Guiding macrophage temporal evolution via integrin targeting on peptide-functionalized titanium surfaces to optimize the host response

The bioinert nature of titanium limits its ability to actively modulate the immune microenvironment, often leading to fibrous encapsulation or aberrant inflammation. Shifting from passive adaptation to actively guiding the temporal transition of macrophages from a pro-inflammatory to a pro-repair phenotype is a key strategy for improving implant performance. In this study, a functionalized titanium surface was constructed using a titanium binding peptide-linker-RGD (TiBP-linker-RGD), aiming to elucidate how interfacial properties dynamically regulate this process through specific activation of the Integrin signaling axis. Transcriptomic analysis revealed that the surface triggered a specific adhesion-dependent functional priming state at the early stage (Day 1), characterized by significant upregulation of interferon-associated and adhesion genes. Crucially, Integrin blockade experiments confirmed that this initial activation strictly depended on the RGD-integrin αvβ3 signaling axis, thereby distinguishing it from a nonspecific inflammatory response. Subsequently (Day 4), this primed inflammatory state timely evolved into a pro-repair phenotype characterized by low ROS and high IL-10 secretion. In vitro co-culture experiments demonstrated that this microenvironment optimized the Collagen I/III synthesis ratio in fibroblasts. The in vivo air pouch model further confirmed that the functionalized surface significantly reduced inflammatory infiltration and promoted the formation of a thinner, more loosely organized tissue interface. This study describes the molecular pathway from immune priming to tissue repair, providing a theoretical foundation for designing immunomodulatory implants that exploit the host's intrinsic healing mechanisms.