Topographical Regulation of Macrophage-Mediated Osteoimmunomodulation for Bone Regeneration

The immune response plays a critical role in determining the fate of bone biomaterials, with macrophages serving as central orchestrators of the osteoimmune network. Topographical features have emerged as a powerful physical cue that can modulate macrophage function independent of biochemical signals, offering a stable and controllable strategy for immunomodulation in bone regeneration. This review systematically summarizes recent advances in understanding how topographical features regulate macrophage behavior and the underlying mechanotransduction mechanisms. We first discuss the role of macrophages in bone homeostasis, highlighting their functional plasticity and dynamic polarization during the healing process. We then provide an overview of micro- and nanofabrication techniques for constructing topographical features on biomaterial surfaces, including top-down approaches such as photolithography, etching, as well as bottom-up strategies like electrospinning and self-assembly. Subsequently, we examine the effects of topography on key macrophage behaviors and functions, including adhesion, migration, proliferation, polarization, and phagocytosis. We further dissect the molecular mechanisms by which cells sense and transduce topographical signals, focusing on integrin-mediated focal adhesion, cytoskeletal remodeling, nuclear mechanotransduction, and downstream signaling pathways, including YAP/TAZ, MRTF-A, RhoA/ROCK, and PI3K-AKT-mTOR. Emerging evidence on epigenetic regulation by topographical cues is also discussed. Finally, we present future perspectives on dynamic topography, machine learning-assisted high-throughput screening, the modulation of macrophage subtypes, and the integration of bactericidal and immunomodulatory functions. By bridging materials science and immunology, this review aims to provide a theoretical foundation for the rational design of next-generation immunomodulatory biomaterials for bone regeneration.