REVIEW article
Front. Cell Dev. Biol.
Sec. Cell Adhesion and Migration
Volume 13 - 2025 | doi: 10.3389/fcell.2025.1684357
This article is part of the Research TopicAdvancing Bone and Soft Tissue Repair: Bioengineering from Cellular Insights to Clinical ApplicationsView all 3 articles
From Macrophage Polarization to Clinical Translation: Immunomodulatory Hydrogels for Infection-Associated Bone Regeneration
Provisionally accepted
- 1Affiliated Hospital of North Sichuan Medical College, Nanchong, China
- 2Management and Science University, Shah Alam, Malaysia
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Bone infections such as osteomyelitis and fracture-related infections are a significant clinical challenge, characterized by complex interactions between pathogenic microorganisms, disrupted immune responses, and impaired regenerative processes. A pathological hallmark of these conditions is the persistent pro-inflammatory macrophage (M1) polarization, which prevents the essential transition to anti-inflammatory M2 macrophages required for successful bone healing. This review examines the emerging paradigm of immunomodulatory hydrogels as a multifaceted therapeutic strategy that addresses both infection control and bone regeneration through targeted modulation of macrophage polarization. We systematically analyze the fundamental role of macrophage phenotypic switching in osteoimmune responses, demonstrating how infection disrupts the normal M1-to-M2 transition and perpetuates a chronic inflammatory state that impairs osteogenesis while promoting bone resorption. The review details innovative hydrogel design strategies that incorporate antimicrobial agents, immunomodulatory factors, and bioactive components to create materials capable of eliminating pathogens while simultaneously steering macrophages toward a pro-regenerative phenotype. Key approaches include integration of sequential drug-release systems, reactive oxygen species (ROS)-scavenging mechanisms, photothermal activation, and cell delivery platforms within biodegradable hydrogel matrices. Recent advances in multifunctional hydrogel systems have demonstrated superior performance compared to conventional treatments – including enhanced bacterial clearance, accelerated bone healing, and reduced infection recurrence rates in preclinical models. The pathway from laboratory findings to clinical application is critically evaluated, addressing challenges in biocompatibility, manufacturing consistency, regulatory approval, and clinical trial design. This comprehensive analysis reveals that immunomodulatory hydrogels represent a promising convergence of infection control and regenerative medicine, offering new therapeutic avenues for treating complex bone defects where traditional approaches have proven insufficient.
Keywords: immunomodulatory hydrogels, Macrophage polarization, Bone Regeneration, Osteomyelitis, osteoimmunology, Infection Control, Tissue Engineering
Received: 12 Aug 2025; Accepted: 04 Sep 2025.
Copyright: © 2025 Zhang, Tan, Wang, Wu and Zhang. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Suk Fei Tan, Management and Science University, Shah Alam, Malaysia
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