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 in vitro and in vivo assays confirmed that the dual-loaded bilayer-hydrogel reduced post-traumatic inflammation and enhanced cartilage regeneration by effectively scavenging ROS and reprogramming macrophages.The proposed platform provides multi-staged therapy,which allows for the optimal harnessing of Exos as a therapeutic for cartilage regeneration.