In the current study, polylactic acid (PLA)/graphene oxide (GO) based composite scaffolds were fabricated by electrospinning method and then covalently modified with bone-forming peptide-3 (BFP-3)-loaded thiol-functionalized dendritic mesoporous silica nanoparticles (BFP-3@HS-DMSNs) and RGD. In this regard, PLA electrospinning nanofibers and composite of PLA/GO electrospinning nanofibers containing 0.02, 0.01, 0.04, 0.1, 0.2 % of GO were prepared and characterized in terms of mechanical strength, nanofibers diameter, thermal stability, crystallinity, specific surface area, total pore volume and cell adhesion properties. Among the prepared composites, PLA nanofibers containing 0.02 % GO demonstrated superior mechanical and morphological characteristics along with better cell adhesion for mesenchymal stem cell. Then, the PLA/0.02 %GO nanofiber was treated with plasma and consequently modified with N-(2-aminoethyl)maleimide linker which was applied for Cys-RGD and BFP-3@HS-DMSNs conjugation. The obtained results showed desirable adhesion of PLA/0.02 %GO nanofiber after incorporation of RGD (5 % of maleimide groups of the linker) and DMSNs which significantly increase cell adhesion potency (1.53 folds). By incorporation of BFP-3@HS-DMSNs (equivalent to 0.1 µg of BFP-3) to the RGD-tagged PLA/0.02 %GO nanofiber, the scaffold demonstrated better cytocompatibility and MSC differentiation to osteoblast based on biomineralization assay via alizarin red (4.2 folds) and alkaline phosphatase activity (1.7 folds) tests. In preclinical stage, after skull defect creation in rabbits, 5 treatments groups comprising PLA/0.02 %GO nanofiber, PLA/0.02 %GO/DMSNs, PLA/0.02 %GO/DMSNs/Cys-RGD, PLA/0.02 %GO/BFP-3@DMSNs and PLA/0.02%GO/BFP-3@DMSNs/Cys-RGD were used for bone regeneration in skull defects. After 3 months, the implantation of PLA/0.02GO/BFP-3@DMSNs/Cys-RGD showed higher bone regeneration based on CBCT imaging (18.875 mm2 bone formed area) in comparison with other treatment groups. This hybrid multimodal platform is purposely organized interactive processes which lead to potential bone regeneration.
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