Control of Matrix Stiffness Using Methacrylate–Gelatin Hydrogels for a Macrophage-Mediated Inflammatory Response
Abstract
The successful tissue integration of a biomedical material is mainly determined by the inflammatory response after implantation. Macrophage behavior toward implanted materials is pivotal to determine the extent of the inflammatory response. Hydrogels with different properties have been developed for various biomedical applications such as wound dressings or cell-loaded scaffolds. However, there is limited investigation available on the effects of hydrogel mechanical properties on macrophage behavior and the further host inflammatory response. To this end, methacrylate-gelatin (GelMA) hydrogels were selected as a model material to study the effect of hydrogel stiffness (2, 10, and 29 kPa) on macrophage phenotype in vitro and the further host inflammatory response in vivo. Our data showed that macrophages seeded on stiffer surfaces tended to induce macrophages toward a proinflammatory (M1) phenotype with increased macrophage spreading, more defined F-actin and focal adhesion staining, and more proinflammatory cytokine secretion and cluster of differentiation (CD) marker expression compared to those on surfaces with a lower stiffness. When these hydrogels were further subcutaneously implanted in mice to assess their inflammatory response, GelMA hydrogels with a lower stiffness showed more macrophage infiltration but thinner fibrotic capsule formation. The more severe inflammatory response can be attributed to the higher percentage of M1 macrophages induced by GelMA hydrogels with a higher stiffness. Collectively, our data demonstrated that macrophage behavior and the further inflammatory response are mechanically regulated by hydrogel stiffness. The macrophage phenotype rather than the macrophage number predominately determined the inflammatory response after the implantation, which can provide new insights into the future design and application of novel hydrogel-based biomaterials.
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Current literature on the effects of material stiffness on macrophage activation presents conflicting results.
“However, current literature on the effects of material stiffness on macrophage activation presents conflicting results.”
From Soft tissue-mimicking hydrogel stiffness modulates polarisation of human monocyte-derived macrophages (2025) · cites this paper as [15]
The stiffness-dependent trend observed in this study aligns with previous reports that increased stiffness promotes a shift towards M1-like macrophage phenotype.
“The stiffness-dependent trend observed in our study aligns with several previous reports in which increased stiffness promoted a shift towards M1-like macrophage phenotype.”
From Soft tissue-mimicking hydrogel stiffness modulates polarisation of human monocyte-derived macrophages (2025) · cites this paper as [15]
Several studies have reported that stiffer substrates promote M1 polarisation.
“Several studies have reported that stiffer substrates promote M1 polarisation.”
From Soft tissue-mimicking hydrogel stiffness modulates polarisation of human monocyte-derived macrophages (2025) · cites this paper as [15]
Zhuang et al. showed that increasing GelMA stiffness (2-29 kPa) enhanced inflammatory signalling and M1 polarisation.
“Similarly, Zhuang et al. showed that increasing GelMA stiffness (2-29 kPa) enhanced inflammatory signalling and M1 polarisation 15”
From Soft tissue-mimicking hydrogel stiffness modulates polarisation of human monocyte-derived macrophages (2025) · cites this paper as [15]
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Beyond Needles: Immunomodulatory Hydrogel-Guided Vaccine Delivery Systems
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- Authors
- Zhuang, Z., Zhang, Y., Sun, S., Li, Q., Chen, K., An, C., Wang, L., van den Beucken, J. J. J. P., & Wang, H.
- Affiliations
- Dalian University of Technology (CN)
- Radboud University Nijmegen (NL)
- Dalian Medical University (CN)
- Regenerative Biomaterials Group, Department of Dentistry, Radboudumc, Geert Grooteplein Zuid 10, Nijmegen 6525GA, The Netherlands
- Corresponding author
- Wang, Huanan
- Venue
- ACS Biomaterials Science & Engineering
- Publisher
- American Chemical Society (ACS)
- Published
- 2020-03-22
- Volume
- 6
- Issue
- 5
- Pages
- 3091-3102
- ISSN
- 2373-9878 (ISSN-L)
- OpenAlex
- W3013067729
- Cited by
- 126
- References
- 55
- Citations by year
- 2026: 19 · 2025: 23 · 2024: 25 · 2023: 28 · 2022: 19 · 2021: 10 · 2020: 2
- FWCI
- 4.93
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- Locations
- ACS Biomaterials Science & Engineering (publishedVersion)
- PubMed (publishedVersion)
- Radboud Repository (Radboud University) (submittedVersion)
- Funders
- Ministry of Education of the People's Republic of China (DUT15RC (3)113)
- Ministry of Science and Technology of the People's Republic of China (2018YFA0703000)
- National Natural Science Foundation of China (31870957, 31900966)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Medicine › Hydrogels: synthesis, properties, applications
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular Mechanics and Interactions
- Health Sciences › Medicine › Surgery › Tissue Engineering and Regenerative Medicine
- Keywords
- hydrogel stiffness, macrophage phenotype, M1 macrophages, inflammatory cytokines, focal adhesions, actin cytoskeleton, macrophage infiltration, fibrotic capsule
- MeSH terms
- Animals, Biocompatible Materials, Gelatin, Macrophages, Methacrylates, Hydrogels, Mice
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