Biomimetic and spatiotemporally sequential hydrogel delivery system with self-healing and adhesion: Triple growth factor for bone defect repair

The healing of bone defects depends on early revascularization for delivery of oxygen, nutrients, growth factors, and stem cells to the injury region but also elimination of metabolic wastes. In this research, the combination of rapidly released VEGF and sustained release of PDGF-BB from the chitosan microspheres in low crosslinked outer layer promoted angiogenesis and vascularization, and sustained release of BMP-2 from the microspheres in high crosslinked inner layer provided structural support and facilitated osteogenic differentiation. In the skull defect model and the subcutaneous implantation model, the combination of triple growth factors significantly accelerated the regeneration of vascularized bone compared with stimulation of sole BMP-2 or only combination of VEGF and PDGF-BB. Notably, the antibacterial effect of QCS/PF hydrogel could effectively avoid the infection risk caused by surgical implantation of Gram-positive Staphylococcus aureus. In brief, the spatiotemporal specificity of the three growth factors was established in the "sandwich" structure QCS/PF (quaternized chitosan (QCS) and the aldehyde group of Pluronic (R) F127 (PF)) hydrogel delivery system, and the controlled and sequential release of the three growth factors within 28 days was achieved to better repair bone defects.