Surface-Mediated Immunomodulation by Electrostatic Immobilization of Naproxen on Plasma-Aminated Poly(ε-caprolactone) Films Rescues Osteogenic Differentiation via Attenuation of NF-κB Signaling

Abstract Chronic inflammation following biomaterial implantation often leads to fibrous encapsulation and compromised osseointegration, particularly in clinically inflamed environments. We developed a surface-functionalized poly(ε-caprolactone) (PCL) platform to modulate the early inflammatory microenvironment via surface-mediated drug release. PCL films were aminated by plasma polymerization, enabling the electrostatic immobilization of naproxen. Surface characterization by zeta potential analysis, X-ray photoelectron spectroscopy (XPS), and atomic force microscopy (AFM) confirmed successful amine functionalization and subsequent naproxen loading. The functionalized films exhibited a pronounced early burst release of naproxen within the initial hours after immersion, addressing the early phase of post-surgical inflammation. In vitro studies using MC3T3-E1 pre-osteoblasts under lipopolysaccharide (LPS)-induced inflammatory conditions showed that naproxen released from the surface significantly reduced pro-inflammatory cytokine secretion, including IL-6 and IL-1β. The cytokine-suppressive effect of the naproxen-functionalized surface was further supported by mechanistic experiments showing that soluble naproxen attenuated LPS-induced NF-κB p65 phosphorylation and nuclear translocation. These results suggest that the anti-inflammatory response mediated by surface-released naproxen is, at least in part, attributable to the intrinsic NF-κB-modulating activity of naproxen. Modulation of the inflammatory microenvironment restored osteogenic differentiation, with increased expression of RUNX2, ALP, and OPN, and enhanced matrix mineralization, as confirmed by Alizarin Red S staining. These findings demonstrate that surface-mediated delivery of naproxen enables temporally controlled osteoimmunomodulation and supports osteogenic function under inflammatory stress, underscoring the potential of this surface-engineering strategy for bone-regenerative applications.