Transmetallic biomimetic Hydrogel implants restore osteogenesis-angiogenesis coupling via Fe/Co ionic microenvironment remodeling for enhancing osteoporotic fracture healing

Abstract

The regeneration of osteoporotic bone fractures remains a significant clinical challenge, primarily due to the iron overload-induced functional impairment in osteoporosis-angiogenesis coupling. Here, we developed a transmetallic biomimetic hydrogel implant (TBH) to address this issue. The TBH was fabricated by crosslinking CP1-modified hyaluronic acid (HA) with catechol-modified chitosan (CS-CT), of which the catechol groups enabled efficient loading of pro-osteogenic Co2+ ions. Upon implantation into osteoporotic bone fracture sites, the transmetallic activity of the hydrogel allows excess Fe3+ ions to competitively replace the pre-incorporated Co2+ ions, driven by the stronger affinity of Fe3+ for catechol groups, effectively sequestering the free iron species to alleviate osteoporosis-associated iron overload while enabling the controlled release of Co2+ locally. Notably, the TBH-enabled iron sequestering substantially mitigates iron overload and restores mitochondrial function in both endothelial cells (ECs) and bone marrow mesenchymal stem cells (MSCs), while the synchronously released Co2+ activates EC metabolism and promotes HIF-1α-driven type H vessel formation as well as driving osteogenic differentiation of MSCs through paracrine signaling. Fe3+-catechol coordination also significantly enhances the mechanical properties of the hydrogel network and optimizes its degradation profiles to match local osteogenesis. In addition, TBH gradually releases osteogenic bovine bone collagen peptides to promote mineralization through spontaneous degradation. These merits cooperatively improve bone regeneration in osteoporotic rat models, providing an approach for osteoporotic bone fracture healing in the clinic.