Available online 16 July 2025

Author links open overlay panel, , , Abstract

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.

Graphical abstractDownload: Download high-res image (205KB)Download: Download full-size imageKeywords

Osteoimmunomodulation

surface geometry

coculture

bone regeneration

immunoengineering

List of abbreviationsBCP

Biphasic Calcium Phosphate

BMP-2

Bone Morphogenetic Protein 2

Dlx5

Distal-less homeobox 5

eNOS

Endothelial nitric oxide synthase

G-OIM

Geometry-induced osteoimmunomodulation

HUVEC

Human Umbilical Vein Endothelial Cell

IAI

Implant-associated infections

iNOS

Inducible Nitric Oxide Synthase

MAPK

Mitogen-Activated Protein Kinase

MCM

Macrophage-conditioned medium

MSC

Mesenchymal Stromal Cell

NF-κB

Nuclear factor kappa-light-chain-enhancer of activated B cells

MyD88

Myeloid differentiation primary response 88

NFAT-c1

Nuclear factor of activated T-cells c1

PI3K

Phosphoinositide 3-Kinase

Rhoa/ROCK

Ras Homolog Family Member A/Rho-Associated Protein Kinase

RUNX2

Runt-Related Transcription Factor 2

TGF-β

Transforming Growth Factor-Beta

TNF-α

Tumor Necrosis Factor-alpha

VEGF

Vascular Endothelial Growth Factor

© 2025 The Authors. Published by Elsevier Inc. on behalf of Acta Materialia Inc.