IL-4/Nanohydroxyapatite Codelivery in a Dual-Bionic Scaffold: Design and Immunomodulatory Endogenous Osteogenesis Mechanism.

Large-scale repairs of bone defects face the challenges of a dynamic extracellular matrix (ECM) signaling deficiency and mismatched hard-tissue biomimicry. This study addressed the limited bioactivity and insufficient endogenous osteogenic capacity of current 3D-printed polycaprolactone/nanohydroxyapatite (PCL/nHA) scaffolds by designing a dual-bionic PCL/nHA scaffold that integrated "soft" ECM signaling with "hard" structural support. The soft hydrogel-based ECM mimicry of the scaffold enabled time-programmed interleukin-4 (IL-4) release to drive macrophage M2 polarization and subsequent anti-inflammatory cytokine (IL-10, TGF-β) secretion, thereby initiating a cascade that enhanced osteogenesis. Structurally, the gyroid architecture of the scaffold replicated natural bone microchannels, while sustained nHA hydrolysis released Ca(2+), synergizing with IL-10 and TGF-β to activate the PI3K-AKT and calcium signaling pathways, upregulating osteogenic and angiogenic markers. The results demonstrated the coupling mechanism between immunomodulation and osteogenic differentiation, presenting a strategy for promoting endogenous bone regeneration.