Programmed core-shell electrospun nanofibers to sequentially regulate osteogenesis-osteoclastogenesis balance for promoting immediate implant osseointegration

The biology of immediate post-extraction implant osseointegration is mediated by a coordinated cascade of osteoblast-osteoclast interactions. The aim of this study was to develop a dual-delivery system that allowed sequential release of substance P (SP) to promote bone regeneration and alendronate (ALN) to reduce bone resorption, which will improve the implant osseointegration. We used coaxial electrospinning to fabricate the core-shell poly lactic-co-glycolic acid (PLGA)/gelatin nanofibers, which consists of SP in the shell and ALN in the core. This programmed delivery system was shown to release SP and ALN sequentially to match the spatio-temporal specificity of bone healing. The migration assay demonstrated that the SP-ALN dual-delivery system increased bone marrow mesenchymal stem cells (BMSCs) transmigration. Besides, the expression of osteogenic/osteoclastic markers, Alizarin Red staining, tartrate-resistant acid phosphatase (TRAP) staining, F-actin staining and bone resorption experiment showed that the dual-delivery system can render a microenvironment favorable for osteogenic differentiation and adverse to osteoclastogenesis. Using a rat immediate implant model, we validated the promoted osteogenic property and osseointegration around the implants of SP-ALN dual-delivery system by micro-computed tomography (micro-CT) and histological analysis. These findings suggest that the dual-delivery system with time-controlled release of SP and ALN by core-shell nanofibers provides a promising strategy to facilitate immediate implant osseointegration through favorable osteogenesis. STATEMENT OF SIGNIFICANCE: Immediate implant placement is potentially challenged by the difficulties in achieving primary implant stability and early osteogenesis. Initial period of osteointegration is regulated by osteoblastic/osteoclastic cells resulting in a coordinated healing process. To have an efficient bone regeneration, the coaxial electrospinning was used to fabricate a programmed dual-delivery system. The SP released rapidly and favored for BMSCs migration and osteogenic differentiation, while the sustained release of ALN can reduce the bone resorption. The rat immediate implant model indicated that the SP-ALN dual-delivery system could present the promoted peri‑implant osteogenic property and osseointegration through modulating the osteogenesis-osteoclastogenesis balance. This work highlights the sequential dual delivery of SP and ALN has a promising potential of achieving enhanced osseointegration for immediate implant placement.