Skip to main content
SpringerLink
Log in

Macrophages: The Bad, the Ugly, and the Good in the Inflammatory Response to Biomaterials

  • Chapter
  • First Online:
The Immune Response to Implanted Materials and Devices

Abstract

Macrophages play a central role in guiding proper organ and tissue development, physiological healing, and in maintaining tissue homeostasis. Further, they are one of the major cell components of the inflammatory response. During healing, macrophages assume a temporal series of distinct phenotypes that guide tissue repair and restoration of tissue homeostasis. Macrophages then decline and the restored tissue is macrophage free. Dysfunction or imbalance in macrophage phenotypes results in compromised healing that is thought to be the root cause of inflammatory diseases. Implanted biomedical devices elicit a robust inflammatory response driven largely by dysfunctional macrophages, which show a significant shift in their physiological behavior. They do not progress through the temporal series of phenotypes and do not decline with time, rather remain with the biomedical device for the life of it (the bad). At the host-device interface macrophages fuse to create large cells, foreign body giant cells. These giant cells are believed to damage the biomedical device at a structural and functional level (the ugly). Significant effort has been put forward to understand the processes leading to the dysfunctional macrophage response to biomedical devices, as well as to design novel approaches to guide the macrophages through the temporal series of phenotypes of physiological healing (the good). In this chapter, the current understanding of the developmental origin of macrophages, their functions in physiological processes, and dysfunction in response to the foreign body will be presented and discussed, as well as approaches to guide them toward resolution of the foreign body-elicited inflammatory response.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Thomas G, Tacke R, Hedrick CC et al (2015) Nonclassical patrolling monocyte function in the vasculature. Arterioscler Thromb Vasc Biol 35(6):1306–1316

    Article  Google Scholar 

  2. McGrath KE, Palis J (2005) Hematopoiesis in the yolk sac: more than meets the eye. Exp Hematol 33(9):1021–1028

    Article  Google Scholar 

  3. McGrath KE, Frame JM, Fegan KH et al (2015) Distinct sources of hematopoietic progenitors emerge before HSCs and provide functional blood cells in the mammalian embryo. Cell Rep 11(12):1892–1904

    Article  Google Scholar 

  4. McGrath KE, Frame JM, Palis J (2016) Early hematopoiesis and macrophage development. Semin Immunol 27(6):379–387

    Article  Google Scholar 

  5. Miyamoto T (2011) Regulators of osteoclast differentiation and cell-cell fusion. Keio J Med 60(4):101–105

    Article  Google Scholar 

  6. Watowich SS, Liu YJ (2010) Mechanisms regulating dendritic cell specification and development. Immunol Rev 238(1):76–92

    Article  Google Scholar 

  7. Jacome-Galarza CE, Lee SK, Lorenzo JA et al (2013) Identification, characterization, and isolation of a common progenitor for osteoclasts, macrophages, and dendritic cells from murine bone marrow and periphery. J Bone Miner Res 28(5):1203–1213

    Article  Google Scholar 

  8. Ginhoux F, Guilliams M (2016) Tissue-resident macrophage ontogeny and homeostasis. Immunity 44(3):439–449

    Article  Google Scholar 

  9. Fogg DK, Sibon C, Miled C et al (2006) A clonogenic bone marrow progenitor specific for macrophages and dendritic cells. Science 311(5757):83–87

    Article  Google Scholar 

  10. Lee J, Breton G, Oliveira TY et al (2015) Restricted dendritic cell and monocyte progenitors in human cord blood and bone marrow. J Exp Med 212(3):385–399

    Article  Google Scholar 

  11. Xiao Y, Zijl S, Wang L et al (2015) Identification of the common origins of osteoclasts, macrophages, and dendritic cells in human hematopoiesis. Stem Cell Reports 4(6):984–994

    Article  Google Scholar 

  12. Hoeffel G, Ginhoux F (2015) Ontogeny of tissue-resident macrophages. Front Immunol 6:486

    Article  Google Scholar 

  13. Lavin Y, Mortha A, Rahman A et al (2015) Regulation of macrophage development and function in peripheral tissues. Nat Rev Immunol 15(12):731–744

    Article  Google Scholar 

  14. Cecchini MG, Hofstetter W, Halasy J et al (1997) Role of CSF-1 in bone and bone marrow development. Mol Reprod Dev 46(1):75–83, discussion 83-84

    Article  Google Scholar 

  15. Nakamichi Y, Udagawa N, Takahashi N (2013) IL-34 and CSF-1: similarities and differences. J Bone Miner Metab 31(5):486–495

    Article  Google Scholar 

  16. Niida S, Kondo T, Hiratsuka S et al (2005) VEGF receptor 1 signaling is essential for osteoclast development and bone marrow formation in colony-stimulating factor 1-deficient mice. Proc Natl Acad Sci U S A 102(39):14016–14021

    Article  Google Scholar 

  17. Dahl R, Walsh JC, Lancki D et al (2003) Regulation of macrophage and neutrophil cell fates by the PU.1:C/EBPalpha ratio and granulocyte colony-stimulating factor. Nat Immunol 4(10):1029–1036

    Article  Google Scholar 

  18. Dahl R, Simon MC (2003) The importance of PU.1 concentration in hematopoietic lineage commitment and maturation. Blood Cells Mol Dis 31(2):229–233

    Article  Google Scholar 

  19. Burda P, Laslo P, Stopka T (2010) The role of PU.1 and GATA-1 transcription factors during normal and leukemogenic hematopoiesis. Leukemia 24(7):1249–1257

    Article  Google Scholar 

  20. Nomura S, Sakuma T, Higashibata Y et al (2001) Molecular cause of the severe functional deficiency in osteoclasts by an arginine deletion in the basic domain of Mi transcription factor. J Bone Miner Metab 19(3):183–187

    Article  Google Scholar 

  21. Epelman S, Lavine KJ, Randolph GJ (2014) Origin and functions of tissue macrophages. Immunity 41(1):21–35

    Article  Google Scholar 

  22. Corliss BA, Azimi MS, Munson JM et al (2016) Macrophages: an inflammatory link between angiogenesis and lymphangiogenesis. Microcirculation 23(2):95–121

    Article  Google Scholar 

  23. Korolnek T, Hamza I (2015) Macrophages and iron trafficking at the birth and death of red cells. Blood 125(19):2893–2897

    Article  Google Scholar 

  24. Mehta NG (1976) Recognition of self and nonself, the crucial role of phagocytosis and lysosomal destruction of antigen. Med Hypotheses 2(4):141–146

    Article  Google Scholar 

  25. Billadeau DD (2008) PTEN gives neutrophils direction. Nat Immunol 9(7):716–718

    Article  Google Scholar 

  26. McDonald B, Pittman K, Menezes GB et al (2010) Intravascular danger signals guide neutrophils to sites of sterile inflammation. Science 330(6002):362–366

    Article  Google Scholar 

  27. Lawrence T, Gilroy DW (2007) Chronic inflammation: a failure of resolution? Int J Exp Pathol 88(2):85–94

    Article  Google Scholar 

  28. Mantovani A, Sica A, Locati M (2005) Macrophage polarization comes of age. Immunity 23(4):344–346

    Article  Google Scholar 

  29. MacLeod AS, Mansbridge JN (2016) The innate immune system in acute and chronic wounds. Adv Wound Care (New Rochelle) 5(2):65–78

    Article  Google Scholar 

  30. Gordon S, Martinez FO (2010) Alternative activation of macrophages: mechanism and functions. Immunity 32(5):593–604

    Article  Google Scholar 

  31. Ward C, Dransfield I, Chilvers ER et al (1999) Pharmacological manipulation of granulocyte apoptosis: potential therapeutic targets. Trends Pharmacol Sci 20(12):503–509

    Article  Google Scholar 

  32. Murray LA, Kramer MS, Hesson DP et al (2010) Serum amyloid P ameliorates radiation-induced oral mucositis and fibrosis. Fibrogenesis Tissue Repair 3:11

    Article  Google Scholar 

  33. Mackaness GB (2014) Pillars article: the immunological basis of acquired cellular resistance. J. Exp. Med. 1964. 120: 105–120. J Immunol 193:3222–3237

    Google Scholar 

  34. Knight JA (2000) Review: free radicals, antioxidants, and the immune system. Ann Clin Lab Sci 30(2):145–158

    Google Scholar 

  35. Olefsky JM, Glass CK (2010) Macrophages, inflammation, and insulin resistance. Annu Rev Physiol 72:219–246

    Article  Google Scholar 

  36. Bouhlel MA, Derudas B, Rigamonti E et al (2007) PPARgamma activation primes human monocytes into alternative M2 macrophages with anti-inflammatory properties. Cell Metab 6(2):137–143

    Article  Google Scholar 

  37. Mantovani A, Biswas SK, Galdiero MR et al (2013) Macrophage plasticity and polarization in tissue repair and remodelling. J Pathol 229(2):176–185

    Article  Google Scholar 

  38. Tugal D, Liao X, Jain MK (2013) Transcriptional control of macrophage polarization. Arterioscler Thromb Vasc Biol 33(6):1135–1144

    Article  Google Scholar 

  39. Date D, Das R, Narla G et al (2014) Kruppel-like transcription factor 6 regulates inflammatory macrophage polarization. J Biol Chem 289(15):10318–10329

    Article  Google Scholar 

  40. Sica A, Mantovani A (2012) Macrophage plasticity and polarization: in vivo veritas. J Clin Invest 122(3):787–795

    Article  Google Scholar 

  41. Guiducci C, Vicari AP, Sangaletti S et al (2005) Redirecting in vivo elicited tumor infiltrating macrophages and dendritic cells towards tumor rejection. Cancer Res 65(8):3437–3446

    Google Scholar 

  42. Saccani A, Schioppa T, Porta C et al (2006) p50 nuclear factor-kappaB overexpression in tumor-associated macrophages inhibits M1 inflammatory responses and antitumor resistance. Cancer Res 66(23):11432–11440

    Article  Google Scholar 

  43. Boehler RM, Kuo R, Shin S et al (2014) Lentivirus delivery of IL-10 to promote and sustain macrophage polarization towards an anti-inflammatory phenotype. Biotechnol Bioeng 111(6):1210–1221

    Article  Google Scholar 

  44. Anderson JM, Rodriguez A, Chang DT (2008) Foreign body reaction to biomaterials. Semin Immunol 20(2):86–100

    Article  Google Scholar 

  45. Luttikhuizen DT, Harmsen MC, Van Luyn MJ (2006) Cellular and molecular dynamics in the foreign body reaction. Tissue Eng 12(7):1955–1970

    Article  Google Scholar 

  46. Shen M, Garcia I, Maier RV et al (2004) Effects of adsorbed proteins and surface chemistry on foreign body giant cell formation, tumor necrosis factor alpha release and procoagulant activity of monocytes. J Biomed Mater Res A 70(4):533–541

    Article  Google Scholar 

  47. Kourtzelis I, Rafail S, DeAngelis RA et al (2013) Inhibition of biomaterial-induced complement activation attenuates the inflammatory host response to implantation. FASEB J 27(7):2768–2776

    Article  Google Scholar 

  48. Tang L (1998) Mechanisms of fibrinogen domains: biomaterial interactions. J Biomater Sci Polym Ed 9(12):1257–1266

    Article  Google Scholar 

  49. Jenney CR, Anderson JM (2000) Adsorbed serum proteins responsible for surface dependent human macrophage behavior. J Biomed Mater Res 49(4):435–447

    Article  Google Scholar 

  50. Brodbeck WG, Nakayama Y, Matsuda T et al (2002) Biomaterial surface chemistry dictates adherent monocyte/macrophage cytokine expression in vitro. Cytokine 18(6):311–319

    Article  Google Scholar 

  51. Patel JD, Krupka T, Anderson JM (2007) iNOS-mediated generation of reactive oxygen and nitrogen species by biomaterial-adherent neutrophils. J Biomed Mater Res A 80(2):381–390

    Article  Google Scholar 

  52. Moore LB, Sawyer AJ, Charokopos A et al (2015) Loss of monocyte chemoattractant protein-1 alters macrophage polarization and reduces NFkB activation in the foreign body response. Acta Biomater 11:37–47

    Article  Google Scholar 

  53. Moore LB, Kyriakides TR (2015) Molecular characterization of macrophage-biomaterial interactions. Adv Exp Med Biol 865:109–122

    Article  Google Scholar 

  54. Sussman EM, Halpin MC, Muster J et al (2014) Porous implants modulate healing and induce shifts in local macrophage polarization in the foreign body reaction. Ann Biomed Eng 42(7):1508–1516

    Article  Google Scholar 

  55. McNally AK, Anderson JM (2015) Phenotypic expression in human monocyte-derived interleukin-4-induced foreign body giant cells and macrophages in vitro: dependence on material surface properties. J Biomed Mater Res A 103(4):1380–1390

    Article  Google Scholar 

  56. Brodbeck WG, Anderson JM (2009) Giant cell formation and function. Curr Opin Hematol 16(1):53–57

    Article  Google Scholar 

  57. Milde R, Ritter J, Tennent GA et al (2015) Multinucleated giant cells are specialized for complement-mediated phagocytosis and large target destruction. Cell Rep 13(9):1937–1948

    Article  Google Scholar 

  58. Helming L, Gordon S (2009) Molecular mediators of macrophage fusion. Trends Cell Biol 19(10):514–522

    Article  Google Scholar 

  59. McInnes A, Rennick DM (1988) Interleukin 4 induces cultured monocytes/macrophages to form giant multinucleated cells. J Exp Med 167(2):598–611

    Article  Google Scholar 

  60. DeFife KM, Jenney CR, McNally AK et al (1997) Interleukin-13 induces human monocyte/macrophage fusion and macrophage mannose receptor expression. J Immunol 158(7):3385–3390

    Google Scholar 

  61. Helming L, Winter J, Gordon S (2009) The scavenger receptor CD36 plays a role in cytokine-induced macrophage fusion. J Cell Sci 122(Pt 4):453–459

    Article  Google Scholar 

  62. Yagi M, Miyamoto T, Sawatani Y et al (2005) DC-STAMP is essential for cell-cell fusion in osteoclasts and foreign body giant cells. J Exp Med 202(3):345–351

    Article  Google Scholar 

  63. Yagi M, Miyamoto T, Toyama Y et al (2006) Role of DC-STAMP in cellular fusion of osteoclasts and macrophage giant cells. J Bone Miner Metab 24(5):355–358

    Article  Google Scholar 

  64. Tsai AT, Rice J, Scatena M et al (2005) The role of osteopontin in foreign body giant cell formation. Biomaterials 26(29):5835–5843

    Article  Google Scholar 

  65. Sissons JR, Peschon JJ, Schmitz F et al (2012) Cutting edge: microRNA regulation of macrophage fusion into multinucleated giant cells. J Immunol 189(1):23–27

    Article  Google Scholar 

  66. Moore LB, Sawyer AJ, Saucier-Sawyer J et al (2016) Nanoparticle delivery of miR-223 to attenuate macrophage fusion. Biomaterials 89:127–135

    Article  Google Scholar 

  67. Kyriakides TR, Foster MJ, Keeney GE et al (2004) The CC chemokine ligand, CCL2/MCP1, participates in macrophage fusion and foreign body giant cell formation. Am J Pathol 165(6):2157–2166

    Article  Google Scholar 

  68. Ratner BD (2016) A pore way to heal and regenerate: 21st century thinking on biocompatibility. Regen Biomater 3(2):107–110

    Article  Google Scholar 

  69. Wynn TA (2004) Fibrotic disease and the T(H)1/T(H)2 paradigm. Nat Rev Immunol 4(8):583–594

    Article  Google Scholar 

  70. Wynn TA, Barron L (2010) Macrophages: master regulators of inflammation and fibrosis. Semin Liver Dis 30(3):245–257

    Article  Google Scholar 

  71. Wynn TA, Vannella KM (2016) Macrophages in tissue repair, regeneration, and fibrosis. Immunity 44(3):450–462

    Article  Google Scholar 

  72. Brown BN, Ratner BD, Goodman SB et al (2012) Macrophage polarization: an opportunity for improved outcomes in biomaterials and regenerative medicine. Biomaterials 33(15):3792–3802

    Article  Google Scholar 

  73. Brown BN, Badylak SF (2013) Expanded applications, shifting paradigms and an improved understanding of host-biomaterial interactions. Acta Biomater 9(2):4948–4955

    Article  Google Scholar 

  74. Alvarez MM, Liu JC, Trujillo-de Santiago G et al (2016) Delivery strategies to control inflammatory response: modulating M1-M2 polarization in tissue engineering applications. J Control Release

    Google Scholar 

  75. Boersema GS, Grotenhuis N, Bayon Y et al (2016) The effect of biomaterials used for tissue regeneration purposes on polarization of macrophages. Biores Open Access 5(1):6–14

    Article  Google Scholar 

  76. Sawada S, Sakaki S, Iwasaki Y et al (2003) Suppression of the inflammatory response from adherent cells on phospholipid polymers. J Biomed Mater Res A 64(3):411–416

    Article  Google Scholar 

  77. Zhang L, Cao Z, Bai T et al (2013) Zwitterionic hydrogels implanted in mice resist the foreign-body reaction. Nat Biotechnol 31(6):553–556

    Article  Google Scholar 

  78. Blakney AK, Swartzlander MD, Bryant SJ (2012) 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 100(6):1375–1386

    Article  Google Scholar 

  79. Ballotta V, Driessen-Mol A, Bouten CV et al (2014) Strain-dependent modulation of macrophage polarization within scaffolds. Biomaterials 35(18):4919–4928

    Article  Google Scholar 

  80. Almeida CR, Serra T, Oliveira MI et al (2014) Impact of 3-D printed PLA- and chitosan-based scaffolds on human monocyte/macrophage responses: unraveling the effect of 3-D structures on inflammation. Acta Biomater 10(2):613–622

    Article  Google Scholar 

  81. Refai AK, Textor M, Brunette DM et al (2004) Effect of titanium surface topography on macrophage activation and secretion of proinflammatory cytokines and chemokines. J Biomed Mater Res A 70(2):194–205

    Article  Google Scholar 

  82. Lee CH, Kim YJ, Jang JH et al (2016) Modulating macrophage polarization with divalent cations in nanostructured titanium implant surfaces. Nanotechnology 27(8):085101

    Article  Google Scholar 

  83. Sanders JE, Stiles CE, Hayes CL (2000) Tissue response to single-polymer fibers of varying diameters: evaluation of fibrous encapsulation and macrophage density. J Biomed Mater Res 52(1):231–237

    Article  Google Scholar 

  84. Garg K, Pullen NA, Oskeritzian CA et al (2013) Macrophage functional polarization (M1/M2) in response to varying fiber and pore dimensions of electrospun scaffolds. Biomaterials 34(18):4439–4451

    Article  Google Scholar 

  85. Garg T, Goyal AK (2014) Biomaterial-based scaffolds—current status and future directions. Expert Opin Drug Deliv 11(5):767–789

    Article  Google Scholar 

  86. Cao D, Wu YP, Fu ZF et al (2011) Cell adhesive and growth behavior on electrospun nanofibrous scaffolds by designed multifunctional composites. Colloids Surf B Biointerfaces 84(1):26–34

    Article  Google Scholar 

  87. van Putten SM, Ploeger DT, Popa ER et al (2013) Macrophage phenotypes in the collagen-induced foreign body reaction in rats. Acta Biomater 9(5):6502–6510

    Article  Google Scholar 

  88. Valentin JE, Stewart-Akers AM, Gilbert TW et al (2009) Macrophage participation in the degradation and remodeling of extracellular matrix scaffolds. Tissue Eng Part A 15(7):1687–1694

    Article  Google Scholar 

  89. Wolf MT, Dearth CL, Ranallo CA et al (2014) Macrophage polarization in response to ECM coated polypropylene mesh. Biomaterials 35(25):6838–6849

    Article  Google Scholar 

  90. Yu T, Wang W, Nassiri S et al (2016) Temporal and spatial distribution of macrophage phenotype markers in the foreign body response to glutaraldehyde-crosslinked gelatin hydrogels. J Biomater Sci Polym Ed 27(8):721–742

    Article  Google Scholar 

  91. Kumar D, Mutreja I, Keshvan PC et al (2015) Organically modified silica nanoparticles interaction with macrophage cells: assessment of cell viability on the basis of physicochemical properties. J Pharm Sci 104(11):3943–3951

    Article  Google Scholar 

  92. Spiller KL, Nassiri S, Witherel CE et al (2015) Sequential delivery of immunomodulatory cytokines to facilitate the M1-to-M2 transition of macrophages and enhance vascularization of bone scaffolds. Biomaterials 37:194–207

    Article  Google Scholar 

  93. Wu M, Hussain S, He YH et al (2001) Genetically engineered macrophages expressing IFN-gamma restore alveolar immune function in scid mice. Proc Natl Acad Sci U S A 98(25):14589–14594

    Article  Google Scholar 

  94. Griffiths L, Binley K, Iqball S et al (2000) The macrophage—a novel system to deliver gene therapy to pathological hypoxia. Gene Ther 7(3):255–262

    Article  Google Scholar 

  95. Eaton KV, Yang HL, Giachelli CM et al (2015) Engineering macrophages to control the inflammatory response and angiogenesis. Exp Cell Res 339(2):300–309

    Article  Google Scholar 

  96. Madden LR, Mortisen DJ, Sussman EM et al (2010) Proangiogenic scaffolds as functional templates for cardiac tissue engineering. Proc Natl Acad Sci U S A 107(34):15211–15216

    Article  Google Scholar 

  97. Badylak SF, Valentin JE, Ravindra AK et al (2008) Macrophage phenotype as a determinant of biologic scaffold remodeling. Tissue Eng Part A 14(11):1835–1842

    Article  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Bioengineering, University of Washington, Seattle, WA, USA

    Marta Scatena, Karen V. Eaton, Melissa F. Jackson, Susan A. Lund & Cecilia M. Giachelli

Authors
  1. Marta Scatena
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Karen V. Eaton
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Melissa F. Jackson
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Susan A. Lund
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Cecilia M. Giachelli
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Cecilia M. Giachelli .

Editor information

Editors and Affiliations

  1. Department of Life and Environmental Sciences, Marche Polytechnic University, Ancona, Italy

    Bruna Corradetti

Rights and permissions

Reprints and permissions

Copyright information

© 2017 Springer International Publishing Switzerland

About this chapter

Cite this chapter

Scatena, M., Eaton, K.V., Jackson, M.F., Lund, S.A., Giachelli, C.M. (2017). Macrophages: The Bad, the Ugly, and the Good in the Inflammatory Response to Biomaterials. In: Corradetti, B. (eds) The Immune Response to Implanted Materials and Devices. Springer, Cham. https://doi.org/10.1007/978-3-319-45433-7_3

Download citation

Publish with us

Policies and ethics

Search

Navigation