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Metal ions as inflammatory initiators of osteolysis

  • Knee Revision Surgery
  • Published:
Archives of Orthopaedic and Trauma Surgery Aims and scope Submit manuscript

Abstract

Osteolysis and aseptic loosening currently contribute 75 % of implant failures. Furthermore, with over four million joint replacements projected to be performed in the United States annually, osteolysis and aseptic loosening may continue to pose a significant morbidity. This paper reviews the osteolysis cascade leading to osteoclast activation and bone resorption at the biochemical level. Additionally, the metal ion release mechanism from metallic implants is elucidated. Even though metal ions are not the predominating initiator of osteolysis, they do increase the concentration of key inflammatory cytokines that stimulate osteoclasts and prove to be a contributor to osteolysis and aseptic loosening. Osteolysis is a competitive mechanism among a number of biological reactions, which includes debris release, macrophage and osteoclast activation, an inflammatory response as well as metal ion release. Pharmacological therapy for component loosening has also been reviewed. A non-surgical treatment of osteolysis has not been found in the literature and thus may become an area of future research. Even though this research is warranted, comprehensively understanding the immune response to orthopedic implants and their metallic ions, and thus, creating improved prostheses appears to be the most cost-effective approach to decrease the morbidity related to osteolysis and to design implants with greater longevity. The ionic forms, cytokines, toxicity, gene expression, biological effects, and hypersensitivity responses of metallic elements from metal implants are summarized as well.

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References

  1. Ollivere B, Wimhurst JA, Clark IM, Donell ST (2012) Current concepts in osteolysis. J Bone Jt Surg Br 94-B:10–15

    Article  Google Scholar 

  2. Singh JA, Vessely MB, Harmsen WS, Schleck CD, Melton LJ, Kurland RL, Berry DJ (2010) A population-based study of trends in the use of total hip and total knee arthroplasty, 1969–2008. Mayo Clin Proc 85(10):898–904

    Article  PubMed Central  PubMed  Google Scholar 

  3. Espigares JLN, Torres EH (2008) Cost-outcome analysis of joint replacement: evidence from a Spanish Public Hospital. Gac Sanit 22(4):337–343

    Article  Google Scholar 

  4. Talmo CT, Aghazadeh M, Bono JV (2012) Perioperative complications following total joint replacement. Clin Geriatr Med 28(3):471–487

    Article  PubMed  Google Scholar 

  5. Talmo CT, Robbins LE, Bono JV (2010) Total joint replacement in the elderly patient. Clin Geriatr Med 26(3):517–529

    Article  PubMed  Google Scholar 

  6. Langlois J, Hamadouche M (2011) New animal models of wear-particle osteolysis. Int Orthop 35:245–251

    Article  PubMed Central  PubMed  Google Scholar 

  7. Gallo J, Goodman SB, Lostak J, Janout M (2012) Advantages and disadvantages of ceramic on ceramic total hip arthroplasty: a review. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 156(3):204–212

    Article  PubMed  Google Scholar 

  8. Charnley J (1971) Present status of total hip replacement. Ann Rheum Dis 30:560

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  9. Sadoghi P, Schröder C, Fottner A, Steinbrück A, Betz O, Müller PE, Jansson V, Andreas Hölzer A (2012) Application and survival curve of total hip arthroplasties: a systematic comparative analysis using worldwide hip arthroplasty registers. Int Orthop 36:2197–2203

    Article  PubMed Central  PubMed  Google Scholar 

  10. Kurtz S, Ong K, Lau E, Mowat F, Halpern M (2007) Projections of primary and revision hip and knee arthroplasty in the United States from 2005 to 2030. J Bone Jt Surg Am 89(4):780–785

    Article  Google Scholar 

  11. Schwab LP, Marlar J, Hasty KA, Smith RA (2011) Macrophage response to high number of titanium particles is cytotoxic and COX-2 mediated and it is not affected by the particle’s endotoxin content or the cleaning treatment. Wiley Online Library

  12. Ingham E, Fisher J, Stone MH (2003) Wear of historical polyethylenes in total hip prostheses. Biomechanical success and biological failure. Hip Int 13(1):17–27

    CAS  PubMed  Google Scholar 

  13. Beck RT, Illingworth KD, Saleh KJ (2011) Review of periprosthetic osteolysis in total joint arthroplasty: an emphasis on host factors and future directions. Wiley Online Library

  14. Sargeant A, Goswami T (2006) Pathophysiological aspects of hip implants. J Surg Orthop Adv 15(2):111–112

    PubMed  Google Scholar 

  15. Sargeant A, Goswami T (2007) Hip implants—paper VI—ion concentrations. Mater Des 28:155–171

    Article  CAS  Google Scholar 

  16. Cooper HJ, Ranawat AS, Potter HG, Foo LF, Koob TW, Ranawat CS (2010) Early reactive synovitis and osteolysis after total hip arthroplasty. Clin Orthop Relat Res 468:3278–3285

    Article  PubMed Central  PubMed  Google Scholar 

  17. Hallab NJ, Jacobs JJ (2009) Biologic effects of implant debris. Bull NYU Hosp Jt Dis 67(2):182–188

    PubMed  Google Scholar 

  18. Desai MA, Bancroft LW (2008) Periprosthetic osteolysis. Orthopedics 31(6):1–5

    Article  Google Scholar 

  19. Fang Q, Wang H, Zhu S, Zhu Q (2011) N-acetyl-l-cysteine inhibits wear particle-induced prosthesis loosening. J Surg Res 168:163–172

    Article  Google Scholar 

  20. Gallo J, Goodman SB, Konttinen YT, Raska M (2012) Particle disease: biological mechanisms of periprosthetic osteolysis in total hip arthroplasty. Innate Immun 1–12

  21. Gallo J, Slouf M, Goodman SB (2010) The relationship of polyethylene wear to particle size, distribution, and number: a possible factor explaining the risk of osteolysis after total hip arthroplasty. Wiley InterScience

  22. Callaghan JJ, Rosenberg AG, Rubash HE (2007) The adult hip 2(2):1505–1506

  23. Schwarz EM, Looney RJ, O’Keefe RJ (2000) Anti-TNF-A therapy as a clinical intervention for periprosthetic osteolysis. Arthritis Res 2:165–168

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  24. Hjorth MH, Soballe K, Jakobsen SS, Lorenzen ND, Mechlenburg L, Stilling M (2014) No association between serum metal ions and implant fixation in large-head metal-on-metal total hip arthroplasty. Acta Orthop 85(4):355–362

    Article  PubMed Central  PubMed  Google Scholar 

  25. Hosman AH, Mei HC, Bulstra SK, Busscher HJ, Neut D (2010) Effects of metal-on-metal wear on the host immune system and infection in hip arthroplasty. Acta Orthopaedica 81(5):526–534

    Article  PubMed Central  PubMed  Google Scholar 

  26. Grosse S, Haugland HK, Lilleng P, Ellison P, Hallan G, Hol PJ (2014) Wear particles and ions from cemented and uncemented titanium-based hip prostheses—a histological and chemical analysis of retrieval material. J Biomed Mater Res B Appl Biomater

  27. Minoda Y, Kobayashi A, Iwaki H, Iwakiri K, Inori F, Sugama R, Ikebuchi M, Kadoya Y, Takaoka K (2009) In vivo analysis of polyethylene wear particles after total knee arthroplasty: the influence of improved materials and designs. J Bone Jt Surg Am 91(Suppl 6):67–73

    Article  Google Scholar 

  28. Shon WY, Gupta S, Biswal S, Han SH, Hong SJ, Moon JG (2009) Pelvic osteolysis relationship to radiographs and polyethylene wear. J Arthroplast 24:743–750

    Article  Google Scholar 

  29. Cadosch D, Chan E, Gautschi OP, Filgueira L (2009) Metal is not inert: role of metal ions released by biocorrosion in aseptic loosening-current concepts. Wiley InterScience

  30. Gallo J, Kamínek P, Tichá V, Řiháková P, Ditmar R (2002) Particle disease. A comprehensive theory of periprosthetic osteolysis: a review. Biomed Pap 146(2):21–28

    Article  Google Scholar 

  31. Sinha R, Peris M (2001) The effects of osteolysis and aseptic loosening. http://www.medscape.org

  32. Yadav J, Samelko L, Gilvar P, McAllister K, Hallab NJ (2013) Osteoclasts lose innate inflammatory reactivity to metal and polymer implant debris compared to monocytes/macrophages. Orthop J 18(7):605–613

    Google Scholar 

  33. Gustafson K, Jakobsen SS, Lorenzen ND, Thyssen JP, Johansen JD, Bonefeld CM, Stilling M, Baad-Hansen T, Søballe K (2014) Metal release and metal allergy after total hip replacement with resurfacing versus conventional hybrid prosthesis. Acta Orthop 85(4):348–354

    Article  PubMed Central  PubMed  Google Scholar 

  34. Gallo J, Raska M, Mrazek F, Petrek M (2008) Bone remodeling, particle disease and individual susceptibility to periprosthetic osteolysis. Physiol Res 57:339–349

    CAS  PubMed  Google Scholar 

  35. Emmanuel AR, Bergin KM, Kelly GE, McCoy GF, Wozniak AP, Quinlan JF (2014) The effect of acetabular inclination on metal ion levels following metal-on-metal hip arthroplasty. J Arthroplast 29(1):186–191

    Article  Google Scholar 

  36. Hallab NJ, Caicedo M, McAllister K, Skipor A, Amstutz H, Jacobs JJ (2013) Asymptomatic prospective and retrospective cohorts with metal-on-metal hip arthroplasty indicate acquired lymphocyte reactivity varies with metal ion levels on a group basis. J Orthop Res 31(2):173–182

    Article  PubMed Central  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  38. Tomazic-Jezic VJ, Merritt K, Umbreit TH (2001) Significance of the type and the size of biomaterial particles on phagocytosis and tissue distribution. J Biomed Mater Res 55:523–529

    Article  CAS  PubMed  Google Scholar 

  39. Chan E, Cadosch D, Gautschi OP, Sprengel K, Filgueira L (2011) Influence of metal ions on human lymphocytes and the generation of titanium specific T lymphocytes. J Appl Biomater Biomech 9:137–143

    CAS  PubMed  Google Scholar 

  40. Cadosch D, Sutanto M, Chan E, Mhawi A, Gautschi OP, Katterfeld B, Simmen HP, Filgueira L (2009) Titanium uptake, induction of RANK-L expression, and enhanced proliferation of human T-Lymphocytes. Wiley InterScience

  41. Caicedo MS, Desai R, McAllister K, Reddy A, Jacobs JJ, Hallab NJ (2008) Soluble and particulate Co-Cr-Mo alloy implant metals activate the inflammasome danger signaling pathway in human macrophages: a novel mechanism for implant debris reactivity. Wiley InterScience

  42. Goodman SB, Ma T (2010) Cellular chemotaxis induced by wear particles from joint replacements. Biomaterials 31:5045–5050

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  43. Niki Y, Matsumoto H, Suda Y, Otani T, Fujikawa K, Toyama Y, Hisamori N, Nozue A (2003) Metal ions induce bone-resorbing cytokine production through the redox pathway in synoviocytes and bone marrow macrophages. Biomaterials 24:1447–1457

    Article  CAS  PubMed  Google Scholar 

  44. Ritchlin CT, Schwarz EM, O’Keefe RJ, Looney RJ (2004) RANK, RANKL and OPG in inflammatory arthritis and periprosthetic osteolysis. J Musculoskel Neuron Interact 4(3):276–284

    CAS  Google Scholar 

  45. Merkel KD, Erdmann JM, McHugh KP, Abu-Amer Y, Ross FP, Teitelbaum SL (1999) Tumor necrosis factor-a mediates orthopedic implant osteolysis. Am J Pathol 154:203–210

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  46. Wang JY, Wicklund BH, Gustilo RB, Tsukayama DT (1996) Titanium, chromium and cobalt ions modulate the release of bone-associated cytokines by human monocytes/macrophages in vitro. Biomaterials 17(23):2233–2240

    Article  CAS  PubMed  Google Scholar 

  47. Hanawa T (2004) Metal ion release from metal implants. Mater Sci Eng 24:745–752

    Article  Google Scholar 

  48. Hallab NJ, Skipor A, Jacobs JJ (2003) Interfacial kinetics of titanium- and cobalt-based implant alloys in human serum: metal release and biofilm formation. Wiley Periodicals

  49. Cadosch D, Chan E, Gautschi O, Meagher J, Zellweger R, Filgueira L (2008) Titanium IV ions induced human osteoclast differentiation and enhanced bone resorption in vitro. Wiley InterScience

  50. Chan EP, Mhawi A, Clode P, Saunders M, Filgueira L (2009) Effects of titanium(IV) ions on human monocyte-derived dendritic cells. Metallomics 1:166–174

    Article  CAS  PubMed  Google Scholar 

  51. 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. Immunology 187:6491–6498

    Article  CAS  Google Scholar 

  52. Haleem-Smith H, Argintar E, Bush C, Hampton D, Postma WF, Chen FH, Rimington T, Lamb J, Tuan RS (2012) Biological responses of human mesenchymal stem cells to titanium wear debris particles. J Orthop Res 30(6):853–863

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  53. Lohmann CH, Dean DD, Oster GK, Casasola D, Buchhorn GH, Fink U, Schwartz Z, Boyan BD (2002) Ceramic and PMMA particles differentially affect osteoblast phenotype. Biomaterials 23:1855–1863

    Article  CAS  PubMed  Google Scholar 

  54. Carr AM, Desteiger R (2008) Osteolysis in patients with a metal-on-metal hip arthroplasty. Anz J Surg 78:144–147

    Article  PubMed  Google Scholar 

  55. Hallab NJ, Caicedo M, Epstein R, McAllister K, Jacobs JJ (2009) In vitro reactivity to implant metals demonstrates a person-dependent association with both T-cell and B-cell activation. Wiley InterScience

  56. Hallab NJ, Caicedo M, Finnegan A, Jacobs JJ (2008) Th1 type lymphocyte reactivity to metals in patients with total hip arthroplasty. J Orthop Surg Res 3:6

    Article  PubMed Central  PubMed  Google Scholar 

  57. Griem P, Gleichmann E (1995) Metal ion induced autoimmunity. Immunology 7:831–838

    CAS  Google Scholar 

  58. Caicedo MS, Pennekamp PH, McAllister K, Jacobs JJ, Hallab NJ (2009) Soluble ions more than particulate cobalt-alloy implant debris induce monocyte costimulatory molecule expression and release of proinflammatory cytokines critical to metal-induced lymphocyte reactivity. Wiley InterScience

  59. Catelas I, Petit A, Zukor DJ, Antoniou J, Huk OL (2003) TNF-α secretion and macrophage mortality induced by cobalt and chromium ions in vitro-qualitative analysis of apoptosis. Biomaterials 24:383–391

    Article  CAS  PubMed  Google Scholar 

  60. Patton MS, Lyon TDB, Ashcroft GP (2008) Levels of systemic metal ions in patients with intramedullary nails. Acta Orthop 79(6):820–825

    Article  PubMed  Google Scholar 

  61. Savarino L, Maci GS, Greco M, Baldini N,Giunti A (2007) Metal ion release from fracture fixation devices: a potential marker of implant failure. Wiley InterScience

  62. Sidaginamale RP, Joyce TJ, Lord JK, Jefferson R, Blaine PG, Nargol AVF, Langton DJ (2013) Blood metal ion testing is an effective screening tool to identify poorly performing metal-on-metal bearing surfaces. Bone Jt Res 2(5):84–95

    Article  CAS  Google Scholar 

  63. Delaunay C, Petit I, Learmonth ID, Oger P, Vendittoli PA (2010) Metal-on-metal bearings total hip arthroplasty: the cobalt and chromium ions release concern. Orthop Traumatol Surg Res 96:894–904

    Article  CAS  PubMed  Google Scholar 

  64. Lin HY, Bumgardner JD (2004) In vitro biocorrosion of Co-Cr-Mo implant alloy by macrophage cells. J Orthop Res 22:1231–1236

    Article  CAS  PubMed  Google Scholar 

  65. Shrivastava R, Upreti RK, Seth PK, Chaturvedi UC (2002) Effects of chromium on the immune system. FEMS Immunol Med Microbiol 34:1–7

    Article  CAS  PubMed  Google Scholar 

  66. Hallab NJ, Vermes C, Messina C, Roebuck KA, Glant TT, Jacobs JJ (2002) Concentration and composition dependent effects of metal ions on human MG63 osteoblasts. J Biomed Mater Res 60(3):420–433

    Article  CAS  PubMed  Google Scholar 

  67. Vermes C, Glant TT, Hallab NJ, Fritz EA, Roebuck KA, Jacobs JJ (2001) The potential role of the osteoblast in the development of periprosthetic osteolysis: review of in vitro osteoblast responses to wear debris, corrosion products, and cytokines and growth factors. J Arthroplast 16:95–100

    Article  CAS  Google Scholar 

  68. Wang JY, Wicklund BH, Gustilo RB, Tsukayama DT (1997) Prosthetic metals interfere with the functions of human osteoblast cells in vitro. Clin Orthop Relat Res 339:216–226

    Article  PubMed  Google Scholar 

  69. Nichols KG, Puleo DA (1997) Effect of metal ions on the formation and function of osteoclastic cells in vitro. J Biomed Mater Res 35:265–271

    Article  CAS  PubMed  Google Scholar 

  70. Burton L, Paget D, Binder NB, Bohnert K, Nestor BJ, Sculco TP, Santambrogio L, Ross FP, Goldring SR, Purdue PE (2012) Orthopedic wear debris mediated inflammatory osteolysis is mediated in part by NALP3 inflammasome activation. Wiley Online Library

  71. Lewis JB, Wataha JC, Randol TM, McCloud VV, Lockwood PE (2003) Metal ions alter lipopolysaccharide-induced NFkb binding in monocytes. Wiley Periodicals, Inc.

  72. Wei S, Siegal GP (2008) Mechanisms modulating inflammatory osteolysis: a review with insights into therapeutic targets. Pathol Res Pract 204:695–706

    Article  PubMed Central  CAS  PubMed  Google Scholar 

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

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  74. Catelas I, Jacobs JJ (2010) Biologic activity of wear particles. Instr Course Lect 59:3–16

    PubMed  Google Scholar 

  75. Ingham E, Fisher J (2000) Biological reactions to wear debris in total joint replacement. Proc Inst Mech Eng H 214(1):21–37

    Article  CAS  PubMed  Google Scholar 

  76. Meneghini RM, Hallab NJ, Jacobs JJ (2005) The biology of alternative bearing surfaces in total joint arthroplasty. Instr Course Lect 54:481–493

    PubMed  Google Scholar 

  77. Nikolaou VS, Edwards MR, Bogoch E, Schemitsch EH, Waddell JP (2012) A prospective randomized controlled trial comparing three alternative bearing surfaces in primary total hip replacement. J Bone Jt Surg Br 94(4):459–465

    Article  CAS  Google Scholar 

  78. Sato T, Nakashima Y, Akiyama M, Yamamoto T, Mawatari T, Itokawa T, Ohishi M, Motomura G, Hirata M, Iwamoto Y (2012) Wear resistant performance of highly cross-linked and annealed ultra-high molecular weight polyethylene against ceramic heads in total hip arthroplasty. J Orthop Res 30(12):2031–2037

    Article  CAS  PubMed  Google Scholar 

  79. Clarke IC (1992) Role of ceramic implants. design and clinical success with total hip prosthetic ceramic-to-ceramic bearings. Clin Orthop Relat Res 282:19–30

    PubMed  Google Scholar 

  80. Dumbleton JH, Manley MT, Edidin AA (2002) A literature review of the association between wear rate and osteolysis in total hip arthroplasty. J Arthroplast 17(5):649–661

    Article  Google Scholar 

  81. Nho Jh, Park JS, Song US, Kim WJ, Suh YS (2013) Ceramic head fracture in ceramic-on-polyethylene total joint arthroplasty. Yonsei Med J 54(6):1550–1553

    Article  PubMed Central  PubMed  Google Scholar 

  82. Bouras T, Repantis T, Fennema P, Kororessis P (2013) Low aseptic loosening and revision rate in Zweymuller-Plus total hip arthroplasty with ceramic-on-ceramic bearings. Eur J Orthop Surg Traumatol

  83. Nehme A, Maalouf G, Tricoire JL, Giordano G, Chiron P, Puget J (2003) Effect of alendronate on periprosthetic bone loss after cemented primary total hip arthroplasty: a prospective randomized study. Rev Chir Orthop Reparatrice Appar Mot 89(7):593–598

    CAS  PubMed  Google Scholar 

  84. Arabmotlagh M, Pilz M, Warzecha J, Rauschmann M (2009) Changes of femoral periprosthetic bone mineral density 6 years after treatment with alendronate following total hip arthroplasty. J Orthop Res 27(2):183–188

    Article  PubMed  Google Scholar 

  85. Tapaninen TS, Venesmaa PK, Jurvelin JS, Miettinen HJA, Kröger HPJ (2010) Alendronate reduces periprosthetic bone loss after uncemented primary total hip arthroplasty—a 5-year follow-up of 16 patients. Scand J Surg 99:32–37

    CAS  PubMed  Google Scholar 

  86. Khurjekar KS, Vidyadhara S, Dheenadhayalan J, Rajasekaran S (2006) Spontaneous rapid osteolysis in paget’s disease after internal fixation of subtrochanteric femoral fracture. Singap Med J 47(10):897–900

    CAS  Google Scholar 

  87. Kinov P, Tivchev P, Doukova P, Leithner A (2006) Effect of risedronate on bone metabolism after total hip arthroplasty: a prospective randomised study. Acta Orthop Belg 72(1):44–50

    PubMed  Google Scholar 

  88. Vasudevan A, DiCarlo EF, Wright T, Chen D, Figgie MP, Goldring SR, Mandl LA (2012) Cellular response to prosthetic wear debris differs in patients with and without rheumatoid arthritis. Arthritis Rheum 64(4):1005–1014

    Article  PubMed Central  PubMed  Google Scholar 

  89. Hagman S, Kirsch J, Kretzer J, Moradi B (2013) In vitro analysis of impact of metal ions on human lymphocyte cultures. Orthopade 42(8):643–650

    Article  Google Scholar 

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Authors and Affiliations

  1. Department of Orthopaedic Surgery, McLaren-Flint Michigan State University, Flint, Michigan, USA

    Kevin Magone

  2. Department of Orthopaedic Surgery, Wright State University, Dayton, Ohio, USA

    Daniel Luckenbill

  3. Department of Biomedical, Industrial and Human Factors Engineering, Wright State University, Dayton, Ohio, USA

    Tarun Goswami

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  1. Kevin Magone
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  2. Daniel Luckenbill
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  3. Tarun Goswami
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Correspondence to Tarun Goswami.

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Magone, K., Luckenbill, D. & Goswami, T. Metal ions as inflammatory initiators of osteolysis. Arch Orthop Trauma Surg 135, 683–695 (2015). https://doi.org/10.1007/s00402-015-2196-8

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