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REVIEW ARTICLE

Macrophage-centered bone regeneration: A review of in vivo efficacy across tailored, hybrid, and 3D-printed biomaterial platforms

Palloma Porto Almeida1 ,  Rhayra Braga Dias1 ,  Kamila Souto Leichtweis1 ,  Bianca Braga Frade1 ,  Sara Gemini-Piperni2 ,  Danielle Cabral Bonfim1*
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1 Laboratory of Stem Cells and Bone Regeneration, Institute of Biomedical Sciences, Federal University of Rio de Janeiro, Rio de Janeiro, Rio de Janeiro, Brazil
2 Laboratory of Biotechnology, Bioengineering, and Nanostructured Biomaterials, Institute of Biomedical Sciences, Federal University of Rio de Janeiro, Rio de Janeiro, Rio de Janeiro, Brazil
IJB, 026050033 https://doi.org/10.36922/IJB026050033
Received: 27 January 2026 | Revised: 27 February 2026 | Accepted: 3 March 2026 | Published online: 23 April 2026
© 2026 by the Author(s). This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution 4.0 International License ( https://creativecommons.org/licenses/by/4.0/ )
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Abstract

Bone tissue engineering has evolved from the passive use of structural fillers to a sophisticated discipline that actively harnesses endogenous regenerative mechanisms. At the core of this paradigm shift lies the immune system, particularly macrophages, as dynamic regulators of repair. Rather than merely suppressing inflammation, contemporary biomaterials are designed to modulate its trajectory, orchestrating the timely transition from a pro-inflammatory (M1) phenotype toward a pro-resolutive (M2) state. This review synthesizes a decade of progress in macrophage-centered bioengineering, focusing on strategies validated in preclinical in vivo models to ensure biological relevance and translational potential. These approaches are categorized across three levels of increasing complexity: (i) tailored biomaterials, where intrinsic physical and chemical properties direct cell fate; (ii) hybrid scaffolds, integrating diverse material classes and advanced delivery systems; and (iii) 3D-printed bioactive constructs, combining structural precision with ions, drugs, or cellular components. Together, these strategies define the emerging field of osteoimmunomodulation, characterized by the design of immuno-instructive materials. By critically evaluating the evolution of these principles, including their translational barriers and potential pitfalls, this review provides key insights into the field’s progression, identifying effective strategies to guide the development of next-generation bone therapies.

Graphical abstract
Keywords
Macrophages
Osteoimmunomodulation
Bone regeneration
Biomaterials
3D printing
Tissue engineering
Funding
This work was supported by the Ministry of Health of Brazil and the National Council for Scientific and Technological Development (grant number 445067/2023-3), the Brazilian National Program of Genomics and Precision Health (grant number 444206/2023-0), the Carlos Chagas Filho Support Foundation of the State of Rio de Janeiro (FAPERJ; grant number E-26/201.403/2022), and the Maria Emilia Foundation (grant number 02/2024). The sponsors had no role in study design, data collection and analysis, decision to publish, or manuscript preparation.
Conflict of interest
The authors declare they have no competing interests.
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International Journal of Bioprinting, Electronic ISSN: 2424-8002 Print ISSN: 2424-7723, Published by AccScience Publishing
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