Programmed biomolecule delivery orchestrate bone tissue regeneration via MSC recruitment and epigenetic modulation

An on-demand delivery of chemotactic and osteogenic biomolecules to induce the recruitment and osteogenic differentiation of endogenous stem cells for in situ bone regeneration is appealing but challenging. To meet the changing demands at different periods of bone regeneration, a programmed delivery system was successfully fabricated by incorporating the near-infrared (NIR) light-responsive polydopamine-coated hydroxylapatite nanoparticles (nHA@PDA) into the thermo-responsive hydroxybutyl chitosan (HBC) hydrogel to regulate the therapeutic concentrations and time points of chemotactic simvastatin (SIM) and osteogenic pargyline (PGL). This smart hydrogel composite could perform an initial rapid release of SIM to meet the need of endogenous stem cell recruitment at the beginning of bone healing. Meanwhile, a flexible and NIR light-triggered increased release of PGL could promote osteogenic differentiation of migrated cells via a safe and stable epigenetic mechanism. Taken together, a well-orchestrated therapeutic timeline of two drugs was obtained in our programmed delivery system, thus enhancing bone regeneration in a highly effective method. In addition, the small molecular drugs utilized in this study were stable, safe, and easy for translation and clinical applications in bone tissue engineering.