Recapitulation of In Situ Endochondral Ossification Using an Injectable Hypoxia‐Mimetic Hydrogel

Abstract Due to the limited ability for perfusion, traditional intramembranous ossification (IMO) often fails to recapitulate the natural regeneration process of most long bones and craniofacial bones. Alternatively, endochondral ossification (ECO) strategy has emerged and has been evidenced to circumvent the drawbacks in the routine application of IMO. Here, an injectable, poly(glycerol sebacate)‐ co ‐poly (ethylene glycol)/polyacrylic acid (PEGS/PAA) hydrogels are successfully developed to induce a hypoxia‐mimicking environment and subsequently recapitulate ECO via in situ iron chelation. With the incorporation of PAA, these hydrogels present remarkable viscoelasticity and high efficacy of iron ion‐chelating after injection, giving rise to the activation of HIF‐1α signaling pathway and suppression of inflammatory responses, and thereby improving chondrogenic differentiation in the early stage and facilitating vascularization in the later stage, which consequently trigger typical ECO. More importantly, through sustained and stable expression of HIF‐1α regulated by PEGS/PAA hydrogels throughout the regeneration, a harmonious chondrogenic/osteogenic balance can be struck and thereby accelerating the progress of ECO compared to the PEGS. The findings provide an efficient strategy to achieve in situ ECO via biomaterial‐based iron ion‐chelating and ensuing hypoxia‐mimicking, representing a novel and promising concept for future application in bone regeneration.