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Manipulation of Macrophages to Enhance Bone Repair and Regeneration

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A Tissue Regeneration Approach to Bone and Cartilage Repair

Part of the book series: Mechanical Engineering Series ((MES))

Abstract

Bone is a unique tissue in that it has the ability to heal itself perfectly, without scarring, under certain conditions. Therapeutic strategies that harness its powerful repair processes have the potential to successfully regenerate bone tissue in large defects, which remain a significant clinical challenge. However, despite the demonstrated importance of the inflammatory response in dictating the success or failure of implanted biomaterials, it is not often considered as an important criterion in the design of tissue engineering scaffolds. This chapter first highlights the role of macrophages in orchestrating the delicate balance between bone formation and resorption. Then, the main strategies that have been explored to actively control the inflammatory response are discussed, including delivery of mesenchymal stem cells, controlled release of immunomodulatory cytokines, and topographical modification of biomaterial scaffolds. Increased understanding of macrophage phenotypes (M1, various M2’s, osteoclasts, etc.) will allow us to design therapeutic strategies that tip the balance toward healthy bone regeneration and away from pathologic bone loss.

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References

  • Alexander KA, Chang MK, Maylin ER, Kohler T, Muller R, Wu AC et al (2011) Osteal macrophages promote in vivo intramembranous bone healing in a mouse tibial injury model. J Bone Miner Res 26(7):1517–1532

    Google Scholar 

  • Alfarsi MA, Hamlet SM, Ivanovski S (2013) Titanium surface hydrophilicity modulates the human macrophage inflammatory cytokine response. J Biomed Mater Res A 102:60–67

    Google Scholar 

  • Ambarus CA, Krausz S, van Eijk M, Hamann J, Radstake TR, Reedquist KA et al (2012) Systematic validation of specific phenotypic markers for in vitro polarized human macrophages. J Immunol Methods 375(1–2):196–206

    Google Scholar 

  • Andersen TL, Sondergaard TE, Skorzynska KE, Dagnaes-Hansen F, Plesner TL, Hauge EM et al (2009) A physical mechanism for coupling bone resorption and formation in adult human bone. Am J Pathol 174(1):239–247

    Google Scholar 

  • Antonios JK, Yao Z, Li C, Rao AJ, Goodman SB (2013) Macrophage polarization in response to wear particles in vitro. Cell Mol Immunol 10(6):471–482

    Google Scholar 

  • Arnold L, Henry A, Poron F, Baba-Amer Y, van Rooijen N, Plonquet A et al (2007) Inflammatory monocytes recruited after skeletal muscle injury switch into antiinflammatory macrophages to support myogenesis. J Exp Med 204(5):1057–1069

    Google Scholar 

  • Awojoodu AO, Ogle ME, Sefcik LS, Bowers DT, Martin K, Brayman KL et al (2013) Sphingosine 1-phosphate receptor 3 regulates recruitment of anti-inflammatory monocytes to microvessels during implant arteriogenesis. Proc Natl Acad Sci USA 110(34):13785–13790

    Google Scholar 

  • Badylak SF, Valentin JE, Ravindra AK, McCabe GP, Stewart-Akers AM (2008) Macrophage phenotype as a determinant of biologic scaffold remodeling. Tissue Eng Part A 14(11):1835–1842

    Google Scholar 

  • Barth KA, Waterfield JD, Brunette DM (2013) The effect of surface roughness on RAW 264.7 macrophage phenotype. J Biomed Mater Res A 101(9):2679–2688

    Google Scholar 

  • Bartneck M, Keul HA, Singh S, Czaja K, Bornemann J, Bockstaller M et al (2010) Rapid uptake of gold nanorods by primary human blood phagocytes and immunomodulatory effects of surface chemistry. ACS Nano 4(6):3073–3086

    Google Scholar 

  • Bartneck M, Heffels KH, Pan Y, Bovi M, Zwadlo-Klarwasser G, Groll J (2012) Inducing healing-like human primary macrophage phenotypes by 3D hydrogel coated nanofibres. Biomaterials 33(16):4136–4146

    Google Scholar 

  • Becker L, Liu NC, Averill MM, Yuan W, Pamir N, Peng Y et al (2012) Unique proteomic signatures distinguish macrophages and dendritic cells. PLoS One 7(3):e33297

    Google Scholar 

  • Betz RR (2002) Limitations of autograft and allograft: new synthetic solutions. Orthopedics 25(5 Suppl):s561–s570

    Google Scholar 

  • 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

    Google Scholar 

  • Bocker W, Docheva D, Prall WC, Egea V, Pappou E, Rossmann O et al (2008) IKK-2 is required for TNF-alpha-induced invasion and proliferation of human mesenchymal stem cells. J Mol Med (Berl) 86(10):1183–1192

    Google Scholar 

  • Bota PC, Collie AM, Puolakkainen P, Vernon RB, Sage EH, Ratner BD et al (2010) Biomaterial topography alters healing in vivo and monocyte/macrophage activation in vitro. J Biomed Mater Res A 95(2):649–657

    Google Scholar 

  • Brown BN, Valentin JE, Stewart-Akers AM, McCabe GP, Badylak SF (2009) Macrophage phenotype and remodeling outcomes in response to biologic scaffolds with and without a cellular component. Biomaterials 30(8):1482–1491

    Google Scholar 

  • Brown BN, Londono R, Tottey S, Zhang L, Kukla KA, Wolf MT et al (2012) Macrophage phenotype as a predictor of constructive remodeling following the implantation of biologically derived surgical mesh materials. Acta Biomater 8(3):978–987

    Google Scholar 

  • Carano RA, Filvaroff EH (2003) Angiogenesis and bone repair. Drug Discov Today 8(21):980–989

    Google Scholar 

  • Cenci S, Weitzmann MN, Roggia C, Namba N, Novack D, Woodring J et al (2000) Estrogen deficiency induces bone loss by enhancing T-cell production of TNF-alpha. J Clin Invest 106(10):1229–1237

    Google Scholar 

  • Champagne CM, Takebe J, Offenbacher S, Cooper LF (2002) Macrophage cell lines produce osteoinductive signals that include bone morphogenetic protein-2. Bone 30(1):26–31

    Google Scholar 

  • Chang MK, Raggatt LJ, Alexander KA, Kuliwaba JS, Fazzalari NL, Schroder K et al (2008) Osteal tissue macrophages are intercalated throughout human and mouse bone lining tissues and regulate osteoblast function in vitro and in vivo. J Immunol 181(2):1232–1244

    Google Scholar 

  • Chehroudi B, Ghrebi S, Murakami H, Waterfield JD, Owen G, Brunette DM (2010) Bone formation on rough, but not polished, subcutaneously implanted Ti surfaces is preceded by macrophage accumulation. J Biomed Mater Res A 93(2):724–737

    Google Scholar 

  • Chen S, Jones JA, Xu Y, Low HY, Anderson JM, Leong KW (2010) Characterization of topographical effects on macrophage behavior in a foreign body response model. Biomaterials 31(13):3479–3491

    Google Scholar 

  • Chen Z, Wu C, Gu W, Klein T, Crawford R, Xiao Y (2014) Osteogenic differentiation of bone marrow MSCs by beta-tricalcium phosphate stimulating macrophages via BMP2 signalling pathway. Biomaterials 35(5):1507–1518

    Google Scholar 

  • Das A, Segar CE, Hughley BB, Bowers DT, Botchwey EA (2013a) The promotion of mandibular defect healing by the targeting of S1P receptors and the recruitment of alternatively activated macrophages. Biomaterials 34(38):9853–9862

    Google Scholar 

  • Das A, Tanner S, Barker DA, Green D, Botchwey EA (2013b) Delivery of S1P receptor-targeted drugs via biodegradable polymer scaffolds enhances bone regeneration in a critical size cranial defect. J Biomed Mater Res A 102:1210–1218

    Google Scholar 

  • Dayan V, Yannarelli G, Billia F, Filomeno P, Wang XH, Davies JE et al (2011) Mesenchymal stromal cells mediate a switch to alternatively activated monocytes/macrophages after acute myocardial infarction. Basic Res Cardiol 106(6):1299–1310

    Google Scholar 

  • Edwards JP, Zhang X, Frauwirth KA, Mosser DM (2006) Biochemical and functional characterization of three activated macrophage populations. J Leukoc Biol 80(6):1298–1307

    Google Scholar 

  • Eslami B, Zhou S, Van Eekeren I, LeBoff MS, Glowacki J (2011) Reduced osteoclastogenesis and RANKL expression in marrow from women taking alendronate. Calcif Tissue Int 88(4):272–280

    Google Scholar 

  • Fantin A, Vieira JM, Gestri G, Denti L, Schwarz Q, Prykhozhij S et al (2010) Tissue macrophages act as cellular chaperones for vascular anastomosis downstream of VEGF-mediated endothelial tip cell induction. Blood 116(5):829–840

    Google Scholar 

  • Gallo J, Goodman SB, Konttinen YT, Wimmer MA, Holinka M (2013) Osteolysis around total knee arthroplasty: a review of pathogenetic mechanisms. Acta Biomater 9(9):8046–8058

    Google Scholar 

  • Ghrebi S, Hamilton DW, Douglas Waterfield J, Brunette DM (2013) The effect of surface topography on cell shape and early ERK1/2 signaling in macrophages; linkage with FAK and Src. J Biomed Mater Res A 101(7):2118–2128

    Google Scholar 

  • Glass GE, Chan JK, Freidin A, Feldmann M, Horwood NJ, Nanchahal J (2011) TNF-alpha promotes fracture repair by augmenting the recruitment and differentiation of muscle-derived stromal cells. Proc Natl Acad Sci USA 108(4):1585–1590

    Google Scholar 

  • Gleissner CA (2012) Macrophage Phenotype Modulation by CXCL4 in Atherosclerosis. Front Physiol 3:1

    MathSciNet  Google Scholar 

  • Green TR, Fisher J, Matthews JB, Stone MH, Ingham E (2000) Effect of size and dose on bone resorption activity of macrophages by in vitro clinically relevant ultra high molecular weight polyethylene particles. J Biomed Mater Res 53(5):490–497

    Google Scholar 

  • Grundnes O, Reikeras O (1993) The importance of the hematoma for fracture healing in rats. Acta Orthop Scand 64(3):340–342

    Google Scholar 

  • Guihard P, Danger Y, Brounais B, David E, Brion R, Delecrin J et al (2012) Induction of osteogenesis in mesenchymal stem cells by activated monocytes/macrophages depends on oncostatin M signaling. Stem Cells 30(4):762–772

    Google Scholar 

  • Hamlet S, Ivanovski S (2011) Inflammatory cytokine response to titanium chemical composition and nanoscale calcium phosphate surface modification. Acta Biomater 7(5):2345–2353

    Google Scholar 

  • Hamlet S, Alfarsi M, George R, Ivanovski S (2012) The effect of hydrophilic titanium surface modification on macrophage inflammatory cytokine gene expression. Clin Oral Implants Res 23(5):584–590

    Google Scholar 

  • Hatton A, Nevelos JE, Matthews JB, Fisher J, Ingham E (2003) Effects of clinically relevant alumina ceramic wear particles on TNF-alpha production by human peripheral blood mononuclear phagocytes. Biomaterials 24(7):1193–1204

    Google Scholar 

  • Hausman MR, Rinker BD (2004) Intractable wounds and infections: the role of impaired vascularity and advanced surgical methods for treatment. Am J Surg 187(5A):44S–55S

    Google Scholar 

  • Hirose N, Maeda H, Yamamoto M, Hayashi Y, Lee GH, Chen L et al (2008) The local injection of peritoneal macrophages induces neovascularization in rat ischemic hind limb muscles. Cell Transplant 17(1–2):211–222

    Google Scholar 

  • Hisatome T, Yasunaga Y, Yanada S, Tabata Y, Ikada Y, Ochi M (2005) Neovascularization and bone regeneration by implantation of autologous bone marrow mononuclear cells. Biomaterials 26(22):4550–4556

    Google Scholar 

  • Hofkens W, Schelbergen R, Storm G, van den Berg WB, van Lent PL (2013) Liposomal targeting of prednisolone phosphate to synovial lining macrophages during experimental arthritis inhibits M1 activation but does not favor M2 differentiation. PLoS One 8(2):e54016

    Google Scholar 

  • Ingham E, Fisher J (2005) The role of macrophages in osteolysis of total joint replacement. Biomaterials 26(11):1271–1286

    Google Scholar 

  • Jung M, Sola A, Hughes J, Kluth DC, Vinuesa E, Vinas JL et al (2012) Infusion of IL-10-expressing cells protects against renal ischemia through induction of lipocalin-2. Kidney Int 81(10):969–982

    Google Scholar 

  • Kaigler D, Pagni G, Park CH, Braun TM, Holman LA, Yi E et al (2013) Stem cell therapy for craniofacial bone regeneration: a randomized, controlled feasibility trial. Cell Transplant 22(5):767–777

    Google Scholar 

  • Kaneko M, Tomita T, Nakase T, Ohsawa Y, Seki H, Takeuchi E et al (2001) Expression of proteinases and inflammatory cytokines in subchondral bone regions in the destructive joint of rheumatoid arthritis. Rheumatology (Oxford) 40(3):247–255

    Google Scholar 

  • Kaplan JM, Youd ME, Lodie TA (2011) Immunomodulatory activity of mesenchymal stem cells. Curr Stem Cell Res Ther 6(4):297–316

    Google Scholar 

  • Khallou-Laschet J, Varthaman A, Fornasa G, Compain C, Gaston AT, Clement M et al (2010) Macrophage plasticity in experimental atherosclerosis. PLoS One 5(1):e8852

    Google Scholar 

  • Kigerl KA, Gensel JC, Ankeny DP, Alexander JK, Donnelly DJ, Popovich PG (2009) Identification of two distinct macrophage subsets with divergent effects causing either neurotoxicity or regeneration in the injured mouse spinal cord. J Neurosci 29(43):13435–13444

    Google Scholar 

  • Kim J, Hematti P (2009) Mesenchymal stem cell-educated macrophages: a novel type of alternatively activated macrophages. Exp Hematol 37(12):1445–1453

    Google Scholar 

  • Kim YH, Furuya H, Tabata Y (2014) Enhancement of bone regeneration by dual release of a macrophage recruitment agent and platelet-rich plasma from gelatin hydrogels. Biomaterials 35(1):214–224

    Google Scholar 

  • Kobayashi K, Takahashi N, Jimi E, Udagawa N, Takami M, Kotake S et al (2000) Tumor necrosis factor alpha stimulates osteoclast differentiation by a mechanism independent of the ODF/RANKL-RANK interaction. J Exp Med 191(2):275–286

    Google Scholar 

  • Krishnamoorthy L (2006) The role of macrophages in human wound healing and their response to a tissue engineered dermal replacement in human chronic wounds. MD thesis, University of Glasgow

    Google Scholar 

  • Lamers E, Walboomers XF, Domanski M, Prodanov L, Melis J, Luttge R et al (2012) In vitro and in vivo evaluation of the inflammatory response to nanoscale grooved substrates. Nanomedicine 8(3):308–317

    Google Scholar 

  • Leidi M, Gotti E, Bologna L, Miranda E, Rimoldi M, Sica A et al (2009) M2 macrophages phagocytose rituximab-opsonized leukemic targets more efficiently than m1 cells in vitro. J Immunol 182(7):4415–4422

    Google Scholar 

  • Loftus EV Jr, Crowson CS, Sandborn WJ, Tremaine WJ, O’Fallon WM, Melton LJ 3rd (2002) Long-term fracture risk in patients with Crohn’s disease: a population-based study in Olmsted County. Minn Gastroenterol 123(2):468–475

    Google Scholar 

  • Lolmede K, Campana L, Vezzoli M, Bosurgi L, Tonlorenzi R, Clementi E et al (2009) Inflammatory and alternatively activated human macrophages attract vessel-associated stem cells, relying on separate HMGB1- and MMP-9-dependent pathways. J Leukoc Biol 85(5):779–787

    Google Scholar 

  • Lu Z, Wang G, Dunstan CR, Chen Y, Lu WY, Davies B et al (2013a) Activation and promotion of adipose stem cells by tumour necrosis factor-alpha preconditioning for bone regeneration. J Cell Physiol 228(8):1737–1744

    Google Scholar 

  • Lu J, Cao Q, Zheng D, Sun Y, Wang C, Yu X et al (2013b) Discrete functions of M2a and M2c macrophage subsets determine their relative efficacy in treating chronic kidney disease. Kidney Int 84(4):745–755

    Google Scholar 

  • Lyons FG, Al-Munajjed AA, Kieran SM, Toner ME, Murphy CM, Duffy GP et al (2010) The healing of bony defects by cell-free collagen-based scaffolds compared to stem cell-seeded tissue engineered constructs. Biomaterials 31(35):9232–9243

    Google Scholar 

  • Madden LR, Mortisen DJ, Sussman EM, Dupras SK, Fugate JA, Cuy JL et al (2010) Proangiogenic scaffolds as functional templates for cardiac tissue engineering. Proc Natl Acad Sci USA 107(34):15211–15216

    Google Scholar 

  • Martin TJ, Sims NA (2005) Osteoclast-derived activity in the coupling of bone formation to resorption. Trends Mol Med 11(2):76–81

    Google Scholar 

  • Matsuo K, Irie N (2008) Osteoclast-osteoblast communication. Arch Biochem Biophys 473(2):201–209

    Google Scholar 

  • Matthews JB, Besong AA, Green TR, Stone MH, Wroblewski BM, Fisher J et al (2000a) Evaluation of the response of primary human peripheral blood mononuclear phagocytes to challenge with in vitro generated clinically relevant UHMWPE particles of known size and dose. J Biomed Mater Res 52(2):296–307

    Google Scholar 

  • Matthews JB, Green TR, Stone MH, Wroblewski BM, Fisher J, Ingham E (2000b) Comparison of the response of primary human peripheral blood mononuclear phagocytes from different donors to challenge with model polyethylene particles of known size and dose. Biomaterials 21(20):2033–2044

    Google Scholar 

  • Mayer A, Roch T, Kratz K, Lendlein A, Jung F (2012) Pro-angiogenic CD14(++) CD16(+) CD163(+) monocytes accelerate the in vitro endothelialization of soft hydrophobic poly (n-butyl acrylate) networks. Acta Biomater 8(12):4253–4259

    Google Scholar 

  • McWhorter FY, Wang T, Nguyen P, Chung T, Liu WF (2013) Modulation of macrophage phenotype by cell shape. Proc Natl Acad Sci USA 110(43):17253–17258

    Google Scholar 

  • Medina RJ, O’Neill CL, O’Doherty TM, Knott H, Guduric-Fuchs J, Gardiner TA et al (2011) Myeloid angiogenic cells act as alternative M2 macrophages and modulate angiogenesis through interleukin-8. Mol Med 17(9–10):1045–1055

    Google Scholar 

  • Menzel-Severing J, Kruse FE, Schlotzer-Schrehardt U (2013) Stem cell-based therapy for corneal epithelial reconstruction: present and future. Can J Ophthalmol 48(1):13–21

    Google Scholar 

  • Mikita J, Dubourdieu-Cassagno N, Deloire MS, Vekris A, Biran M, Raffard G et al (2011) Altered M1/M2 activation patterns of monocytes in severe relapsing experimental rat model of multiple sclerosis. Amelioration of clinical status by M2 activated monocyte administration. Mult Scler 17(1):2–15

    Google Scholar 

  • Mitchell W, Bridget Matthews J, Stone MH, Fisher J, Ingham E (2003) Comparison of the response of human peripheral blood mononuclear cells to challenge with particles of three bone cements in vitro. Biomaterials 24(5):737–748

    Google Scholar 

  • Mishra PK, Wu W, Rozo C, Hallab NJ, Benevenia J, Gause WC (2011) Micrometer-sized titanium particles can induce potent Th2-type responses through TLR4-independent pathways. J Immunol 187(12):6491–6498

    Google Scholar 

  • Mohiuddin M, Pan HA, Hung YC, Huang GS (2012) Control of growth and inflammatory response of macrophages and foam cells with nanotopography. Nanoscale Res Lett 7(1):394

    Google Scholar 

  • Mokarram N, Merchant A, Mukhatyar V, Patel G, Bellamkonda RV (2012) Effect of modulating macrophage phenotype on peripheral nerve repair. Biomaterials 33(34):8793–8801

    Google Scholar 

  • Mosser DM, Edwards JP (2008) Exploring the full spectrum of macrophage activation. Nat Rev Immunol 8(12):958–969

    Google Scholar 

  • Murray PJ, Wynn TA (2011) Protective and pathogenic functions of macrophage subsets. Nat Rev Immunol 11(11):723–737

    Google Scholar 

  • Nich C, Takakubo Y, Pajarinen J, Ainola M, Salem A, Sillat T et al (2013) Macrophages-Key cells in the response to wear debris from joint replacements. J Biomed Mater Res A 101(10):3033–3045

    Google Scholar 

  • Nicolaidou V, Wong MM, Redpath AN, Ersek A, Baban DF, Williams LM et al (2012) Monocytes induce STAT3 activation in human mesenchymal stem cells to promote osteoblast formation. PLoS One 7(7):e39871

    Google Scholar 

  • Outtz HH, Tattersall IW, Kofler NM, Steinbach N, Kitajewski J (2011) Notch1 controls macrophage recruitment and Notch signaling is activated at sites of endothelial cell anastomosis during retinal angiogenesis in mice. Blood 118(12):3436–3439

    Google Scholar 

  • Pajarinen J, Kouri VP, Jamsen E, Li TF, Mandelin J, Konttinen YT (2013) The response of macrophages to titanium particles is determined by macrophage polarization. Acta Biomater 9(11):9229–9240

    Google Scholar 

  • Park SH, Silva M, Bahk WJ, McKellop H, Lieberman JR (2002) Effect of repeated irrigation and debridement on fracture healing in an animal model. J Orthop Res 20(6):1197–1204

    Google Scholar 

  • Paul NE, Skazik C, Harwardt M, Bartneck M, Denecke B, Klee D et al (2008) Topographical control of human macrophages by a regularly microstructured polyvinylidene fluoride surface. Biomaterials 29(30):4056–4064

    Google Scholar 

  • Pazianas M (2011) Osteonecrosis of the jaw and the role of macrophages. J Natl Cancer Inst 103(3):232–240

    Google Scholar 

  • Pederson L, Ruan M, Westendorf JJ, Khosla S, Oursler MJ (2008) Regulation of bone formation by osteoclasts involves Wnt/BMP signaling and the chemokine sphingosine-1-phosphate. Proc Natl Acad Sci USA 105(52):20764–20769

    Google Scholar 

  • Petrie Aronin CE, Shin SJ, Naden KB, Rios PD Jr, Sefcik LS, Zawodny SR et al (2010) The enhancement of bone allograft incorporation by the local delivery of the sphingosine 1-phosphate receptor targeted drug FTY720. Biomaterials 31(25):6417–6424

    Google Scholar 

  • Porcheray F, Viaud S, Rimaniol AC, Leone C, Samah B, Dereuddre-Bosquet N et al (2005) Macrophage activation switching: an asset for the resolution of inflammation. Clin Exp Immunol 142(3):481–489

    Google Scholar 

  • Rao AJ, Gibon E, Ma T, Yao Z, Smith RL, Goodman SB (2012) Revision joint replacement, wear particles, and macrophage polarization. Acta Biomater 8(7):2815–2823

    Google Scholar 

  • Reikeras O, Shegarfi H, Wang JE, Utvag SE (2005) Lipopolysaccharide impairs fracture healing: an experimental study in rats. Acta Orthop 76(6):749–753

    Google Scholar 

  • Rifas L, Arackal S, Weitzmann MN (2003) Inflammatory T cells rapidly induce differentiation of human bone marrow stromal cells into mature osteoblasts. J Cell Biochem 88(4):650–659

    Google Scholar 

  • Roelofs AJ, Thompson K, Ebetino FH, Rogers MJ, Coxon FP (2010) Bisphosphonates: molecular mechanisms of action and effects on bone cells, monocytes and macrophages. Curr Pharm Des 16(27):2950–2960

    Google Scholar 

  • Roh JD, Sawh-Martinez R, Brennan MP, Jay SM, Devine L, Rao DA et al (2010) Tissue-engineered vascular grafts transform into mature blood vessels via an inflammation-mediated process of vascular remodeling. Proc Natl Acad Sci USA 107(10):4669–4674

    Google Scholar 

  • Sarahrudi K, Mousavi M, Thomas A, Eipeldauer S, Vecsei V, Pietschmann P et al (2010) Elevated levels of macrophage colony-stimulating factor in human fracture healing. J Orthop Res 28(5):671–676

    Google Scholar 

  • Schindeler A, McDonald MM, Bokko P, Little DG (2008) Bone remodeling during fracture repair: the cellular picture. Semin Cell Dev Biol 19(5):459–466

    Google Scholar 

  • Schmidt-Bleek K, Schell H, Schulz N, Hoff P, Perka C, Buttgereit F et al (2012) Inflammatory phase of bone healing initiates the regenerative healing cascade. Cell Tissue Res 347(3):567–573

    Google Scholar 

  • Sefcik LS, Aronin CE, Awojoodu AO, Shin SJ, Mac Gabhann F, MacDonald TL et al (2011) Selective activation of sphingosine 1-phosphate receptors 1 and 3 promotes local microvascular network growth. Tissue Eng Part A 17(5-6):617–629

    Google Scholar 

  • Seok J, Warren HS, Cuenca AG, Mindrinos MN, Baker HV, Xu W et al (2013) Genomic responses in mouse models poorly mimic human inflammatory diseases. Proc Natl Acad Sci USA 110(9):3507–3512

    Google Scholar 

  • Spiller KL and Vunjak-Novakovic G (2013) Clinical translation of controlled protein delivery systems for tissue engineering. Drug Deliv Transl Res 1–15. doi: 10.1007/s13346-013-0135-1

  • Spiller K, Anfang R, Johnathan Ng, Nakazawa K, Vunjak-Novakovic G (eds) (2013) Vascularization of bone tissue engineering scaffolds via modulation of macrophage behavior. In: Gordon research conference: biomaterials and tissue engineering, Holderness, NH

    Google Scholar 

  • Spiller KL, Anfang RR, Spiller KJ, Johnathan Ng, Nakazawa KR, Daulton JW et al (2014) The role of macrophage phenotype in vascularization of tissue engineering scaffolds. Biomaterials 35(15):4477–4488

    Google Scholar 

  • Stein M, Keshav S, Harris N, Gordon S (1992) Interleukin 4 potently enhances murine macrophage mannose receptor activity: a marker of alternative immunologic macrophage activation. J Exp Med 176(1):287–292

    Google Scholar 

  • Stout RD, Jiang C, Matta B, Tietzel I, Watkins SK, Suttles J (2005) Macrophages sequentially change their functional phenotype in response to changes in microenvironmental influences. J Immunol 175(1):342–349

    Google Scholar 

  • Sundfeldt M, Carlsson LV, Johansson CB, Thomsen P, Gretzer C (2006) Aseptic loosening, not only a question of wear: a review of different theories. Acta Orthop 77(2):177–197

    Google Scholar 

  • Taira M, Kagiya T, Harada H, Sasaki M, Kimura S, Narushima T et al (2010) Microscopic observations and inflammatory cytokine productions of human macrophage phagocytising submicron titanium particles. J Mater Sci Mater Med 21(1):267–275

    Google Scholar 

  • Telukuntla KS, Suncion VY, Schulman IH, Hare JM (2013) The advancing field of cell-based therapy: insights and lessons from clinical trials. J Am Heart Assoc 2(5):e000338

    Google Scholar 

  • Udagawa N, Takahashi N, Akatsu T, Tanaka H, Sasaki T, Nishihara T et al (1990) Origin of osteoclasts: mature monocytes and macrophages are capable of differentiating into osteoclasts under a suitable microenvironment prepared by bone marrow-derived stromal cells. Proc Natl Acad Sci USA 87(18):7260–7264

    Google Scholar 

  • Valles G, Gil-Garay E, Munuera L, Vilaboa N (2008) Modulation of the cross-talk between macrophages and osteoblasts by titanium-based particles. Biomaterials 29(15):2326–2335

    Google Scholar 

  • Vanos R, Lildhar LL, Lehoux EA, Beaule PE, Catelas I (2013) In vitro macrophage response to nanometer-size chromium oxide particles. J Biomed Mater Res B Appl Biomater 102:149–159

    Google Scholar 

  • Wang Y, Wang YP, Zheng G, Lee VW, Ouyang L, Chang DH et al (2007) Ex vivo programmed macrophages ameliorate experimental chronic inflammatory renal disease. Kidney Int 72(3):290–299

    Google Scholar 

  • Wang Q, Ni H, Lan L, Wei X, Xiang R, Wang Y (2010) Fra-1 protooncogene regulates IL-6 expression in macrophages and promotes the generation of M2d macrophages. Cell Res 20(6):701–712

    Google Scholar 

  • Wooley PH, Morren R, Andary J, Sud S, Yang SY, Mayton L et al (2002) Inflammatory responses to orthopaedic biomaterials in the murine air pouch. Biomaterials 23(2):517–526

    Google Scholar 

  • Wythe SE, Nicolaidou V, Horwood NJ (2014) Cells of the immune system orchestrate changes in bone cell function. Calcif Tissue Int 94(1):98–111

    Google Scholar 

  • Yagil-Kelmer E, Kazmier P, Rahaman MN, Bal BS, Tessman RK, Estes DM (2004) Comparison of the response of primary human blood monocytes and the U937 human monocytic cell line to two difference sizes of alumina ceramic particles. J Orthop Res 22(4):832–838

    Google Scholar 

  • Zaiss MM, Kurowska-Stolarska M, Bohm C, Gary R, Scholtysek C, Stolarski B et al (2011) IL-33 shifts the balance from osteoclast to alternatively activated macrophage differentiation and protects from TNF-alpha-mediated bone loss. J Immunol 186(11):6097–6105

    Google Scholar 

  • Zeisberger SM, Odermatt B, Marty C, Zehnder-Fjallman AH, Ballmer-Hofer K, Schwendener RA (2006) Clodronate-liposome-mediated depletion of tumour-associated macrophages: a new and highly effective antiangiogenic therapy approach. Br J Cancer 95(3):272–281

    Google Scholar 

  • Zhang QZ, Su WR, Shi SH, Wilder-Smith P, Xiang AP, Wong A et al (2010) Human gingiva-derived mesenchymal stem cells elicit polarization of M2 macrophages and enhance cutaneous wound healing. Stem Cells 28(10):1856–1868

    Google Scholar 

  • Zizzo G, Hilliard BA, Monestier M, Cohen PL (2012) Efficient clearance of early apoptotic cells by human macrophages requires M2c polarization and MerTK induction. J Immunol 189(7):3508–3520

    Google Scholar 

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Authors and Affiliations

  1. School of Biomedical Engineering, Science, and Health Systems, Drexel University, Philadelphia, USA

    Sina Nassiri, Pamela Graney & Kara L. Spiller

Authors
  1. Sina Nassiri
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  2. Pamela Graney
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  3. Kara L. Spiller
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Correspondence to Kara L. Spiller .

Editor information

Editors and Affiliations

  1. Tissue Engineering and Biomaterials Research Unit, University of Sydney, Sydney, New South Wales, Australia

    Hala Zreiqat

  2. Biomedical Engineering, University of Sydney, Sydney, New South Wales, Australia

    Colin R. Dunstan

  3. Department of Developmental Biology, Harvard School of Dental Medicine, Boston, Massachusetts, USA

    Vicki Rosen

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© 2015 Springer International Publishing Switzerland

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Nassiri, S., Graney, P., Spiller, K.L. (2015). Manipulation of Macrophages to Enhance Bone Repair and Regeneration. In: Zreiqat, H., Dunstan, C., Rosen, V. (eds) A Tissue Regeneration Approach to Bone and Cartilage Repair. Mechanical Engineering Series. Springer, Cham. https://doi.org/10.1007/978-3-319-13266-2_5

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  • DOI: https://doi.org/10.1007/978-3-319-13266-2_5

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  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-319-13265-5

  • Online ISBN: 978-3-319-13266-2

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