Emerging Strategies for Biomaterials-Mediated Reprogramming of Macrophages in Tissue Repair and Regeneration

Miao Zhang; Jeeyoon Park; Juejie Chen; Linyang Liu; Anthony S. Weiss; Ziyu Wang

doi:10.53941/rmd.2026.100011

Abstract

Adult tissue repair is often limited, resulting in fibrotic scar formation rather than functional regeneration. Macrophages are central regulators of this process, driving inflammation, tissue formation, and remodeling. Increasing evidence demonstrates that macrophages exhibit substantial heterogeneity and plasticity, transitioning along a continuum of phenotypes in response to evolving microenvironmental cues rather than existing as discrete M1/M2 subsets. This functional diversity reflects their critical role across all stages of tissue repair, from early inflammatory responses to later regenerative and remodeling phases. Recent advances in bioengineering have enabled the development of biomaterial-based strategies to reprogram macrophages and enhance tissue repair. These include the controlled delivery of immunomodulatory biochemical signals, such as cytokines, proteins, and metabolites; the engineering of matrix biophysical properties, including stiffness, viscoelasticity, and topography; and the enhancement of efferocytosis to promote inflammation resolution and tissue homeostasis. These approaches demonstrate that macrophage behavior can be modulated through both biochemical and physical cues to improve regenerative outcomes across diverse tissue contexts. This review summarises current understanding of macrophage heterogeneity and plasticity during tissue repair and highlights emerging biomaterials-driven strategies for macrophage reprogramming, providing a framework for leveraging macrophage function to support effective tissue regeneration.

References

1.
Yun, M.H. Changes in Regenerative Capacity through Lifespan. Int. J. Mol. Sci. 2015, 16, 25392–25432.
2.
Wells, J.M.; Watt, F.M. Diverse Mechanisms for Endogenous Regeneration and Repair in Mammalian Organs. Nature 2018, 557, 322–328. https://doi.org/10.1038/s41586-018-0073-7.
3.
Linehan, E.; Fitzgerald, D.C. Ageing and the Immune System: Focus on Macrophages. Eur. J. Microbiol. Immunol. 2015, 5, 14–24. https://doi.org/10.1556/eujmi-d-14-00035.
4.
Martin, P.; Pardo-Pastor, C.; Jenkins, R.G.; et al. Imperfect Wound Healing Sets the Stage for Chronic Diseases. Science 2024, 386, eadp2974.
5.
Eming, S.A.; Martin, P.; Tomic-Canic, M. Wound Repair and Regeneration: Mechanisms, Signaling, and Translation. Sci. Transl. Med. 2014, 6, 265sr6. https://doi.org/10.1126/scitranslmed.3009337.
6.
Liu, Y.; Xu, R.; Gu, H.; et al. Metabolic Reprogramming in Macrophage Responses. Biomark. Res. 2021, 9, 1. https://doi.org/10.1186/s40364-020-00251-y.
7.
Theocharidis, G.; Thomas, B.E.; Sarkar, D.; et al. Single Cell Transcriptomic Landscape of Diabetic Foot Ulcers. Nat. Commun. 2022, 13, 181.
8.
Godwin, J.W.; Pinto, A.R.; Rosenthal, N.A. Macrophages Are Required for Adult Salamander Limb Regeneration. Proc. Natl. Acad. Sci. USA 2013, 110, 9415–9420. https://doi.org/10.1073/pnas.1300290110.
9.
Aurora, A.B.; Porrello, E.R.; Tan, W.; et al. Macrophages Are Required for Neonatal Heart Regeneration. J. Clin. Invest. 2014, 124, 1382–1392. https://doi.org/10.1172/jci72181.
10.
Wynn, T.A.; Vannella, K.M. Macrophages in Tissue Repair, Regeneration, and Fibrosis. Immunity 2016, 44, 450–462. https://doi.org/10.1016/j.immuni.2016.02.015.
11.
Hashimoto, D.; Chow, A.; Noizat, C.; et al. Tissue-Resident Macrophages Self-Maintain Locally throughout Adult Life with Minimal Contribution from Circulating Monocytes. Immunity 2013, 38, 792–804. https://doi.org/10.1016/j.immuni.2013.04.004.
12.
Davies, L.C.; Jenkins, S.J.; Allen, J.E.; et al. Tissue-Resident Macrophages. Nat. Immunol. 2013, 14, 986–995. https://doi.org/10.1038/ni.2705.
13.
Boniakowski, A.E.; Kimball, A.S.; Jacobs, B.N.; et al. Macrophage-Mediated Inflammation in Normal and Diabetic Wound Healing. J. Immunol. 2017, 199, 17–24. https://doi.org/10.4049/jimmunol.1700223.
14.
Yan, L.; Wang, J.; Cai, X.; et al. Macrophage Plasticity: Signaling Pathways, Tissue Repair, and Regeneration. MedComm 2024, 5, e658. https://doi.org/10.1002/mco2.658.
15.
Troidl, C.; Möllmann, H.; Nef, H.; et al. Classically and Alternatively Activated Macrophages Contribute to Tissue Remodelling after Myocardial Infarction. J. Cell. Mol. Med. 2009, 13, 3485–3496. https://doi.org/10.1111/j.1582-4934.2009.00707.x.
16.
Smigiel, K.S.; Parks, W.C. Macrophages, Wound Healing, and Fibrosis: Recent Insights. Curr. Rheumatol. Rep. 2018, 20, 17. https://doi.org/10.1007/s11926-018-0725-5.
17.
Guan, F.; Wang, R.; Yi, Z.; et al. Tissue Macrophages: Origin, Heterogeneity, Biological Functions, Diseases and Therapeutic Targets. Signal Transduct. Target. Ther. 2025, 10, 93. https://doi.org/10.1038/s41392-025-02124-y.
18.
Mantovani, A.; Sozzani, S.; Locati, M.; et al. Macrophage Polarization: Tumor-Associated Macrophages as a Paradigm for Polarized M2 Mononuclear Phagocytes. Trends Immunol. 2002, 23, 549–555. https://doi.org/10.1016/s1471-4906(02)02302-5.
19.
Mantovani, A.; Sica, A.; Sozzani, S.; et al. The Chemokine System in Diverse Forms of Macrophage Activation and Polarization. Trends Immunol. 2004, 25, 677–686. https://doi.org/10.1016/j.it.2004.09.015.
20.
Anders, C.B.; Lawton, T.M.; Smith, H.L.; et al. Use of Integrated Metabolomics, Transcriptomics, and Signal Protein Profile to Characterize the Effector Function and Associated Metabotype of Polarized Macrophage Phenotypes. J. Leukoc. Biol. 2022, 111, 667–693. https://doi.org/10.1002/jlb.6a1120-744r.
21.
Shapouri-Moghaddam, A.; Mohammadian, S.; Vazini, H.; et al. Macrophage Plasticity, Polarization, and Function in Health and Disease. J. Cell. Physiol. 2018, 233, 6425–6440. https://doi.org/10.1002/jcp.26429.
22.
Fuchs, A.L.; Costello, S.M.; Schiller, S.M.; et al. Primary Human M2 Macrophage Subtypes Are Distinguishable by Aqueous Metabolite Profiles. Int. J. Mol. Sci. 2024, 25, 2407.
23.
Martinez, F.O.; Gordon, S. The M1 and M2 Paradigm of Macrophage Activation: Time for Reassessment. F1000Prime Rep. 2014, 6, 13. https://doi.org/10.12703/p6-13.
24.
Murray, P.J. Macrophage Polarization. Annu. Rev. Physiol. 2017, 79, 541–566. https://doi.org/10.1146/annurev-physiol-022516-034339.
25.
Miyake, K.; Ito, J.; Takahashi, K.; et al. Single-Cell Transcriptomics Identifies the Differentiation Trajectory from Inflammatory Monocytes to Pro-Resolving Macrophages in a Mouse Skin Allergy Model. Nat. Commun. 2024, 15, 1666. https://doi.org/10.1038/s41467-024-46148-4.
26.
Evans, T.A.; Barkauskas, D.S.; Myers, J.T.; et al. High-Resolution Intravital Imaging Reveals That Blood-Derived Macrophages but Not Resident Microglia Facilitate Secondary Axonal Dieback in Traumatic Spinal Cord Injury. Exp. Neurol. 2014, 254, 109–120. https://doi.org/10.1016/j.expneurol.2014.01.013.
27.
Lu, J.; Chen, N.; Zong, M.; et al. Single-Cell Transcriptomic Analysis of Interactions of Peritoneal Mesenchymal Stem Cells with Macrophages in Prevention of Peritoneal Membrane Injury. Biochem. Biophys. Res. Commun. 2025, 781, 152491. https://doi.org/10.1016/j.bbrc.2025.152491.
28.
Liu, X.; Chen, W.; Zhu, G.; et al. Single-Cell RNA Sequencing Identifies an Il1rn⁺/Trem1⁺ Macrophage Subpopulation as a Cellular Target for Mitigating the Progression of Thoracic Aortic Aneurysm and Dissection. Cell Discov. 2022, 8, 11. https://doi.org/10.1038/s41421-021-00362-2.
29.
Hou, P.; Fang, J.; Liu, Z.; et al. Macrophage Polarization and Metabolism in Atherosclerosis. Cell Death Dis. 2023, 14, 691. https://doi.org/10.1038/s41419-023-06206-z.
30.
Epelman, S.; Lavine, K.J.; Beaudin, A.E.; et al. Embryonic and Adult-Derived Resident Cardiac Macrophages Are Maintained through Distinct Mechanisms at Steady State and during Inflammation. Immunity 2014, 40, 91–104. https://doi.org/10.1016/j.immuni.2013.11.019.
31.
Coulis, G.; Jaime, D.; Guerrero-Juarez, C.; et al. Single-Cell and Spatial Transcriptomics Identify a Macrophage Population Associated with Skeletal Muscle Fibrosis. Sci. Adv. 2023, 9, eadd9984. https://doi.org/10.1126/sciadv.add9984.
32.
Chen, S.; Saeed, A.F.U.H.; Liu, Q.; et al. Macrophages in Immunoregulation and Therapeutics. Signal Transduct. Target. Ther. 2023, 8, 207. https://doi.org/10.1038/s41392-023-01452-1.
33.
Mantovani, A.; Marchesi, F.; Malesci, A.; et al. Tumour-Associated Macrophages as Treatment Targets in Oncology. Nat. Rev. Clin. Oncol. 2017, 14, 399–416. https://doi.org/10.1038/nrclinonc.2016.217.
34.
Ring, N.G.; Herndler-Brandstetter, D.; Weiskopf, K.; et al. Anti-SIRPα Antibody Immunotherapy Enhances Neutrophil and Macrophage Antitumor Activity. Proc. Natl. Acad. Sci. USA 2017, 114, E10578–E10585. https://doi.org/10.1073/pnas.1710877114.
35.
Spiller, K.L.; Koh, T.J. Macrophage-Based Therapeutic Strategies in Regenerative Medicine. Adv. Drug Deliv. Rev. 2017, 122, 74–83. https://doi.org/10.1016/j.addr.2017.05.010.
36.
Reeves, A.R.; Spiller, K.L.; Freytes, D.O.; et al. Controlled Release of Cytokines Using Silk-Biomaterials for Macrophage Polarization. Biomaterials 2015, 73, 272–283. https://doi.org/10.1016/j.biomaterials.2015.09.027.
37.
Taraballi, F.; Corradetti, B.; Minardi, S.; et al. Biomimetic Collagenous Scaffold to Tune Inflammation by Targeting Macrophages. J. Tissue Eng. 2016, 7, 2041731415624667. https://doi.org/10.1177/2041731415624667.
38.
Bessa-Gonçalves, M.; Ribeiro-Machado, C.; Costa, M.; et al. Magnesium Incorporation in Fibrinogen Scaffolds Promotes Macrophage Polarization towards M2 Phenotype. Acta Biomater. 2023, 155, 667–683. https://doi.org/10.1016/j.actbio.2022.10.046.
39.
Qiao, W.; Wong, K.H.M.; Shen, J.; et al. TRPM7 Kinase-Mediated Immunomodulation in Macrophage Plays a Central Role in Magnesium Ion-Induced Bone Regeneration. Nat. Commun. 2021, 12, 2885. https://doi.org/10.1038/s41467-021-23005-2.
40.
Zhang, W.; Yang, X.; Huang, X.; et al. Bioinspired Nanovesicles Released from Injectable Hydrogels Facilitate Diabetic Wound Healing by Regulating Macrophage Polarization and Endothelial Cell Dysfunction. J. Nanobiotechnol. 2023, 21, 358. https://doi.org/10.1186/s12951-023-02119-3.
41.
Shahbazi, M.-A.; Sedighi, M.; Bauleth-Ramos, T.; et al. Targeted Reinforcement of Macrophage Reprogramming toward M2 Polarization by IL-4-Loaded Hyaluronic Acid Particles. ACS Omega 2018, 3, 18444–18455. https://doi.org/10.1021/acsomega.8b03182.
42.
Mahon, O.R.; Browe, D.C.; Gonzalez-Fernandez, T.; et al. Nano-Particle Mediated M2 Macrophage Polarization Enhances Bone Formation and MSC Osteogenesis in an IL-10 Dependent Manner. Biomaterials 2020, 239, 119833. https://doi.org/10.1016/j.biomaterials.2020.119833.
43.
Raimondo, T.M.; Mooney, D.J. Functional Muscle Recovery with Nanoparticle-Directed M2 Macrophage Polarization in Mice. Proc. Natl. Acad. Sci. USA 2018, 115, 10648–10653. https://doi.org/10.1073/pnas.1806908115.
44.
Zhang, G.; Pan, R.; Lai, S.; et al. Phosphatidylserine-Functional Polydimethylsiloxane Substrates Regulate Macrophage M2 Polarization via Modulus-Dependent NF-κB/PPARγ Pathway. Biomater. Adv. 2024, 165, 213997. https://doi.org/10.1016/j.bioadv.2024.213997.
45.
Zhou, Y.-W.; Wu, Y. Substrate Viscoelasticity Amplifies Distinctions between Transient and Persistent LPS-Induced Signals. Adv. Healthc. Mater. 2022, 11, 2102271. https://doi.org/10.1002/adhm.202102271.
46.
Han, R.; Ren, Z.; Wang, Q.; et al. Synthetic Biomimetic Liposomes Harness Efferocytosis Machinery for Highly Efficient Macrophages-Targeted Drug Delivery to Alleviate Inflammation. Adv. Sci. 2024, 11, 2308325.
47.
Yuan, S.; Chai, Y.; Xu, J.; et al. Engineering Efferocytosis-Mimicking Nanovesicles to Regulate Joint Anti-Inflammation and Peripheral Immunosuppression for Rheumatoid Arthritis Therapy. Adv. Sci. 2024, 11, 2404198.
48.
Cai, S.; Gao, J.; Weng, X.; et al. Synergistic Enhancement of Efferocytosis and Cholesterol Efflux via Macrophage Biomimetic Nanoparticle to Attenuate Atherosclerosis Progression. Bioact. Mater. 2026, 55, 131–143.
49.
Geng, R.; Lin, Y.; Ji, M.; et al. MFG-E8 Promotes Tendon-Bone Healing by Regulating Macrophage Efferocytosis and M2 Polarization after Anterior Cruciate Ligament Reconstruction. J. Orthop. Transl. 2022, 34, 11–21.
50.
Li, B.; Liang, F.; Gao, Z.; et al. Co-Assembled Polypeptides-Adsorbing Bridge Molecules to Enhance Macrophage Efferocytosis for the Resolution of Periodontitis Inflammation. Acta Biomater. 2025, 205, 601–615.
51.
Shi, H.; Wang, X.; Sloas, C.; et al. Impaired TIM4-Mediated Efferocytosis by Liver Macrophages Contributes to Fibrosis in Metabolic Dysfunction–Associated Steatohepatitis. Sci. Transl. Med. 2025, 17, eadv2106.
52.
Morioka, S.; Kajioka, D.; Yamaoka, Y.; et al. Chimeric Efferocytic Receptors Improve Apoptotic Cell Clearance and Alleviate Inflammation. Cell 2022, 185, 4887–4903.e17.
53.
Shao, L.; Zhang, Y.; Yang, Z.; et al. Synthetic Efferocytic Receptor Microglia Enhances Anti-Inflammatory Clearance of Amyloid-β for AD Treatment in Mice. Sci. Adv. 2025, 11, eads6613.
54.
Bian, Z.; Gong, Y.; Huang, T.; et al. Deciphering Human Macrophage Development at Single-Cell Resolution. Nature 2020, 582, 571–576. https://doi.org/10.1038/s41586-020-2316-7.
55.
Lavine, K.J.; Epelman, S.; Uchida, K.; et al. Distinct Macrophage Lineages Contribute to Disparate Patterns of Cardiac Recovery and Remodeling in the Neonatal and Adult Heart. Proc. Natl. Acad. Sci. USA 2014, 111, 16029–16034. https://doi.org/10.1073/pnas.1406508111.
56.
Jin, K.; Gao, S.; Yang, P.; et al. Single-Cell RNA Sequencing Reveals the Temporal Diversity and Dynamics of Cardiac Immunity after Myocardial Infarction. Small Methods 2022, 6, e2100752. https://doi.org/10.1002/smtd.202100752.
57.
Okabe, Y.; Medzhitov, R. Tissue Biology Perspective on Macrophages. Nat. Immunol. 2016, 17, 9–17. https://doi.org/10.1038/ni.3320.
58.
Dick, S.A.; Macklin, J.A.; Nejat, S.; et al. Self-Renewing Resident Cardiac Macrophages Limit Adverse Remodeling Following Myocardial Infarction. Nat. Immunol. 2019, 20, 29–39. https://doi.org/10.1038/s41590-018-0272-2.
59.
Gurtner, G.C.; Werner, S.; Barrandon, Y.; et al. Wound Repair and Regeneration. Nature 2008, 453, 314–321. https://doi.org/10.1038/nature07039.
60.
James, R.; Kesturu, G.; Balian, G.; et al. Tendon: Biology, Biomechanics, Repair, Growth Factors, and Evolving Treatment Options. J. Hand Surg. Am. 2008, 33, 102–112. https://doi.org/10.1016/j.jhsa.2007.09.007.
61.
Choi, B.; Lee, C.; Yu, J.-W. Distinctive Role of Inflammation in Tissue Repair and Regeneration. Arch. Pharmacal Res. 2023, 46, 78–89. https://doi.org/10.1007/s12272-023-01428-3.
62.
Zindel, J.; Kubes, P. DAMPs, PAMPs, and LAMPs in Immunity and Sterile Inflammation. Annu. Rev. Pathol. 2020, 15, 493–518. https://doi.org/10.1146/annurev-pathmechdis-012419-032847.
63.
Minutti, C.M.; Knipper, J.A.; Allen, J.E.; et al. Tissue-Specific Contribution of Macrophages to Wound Healing. Semin. Cell Dev. Biol. 2017, 61, 3–11. https://doi.org/10.1016/j.semcdb.2016.08.006.
64.
Fu, M.; Jia, S.; Xu, L.; et al. Single-Cell Multiomic Analysis Identifies Macrophage Subpopulations in Promoting Cardiac Repair. J. Clin. Invest. 2024, 134, e175297. https://doi.org/10.1172/JCI175297.
65.
Deonarine, K.; Panelli, M.C.; Stashower, M.E.; et al. Gene Expression Profiling of Cutaneous Wound Healing. J. Transl. Med. 2007, 5, 11. https://doi.org/10.1186/1479-5876-5-11.
66.
Jung, S.-H.; Hwang, B.-H.; Shin, S.; et al. Spatiotemporal Dynamics of Macrophage Heterogeneity and a Potential Function of Trem2ʰⁱ Macrophages in Infarcted Hearts. Nat. Commun. 2022, 13, 4580. https://doi.org/10.1038/s41467-022-32284-2.
67.
Li, L.; Cao, J.; Li, S.; et al. M2 Macrophage-Derived sEV Regulate Pro-Inflammatory CCR2⁺ Macrophage Subpopulations to Favor Post-AMI Cardiac Repair. Adv. Sci. 2023, 10, 2202964. https://doi.org/10.1002/advs.202202964.
68.
Yao, W.; Chen, Y.; Li, Z.; et al. Single Cell RNA Sequencing Identifies a Unique Inflammatory Macrophage Subset as a Druggable Target for Alleviating Acute Kidney Injury. Adv. Sci. 2022, 9, 2103675.
69.
Zhang, X.; Xiao, Y.; Hu, B.; et al. Multi-Omics Analysis of Human Tendon Adhesion Reveals That ACKR1-Regulated Macrophage Migration Is Involved in Regeneration. Bone Res. 2024, 12, 27. https://doi.org/10.1038/s41413-024-00324-w.
70.
Lucas, T.; Waisman, A.; Ranjan, R.; et al. Differential Roles of Macrophages in Diverse Phases of Skin Repair. J. Immunol. 2010, 184, 3964–3977. https://doi.org/10.4049/jimmunol.0903356.
71.
Boyette, L.B.; Macedo, C.; Hadi, K.; et al. Phenotype, Function, and Differentiation Potential of Human Monocyte Subsets. PLoS ONE 2017, 12, e0176460. https://doi.org/10.1371/journal.pone.0176460.
72.
Nahrendorf, M.; Swirski, F.K.; Aikawa, E.; et al. The Healing Myocardium Sequentially Mobilizes Two Monocyte Subsets with Divergent and Complementary Functions. J. Exp. Med. 2007, 204, 3037–3047. https://doi.org/10.1084/jem.20070885.
73.
Ishida, Y.; Gao, J.-L.; Murphy, P.M. Chemokine Receptor CX3CR1 Mediates Skin Wound Healing by Promoting Macrophage and Fibroblast Accumulation and Function. J. Immunol. 2008, 180, 569–579. https://doi.org/10.4049/jimmunol.180.1.569.
74.
Bajpai, G.; Schneider, C.; Wong, N.; et al. The Human Heart Contains Distinct Macrophage Subsets with Divergent Origins and Functions. Nat. Med. 2018, 24, 1234–1245. https://doi.org/10.1038/s41591-018-0059-x.
75.
Bart, V.M.; Pickering, R.J.; Taylor, P.R.; et al. Macrophage Reprogramming for Therapy. Immunology 2021, 163, 128–144.
76.
Wang, Z.; Shi, H.; Silveira, P.A.; et al. Tropoelastin Modulates Systemic and Local Tissue Responses to Enhance Wound Healing. Acta Biomater. 2024, 184, 54–67. https://doi.org/10.1016/j.actbio.2024.06.009.
77.
Xu, H.; Zhu, Y.; Hsiao, A.W.-T.; et al. Bioactive Glass-Elicited Stem Cell-Derived Extracellular Vesicles Regulate M2 Macrophage Polarization and Angiogenesis to Improve Tendon Regeneration and Functional Recovery. Biomaterials 2023, 294, 121998. https://doi.org/10.1016/j.biomaterials.2023.121998.
78.
Zhang, J.; Shi, H.; Zhang, N.; et al. Interleukin-4-Loaded Hydrogel Scaffold Regulates Macrophages Polarization to Promote Bone Mesenchymal Stem Cells Osteogenic Differentiation via TGF-β1/Smad Pathway for Repair of Bone Defect. Cell Prolif. 2020, 53, e12907. https://doi.org/10.1111/cpr.12907.
79.
Ajeeb, R.; Catelain, C.; Joshi, H.A.; et al. Recombinant Cytokine Bioconjugates with Degradable Nanogel Substrates for Macrophage Immunotherapy. Acta Biomater. 2025, 201, 604–617. https://doi.org/10.1016/j.actbio.2025.05.066.
80.
Liao, Y.; Zhang, Y.; Blum, N.T.; et al. Biomimetic Hybrid Membrane-Based Nanoplatforms: Synthesis, Properties and Biomedical Applications. Nanoscale Horiz. 2020, 5, 1293–1302. https://doi.org/10.1039/d0nh00267d.
81.
Fang, R.H.; Kroll, A.V.; Gao, W.; et al. Cell Membrane Coating Nanotechnology. Adv. Mater. 2018, 30, e1706759. https://doi.org/10.1002/adma.201706759.
82.
Spiller, K.L.; Anfang, R.R.; Spiller, K.J.; et al. The Role of Macrophage Phenotype in Vascularization of Tissue Engineering Scaffolds. Biomaterials 2014, 35, 4477–4488. https://doi.org/10.1016/j.biomaterials.2014.02.012.
83.
Spiller, K.L.; Nassiri, S.; Witherel, C.E.; et al. Sequential Delivery of Immunomodulatory Cytokines to Facilitate the M1-to-M2 Transition of Macrophages and Enhance Vascularization of Bone Scaffolds. Biomaterials 2015, 37, 194–207. https://doi.org/10.1016/j.biomaterials.2014.10.017.
84.
Huang, J.; Wei, J.; Xia, X.; et al. A Sequential Macrophage Activation Strategy for Bone Regeneration: A Micro/Nano Strontium-Releasing Composite Scaffold Loaded with Lipopolysaccharide. Mater. Today Bio 2024, 26, 101063. https://doi.org/10.1016/j.mtbio.2024.101063.
85.
Sapudom, J.; Tipay, P.; Teo, J.C.M. Mechano-Mediated M2 Macrophage Polarization and Immune Suppression in Stiffened Tumor Microenvironment. bioRxiv 2024. https://doi.org/10.1101/2024.07.29.605566.
86.
Patel, N.R.; Bole, M.; Chen, C.; et al. Cell Elasticity Determines Macrophage Function. PLoS ONE 2012, 7, e41024. https://doi.org/10.1371/journal.pone.0041024.
87.
Meizlish, M.L.; Kimura, Y.; Pope, S.D.; et al. Mechanosensing Regulates Tissue Repair Program in Macrophages. Sci. Adv. 2024, 10, eadk6906. https://doi.org/10.1126/sciadv.adk6906.
88.
Atcha, H.; Jairaman, A.; Holt, J.R.; et al. Mechanically Activated Ion Channel Piezo1 Modulates Macrophage Polarization and Stiffness Sensing. Nat. Commun. 2021, 12, 3256. https://doi.org/10.1038/s41467-021-23482-5.
89.
Lee, M.; Du, H.; Winer, D.A.; et al. Mechanosensing in Macrophages and Dendritic Cells in Steady-State and Disease. Front. Cell Dev. Biol. 2022, 10, 1044729. https://doi.org/10.3389/fcell.2022.1044729.
90.
Okamoto, T.; Takagi, Y.; Kawamoto, E.; et al. Reduced Substrate Stiffness Promotes M2-like Macrophage Activation and Enhances Peroxisome Proliferator-Activated Receptor γ Expression. Exp. Cell Res. 2018, 367, 264–273. https://doi.org/10.1016/j.yexcr.2018.04.005.
91.
Meli, V.S.; Atcha, H.; Veerasubramanian, P.K.; et al. YAP-Mediated Mechanotransduction Tunes the Macrophage Inflammatory Response. Sci. Adv. 2020, 6, eabb8471. https://doi.org/10.1126/sciadv.abb8471.
92.
Sridharan, R.; Cavanagh, B.; Cameron, A.R.; et al. Material Stiffness Influences the Polarization State, Function and Migration Mode of Macrophages. Acta Biomater. 2019, 89, 47–59. https://doi.org/10.1016/j.actbio.2019.02.048.
93.
Blakney, A.K.; Swartzlander, M.D.; Bryant, S.J. The Effects of Substrate Stiffness on the In Vitro Activation of Macrophages and In Vivo Host Response to Poly(Ethylene Glycol)-Based Hydrogels. J. Biomed. Mater. Res. A 2012, 100, 1375–1386. https://doi.org/10.1002/jbm.a.34104.
94.
Mei, F.; Guo, Y.; Wang, Y.; et al. Matrix Stiffness Regulates Macrophage Polarisation via the Piezo1-YAP Signalling Axis. Cell Prolif. 2024, 57, e13640. https://doi.org/10.1111/cpr.13640.
95.
Hsieh, J.Y.; Keating, M.T.; Smith, T.D.; et al. Matrix Crosslinking Enhances Macrophage Adhesion, Migration, and Inflammatory Activation. APL Bioeng. 2019, 3, 016103. https://doi.org/10.1063/1.5067301.
96.
Chinetti, G.; Griglio, S.; Antonucci, M.; et al. Activation of Proliferator-Activated Receptors α and γ Induces Apoptosis of Human Monocyte-Derived Macrophages. J. Biol. Chem. 1998, 273, 25573–25580. https://doi.org/10.1074/jbc.273.40.25573.
97.
Pascual, G.; Fong, A.L.; Ogawa, S.; et al. A SUMOylation-Dependent Pathway Mediates Transrepression of Inflammatory Response Genes by PPAR-γ. Nature 2005, 437, 759–763. https://doi.org/10.1038/nature03988.
98.
Chen, M.; Zhang, Y.; Zhou, P.; et al. Substrate Stiffness Modulates Bone Marrow-Derived Macrophage Polarization through NF-κB Signaling Pathway. Bioact. Mater. 2020, 5, 880–890. https://doi.org/10.1016/j.bioactmat.2020.05.004.
99.
Anderson, J.M.; Rodriguez, A.; Chang, D.T. Foreign Body Reaction to Biomaterials. Semin. Immunol. 2008, 20, 86–100. https://doi.org/10.1016/j.smim.2007.11.004.
100.
Chaudhuri, O.; Cooper-White, J.; Janmey, P.A.; et al. Effects of Extracellular Matrix Viscoelasticity on Cellular Behaviour. Nature 2020, 584, 535–546. https://doi.org/10.1038/s41586-020-2612-2.
101.
Tao, D.; Wang, H.; Chang, S.; et al. Matrix Viscoelasticity Orchestrates Osteogenesis via Mechanotransduction Mediated Metabolic Switch in Macrophages. Adv. Healthc. Mater. 2025, 14, e2405097. https://doi.org/10.1002/adhm.202405097.
102.
Coser, C.; di Bari, V.; Ghaemmaghami, A.M.; et al. Hydrogel Viscoelasticity Regulates Human Monocyte-Derived Macrophage Morphology and Phenotype in 2D Culture. Acta Biomater. 2026, 216, 234–247. https://doi.org/10.1016/j.actbio.2026.04.032.
103.
Kalashnikov, N.; Moraes, C. Substrate Viscoelasticity Affects Human Macrophage Morphology and Phagocytosis. Soft Matter 2023, 19, 2438–2445. https://doi.org/10.1039/D2SM01683D.
104.
Sanders, J.E.; Bale, S.D.; Neumann, T. Tissue Response to Microfibers of Different Polymers: Polyester, Polyethylene, Polylactic Acid, and Polyurethane. J. Biomed. Mater. Res. 2002, 62, 222–227. https://doi.org/10.1002/jbm.10285.
105.
Garg, K.; Pullen, N.A.; Oskeritzian, C.A.; et al. Macrophage Functional Polarization (M1/M2) in Response to Varying Fiber and Pore Dimensions of Electrospun Scaffolds. Biomaterials 2013, 34, 4439–4451. https://doi.org/10.1016/j.biomaterials.2013.02.065.
106.
Cao, H.; Mchugh, K.; Chew, S.Y.; et al. The Topographical Effect of Electrospun Nanofibrous Scaffolds on the In Vivo and In Vitro Foreign Body Reaction. J. Biomed. Mater. Res. A 2010, 93, 1151–1159.
107.
Madden, L.R.; Mortisen, D.J.; Sussman, E.M.; et al. Proangiogenic Scaffolds as Functional Templates for Cardiac Tissue Engineering. Proc. Natl. Acad. Sci. USA 2010, 107, 15211–15216. https://doi.org/10.1073/pnas.1006442107.
108.
Yin, Y.; He, X.-T.; Wang, J.; et al. Pore Size-Mediated Macrophage M1-to-M2 Transition Influences New Vessel Formation within the Compartment of a Scaffold. Appl. Mater. Today 2020, 18, 100466. https://doi.org/10.1016/j.apmt.2019.100466.
109.
Sussman, E.M.; Halpin, M.C.; Muster, J.; et al. Porous Implants Modulate Healing and Induce Shifts in Local Macrophage Polarization in the Foreign Body Reaction. Ann. Biomed. Eng. 2014, 42, 1508–1516. https://doi.org/10.1007/s10439-013-0933-0.
110.
Bota, P.C.S.; Collie, A.M.B.; Puolakkainen, P.; et al. Biomaterial Topography Alters Healing In Vivo and Monocyte/Macrophage Activation In Vitro. J. Biomed. Mater. Res. A 2010, 95, 649–657. https://doi.org/10.1002/jbm.a.32893.
111.
McWhorter, F.Y.; Wang, T.; Nguyen, P.; et al. Modulation of Macrophage Phenotype by Cell Shape. Proc. Natl. Acad. Sci. USA 2013, 110, 17253–17258. https://doi.org/10.1073/pnas.1308887110.
112.
Vassey, M.J.; Figueredo, G.P.; Scurr, D.J.; et al. Immune Modulation by Design: Using Topography to Control Human Monocyte Attachment and Macrophage Differentiation. Adv. Sci. 2020, 7, 1903392. https://doi.org/10.1002/advs.201903392.
113.
Sridharan, R.; Cameron, A.R.; Kelly, D.J.; et al. Biomaterial Based Modulation of Macrophage Polarization: A Review and Suggested Design Principles. Mater. Today 2015, 18, 313–325. https://doi.org/10.1016/j.mattod.2015.01.019.
114.
Rodriguez Ayala, A.; Christ, G.; Griffin, D. Cell-Scale Porosity Minimizes Foreign Body Reaction and Promotes Innervated Myofiber Formation after Volumetric Muscle Loss. npj Regener. Med. 2025, 10, 12. https://doi.org/10.1038/s41536-025-00395-1.
115.
Choi, S.-W.; Zhang, Y.; MacEwan, M.R.; et al. Neovascularization in Biodegradable Inverse Opal Scaffolds with Uniform and Precisely Controlled Pore Sizes. Adv. Healthc. Mater. 2013, 2, 145–154. https://doi.org/10.1002/adhm.201200106.
116.
He, H.; Xu, J.; Warren, C.M.; et al. Endothelial Cells Provide an Instructive Niche for the Differentiation and Functional Polarization of M2-like Macrophages. Blood 2012, 120, 3152–3162. https://doi.org/10.1182/blood-2012-04-422758.
117.
Wang, Z.; Cui, Y.; Wang, J.; et al. The Effect of Thick Fibers and Large Pores of Electrospun Poly(ε-Caprolactone) Vascular Grafts on Macrophage Polarization and Arterial Regeneration. Biomaterials 2014, 35, 5700–5710. https://doi.org/10.1016/j.biomaterials.2014.03.078.
118.
Foroozandeh, P.; Aziz, A.A. Insight into Cellular Uptake and Intracellular Trafficking of Nanoparticles. Nanoscale Res. Lett. 2018, 13, 339. https://doi.org/10.1186/s11671-018-2728-6.
119.
Luu, T.U.; Gott, S.C.; Woo, B.W.; et al. Micro- and Nanopatterned Topographical Cues for Regulating Macrophage Cell Shape and Phenotype. ACS Appl. Mater. Interfaces 2015, 7, 28665–28672. https://doi.org/10.1021/acsami.5b10589.
120.
Jain, N.; Vogel, V. Spatial Confinement Downsizes the Inflammatory Response of Macrophages. Nat. Mater. 2018, 17, 1134–1144. https://doi.org/10.1038/s41563-018-0190-6.
121.
Wissing, T.B.; Bonito, V.; van Haaften, E.E.; et al. Macrophage-Driven Biomaterial Degradation Depends on Scaffold Microarchitecture. Front. Bioeng. Biotechnol. 2019, 7, 87. https://doi.org/10.3389/fbioe.2019.00087.
122.
Moon, B.; Yang, S.; Moon, H.; et al. After Cell Death: The Molecular Machinery of Efferocytosis. Exp. Mol. Med. 2023, 55, 1644–1651.
123.
Zhong, X.; Lee, H.N.; Kim, S.H.; et al. Myc-nick Promotes Efferocytosis through M2 Macrophage Polarization during Resolution of Inflammation. FASEB J. 2018, 32, 5312–5325.
124.
Gerlach, B.D.; Ampomah, P.B.; Yurdagul, A.; et al. Efferocytosis Induces Macrophage Proliferation to Help Resolve Tissue Injury. Cell Metab. 2021, 33, 2445–2463.e8.
125.
Ngai, D.; Schilperoort, M.; Tabas, I. Efferocytosis-Induced Lactate Enables the Proliferation of Pro-Resolving Macrophages to Mediate Tissue Repair. Nat. Metab. 2023, 5, 2206–2219.
126.
Yurdagul, A., Jr.; Subramanian, M.; Wang, X.; et al. Macrophage Metabolism of Apoptotic Cell-Derived Arginine Promotes Continual Efferocytosis and Resolution of Injury. Cell Metab. 2020, 31, 518–533.e10. https://doi.org/10.1016/j.cmet.2020.01.001.
127.
Wang, Y.; Subramanian, M.; Yurdagul, A.; et al. Mitochondrial Fission Promotes the Continued Clearance of Apoptotic Cells by Macrophages. Cell 2017, 171, 331–345.e22.
128.
Sukka, S.R.; Ampomah, P.B.; Darville, L.N.; et al. Efferocytosis Drives a Tryptophan Metabolism Pathway in Macrophages to Promote Tissue Resolution. Nat. Metab. 2024, 6, 1736–1755.
129.
Proto, J.D.; Doran, A.C.; Gusarova, G.; et al. Regulatory T Cells Promote Macrophage Efferocytosis during Inflammation Resolution. Immunity 2018, 49, 666–677.e6.
130.
Ampomah, P.B.; Cai, B.; Sukka, S.R.; et al. Macrophages Use Apoptotic Cell-Derived Methionine and DNMT3A during Efferocytosis to Promote Tissue Resolution. Nat. Metab. 2022, 4, 444–457.
131.
Lin, D.; Kang, X.; Shen, L.; et al. Efferocytosis and Its Associated Cytokines: A Light on Non-Tumor and Tumor Diseases? Mol. Ther.-Oncolytics 2020, 17, 394–407.
132.
Nishi, C.; Yanagihashi, Y.; Segawa, K.; et al. MERTK Tyrosine Kinase Receptor Together with TIM4 Phosphatidylserine Receptor Mediates Distinct Signal Transduction Pathways for Efferocytosis and Cell Proliferation. J. Biol. Chem. 2019, 294, 7221–7230. https://doi.org/10.1074/jbc.RA118.006628.
133.
Garcia-Loza, I.; Perna-Barrull, D.; Aguilera, E.; et al. Targeting Macrophages with Phosphatidylserine-Rich Liposomes as a Potential Antigen-Specific Immunotherapy for Type 1 Diabetes. J. Autoimmun. 2024, 145, 103196. https://doi.org/10.1016/j.jaut.2024.103196.
134.
Galvan, M.D.; Foreman, D.B.; Zeng, E.; et al. Complement Component C1q Regulates Macrophage Expression of Mer Tyrosine Kinase to Promote Clearance of Apoptotic Cells. J. Immunol. 2012, 188, 3716–3723. https://doi.org/10.4049/jimmunol.1102920.
135.
Ding, L.; Zhang, T.; Pan, Y.; et al. Stem Cell-Derived Biomimetic Apoptotic Vesicles Enhance Macrophage Efferocytosis via C1qbp to Accelerate Diabetic Wound Healing. Nano Res. 2026, 19, 94908650. https://doi.org/10.26599/NR.2026.94908650.
136.
Singh, A.; Chakraborty, S.; Wong, S.W.; et al. Nanoparticle Targeting of De Novo Profibrotic Macrophages Mitigates Lung Fibrosis. Proc. Natl. Acad. Sci. USA 2022, 119, e2121098119. https://doi.org/10.1073/pnas.2121098119.
137.
Wang, S.; Xiao, Y.; Tian, J.; et al. Targeted Macrophage CRISPR-Cas13 mRNA Editing in Immunotherapy for Tendon Injury. Adv. Mater. 2024, 36, 2311964. https://doi.org/10.1002/adma.202311964.
138.
Xu J; Zheng M; Feng Z; et al. CCL4L2 Participates in Tendinopathy Progression by Promoting Macrophage Inflammatory Responses: A Single-Cell Analysis. J. Orthop. Surg. Res. 2024, 19, 836.
139.
Cheng, X.; Sui, H.; Chen, F.; et al. Nanomaterial-Mediated Reprogramming of Macrophages to Inhibit Refractory Muscle Fibrosis. Adv. Mater. 2024, 36, 2410368.
140.
Chen, Y.; Chen, W.; Ren, Y.; et al. Macrophage-Targeted Efferocytosis Therapy Promotes Diabetic Wound Healing via Cellular Level Debridement. Adv. Funct. Mater. 2025, 35, 2503035. https://doi.org/10.1002/adfm.202503035.
141.
Leuschner, F.; Dutta, P.; Gorbatov, R.; et al. Therapeutic siRNA Silencing in Inflammatory Monocytes in Mice. Nat. Biotechnol. 2011, 29, 1005–1010. https://doi.org/10.1038/nbt.1989.
142.
Majmudar, M.D.; Keliher, E.J.; Heidt, T.; et al. Monocyte-Directed RNAi Targeting CCR2 Improves Infarct Healing in Atherosclerosis-Prone Mice. Circulation 2013, 127, 2038–2046. https://doi.org/10.1161/CIRCULATIONAHA.112.000116.
143.
Olingy, C.E.; San Emeterio, C.L.; Ogle, M.E.; et al. Non-Classical Monocytes Are Biased Progenitors of Wound Healing Macrophages during Soft Tissue Injury. Sci. Rep. 2017, 7, 447. https://doi.org/10.1038/s41598-017-00477-1.
144.
Carrizo, G.E.; Lin, P.; Lee, S.H.; et al. The Transition from Monocyte to Tissue-Resident Macrophage Requires DHPS. Nature 2026, 651, 763–774. https://doi.org/10.1038/s41586-025-09972-2.
145.
Chelvarajan, R.L.; Liu, Y.; Popa, D.; et al. Molecular Basis of Age-Associated Cytokine Dysregulation in LPS-Stimulated Macrophages. J. Leukoc. Biol. 2006, 79, 1314–1327. https://doi.org/10.1189/jlb.0106024.
146.
Verschoor, C.P.; Johnstone, J.; Loeb, M.; et al. Anti-Pneumococcal Deficits of Monocyte-Derived Macrophages from the Advanced-Age, Frail Elderly and Related Impairments in PI3K-AKT Signaling. Hum. Immunol. 2014, 75, 1192–1196. https://doi.org/10.1016/j.humimm.2014.10.004.

Scilight Press

Author Information

Abstract

Keywords

References

About Scilight

Journals

Publishing Policies

Contact Us