Configuration-Dependent Nanoarchitectonic Effects of Linear and Cyclic Calcium Polyphosphates on Mitochondrial Energy...

Bone regeneration is an energy-intensive process requiring coordinated regulation of ionic microenvironments and cellular metabolism. Yet, current biomaterials rarely address the dynamic energy requirements of osteogenesis. Inorganic calcium polyphosphates (CPPs), featuring high-energy phosphoanhydride bonds and tunable degradation profiles, offer a promising bioenergetic strategy for metabolically responsive bone repair. Herein, three CPPs with distinct configurations: linear Ca-TPP, cyclic Ca-TMP, and Ca-HMP were synthesized, and their osteogenic effects were systematically investigated by integrating molecular dynamics (MD) simulations with experimental approaches. The results indicate that the configuration-dependent nanoarchitectonic features of CPPs, including phosphate-unit number, charge density, and molecular configuration, govern their stability, solubility, and ion-release behaviors. Specifically, Ca-HMP forms stable assemblies that support sustained phosphate release and long-term energy supply; Ca-TMP displays faster hydrolysis kinetics, preferentially enhancing mitochondrial functional activation and oxidative phosphorylation (OXPHOS); Ca-TPP contributes primarily to extracellular matrix maturation. Importantly, all CPPs exhibit superior pro-osteogenic efficacy compared with crystalline calcium phosphate (Ca-P). CPPs can reprogram cellular metabolism by elevating intracellular ATP levels, increasing mitochondrial membrane potential, and upregulating metabolic and osteogenic genes (including GAPDH, ATP5F1A, ALP, and BMP-2), which is mediated via the activation of AMPK, mTOR, and PI3K-AKT signaling pathways, collectively improving osteogenic differentiation over Ca-P controls. These findings establish CPPs as a class of "smart" metabolic materials that synchronize energy availability with osteogenic demands, providing a promising paradigm for bone regeneration.