Biomaterial multiscale geometry for regenerative immunoengineering of bone tissue

Osteoimmunomodulation (OIM) is emerging as a key biofunctionality of orthopedic implants. Biomaterial surface geometries can modulate the interactions between immune cells and osteoprogenitors at the bone-implant interface, positively affecting osteogenic differentiation and implant osseointegration. This review highlights the recent advancements in geometry-induced OIM (G-OIM) across multiple length scales (nano to mesoscale, including multiscale topographies and 3D scaffolds), identifying relations between specific geometries and subsequent mechanisms of OIM, as provided by the coculture model used. Our review reveals surface geometries with OIM potential at each length scale. These effects can be mediated by both M1 and M2 macrophages, wherein the pathway depends on the shape and length scale of the geometrical cues provided (e.g., integrin-mediated mechanotransduction for nanoscale topographies and macrophage contact inhibition for micropatterns). Most studies assess G-OIM predominantly based on geometry-induced macrophage polarization and its paracrine effect on osteoprogenitors. However, few studies utilizing direct coculture reveal the key role of the direct interplay between macrophages, osteoprogenitors, and biomaterial for OIM. The novel field of G-OIM is advancing at a high pace. It could benefit from improved, clinically relevant coculture models involving human-derived cells and technological developments in biomaterial design and fabrication. Such advances could establish (G-)OIM as a transformative approach for regenerative immunoengineering of orthopedic implants. STATEMENT OF SIGNIFICANCE: Osteoimmunomodulation, the ability of biomaterials to modulate the interactions between immune cells and skeletal cells to enhance osteogenesis, is increasingly recognized as a crucial biofunctionality for orthopedic biomaterials. Various biomaterial surface geometries can be used to target osteoimmune pathways. Given the complexity of these interactions, suitable coculture models are essential for studying the underlying cellular mechanisms. This review reveals the state-of-the-art results on geometry-induced osteoimmunomodulation. Not only does this review discuss approaches that have been taken thus far in terms of biomaterial geometry design at various length scales, but it also highlights the role of the coculture model in osteoimmunomodulation and the importance of advances in these in vitro models to improve the translation of research to clinical practice.