Responsive bone regeneration membranes targeting Macrophages: A novel strategy for promoting bone defect repair and regeneration
Source abstract
Abstract
• Proposes a materials-centered framework for macrophage-targeted bone regeneration membranes. • Elucidates how responsive materials regulate macrophage behavior and the healing microenvironment. • Shows that multifunctional membranes enhance bone regeneration via immunomodulation and controlled bioactivity. • Identifies challenges in material design and multifunctional integration for clinically translatable bone repair. Background. Bone defects caused by trauma, infection, tumors, and metabolic disorders remain difficult to treat due to hostile microenvironments and the limited functionality of conventional materials. With the rapid development of materials science, bone regeneration strategies have shifted from passive barrier membranes to multifunctional responsive systems capable of actively regulating the repair process. Among these, macrophage-mediated immunomodulation has emerged as a critical mechanism for coordinating inflammation, angiogenesis, and osteogenesis; however, a material-centered synthesis of this field remains lacking. Methods: This study systematically reviews macrophage-targeted responsive bone regeneration membranes, with a focus on material design strategies, microenvironment-responsive mechanisms, and immunoregulatory functions. Results: Advanced membrane systems integrate responsive elements (e.g., pH, ROS, and enzyme sensitivity), controlled drug delivery, and physicochemical surface functionalization to precisely modulate macrophage polarization, activate osteogenic signaling pathways, and enhance bone regeneration performance. Conclusions: Responsive membrane design represents a promising materials-driven strategy for precise bone repair. Nevertheless, challenges remain in structural optimization, multifunctional integration, scalable fabrication, and clinical translation, highlighting the need for further innovation toward high-performance and application-oriented biomaterials.
Source: openalex_inverted_index · Quality: baseline
Research context
OpenAlex topics: Bone Tissue Engineering Materials · Graphene and Nanomaterials Applications · Immune cells in cancer
SciVX discovery tags are terminology-based. OpenAlex topics are source-provided classifications.
References (100+)
Show source-provided references
1. the advances in nanomedicine for bone and cartilage repair10.1186/s12951-022-01342-8 ↗
2. Heng · 2023 · 10
3. biodegradable metals for bone defect repair: a systematic review and meta-analysis based on animal studies
4. a multifunctional composite scaffold responds to microenvironment and guides osteogenesis for the repair of infected bone defects10.1186/s12951-024-02823-8 ↗
5. a comparative study of autogenous, allograft and artificial bone substitutes on bone regeneration and immunotoxicity in rat femur defect model
6. immunomodulatory multifunctional janus collagen-based membrane for advanced bone regeneration10.1038/s41467-025-59651-z ↗
7. bioinspired membrane provides periosteum-mimetic microenvironment for accelerating vascularized bone regeneration10.1016/j.biomaterials.2020.120561 ↗
8. guided bone regeneration is promoted by the molecular events in the membrane compartment10.1016/j.biomaterials.2016.01.034 ↗
9. electrospun nanofibrous membranes meet antibacterial nanomaterials: from preparation strategies to biomedical applications
10. Zheng, biodegradable zinc-based alloys for guided bone regeneration membranes: feasibility
11. biocompatible chitin-based janus hydrogel membranes for periodontal repair10.1016/j.actbio.2024.10.038 ↗
12. macrophage biology in development, homeostasis and disease10.1038/nature12034 ↗
13. m2 macrophage-derived exosomes promote diabetic fracture healing by acting as an immunomodulator
14. bone matrix-mimetic multi-ion doped hydroxyapatite nanorod arrays for enhanced immuno-osteogenesis and prevention of aseptic loosening
15. an engineered m2 macrophage-derived exosomes-loaded electrospun biomimetic periosteum promotes cell recruitment, immunoregulation, and angiogenesis in bone regeneration
16. nanoscaled bionic periosteum orchestrating the osteogenic microenvironment for sequential bone regeneration10.1021/acsami.0c06906 ↗
17. a multifunctional neuromodulation platform utilizing schwann cell-derived exosomes orchestrates bone microenvironment via immunomodulation, angiogenesis and osteogenesis
18. effects of exosomes from lps-activated macrophages on adipocyte gene expression, differentiation, and insulin-dependent glucose uptake10.1007/s13105-018-0622-4 ↗
19. modulating macrophage activities to promote endogenous bone regeneration: biological mechanisms and engineering approaches
20. molecular mechanisms controlling bone formation during fracture healing and distraction osteogenesis10.1177/154405910808700215 ↗
21. extracellular vesicle activities regulating macrophage- and tissue-mediated injury and repair responses10.1016/j.apsb.2020.12.014 ↗
22. layer-by-layer nanofiber-enabled engineering of biomimetic periosteum for bone repair and reconstruction10.1016/j.biomaterials.2018.08.028 ↗
23. mechanisms of bone development and repair10.1038/s41580-020-00279-w ↗
24. a ph-mediated electronic wound dressing for controlled drug delivery10.1002/adhm.201800396 ↗
25. a ph/ros dual responsive smart microgel mirna delivery system for repair of intervertebral disc degeneration10.1039/D5TB01505G ↗
26. enzyme-responsive liposomes target endoplasmic reticulum stress-mediated apoptosis for rheumatoid arthritis therapy10.1016/j.phymed.2025.157299 ↗
27. microenvironment-responsive nanomedicines: a promising direction for tissue regeneration
28. thioether phosphatidylcholine liposomes: a novel ros-responsive platform for drug delivery10.1021/acsami.9b08901 ↗
29. ros-cleavable diselenide nanomedicine for nir-controlled drug release and on-demand synergistic chemo-photodynamic therapy10.1016/j.actbio.2022.09.061 ↗
30. microenvironment-responsive injectable hydrogel for neuro-vascularized bone regeneration
31. Tetrahedral DNA Nanoframework-based Multivalent Aptamers Functionalized Biomimetic Hydrogel Scaffold Enhances Osteochondral Regeneration by Recruitment and Protection of Endogenous Stem Cells10.1002/adfm.202502871 ↗
32. expression of cathepsin k and matrix metalloproteinase 1 indicate persistent osteodestructive activity in long-standing ankylosing spondylitis10.1136/ard.2008.092494 ↗
33. bio-inspired biomaterial coating for enzyme responsive release of antimicrobial peptides
34. Hikku, nano-hydroxyapatite/collagen composite as scaffold material for bone regeneration10.1088/1748-605X/acc99e ↗
35. Xie · 2025 · 12
36. J. Marcos Batista, S. Rajasekaran, B. Huynh, T. Ghosh, M.E. Marinho, J. Corcoran, M.A.C. Sinhoreti, A.P.P. Fugolin, assessment of physicochemical properties and biological responses of chemically surface-modified microcapsules for self-healing dental restorative materials, Materials & design 259 (2025).10.1016/j.matdes.2025.114910 ↗
37. multifunctional composite scaffold with nanosilver, graphene oxide, and macrophage membrane vesicles for sequential treatment of infected bone defects10.1002/adhm.202400346 ↗
38. biomimicking design of artificial periosteum for promoting bone healing10.1016/j.jot.2022.05.013 ↗
39. bone physiological microenvironment and healing mechanism: basis for future bone-tissue engineering scaffolds
40. interfacial delivery of carbon monoxide via smart titanium implant coating for enhanced soft tissue integration with switchable antibacterial and immunomodulatory properties
41. 3d biomimetic optoelectronic scaffold repairs cranial defects10.1126/sciadv.abq7750 ↗
42. Xue · 2024 · 11
43. restoration of electrical microenvironment enhances bone regeneration under diabetic conditions by modulating macrophage polarization
44. Natural collagen scaffold with intrinsic piezoelectricity for enhanced bone regeneration
45. Pei · 2025 · 12
46. 3d printed hydroxyapatite - zn(2+) functionalized starch composite bone grafts for orthopedic and dental applications10.1016/j.matdes.2022.110903 ↗
47. tissue engineered bone mimetics to study bone disorders exvivo: role of bioinspired materials10.1016/j.biomaterials.2018.06.005 ↗
48. the effect of a bionic bone ionic environment on osteogenesis, osteoimmunology, and in situ bone tissue engineering10.1016/j.biomaterials.2023.122410 ↗
49. a review of biomimetic scaffolds for bone regeneration: toward a cell-free strategy10.1002/btm2.10206 ↗
50. biomechanical characteristics and analysis approaches of bone and bone substitute materials10.3390/jfb14040212 ↗
51. integrated evaluation of biomechanical and biological properties of the biomimetic structural bone scaffold: biomechanics, simulation analysis, and osteogenesis
52. exosomes from adipose-derived stem cells regulate m1/m2 macrophage phenotypic polarization to promote bone healing via mir-451a/mif10.1186/s13287-022-02823-1 ↗
53. lactobacillus plantarum-derived extracellular vesicles induce anti-inflammatory m2 macrophage polarization in vitro10.1080/20013078.2020.1793514 ↗
54. renal transplant recipients receiving loop diuretic therapy have increased urinary tract infection rate and altered medullary macrophage polarization marker expression10.1016/j.kint.2018.06.029 ↗
55. targeting and repolarizing m2-like tumor-associated macrophage-mediated mr imaging and tumor immunotherapy by biomimetic nanoparticles10.1186/s12951-023-02122-8 ↗
56. mef2c promotes m1 macrophage polarization and th1 responses10.1038/s41423-022-00841-w ↗
57. lipid synthesis, triggered by pparγ t166 dephosphorylation, sustains reparative function of macrophages during tissue repair10.1038/s41467-024-51736-5 ↗
58. therapeutic properties of m2 macrophages in chronic wounds: an innovative area of biomaterial-assisted m2 macrophage targeted therapy10.1007/s12015-024-10806-3 ↗
59. mechanisms of immune suppression by myeloid-derived suppressor cells: the role of interleukin-10 as a key immunoregulatory cytokine10.1098/rsob.200111 ↗
60. the contribution of macrophage plasticity to inflammatory arthritis and their potential as therapeutic targets10.3390/cells13181586 ↗
61. functional diversity of disorder-specific macrophages involved in various diseases10.1186/s41232-025-00390-5 ↗
62. macrophage-derived oncostatin m/bone morphogenetic protein 6 in response to mg-based materials influences pro-osteogenic activity of human umbilical cord perivascular cells10.1016/j.actbio.2020.12.016 ↗
63. induction of unique macrophage subset by simultaneous stimulation with lps and il-410.3389/fimmu.2023.1111729 ↗
64. osteoinduction and osteoimmunology: emerging concepts10.1111/prd.12519 ↗
65. immunomodulatory effects and mechanisms of two-dimensional black phosphorus on macrophage polarization and bone regeneration10.2147/IJN.S508309 ↗
66. mesenchymal stem cell-macrophage crosstalk and bone healing10.1016/j.biomaterials.2017.12.025 ↗
67. 3d printed strontium-doped calcium phosphate ceramic scaffold enhances early angiogenesis and promotes bone repair through the regulation of macrophage polarization
68. bone regeneration in inflammation with aging and cell-based immunomodulatory therapy10.1186/s41232-023-00279-1 ↗
69. nano-particle mediated m2 macrophage polarization enhances bone formation and msc osteogenesis in an il-10 dependent manner10.1016/j.biomaterials.2020.119833 ↗
70. the effects of conditioned media generated by polarized macrophages on the cellular behaviours of bone marrow mesenchymal stem cells10.1111/jcmm.13431 ↗
71. crosstalk between macrophages and mesenchymal stem cells shape patterns of osteogenesis and immunomodulation in mineralized collagen scaffolds
72. mesenchymal stem/stromal cells (mscs): role as guardians of inflammation10.1038/mt.2011.211 ↗
73. cd200-cd200r1 signalling attenuates imiquimod-induced psoriatic inflammation by inhibiting the activation of skin inflammatory macrophages10.1016/j.intimp.2019.106046 ↗
74. ephb4/ tnfr2/erk/mapk signaling pathway comprises a signaling axis to mediate the positive effect of tnf-α on osteogenic differentiation10.1186/s12860-020-00273-2 ↗
75. strategies of macrophages to maintain bone homeostasis and promote bone repair: a narrative review10.3390/jfb14010018 ↗
76. cd169(+) macrophages are critical for osteoblast maintenance and promote intramembranous and endochondral ossification during bone repair10.1016/j.biomaterials.2017.10.033 ↗
77. gm-csf in inflammation and autoimmunity10.1016/S1471-4906(02)02260-3 ↗
78. maintaining homeostatic control of periodontal bone tissue10.1111/prd.12368 ↗
79. obesity and lipid metabolism in the development of osteoporosis (review)10.3892/ijmm.2024.5385 ↗
80. Jin, immunometabolism of macrophages in the bone microenvironment: a new perspective for bone healing therapy
81. focusing on ob-oc-mφ axis and mir-23a to explore the pathogenesis and treatment strategy of osteoporosis10.3389/fendo.2022.891313 ↗
82. exosomal osteoclast-derived mirna in rheumatoid arthritis: from their pathogenesis in bone erosion to new therapeutic approaches10.3390/ijms25031506 ↗
83. macrophage-endothelial cell crosstalk orchestrates neutrophil recruitment in inflamed mucosa10.1172/JCI170733 ↗
84. endothelial and macrophage interactions in the angiogenic niche10.1016/j.cytogfr.2024.07.005 ↗
85. crosstalk between h-type vascular endothelial cells and macrophages: a potential regulator of bone homeostasis10.2147/JIR.S502604 ↗
86. X. Li, Y. Long, Y. Zhu, J. Gu, P. Zhou, C. Miao, endothelial-derived ccl7 promotes macrophage polarization and aggravates septic acute lung injury via ccr1-mediated stat1 succinylation, Advanced science (Weinheim, Baden-Wurttemberg, Germany) 12(38) (2025) e06209.10.1002/advs.202506209 ↗
87. regulating macrophage glucose metabolism homeostasis via mitochondrial rheostats by short fiber-microsphere scaffolds for bone repair
88. amorphous calcium zinc phosphate promotes macrophage-driven alveolar bone regeneration via modulation of energy metabolism and mitochondrial homeostasis
89. krebs cycle reborn in macrophage immunometabolism10.1146/annurev-immunol-081619-104850 ↗
90. protein o-glcnacylation reprograms macrophage-mediated bone remodeling in medication-related osteonecrosis of the jaw10.1016/j.ijbiomac.2025.144342 ↗
91. mitochondrial dysfunction promotes the transition of precursor to terminally exhausted t cells through hif-1α-mediated glycolytic reprogramming10.1038/s41467-023-42634-3 ↗
92. an engineered enzyme that targets circulating lactate to alleviate intracellular nadh:nad(+) imbalance10.1038/s41587-019-0377-7 ↗
93. G. Yang, J.S. Ni, Y. Li, M. Zha, Y. Tu, K. Li, acceptor engineering for optimized ros generation facilitates reprogramming macrophages to m1 phenotype in photodynamic immunotherapy, Angewandte Chemie (International ed. in English) 60(10) (2021) 5386-5393.10.1002/anie.202013228 ↗
94. regulations of glycolytic activities on macrophages functions in tumor and infectious inflammation10.3389/fcimb.2020.00287 ↗
95. selenium-doped mesoporous bioactive glass regulates macrophage metabolism and polarization by scavenging ros and promotes bone regeneration in vivo10.1021/acsami.3c03446 ↗
96. gapdh-silence microsphere via reprogramming macrophage metabolism and eradicating bacteria for diabetic infection bone regeneration10.1186/s12951-024-02787-9 ↗
97. polarized macrophages in periodontitis: characteristics, function, and molecular signaling10.3389/fimmu.2021.763334 ↗
98. inhibition of nemo alleviates arthritis by blocking the m1 macrophage polarization10.1016/j.intimp.2023.109983 ↗
99. quercetin-loaded mesoporous nano-delivery system remodels osteoimmune microenvironment to regenerate alveolar bone in periodontitis via the mir-21a-5p/pdcd4/nf-κb pathway10.1186/s12951-024-02352-4 ↗
100. effects of irf1 and ifn-β interaction on the m1polarization of macrophages and its antitumor function10.3892/ijmm.2016.2583 ↗