Microenvironment responsive hypoxia-mimetic DFO composite hydrogel for on-demand neovascularization to promote tendon-to-bone healing

Due to the particularity of the tendon-to-bone interface, the integration of tendon graft and bone after anterior cruciate ligament (ACL) reconstruction is the key to the success of the surgery. This reconstruction requires early on-demand angiogenesis and osteogenesis to promote early and rapid healing of the tendon-to-bone interface. Here, a hypoxic-mimetic 3D porous hydrogel was prepared with a multi-responsive hybrid interpenetrating network to the tendon-to-bone interfacial microenvironment under a highly hypoxic, acidic, reactive oxygen species (ROS), and related enzyme-enriched state. The hypoxia agent DFO can be effectively control-released adaptive to the stimulation of tendon-to-bone interfacial microenvironment, to upregulate HIF-1α, promote the expression of vascular endothelial growth factor, bone morphogenetic protein 2 and runt-related transcription factor 2, thereby promoting rapid early angiogenesis and bone formation on demand. At the same time, it can effectively resist oxidative stress, reduce ROS and the inflammatory response, promote better integration of the tendon-to-bone interface. Furthermore, in vivo experiments combining micro-CT, histological and biomechanical analysis also showed effective promotion of early and rapid tendon-to-bone healing. In conclusion, our study may provide a new therapeutic strategy for the integration of the tendon-to-bone interface.