Repairing osteoporotic bone defects under iron overload: A chitosan-hyaluronic acid hydrogel via synergistic iron chelation and ROS responsiveness

Iron overload in the bone microenvironment elevates reactive oxygen species (ROS) and triggers osteoblast ferroptosis, exacerbating osteoporosis. We developed a genipin-crosslinked hydrogel composed of 3-aminophenylboronic acid-grafted hyaluronic acid and hydrocaffeic acid (DHCA)-grafted chitosan (CS-DHCA/HA-3-APBA) and loaded with chromium picolinate (CrPic). In the environment of osteoporosis, Fe 3+ coordination compacted the network and increased compressive modulus by approximately twofold, while elevated ROS accelerated network degradation, supporting ROS-responsive CrPic release, whereas under physiological buffer conditions the release remained slow and stable. In vitro, in iron-overloaded rat bone marrow mesenchymal stem cells (rBMSCs), the CS-DHCA/HA-3-APBA/CrPic hydrogel lowered ROS, preserved mitochondrial membrane potential, blocked ferroptosis, and restored migration and osteogenic differentiation. Treated cells showed alkaline phosphatase activity and mineral deposition near control levels despite iron overload. In vivo, in rabbits with iron overload-induced osteoporosis, defects treated with the Fe 3+ -chelating, CrPic-loaded hydrogel (F-Gel@CrPic) formed robust new bone. At 4 weeks, BV/TV in this group was about 30 %, roughly threefold higher than in untreated defects, and it nearly doubled again by 8 weeks, approaching healthy levels. New bone showed higher mineral density and markedly reduced iron deposition. This work highlights the unique ability of engineered hyaluronic acid/chitosan hydrogels to actively correct a pathological microenvironment and achieve functional tissue repair, showcasing the promise of natural polysaccharide-based engineering for advanced therapy.