Ferric ion-crosslinked hydrogel patch loaded with IGF-1R inhibitor for the treatment of heterotopic ossification through microenvironment multifaceted regulation.

Abstract

Heterotopic ossification (HO), characterized by pathological bone formation in soft tissues, leads to joint dysfunction and pain, with limited clinical treatments available. The post-injury microenvironmental dyshomeostasis, including the aberrant inflammatory response and imbalanced osteoblast/osteoclast differentiation, serves as a critical factor in the pathogenesis of HO. In this study, excessive insulin-like growth factor (IGF-1) was demonstrated to participate in the process of HO by inducing the abnormal differentiation of tendon-derived stem cells (TDSCs). Herein, we fabricated a targeted drug delivery system by loading picropodophyllin (PPP), an IGF-1 receptor (IGF-1R) inhibitor, into mesoporous silica nanoparticles (MSNs). This MSN-based system was then integrated into a multifunctional hydrogel patch (PCL@HA-ADH@PA/Fe) to produce the composite system PCL@HA-ADH@PA/Fe@MSNP, aiming to remodel the microenvironment in HO. The composite hydrogel patch exerted multifaceted therapeutic effects. It not only restored immune homeostasis but also suppressed osteogenesis while enhancing osteoclastogenesis, which was attributed to the sustained release of PPP and ferric ions. Mechanistically, these regulatory effects were mediated through the suppression of the PI3K-Akt signaling pathway and the activation of mitophagy. In conclusion, the PCL@HA-ADH@PA/Fe@MSNP patch developed based on the "microenvironment multifaceted regulation" strategy enables synergistic HO prevention, providing a promising and translatable therapeutic approach for tendon repair.