Nanocomposite hydrogels optimize the microenvironment by exterior/interior crosstalk for reprogramming osteoporotic homeostasis in bone defect healing.

Discovering new tactics for healing bone defects becomes a worldwide challenge in osteoporosis patients. The disordered acidic microenvironment plays a pivotal role in driving the imbalance of bone homeostasis regulated by osteoblasts and osteoclasts. However, the scarcity of hydrogel materials developed to optimize local bone microenvironment has made osteoporotic defect healing more challenging. Herein, we present innovative nanocomposite hydrogels with precisely engineered microarchitectures designed to optimize the acidic microenvironment by facilitating crosstalk between exterior and interior spaces, aimed at enhancing the reconstruction of osteoporotic bone defects. The chlorogenic acid grafted chitosan as double-sided crosslinkers is specially designed to not only combine with acid-reversible Laponite® nanosheet via interfacial interactions but also integrate with gold nanorod (a typical photothermal agent) through catechol-Au bond. The supramolecular construction of nanocomposite hydrogels holds promise for achieving a highly continuous and homogeneous pore network microarchitecture. As expected, hydrogels display outstanding spatiotemporal local mild hyperthermia, which accelerates the neutralization reaction between OH- ions released from Laponite® and hydrogen ions (pH ∼ 4.0). The optimized microenvironment restores osteoclast/osteoblast homeostasis, resulting in the promotion of osteoblastogenesis and inhibition of osteoclastogenesis, thereby facilitating the healing of osteoporotic bone defects. This work is hoped to design versatile hydrogels for optimizing the microenvironment, displaying promising integrative substitute materials for clinically effective treatment of osteoporotic bone defects.