In situ controlled release of stromal cell-derived factor-1 alpha and antimiR-138 for on-demand cranial bone regeneration

Bone regeneration involves complex physiological processes, which is generally regulated and controlled by multiple bioactive molecules. In situ controlled release of combined bioactive factors in a spatiotemporal sequence for adapting the demand of bone regeneration is a desired strategy. In this study, nanoparticle/hydrogel composite system was constructed by incorporating stromal cell derived factor-1 alpha (SDF-1 alpha) and chitosan/tri-polyphosphate/ hyaluronic acid/antimiRNA-138 nanoparticles (CTH/antimiR-138 NPs) in chitosan/beta-sodium glycerol phosphate (CS/GP) hydrogel for rat critical-size calvarial bone regeneration. The fast release of SDF-1 alpha promoted the migration of mesenchymal stem cells (MSCs) for 6 d, while the sustained release of antimiR-138 from the nanoparticle/hydrogel compound enhanced the osteogenic differentiation of MSCs over 21 d. 8 weeks after surgery, calvarial specimens were evaluated by microcomputed tomography (mu-CT), histological analysis and immunohistochemistry. Comparing with blank group and hydrogel group, hydrogels incorporated with SDF-1 alpha and/or CTH/antimiR-138 NPs significantly enhanced bone regeneration (p < 0.05). In addition, the expression of collagen type-1 (COL-1), osteopontin (OPN) and osteocalcin (OCN) proteins were enhanced in the combined drug group (incorporated both SDF-1 alpha and CTH/antimiR-138 NPs) in comparison to the hydrogel group. Our research indicated the in situ formation of NPs/hydrogel composite could provide temporal sequence-release of SDF-1 alpha and CTH/antimiR-138 NPs for on-demand MSCs homing and cranial bone regeneration.