Immunomodulatory and dentinogenic potential of surface-engineered hesperetin-functionalized composite scaffolds for...

Maintaining dental pulp vitality and promoting dentin regeneration in inflamed environments requires biomaterials that not only support cell differentiation but also actively regulate immune signaling. Here, we present a bioinstructive, immunomodulatory nanofibrous platform composed of polycaprolactone and nano-hydroxyapatite (PCL/nHA), surface-engineered through alkaline hydrolysis (H-) to enhance hydrophilicity and loaded with the flavonoid hesperetin (+HT) for sustained bioactive release. Physicochemical analyses confirmed improved surface wettability, calcium ion release, and diffusion-driven hesperetin delivery, all without compromising the scaffold's structure. In vitro, the scaffolds facilitated the migration, proliferation, and odontogenic differentiation of human dental pulp cells, leading to a significant increase in mineralized matrix formation. Using lipopolysaccharide-stimulated macrophages and a 3D inflammatory pulp capping model, the scaffolds modulated immune responses by downregulating pro-inflammatory cytokines and upregulating pro-resolving mediators, while also promoting dentinogenic and angiogenic gene expression. In vivo, subcutaneous implantation demonstrated favorable host integration, reduced inflammatory infiltration, early M2-skewed macrophage polarization, and organized extracellular matrix formation. Overall, this study introduces a surface-engineered, flavonoid-releasing scaffold as a bioinstructive platform that combines immunomodulation and odontoblastic signaling, providing mechanistic insight for designing next-generation materials aimed at regenerating the dentin-pulp interface under inflammatory conditions.