high phenotype with decreased TNF-α and increased IL-10 secretion, indicating the establishment of a pro-resolution immune microenvironment. Collectively, HACys-VEGF@Coll-A forms a dynamic, remodelable scaffold that integrates preformed vascular conduits while supporting osteogenesis and tempering inflammation, thereby addressing major barriers to cranial defect repair and warranting further in vivo evaluation of release kinetics, channel architecture, and mechanics.