An injectable hydrogel dotted with dexamethasone acetate-encapsulated ROS-scavenging micelles for combinatorial therapy of osteoarthritis

Abstract Selective exhaustion of over-expressed reactive oxygen species (ROS) is of great significance in the therapy of osteoarthritis (OA) due to the inhibiting effect on oxidative stress and inflammation. Herein, a ROS-scavenging and drug-release platform was prepared via encapsulating dexamethasone acetate (DA)-loaded ROS erasable poly(ethylene glycol)-b-polythioketal-b-poly(ethylene glycol) (PEG-PTK-PEG) micelles (PDM) into an injectable hydrogel. The hydrogel (HDH@PDM) was constructed by Schiff base reaction between hydrazide-grafted hyaluronic acid (HA-ADH) and aldehyde-modified dextran (Dex-ALH), achieving a self-healing property for viscosupplementation. The PDM imparted enhanced antioxidant capability to the hydrogel, which in turn endowed the PDM with prolonged retention and sustained DA release. The intraarticularly administered multifunctional injectable hydrogel potently diminished inflammation via depleting ROS and suppressing inflammatory cytokines as well as downregulating pro-inflammatory M1 macrophages ratio in a rat OA model. The developed therapeutic system significantly alleviated OA symptoms, embodying in excellent capability of preventing cartilage extracellular matrix degeneration with negligible toxicity in vivo.