Bone matrix-mimetic multi-ion doped hydroxyapatite nanorod arrays for enhanced immuno-osteogenesis and prevention of aseptic loosening

Inflammatory responses triggered by foreign body rejection or detached wear particles are major contributors to the failure of titanium (Ti)-based orthopedic implants. One of the most common complications is aseptic loosening. To address this challenge, a nanorod-arrayed hydroxyapatite (HA) coating co-doped with multiple ions (Sr²⁺, Mg²⁺, Zn²⁺, CO₃ ^2-, and SiO₄ ^4-) was developed, to mimic the bone matrix and enhance immuno-osteogenesis. The coating exhibits strong adhesion strength and long-term interfacial stability. Ion-induced lattice distortion accelerates HA degradation, promoting the doped-ion release. These bioactive ions drive macrophage (MΦs) polarization from pro-inflammatory M1 to anti-inflammatory M2 phenotype, thereby enhancing vascularized osseointegration. To evaluate the risk of aseptic loosening induced by detached nanorods, we synthesized nanorod-like particles with identical composition and morphology to those in the arrayed coating. Their effects on MΦ polarization and the underlying mechanisms were then systematically investigated. Compared to undoped particles, multi-ion doped HA nanoparticles are more easily phagocytosed and degraded within lysosomes, enabling faster ion release and thereby facilitating M1-M2 transition. Transcriptomic analysis reveals that the nanoparticle degradation-mediated ion release elevates intracellular calcium levels in MΦs, which activates antioxidant pathways and induces a metabolic shift toward fatty acid oxidation. This metabolic reprogramming subsequently activates immunoregulatory pathways, with the PPAR pathway serving as a central axis, thereby promoting M2 polarization, inhibiting osteoclastogenesis, and ultimately preventing aseptic loosening. Collectively, this study presents a coating design that not only promotes osseointegration but also retains anti-inflammatory potential even in the event of particle detachment, offering a promising strategy to mitigate aseptic loosening.