Temporally programmed dual-function scaffold with simultaneous cellulose and calcium lactate regeneration for enhanced osteogenesis via lactate-induced OR5AN1 activation.

Electrospun scaffolds that couple structural guidance with cell-instructive cues remain a key objective in bone regeneration. Here, we developed a multifunctional PCL/cellulose scaffold that exploits lactic acid (LA) as a triple-role reagent-an electrospinning plasticizer, a precursor for in situ calcium lactate (CaL) formation, and a handle for chemokine conjugation. LA incorporation enables the formation of ultrafine nanofibers with a surface-enriched outer region; subsequent Ca(OH)₂ treatment simultaneously deacetylates cellulose acetate (CA) to cellulose and converts LA into a conformal CaL coating, yielding a hydrophilic and osteoconductive interface. SDF1 is covalently immobilized via EDC/NHS chemistry, producing an initial burst release followed by sustained release over 28 days, while CaL provides a gradual lactate reservoir and complete calcium release within 7 days. Mechanistically, lactate derived from CaL is associated with the upregulation of the human olfactory receptor OR5AN1 in h-BMMSCs, accompanied by time-dependent intracellular Ca2+ influx and increased expression of osteogenic markers. In a rat femoral defect model, CaL/SDF1 scaffolds accelerate bone healing, with histological and immunostaining analyses confirming enhanced matrix formation and maturation. By integrating topographical, biochemical, and metabolic signaling into a single platform, this work presents a strategy to modulate Ca2+ signaling and osteogenesis.