Abstract Through biomimicry of natural biomineralization processes, biomimetic mineralized hydrogels have demonstrated exceptional osteoconductive and osteoinductive properties. However, given the stage‐specific nature of bone repair, developing hydrogels capable of sequential multifactor release to match the evolving biological requirements in bone regeneration remains a significant challenge. Here, a magnesium calcium phosphate mineralized hydrogel (MCPMH) is reported with sequential multifactor release behavior. The MCPMH is facilely prepared by directly mixing sodium hyaluronate (HA), alendronate sodium (ADA), Ca 2+ , and Mg 2+ in deionized water. It undergoes spontaneous mineralization, transitioning from a soft (≈2 kPa) to a stiff (≈92 kPa) hydrogel. Mechanistic studies reveal that ADA and Ca 2+ are stably entrapped within calcium phosphate (CaP) crystals, while Mg 2+ forms a loosely bound complex with ADA. This structure enables an on‐demand sequential release profile, i.e., quick early‐stage Mg 2+ release to promote angiogenesis, followed by sustained release of Ca 2+ and ADA for osteogenesis and remodeling. Moreover, in vivo evaluation in a rat critical‐sized calvarial defect model confirmed MCPMH's superior bone regeneration capacity. Overall, this work delineates a holistic strategy for fabricating biomimetic mineralized hydrogels with sequential multifactor release capabilities, underscoring their substantial promise as artificial bone repair materials in clinical settings.
Zhao et al. (2025) studied this question.