Enhanced surface hydrophilicity improves osseointegration of titanium implants <i>via</i> integrin-mediated osteoimmunomodulation

Titanium (Ti) implants have become widespread especially in dentistry and orthopedics, where macrophage-driven osteoimmunomodulation is crucial to their success. Hydrophilic modification of Ti represents a promising strategy to enhance its immune and osteogenic responses. Herein, the osteoimmunomodulatory performance and integrin-mediated mechanism of novel non-thermal atmospheric plasma (NTAP) treatment to induce a hydrophilic Ti were investigated for the first time. Compared to a hydrophobic surface, NTAP-modified Ti possessed a 3-fold increase of pro-healing M2 macrophage makers, and the doubled osteogenic differentiation of mesenchymal stem cells was demonstrated in this immune microenvironment, thus improving early osseointegration. Mechanistically, the ameliorative osteoimmunomodulatory properties of NTAP were attributed to its positive and negative modulation in macrophages' integrin β1 or β2, and the subsequent FAK-PI3K/Akt or NF-κB signaling pathway. Collectively, this study highlighted the role of integrins and related signaling pathways in hydrophilic implant-caused macrophage polarization, therefore inventively unveiling the underlying mechanism of NTAP-enhanced osteoimmunomodulation. Furthermore, it established a robust theoretical foundation for the clinical application of this cost-effective, versatile, and transformation-valuable surface engineering strategy for the development of next-generation Ti implants.