Bioadhesive calcium phosphate cement with nano-whitlockite for vascularized bone regeneration

Calcium phosphate cements are widely used in bone repair but are limited by inadequate mechanical strength, weak bone adhesion, slow resorption, and limited angiogenic activity. Here, we developed a multifunctional bone cement based on tetracalcium phosphate and phosphoserine, incorporating poly(methyl vinyl ether-alt-maleic acid) (PMVE-MA) and Mg-containing nano-whitlockite (nWH). The optimized formulation, C-PM15-W20, exhibited significantly enhanced compressive and adhesive strength compared with a commercial hydroxyapatite-forming cement. It also demonstrated favorable handling characteristics, aqueous stability, and gradual degradation under both physiological and mildly acidic conditions. In a synthetic osteoporotic bone model, C-PM15-W20 achieved pedicle screw pull-out strength comparable to commercial PMMA and hydroxyapatite-forming cement controls. In vitro, nWH incorporation promoted HUVEC migration and tube formation while enhancing osteogenic differentiation and matrix mineralization, whereas PMVE-MA-containing formulations reduced LPS-stimulated IL-1β and TNF-α expression, indicating modulation of selected pro-inflammatory responses. In vivo, C-PM15-W20 enhanced bone regeneration in rat calvarial and rabbit iliac defect models, with increased new bone formation. Specifically, the rat calvarial model showed increased new bone formation and vascularization, while rabbit iliac model showed increased new bone formation and bone-material contact. Collectively, these findings demonstrate that C-PM15-W20 integrates improved mechanical performance, bone adhesion, degradability, angiogenic activity, and osteogenic potential, supporting its potential as a multifunctional bone cement for regenerative bone repair.