Ion-Engineered Microcryogels via Osteogenesis-Angiogenesis Coupling and Inflammation Reversing Augment Vascularized Bone Regeneration

Native bone inherently requires a balanced ionic microenvironment to maintain bone homeostasis. Hence, scaffolds designed for the sustained release of therapeutic ions into bone defects hold great promise for bone regeneration. Magnesium (Mg) and silicon (Si) are essential elements, which play crucial roles in the process of bone regeneration, impacting immunomodulation, angiogenesis, and osteogenesis. Herein, porous cryogel-type organic-inorganic composite microspheres are developed as injectable microscaffolds (denoted as GMN). GMN enables sustained release of Mg/Si ions at an optimized ratio, achieving the most significant synergistic effect on vascularized bone regeneration. Various conditioned media are obtained to explore angiogenesis-osteogenesis coupling, as well as the crosstalk between bone marrow mesenchymal stromal cells (BMSCs) and macrophages. Meanwhile, autocrine and paracrine effects simultaneously play synergistic modulating functions in determining cell fates under the guidance of Mg/Si ions and biofactors secreted by cells. Overall, the Mg/Si ion-engineering microscaffolds create a conducive microenvironment to efficiently augment the regeneration of vascularized bone tissue in vivo, offering a versatile platform for tissue engineering. The porous organic-inorganic composite microcryogels (denoted as GMN) enable sustained release of magnesium/silicon (Mg/Si) ions at an optimized ratio. Mg/Si ion-engineered microcryogels enable robust vascularized bone regeneration via effectively modulating osteogenesis-angiogenesis coupling and creating a beneficial immune microenvironment at the defect site, hence providing a generalizable platform for tissue engineering. image