Continuous Infusion of UHMWPE Particles Induces Increased Bone Macrophages and Osteolysis



Aseptic loosening and periprosthetic osteolysis resulting from wear debris are major complications of total joint arthroplasty. Monocyte/macrophages are the key cells related to osteolysis at the bone-implant interface of joint arthroplasties. Whether the monocyte/macrophages found at the implant interface in the presence of polyethylene particles are locally or systemically derived is unknown.


We therefore asked (1) whether macrophages associated with polyethylene particle-induced chronic inflammation are recruited locally or systemically and (2) whether the recruited macrophages are associated with enhanced osteolysis locally.


Noninvasive in vivo imaging techniques (bioluminescence and microCT) were used to investigate initial macrophage migration systemically from a remote injection site to polyethylene wear particles continuously infused into the femoral canal. We used histologic and immunohistologic staining to confirm localization of migrated macrophages to the polyethylene particle-treated femoral canals and monitor cellular markers of bone remodeling.


The values for bioluminescence were increased for animals receiving UHMWPE particles compared with the group in which the carrier saline was infused. At Day 8, the ratio of bioluminescence (operated femur divided by nonoperated contralateral femur of each animal) for the UHMWPE group was 13.95 ± 5.65, whereas the ratio for the saline group was 2.60 ± 1.14. Immunohistologic analysis demonstrated the presence of reporter macrophages in the UHMWPE particle-implanted femora only. MicroCT scans showed the bone mineral density for the group with both UHMWPE particles and macrophage was lower than the control groups.


Infusion of clinically relevant polyethylene particles, similar to the human scenario, stimulated systemic migration of remotely injected macrophages and local net bone resorption.

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  1. 1.

    Amstutz HC, Campbell P, Kossovsky N, Clarke IC. Mechanism and clinical significance of wear debris-induced osteolysis. Clin Orthop Relat Res. 1992;276:7–18.

    PubMed  Google Scholar 

  2. 2.

    Archibeck MJ, Jacobs JJ, Roebuck KA, Glant TT. The basic science of periprosthetic osteolysis. Instr Course Lect. 2001;50:185–195.

    CAS  PubMed  Google Scholar 

  3. 3.

    Athanasou NA, Quinn J, Bulstrode CJ. Resorption of bone by inflammatory cells derived from the joint capsule of hip arthroplasties. J Bone Joint Surg Br. 1992;74:57–62.

    CAS  PubMed  Google Scholar 

  4. 4.

    Bauer TW. Particles and periimplant bone resorption. Clin Orthop Relat Res. 2002;405:138–143.

    Article  PubMed  Google Scholar 

  5. 5.

    Campbell P, Ma S, Yeom B, McKellop H, Schmalzried TP, Amstutz HC. Isolation of predominantly submicron-sized UHMWPE wear particles from periprosthetic tissues. J Biomed Mater Res. 1995;29:127–131.

    CAS  Article  PubMed  Google Scholar 

  6. 6.

    Contag PR, Olomu IN, Stevenson DK, Contag CH. Bioluminescent indicators in living mammals. Nat Med. 1998;4:245–247.

    CAS  Article  PubMed  Google Scholar 

  7. 7.

    De A, Lewis XZ, Gambhir SS. Noninvasive imaging of lentiviral-mediated reporter gene expression in living mice. Mol Ther. 2003;7:681–691.

    CAS  Article  PubMed  Google Scholar 

  8. 8.

    Dean DD, Schwartz Z, Blanchard CR, Liu Y, Agrawal CM, Lohmann CH, Sylvia VL, Boyan BD. Ultrahigh molecular weight polyethylene particles have direct effects on proliferation, differentiation, and local factor production of MG63 osteoblast-like cells. J Orthop Res. 1999;17:9–17.

    CAS  Article  PubMed  Google Scholar 

  9. 9.

    Decaris E, Guingamp C, Chat M, Philippe L, Grillasca JP, Abid A, Minn A, Gillet P, Netter P, Terlain B. Evidence for neurogenic transmission inducing degenerative cartilage damage distant from local inflammation. Arthritis Rheum. 1999;42:1951–1960.

    CAS  Article  PubMed  Google Scholar 

  10. 10.

    Donaldson LF, Seckl JR, McQueen DS. A discrete adjuvant-induced monoarthritis in the rat: effects of adjuvant dose. J Neurosci Methods. 1993;49:5–10.

    CAS  Article  PubMed  Google Scholar 

  11. 11.

    Doorn PF, Campbell PA, Worrall J, Benya PD, McKellop HA, Amstutz HC. Metal wear particle characterization from metal on metal total hip replacements: transmission electron microscopy study of periprosthetic tissues and isolated particles. J Biomed Mater Res. 1998;42:103–111.

    CAS  Article  PubMed  Google Scholar 

  12. 12.

    Endres S, Bartsch I, Sturz S, Kratz M, Wilke A. Polyethylene and cobalt-chromium molybdenium particles elicit a different immune response in vitro. J Mater Sci Mater Med. 2008;19:1209–1214.

    CAS  Article  PubMed  Google Scholar 

  13. 13.

    Gao J, Dennis JE, Muzic RF, Lundberg M, Caplan AI. The dynamic in vivo distribution of bone marrow-derived mesenchymal stem cells after infusion. Cells Tissues Organs. 2001;169:12–20.

    CAS  Article  PubMed  Google Scholar 

  14. 14.

    Glant TT, Jacobs JJ, Molnar G, Shanbhag AS, Valyon M, Galante JO. Bone resorption activity of particulate-stimulated macrophages. J Bone Miner Res. 1993;8:1071–1079.

    CAS  Article  PubMed  Google Scholar 

  15. 15.

    Golay J, Introna M. Chemokines and antagonists in non-Hodgkin’s lymphoma. Expert Opin Ther Targets. 2008;12:621–635.

    CAS  Article  PubMed  Google Scholar 

  16. 16.

    Green TR, Fisher J, Matthews JB, Stone MH, Ingham E. 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 (Appl Biomater). 2000;53:490–497.

    CAS  Article  Google Scholar 

  17. 17.

    Horowitz SM, Gonzales JB. Effects of polyethylene on macrophages. J Orthop Res. 1997;15:50–56.

    CAS  Article  PubMed  Google Scholar 

  18. 18.

    Iwase MK, Kang J, Kobayashi Y, Itoh M, Itoh T. A novel bisphosphonate inhibits inflammatory bone resorption in a rat osteolysis model with continuous infusion of polyethylene particles. J Orthop Res. 2002;20:499–505.

    CAS  Article  PubMed  Google Scholar 

  19. 19.

    Kadoya Y, Revell PA, al-Saffar N, Kobayashi A, Scott G, Freeman MA. Bone formation and bone resorption in failed total joint arthroplasties: histomorphometric analysis with histochemical and immunohistochemical technique. J Orthop Res. 1996;14:473–482.

    CAS  Article  PubMed  Google Scholar 

  20. 20.

    Kahn AJ, Stewart CC, Teitelbaum SL. Contact-mediated bone resorption by human monocytes in vitro. Science. 1978;199:988–990.

    CAS  Article  PubMed  Google Scholar 

  21. 21.

    Kelly S, Dunham JP, Donaldson LF. Sensory nerves have altered function contralateral to a monoarthritis and may contribute to the symmetrical spread of inflammation. Eur J Neurosci. 2007;26:935–942.

    Article  PubMed  Google Scholar 

  22. 22.

    Kim KJ, Kobayashi Y, Itoh T. Osteolysis model with continuous infusion of polyethylene particles. Clin Orthop Relat Res. 1998;352:46–52.

    Article  PubMed  Google Scholar 

  23. 23.

    Kumagai K, Vasanji A, Drazba JA, Butler RS, Muschler GF. Circulating cells with osteogenic potential are physiologically mobilized into the fracture healing site in the parabiotic mice model. J Orthop Res. 2008;26:165–175.

    Article  PubMed  Google Scholar 

  24. 24.

    Kuppen PJ, Marinelli A, Camps JA, Pauwels EK, van de Velde CJ, Fleuren GJ, Eggermont AM. Biodistribution of lymphokine-activated killer (LAK) cells in Wag rats after hepatic-artery or jugular-vein infusion. Int J Cancer. 1992;52:266–270.

    CAS  Article  PubMed  Google Scholar 

  25. 25.

    Ma T, Huang Z, Ren PG, McCally R, Lindsey D, Smith RL, Goodman SB. An in vivo murine model of continuous intramedullary infusion of polyethylene particles. Biomaterials. 2008;29:3738–3742.

    CAS  Article  PubMed  Google Scholar 

  26. 26.

    Ma T, Ortiz SG, Huang Z, Ren P, Smith RL, Goodman SB. In vivo murine model of continuous intramedullary infusion of particles—a preliminary study. J Biomed Mater Res B Appl Biomater. 2009;88:250–253.

    PubMed  Google Scholar 

  27. 27.

    Mansfield JR, Gossage KW, Hoyt CC, Levenson RM. Autofluorescence removal, multiplexing, and automated analysis methods for in-vivo fluorescence imaging. J Biomed Opt. 2005;10:41207.

    Article  PubMed  Google Scholar 

  28. 28.

    Mansfield JR, Hoyt C, Levenson RM. Visualization of microscopy-based spectral imaging data from multi-label tissue sections. Curr Protoc Mol Biol. 2008;14:19.

    PubMed  Google Scholar 

  29. 29.

    Mundy CR, Altman AJ, Gondek MD, Bandelin JG. Direct resorption of bone by human monocytes. Science. 1977;196:1109–1111.

    CAS  Article  PubMed  Google Scholar 

  30. 30.

    Orishimo KF, Claus AM, Sychterz CJ, Engh CA. Relationship between polyethylene wear and osteolysis in hips with a second-generation porous-coated cementless cup after seven years of follow-up. J Bone Joint Surg Am. 2003;85:1095–1099.

    PubMed  Google Scholar 

  31. 31.

    Ortiz SG, Ma T, Epstein NJ, Smith RL, Goodman SB. Validation and quantification of an in vitro model of continuous infusion of submicron-sized particles. J Biomed Mater Res B Appl Biomater. 2008;84:328–333.

    PubMed  Google Scholar 

  32. 32.

    Ortiz SG, Ma T, Regula D, Smith RL, Goodman SB. Continuous intramedullary polymer particle infusion using a murine femoral explant model. J Biomed Mater Res B Appl Biomater. 2008;87:440–446.

    PubMed  Google Scholar 

  33. 33.

    Pandey R, Quinn J, Joyner C, Murray DW, Triffitt JT, Athanasou NA. Arthroplasty implant biomaterial particle associated macrophages differentiate into lacunar bone resorbing cells. Ann Rheum Dis. 1996;55:388–395.

    CAS  Article  PubMed  Google Scholar 

  34. 34.

    Purdue PE, Koulouvaris P, Potter HG, Nestor BJ, Sculco TP. The cellular and molecular biology of periprosthetic osteolysis. Clin Orthop Relat Res. 2007;454:251–261.

    Article  PubMed  Google Scholar 

  35. 35.

    Quinn J, Joyner C, Triffitt JT, Athanasou NA. Polymethylmethacrylate-induced inflammatory macrophages resorb bone. J Bone Joint Surg Br. 1992;74:652–658.

    CAS  PubMed  Google Scholar 

  36. 36.

    Ren PG, Lee SW, Biswal S, Goodman SB. Systemic trafficking of macrophages induced by bone cement particles in nude mice. Biomaterials. 2008;29:4760–4765.

    CAS  Article  PubMed  Google Scholar 

  37. 37.

    Ren W, Markel DC, Schwendener R, Ding Y, Wu B, Wooley PH. Macrophage depletion diminishes implant-wear-induced inflammatory osteolysis in a mouse model. J Biomed Mater Res A. 2008;85:1043–1051.

    PubMed  Google Scholar 

  38. 38.

    Ren W, Wu B, Mayton L, Wooley PH. Polyethylene and methyl methacrylate particle-stimulated inflammatory tissue and macrophages up-regulate bone resorption in a murine neonatal calvaria in vitro organ system. J Orthop Res. 2002;20:1031–1037.

    CAS  Article  PubMed  Google Scholar 

  39. 39.

    Sabokbar A, Itonaga I, Sun SG, Kudo O, Athanasou NA. Arthroplasty membrane-derived fibroblasts directly induce osteoclast formation and osteolysis in aseptic loosening. J Orthop Res. 2005;23:511–519.

    CAS  Article  PubMed  Google Scholar 

  40. 40.

    Sabokbar A, Pandey R, Quinn JM, Athanasou NA. Osteoclastic differentiation by mononuclear phagocytes containing biomaterial particles. Arch Orthop Trauma Surg. 1998;117:136–140.

    CAS  Article  PubMed  Google Scholar 

  41. 41.

    Schmalzried TP, Jasty M, Harris TP. Periprosthetic bone loss in total hip arthroplasty. Polyethylene wear debris and the concept of the effective joint space. J Bone Joint Surg Am. 1992;74:849–863.

    CAS  PubMed  Google Scholar 

  42. 42.

    Shanbhag AS, Jacobs JJ, Black J, Galante JO, Glant TT. Macrophage/particle interactions: effect of size, composition and surface area. J Biomed Mater Res. 1994;28:81–90.

    CAS  Article  PubMed  Google Scholar 

  43. 43.

    Suchard SJ, Stetsko DK, Davis PM, Skala S, Potin D, Launay M, Dhar TG, Barrish JC, Susulic V, Shuster DJ, McIntyre KW, McKinnon M, Salter-Cid L. An LFA-1 (αLβ2) small-molecule antagonist reduces inflammation and joint destruction in murine models of arthritis. J Immunol. 2010;184:3917–3926.

    CAS  Article  PubMed  Google Scholar 

  44. 44.

    Urban RM, Jacobs JJ, Tomlinson MJ, Gavrilovic J, Black J, Peoc’h M. Dissemination of wear particles to the liver, spleen, and abdominal lymph nodes of patients with hip or knee replacement. J Bone Joint Surg Am. 2000;82:457–476.

    CAS  Article  PubMed  Google Scholar 

  45. 45.

    von Knoch M, Jewison DE, Sibonga JD, Sprecher C, Morrey BF, Loer F, Berry DJ, Scully SP. The effectiveness of polyethylene versus titanium particles in inducing osteolysis in vivo. J Orthop Res. 2004;22:237–243.

    Article  Google Scholar 

  46. 46.

    Wang ML, Sharkey PF, Tuan RS. Particle bioreactivity and wear-mediated osteolysis. J Arthroplasty. 2004;19:1028–1038.

    Article  PubMed  Google Scholar 

  47. 47.

    Woodside DG, Vanderslice P. Cell adhesion antagonists: therapeutic potential in asthma and chronic obstructive pulmonary disease. BioDrugs. 2008;22:85–100.

    CAS  Article  PubMed  Google Scholar 

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We thank Dr Afraaz Irani for performing the bone mineral density analysis of the microCT scans. We thank Dr Gobalakrishnan Sundaresan who supplied the Fluc and GFP expressing RAW264.7 macrophage cell line, Dr Timothy Wright (Hospital for Special Surgery, New York, NY) who supplied the UHMWPE particles, and Stephanie Byun for sectioning of samples used in this study. We also thank Dr Lane Smith, Dr Sam Gambhir, and Dr Chris Contag for their helpful advice.

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Corresponding author

Correspondence to Stuart B. Goodman MD, PhD.

Additional information

One or more of the authors (SBG, SB, TM, P-GR) have received funding from the National Institutes of Health, National Institute of Arthritis, Musculoskeletal and Skin Diseases, Grant #1R01AR055650 in support of this study.

Each author certifies that his or her institution has approved the animal protocol for this investigation and that all investigations were conducted in conformity with ethical principles of research.

This work was performed at the Orthopaedic Research Laboratories and the Stanford Small Animal Imaging Facility at the Clarke Center at Stanford University, Stanford, CA, USA.

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Ren, PG., Irani, A., Huang, Z. et al. Continuous Infusion of UHMWPE Particles Induces Increased Bone Macrophages and Osteolysis. Clin Orthop Relat Res 469, 113–122 (2011).

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  • Bone Mineral Density
  • Wear Debris
  • Wear Particle
  • Total Joint Arthroplasty