Localized delivery of FTY-720 from 3D printed cell-laden gelatin/silk fibroin composite scaffolds for enhanced vascularized bone regeneration

Abstract

Three-dimensional (3D) printing can construct products with accurate complex architecture. Engineered bone tissues that can promote vascularization and regulate directed differentiation of bone marrow-derived mesenchymal stem cells (BMSCs) are considered as an ideal substitute the healing of bone for bone defects treatment. Herein, we fabricated a 3D printed BMSCs-laden scaffold using methacrylated gelatin and methacrylated silk fibroin (GelMA/SFMA) based bioinks along with localized sustained release of a small molecule drug fingolimod (FTY-720) for the synergistic interactions of vascularization and osteogenesis during bone repair. The GelMA/SFMA bioink showed significant advantages due to their tunable rheology, rapid thermal crosslinking, and improved shape fidelity following bioprinting. The in vitro experiments demonstrated that high cell viability of cells-laden constructs, while FTY-720-containing scaffolds significantly promoted migration and induced tube-like structure formation of human umbilical vein endothelial cells (HUVECs) as well as expressed high osteogenic-related genes expression of BMSCs. The implantation in a critical-size rat cranial defect model further revealed that FTY-720-loaded scaffolds significantly promoted vascularization and bone regeneration. Furthermore, scaffolds carrying BMSCs and FTY-720 were more osteogenic in vivo than scaffolds carrying BMSCs alone. Therefore, the constructed BMSCs-laden and FTY-720-loaded GelMA/SFMA scaffolds would be an ideal candidate with required structure and desired function for vascularization of bone regeneration.