Fabrication of Hydrogel-Coated Poly(l-lactic Acid) Microspheres for Chondrogenic and Osteogenic Differentiation of Mesenchymal Stem Cells

Microspheres have been widely applied in osteoarthritis (OA) treatment and tissue engineering because of their favorable biocompatibility and drug delivery capabilities. However, single-component microspheres often fail to provide satisfactory therapeutic outcomes under the complex mechanical environment of the joint, particularly under persistent friction and shear stress. In this study, poly(l-lactic acid) (PLLA)–gelatin grafted with hydroxyphenyl propionic acid (GelHPA) core–shell microspheres were successfully fabricated via an in situ enzymatic cross-linking method. The PLLA core provides structural support and serves as a reservoir for bioactive agents, such as kartogenin (KGN) and nanohydroxyapatite (nHA), while the GelHPA shell offers a hydrated, gelatin-derived interface with improved cytocompatibility and lubrication-related properties. The GelHPA shell supported cell adhesion and spreading on the microsphere surface, while KGN- and nHA-loaded microspheres promoted chondrogenic and osteogenic differentiation of mesenchymal stem cells, respectively. Overall, the PLLA-GelHPA core–shell microsphere system integrates mechanical support with biological functionality, offering a promising injectable platform for OA-related osteochondral repair and tissue engineering applications.