Exosomes loaded a smart bilayer-hydrogel scaffold with ROS-scavenging and macrophage-reprogramming properties for repairing cartilage defect

Enhancing the regeneration of cartilage defects remains challenging owing to limited innate self-healing as well as acute inflammation arising from the overexpression of reactive oxygen species (ROS) in post-traumatic microenvironments. Recently, stem cell-derived exosomes (Exos) have been developed as potential cell-free therapy for cartilage regeneration. Although this approach promotes chondrogenesis, it neglects the emerging inflammatory microenvironment. In this study, a smart bilayer-hydrogel dual-loaded with sodium diclofenac (DC), an anti-inflammatory drug, and Exos from bone marrow-derived mesenchymal stem cells was developed to mitigate initial-stage inflammation and promote late-stage stem-cell recruitment and chondrogenic differentiation. First, the upper-hydrogel composed of phenylboronic-acid-crosslinked polyvinyl alcohol degrades in response to elevated levels of ROS to release DC, which mitigates oxidative stress, thus reprogramming macrophages to the pro-healing state. Subsequently, Exos are slowly released from the lower-hydrogel composed of hyaluronic acid into an optimal microenvironment for the stimulation of chondrogenesis. Both