Injectable Hydrogel Microspheres for Osteoarthritis Therapy via Endogenous Mesenchymal Stem Cells Homing and Chondrogenic Differentiation Enhancement.

Abstract

Osteoarthritis (OA) involves progressive cartilage degradation and a chronic inflammatory microenvironment. Here, we develop injectable hydrogel microspheres featuring an interpenetrating polymer network (IPN) and the capability to anchor in situ to the cartilage matrix for OA treatment. Using microfluidics, we fabricate platelet-derived growth factor-BB (PDGF-BB)-loaded IPN microspheres (GS/GF) and apply a polydopamine (PDA) coating via self-polymerization to form core-shell GS/GF-PDA/DS microspheres loaded with diclofenac sodium (DS). Upon intra-articular injection, the PDA shell enabled targeted adhesion to cartilage defects through catechol-mediated bioadhesion, while released DS and PDA collectively alleviate inflammation by scavenging reactive oxygen species, suppressing pro-inflammatory cytokines, and modulating macrophage polarization. Concurrently, PDGF-BB release enhances endogenous mesenchymal stem cell (MSC) recruitment. The IPN structure improves mechanical robustness and provides a dynamic microenvironment conducive to chondrogenic differentiation of recruited MSCs. In vitro, the GS/GF-PDA/DS microspheres exhibit good injectability and cartilage-anchoring ability. In addition, they modulate macrophage polarization, attenuate chondrocyte inflammation, and facilitate both the migration and chondrogenic differentiation of MSCs. In vivo, the GS/GF-PDA/DS microspheres significantly reduce synovial inflammation and accelerate cartilage regeneration in rats. This study presents a biofunctional material system that integrates immunomodulation, stem cell recruitment, and cartilage repair for comprehensive OA therapy.