Diabetic implant osseointegration presents a significant clinical challenge due to complex pathophysiology and limited therapeutic options. Mitochondrial dysfunction and endoplasmic reticulum (ER) stress act synergistically through a vicious cycle, collectively leading to osteoblast failure and reduced bone formation, which are key contributors to abnormal bone metabolism in the diabetic state. This study developed an injectable photocrosslinkable silk fibroin hydrogel incorporating Mdivi-1 (Mdi@SilMA), which integrates shear-thinning injectability, sustained drug release, mitochondrial function regulation, and bone formation promotion. In vivo investigations demonstrated that Mdi@SilMA significantly enhanced d... More
Diabetic implant osseointegration presents a significant clinical challenge due to complex pathophysiology and limited therapeutic options. Mitochondrial dysfunction and endoplasmic reticulum (ER) stress act synergistically through a vicious cycle, collectively leading to osteoblast failure and reduced bone formation, which are key contributors to abnormal bone metabolism in the diabetic state. This study developed an injectable photocrosslinkable silk fibroin hydrogel incorporating Mdivi-1 (Mdi@SilMA), which integrates shear-thinning injectability, sustained drug release, mitochondrial function regulation, and bone formation promotion. In vivo investigations demonstrated that Mdi@SilMA significantly enhanced diabetic osseointegration compared to plain silk hydrogels by suppressing pathological mitochondrial fission, restoring HO-1-mediated antioxidant defenses, and preserving osteogenic capacity through RANKL/OPG axis modulation. The therapeutic efficacy of Mdivi-1 stems from its targeted binding to the GTPase domain of Drp1, which results in the restoration of mitochondrial homeostasis by mitochondrial dynamic recovery, ROS elimination, and subsequent ER stress mitigation. This coordinated action facilitates mitochondrial quality control, reestablishes cellular functional homeostasis, and ultimately promotes osteogenesis. These findings establish Mdivi-1 as a promising therapeutic agent while providing a novel theoretical framework for targeting ER-mitochondrial crosstalk in diabetic bone metabolism.
