Modulation of Macrophage Polarization for Bone Tissue Engineering Applications

  • Zahra Jamalpoor Trauma Research Center, AJA University of Medical Sciences, Tehran, Iran
  • Alireza Asgari Aerospace Medicine Research Center, AJA University of Medical Sciences, Tehran, Iran
  • Mohammad Hossein Lashkari Department of Surgery, Faculty of Medicine, AJA University of Medical Sciences, Tehran, Iran
  • Abbas Mirshafiey Department of Immunology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
  • Monireh Mohsenzadegan Department of Medical Laboratory Science, Faculty of Allied Medical Sciences, Iran University of Medical Sciences, Tehran, Iran
Keywords: Bone repair, Bone tissue engineering, Macrophage polarization, Osteogenesis


Innate immune cells play a crucial role in bone development and repair. Macrophages are the main effector cells in immune responses to implants and are indispensable for bone healing success. The heterogeneity and plasticity of macrophages make them a prime target for immune system modulation to enhance bone repair and regeneration. It is believed that the polarization of macrophage phenotype towards the anti-inflammatory M2, rather than the inflammatory M1 phenotype, promotes osteogenesis. Tissue-engineered bioimplants are potentially capable of producing signals to modulate macrophage polarization. Therefore, development of smart immunomodulatory bioimplants via manipulation of their properties seem a promising strategy for tuning immune responses to optimize bone repair without any unwanted inflammatory reactions. The purpose of the present review is to summarize the currently available studies performed on the effects of macrophage polarization, especially towards M2 phenotype, both in bone repair and in bioimplant-stimulated osteogenesis. Moreover, this literature highlights the need to focus future studies on the development of smart immunomodulatory implants capable of switching macrophage polarization-enhancing bone implant-host tissue integration.


1. Bartneck M, Heffels K-H, Pan Y, Bovi M, Zwadlo-Klarwasser G, Groll J. Inducing healing-like human primary macrophage phenotypes by 3D hydrogel coated nanofibres. Biomaterials 2012; 33(16):4136-46.
2. Ogle ME, Segar CE, Sridhar S, Botchwey EA. Monocytes and macrophages in tissue repair: Implications for immunoregenerative biomaterial design. Exp Biol Med 2016; 241(10):1084-97.
3. Das TP, Suman S, Damodaran C. Induction of reactive oxygen species generation inhibits epithelial–mesenchymal transition and promotes growth arrest in prostate cancer cells. Mol Carcinog 2014; 53(7):537-47.
4. Brown BN, Ratner BD, Goodman SB, Amar S, Badylak SF. Macrophage polarization: an opportunity for improved outcomes in biomaterials and regenerative medicine. Biomaterials 2012; 33(15):3792-802.
5. Martinez FO, Sica A, Mantovani A, Locati M. Macrophage activation and polarization. Front Biosci 2008; 13(15):453-61.
6. Mantovani A, Sozzani S, Locati M, Allavena P, Sica A. Macrophage polarization: tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes. Trends Immunol 2002; 23(11):549-55.
7. Mills CD, Kincaid K, Alt JM, Heilman MJ, Hill AM. M-1/M-2 macrophages and the Th1/Th2 paradigm. J Immunol 2000; 164(12):6166-73.
8. Mohsenzadegan M, Fayazi MR, Abdolmaleki M, Bakhshayesh M, Seif F, Mousavizadeh K. Direct immunomodulatory influence of IFN-β on human astrocytoma cells.Immunopharmacol Immunotoxicol 2015; 37(2):214-9.
9. Das A, Ganesh K, Khanna S, Sen CK, Roy S. Engulfment of apoptotic cells by macrophages: a role of microRNA-21 in the resolution of wound inflammation. J Immunol 2014; 192(3):1120-9.
10. Das A, Sinha M, Datta S, Abas M, Chaffee S, Sen CK, et al. Monocyte and macrophage plasticity in tissue repair and regeneration. Am J Pathol 2015; 185(10):2596-606.
11. Jafarnezhad-Ansariha F, Yekaninejad MS, Jamshidi A-r, Mansouri R, Vojdanian M, Mahmoudi M, et al. The effects of β-d-mannuronic acid (M2000), as a novel NSAID, on COX1 and COX2 activities and gene expression in ankylosing spondylitis patients and the murine monocyte/macrophage, J774 cell line. Inflammopharmacology 2017:1-10.
12. Gordon S, Taylor PR. Monocyte and macrophage heterogeneity. Nat Rev Immunol 2005; 5(12):953-64.
13. Ovchinnikov DA. Macrophages in the embryo and beyond: much more than just giant phagocytes. Genesis 2008; 46(9):447-62.
14. Yona S, Kim K-W, Wolf Y, Mildner A, Varol D, Breker M, et al. Fate mapping reveals origins and dynamics of monocytes and tissue macrophages under homeostasis. Immunity 2013; 38(1):79-91.
15. Raggatt LJ, Wullschleger ME, Alexander KA, Wu AC, Millard SM, Kaur S, et al. Fracture healing via periosteal callus formation requires macrophages for both initiation and progression of early endochondral ossification. Am J Pathol 2014; 184(12):3192-204.
16. Cho SW, Soki FN, Koh AJ, Eber MR, Entezami P, Park SI, et al. Osteal macrophages support physiologic skeletal remodeling and anabolic actions of parathyroid hormone in bone. Proc Natl Acad Sci U S A 2014; 111(4):1545-50.
17. Miron RJ, Zohdi H, Fujioka-Kobayashi M, Bosshardt DD. Giant cells around bone biomaterials: Osteoclasts or multi-nucleated giant cells? Acta Biomater 2016; 46:15-28.
18. Chang MK, Raggatt L-J, Alexander KA, Kuliwaba JS, Fazzalari NL, Schroder K, et al. Osteal tissue macrophages are intercalated throughout human and mouse bone lining tissues and regulate osteoblast function in vitro and in vivo. J Immunol 2008; 181(2):1232-44.
19. Winkler IG, Sims NA, Pettit AR, Barbier V, Nowlan B, Helwani F, et al. Bone marrow macrophages maintain hematopoietic stem cell (HSC) niches and their depletion mobilizes HSCs. Blood 2010; 116(23):4815-28.
20. Kaur S, Raggatt LJ, Batoon L, Hume DA, Levesque J-P, Pettit AR, editors. Role of bone marrow macrophages in controlling homeostasis and repair in bone and bone marrow niches. Semin Cell Dev Biol 2017; 61:12-21.
21. Murray PJ. Macrophage polarization. Annu Rev Physiol 2017; 79:541-66.
22. Mosser DM. The many faces of macrophage activation. J Leukoc Biol 2003; 73(2):209-12.
23. Genin M, Clement F, Fattaccioli A, Raes M, Michiels C. M1 and M2 macrophages derived from THP-1 cells differentially modulate the response of cancer cells to etoposide. BMC cancer 2015; 15(1):577.
24. Mosser DM, Edwards JP. Exploring the full spectrum of macrophage activation. Nat Rev Immunol 2008; 8(12):958-69.
25. Guihard P, Danger Y, Brounais B, David E, Brion R, Delecrin J, et al. Induction of osteogenesis in mesenchymal stem cells by activated monocytes/macrophages depends on oncostatin M signaling. Stem cells 2012; 30(4):762-72.
26. Woo SR, Corrales L, Gajewski TF. Innate immune recognition of cancer. Annu Rev Immunol 2015; 33:445-74
27. Martinez FO, Helming L, Gordon S. Alternative activation of macrophages: an immunologic functional perspective. Annu Rev Immunol 2009; 27:451-83.
28. Fard NA, Tabrizian N, Mirzaei R, Hadjati J, Zavareh FT, Nodeh ARS, et al. Efficacy and Safety of G2013 as a Novel Immunosuppressive Agent on Differentiation, Maturation and Function of Human Dendritic Cells. Iran J Public Health 2017; 46(2):216-221.
29. Champagne C, Takebe J, Offenbacher S, Cooper L. Macrophage cell lines produce osteoinductive signals that include bone morphogenetic protein-2. Bone 2002; 30(1):26-31.
30. Assoian RK, Fleurdelys BE, Stevenson HC, Miller PJ, Madtes DK, Raines EW, et al. Expression and secretion of type beta transforming growth factor by activated human macrophages. Proc Natl Acad Sci U S A 1987; 84(17):6020-4.
31. Takahashi F, Takahashi K, Shimizu K, Cui R, Tada N, Takahashi H, et al. Osteopontin is strongly expressed by alveolar macrophages in the lungs of acute respiratory distress syndrome. Lung. 2004; 182(3):173-85.
32. Kreutz M, Andreesen R, Krause SW, Szabo A, Ritz E, Reichel H. 1, 25-dihydroxyvitamin D3 production and vitamin D3 receptor expression are developmentally regulated during differentiation of human monocytes into macrophages. Blood 1993; 82(4):1300-7.
33. Rőszer T. Understanding the mysterious M2 macrophage through activation markers and effector mechanisms. Mediators Inflamm 2015; 2015:816460.
34. Knipper JA, Willenborg S, Brinckmann J, Bloch W, Maaß T, Wagener R, et al. Interleukin-4 receptor α signaling in myeloid cells controls collagen fibril assembly in skin repair. Immunity 2015; 43(4):803-16.
35. Jetten N, Verbruggen S, Gijbels MJ, Post MJ, De Winther MP, Donners MM. Anti-inflammatory M2, but not pro-inflammatory M1 macrophages promote angiogenesis in vivo. Angiogenesis 2014; 17(1):109-18.
36. Murray PJ, Allen JE, Biswas SK, Fisher EA, Gilroy DW, Goerdt S, et al. Macrophage activation and polarization: nomenclature and experimental guidelines. Immunity 2014; 41(1):14-20.
37. Wang Q, Ni H, Lan L, Wei X, Xiang R, Wang Y. Fra-1 protooncogene regulates IL-6 expression in macrophages and promotes the generation of M2d macrophages. Cell Res 2010; 20(6):701-12.
38. Ferrante CJ, Pinhal-Enfield G, Elson G, Cronstein BN, Hasko G, Outram S, et al. The adenosine-dependent angiogenic switch of macrophages to an M2-like phenotype is independent of interleukin-4 receptor alpha (IL-4Rα) signaling. Inflammation 2013; 36(4):921-31.
39. Sridharan R, Cameron AR, Kelly DJ, Kearney CJ, O’Brien FJ. Biomaterial based modulation of macrophage polarization: a review and suggested design principles. Materials Today. 2015;18(6):313-25.
40. Schindeler A, McDonald MM, Bokko P, Little DG, editors. Bone remodeling during fracture repair:
The cellular picture. Semin Cell Dev Biol 2008; 19(5):459-66.
41. Ren PG, Huang Z, Ma T, Biswal S, Smith RL, Goodman SB. Surveillance of systemic trafficking of macrophages induced by UHMWPE particles in nude mice by noninvasive imaging. J Biomed Mater Res A 2010; 94(3):706-11.
42. Sinder BP, Pettit AR, McCauley LK. Macrophages: their emerging roles in bone. J Bone Miner Res 2015; 30(12):2140-9.
43. Xing Z, Lu C, Hu D, Yu Y-y, Wang X, Colnot C, et al. Multiple roles for CCR2 during fracture healing. Dis Model Mech 2010; 3(7-8):451-8.
44. Valladares RD, Nich C, Zwingenberger S, Li C, Swank KR, Gibon E, et al. Toll‐like receptors‐2 and 4 are overexpressed in an experimental model of particle‐induced osteolysis. J Biomedical Materials Research Part A 2014; 102(9):3004-11.
45. Rao AJ, Gibon E, Ma T, Yao Z, Smith RL, Goodman SB. Revision joint replacement, wear particles, and macrophage polarization. Acta Acta Biomater 2012; 8(7):2815-23.
46. Gerstenfeld L, Cho T-J, Kon T, Aizawa T, Cruceta J, Graves B, et al. Impaired intramembranous bone formation during bone repair in the absence of tumor necrosis factor-alpha signaling. Cells Tissues Organs 2001; 169(3):285-94.
47. Gibon E, Lu L, Goodman SB. Aging, inflammation, stem cells, and bone healing. Stem Cell Res Ther 2016; 7(1):44.
48. Einhorn TA, Majeska RJ, Rush EB, Levine PM, Horowitz MC. The expression of cytokine activity by fracture callus. J Bone Miner Res 1995; 10(8):1272-81.
49. Guihard P, Boutet M-A, Brounais-Le Royer B, Gamblin A-L, Amiaud J, Renaud A, et al. Oncostatin m, an inflammatory cytokine produced by macrophages, supports intramembranous bone healing in a mouse model of tibia injury. Am J Pathol 2015; 185(3):765-75.
50. Gordon S. Alternative activation of macrophages. Nat Rev Immunol 2003; 3(1):23-35.
51. Song E, Ouyang N, Hörbelt M, Antus B, Wang M, Exton MS. Influence of alternatively and classically activated macrophages on fibrogenic activities of human fibroblasts. Cell immunol 2000; 204(1):19-28.
52. Maresz K, Ponomarev ED, Barteneva N, Tan Y, Mann MK, Dittel BN. IL-13 induces the expression of the alternative activation marker Ym1 in a subset of testicular macrophages. J Reprod Immunol 2008; 78(2):140-8.
53. Muller PA, Koscsó B, Rajani GM, Stevanovic K, Berres M-L, Hashimoto D, et al. Crosstalk between muscularis macrophages and enteric neurons regulates gastrointestinal motility. Cell 2014; 158(2):300-13.
54. Kan L, Liu Y, McGuire TL, Berger DMP, Awatramani RB, Dymecki SM, et al. Dysregulation of local stem/progenitor cells as a common cellular mechanism for heterotopic ossification. Stem cells 2009; 27(1):150-6.
55. Benoit M, Desnues B, Mege J-L. Macrophage polarization in bacterial infections. J Immunol 2008; 181(6):3733-9.
56. Hamilton JA, Tak PP. The dynamics of macrophage lineage populations in inflammatory and autoimmune diseases. Arthritis Rheum 2009; 60(5):1210-21.
57. Wu X, Xu W, Feng X, He Y, Liu X, Gao Y, et al. TNF-a mediated inflammatory macrophage polarization contributes to the pathogenesis of steroid-induced osteonecrosis in mice. Int J Immunopathol Pharmacol 2015; 28(3):351-61.
58. Jamalpoor Z, Mirzadeh H, Joghataei MT, Zeini D, Bagheri‐Khoulenjani S, Nourani MR. Fabrication of cancellous biomimetic chitosan‐based nanocomposite scaffolds applying a combinational method for bone tissue engineering. J Biomed Mater Res A 2015; 103(5):1882-92.
59. Jamalpoor Z, Ebrahimi M, Amirizadeh N, Mansoori K, Asgari A, Nourani M. Fibrin sealant as scaffold can be a suitable substitute to autograft in short peripheral nerve defect in rats. J Dev Biol Tissue Eng 2011; 3(6):75-9.
60. Pati F, Song TH, Rijal G, Jang J, Kim SW, Cho DW. Ornamenting 3D printed scaffolds with cell-laid extracellular matrix for bone tissue regeneration. Biomaterials 2015; 37:230-41.
61. Karimpour Malekshah A, Talebpour Amiri F, Ghaffari E, Alizadeh A, Jamalpoor Z, Mirhosseini M, et al. Growth and chondrogenic differentiation of mesenchymal stem cells derived from human adipose tissue on chitosan scaffolds. J Babol Uni Med Sci 2016; 18(9):32-8.
62. Bose S, Roy M, Bandyopadhyay A. Recent advances in bone tissue engineering scaffolds. Trends Biotechnol 2012; 30(10):546-54.
63. Anderson JM, Rodriguez A, Chang DT, editors. Foreign body reaction to biomaterials. Semin Immunol 2008; 20(2):86-100.
64. Lee C-H, Kim Y-J, Jang J-H, Park J-W. Modulating macrophage polarization with divalent cations in nanostructured titanium implant surfaces. Nanotechnology. 2016; 27(8):085101.
65. Staiger MP, Pietak AM, Huadmai J, Dias G. Magnesium and its alloys as orthopedic biomaterials: a review. Biomaterials 2006; 27(9):1728-34.
66. Chen Z, Mao X, Tan L, Friis T, Wu C, Crawford R, et al. Osteoimmunomodulatory properties of magnesium scaffolds coated with β-tricalcium phosphate. Biomaterials 2014; 35(30):8553-65.
67. Barth KA, Waterfield JD, Brunette DM. The effect of surface roughness on RAW 264.7 macrophage phenotype. J Biomed Mater Res A 2013; 101(9):2679-88.
68. Horwood NJ. Macrophage polarization and bone formation: a review. Clin Rev Allergy Immunol 2016; 51(1):79-86.
69. Gong L, Zhao Y, Zhang Y, Ruan Z. The macrophage polarization regulates MSC osteoblast differentiation in vitro. Ann Clin Lab Sci 2016; 46(1):65-71.
70. Nicolaidou V, Wong MM, Redpath AN, Ersek A, Baban DF, Williams LM, et al. Monocytes induce STAT3 activation in human mesenchymal stem cells to promote osteoblast formation. PloS one 2012; 7(7):e39871.
71. Mirshafiey A, Taeb M, Mortazavi-Jahromi S, Ansariha FJ, Rehm BH, Esposito E, et al. Introduction of β-D-mannuronic acid (M2000) as a novel NSAID with immunosuppressive property based on COX-1/COX-2 activity and gene expression. Pharmacol Rep 2017; 69(5):1067-72.
72. Alvarez MM, Liu JC, Trujillo-de Santiago G, Cha B-H, Vishwakarma A, Ghaemmaghami AM, et al. Delivery strategies to control inflammatory response: Modulating M1–M2 polarization in tissue engineering applications. J Control Release 2016; 240:349-63.
73. Schlundt C, El Khassawna T, Serra A, Dienelt A, Wendler S, Schell H, et al. Macrophages in bone fracture healing: their essential role in endochondral ossification. Bone 2018; 106:78-89.
74. Loi F, Córdova LA, Zhang R, Pajarinen J, Lin T-h, Goodman SB, et al. The effects of immunomodulation by macrophage subsets on osteogenesis in vitro. Stem Cell Res Ther 2016; 7(1):15.
75. Silfverswärd CJ, Larsson S, Ohlsson C, Frost A, Nilsson O. Reduced cortical bone mass in mice with inactivation of interleukin‐4 and interleukin‐13. J Orthop Res 2007; 25(6):725-31.
76. Silfverswärd CJ, Sisask G, Larsson S, Ohlsson C, Frost A, Ljunggren Ö, et al. Bone formation in interleukin‐4 and interleukin‐13 depleted mice. Acta Orthop 2008; 79(3):410-20.
77. Österman T, Virtamo T, Lauren L, Kippo K, Pasanen I, Hannuniemi R, et al. Slow-release clodronate in prevention of inflammation and bone loss associated with adjuvant arthritis. J Pharmacol Exp Ther 1997; 280(2):1001-7.
78. Mirshafiey A, Mohsenzadegan M. TGF-beta as a promising option in the treatment of multiple sclerosis. Neuropharmacology 2009; 56(6-7):929-36.
How to Cite
Jamalpoor Z, Asgari A, Lashkari MH, Mirshafiey A, Mohsenzadegan M. Modulation of Macrophage Polarization for Bone Tissue Engineering Applications. ijaai. 17(5):398-0.
Review Article(s)