Inflammation‐Responsive Hydrogel Spray for Synergistic Prevention of Traumatic Heterotopic Ossification via Dual‐Homeostatic Modulation Strategy

Traumatic heterotopic ossification (THO) represents one of the most prominent contributors to post-traumatic joint dysfunction, which currently lacks an effective and definitive preventative approach. Inflammatory activation due to immune dyshomeostasis during the early stages of trauma is believed to be critical in initiating the THO disease process. This study proposes a dual-homeostatic modulation (DHM) strategy to synergistically prevent THO without compromising normal trauma repair by maintaining immune homeostasis and inducing stem cell homeostasis. A methacrylate-hyaluronic acid-based hydrogel spray device encapsulating a curcumin-loaded zeolitic imidazolate framework-8@ceric oxide (ZIF-8@CeO2, CZC) nanoparticles (CZCH) is designed. Photo-crosslinked CZCH is used to form hydrogel films fleetly in periosteal soft tissues to achieve sustained curcumin and CeO2 nanoparticles release in response to acidity and reactive oxygen species (ROS) in the inflammatory microenvironment. In vitro experiments and RNA-seq results demonstrated that CZCH achieved dual-homeostatic regulation of inflammatory macrophages and stem cells through immune repolarization and enhanced efferocytosis, maintaining immune cell homeostasis and normal differentiation. These findings of the DHM strategy are also validated by establishing THO mice and rat models. In conclusion, the CZCH hydrogel spray developed based on the DHM strategy enables synergistic THO prevention, providing a reference for a standard procedure of clinical operations.