Tailored Ion Release of Polycaprolactone and Calcium Silicate Composite Fibers Attenuates Neutrophil Extracellular...

While calcium silicate (CS) remains a gold standard material for vital pulp therapy, its clinical efficacy is frequently compromised by an abrupt ion release during the initial setting phase that induces extreme alkalinity and acute cytotoxicity. We engineered electrospun poly-ε-caprolactone (PCL)/CS composite fibers to reconfigure CS hydration kinetics, achieving sustained and controlled ion release. In vitro evaluation using phase-specific eluates and defined pH/Ca²⁺ conditions demonstrated that CS eluates from the initial setting phase induced significant cytotoxicity and excessive NETosis in primary neutrophils, whereas PCL/CS eluates maintained both at control levels. Mechanistically, neutrophil extracellular traps (NETs) isolated from CS-stimulated neutrophils directly drove M1 macrophage polarization, while PCL/CS eluates promoted an anti-inflammatory and proregenerative macrophage phenotype. PCL/CS eluates, conditioned media from PCL/CS-treated macrophages, and PCL/CS nanofibrous substrates all promoted odontoblastic differentiation. In vivo validation using a rat molar pulp exposure model revealed that during the early host response (at days 2 and 7), CS provoked marked neutrophil infiltration and excessive NETosis, whereas PCL/CS attenuated the acute inflammatory response and promoted timely inflammatory resolution and M2 macrophage polarization. At 8 weeks, the PCL/CS group exhibited improved dentin-pulp regeneration characterized by organized tubular dentin and polarized odontoblasts, rather than amorphous osteodentin typically observed with CS. PCL/CS also mitigated furcal bone resorption. These findings indicate that immune modulation through tailored ion release via the NETosis-macrophage axis represents an effective strategy for supporting dentin-pulp complex regeneration.