Abstract
Metal toxicity from sources such as orthopaedic implants was investigated in terms of immune system hyper-reactivity to metal implant alloy degradation products. Lymphocyte response to serum protein complexed with metal from implant alloy degradation was investigated in this in vitro study using primary human lymphocytes from healthy volunteers (n = 10). Cobalt chromium molybdenum alloy (Co‐Cr‐Mo, ASTM F‐75) and titanium alloy (Ti‐6Al‐4V, ASTM F‐136) beads (70 μm) were incubated in agitated human serum at 37 degrees Celsius to simulate naturally occurring metal implant alloy degradation processes. Particulate free serum samples, which were incubated with metal, were then separated into molecular weight based fractions. The amounts of soluble Cr and Ti within each serum fraction were measured and correlated with lymphocyte proliferation response to the individual serum fractions. Lymphocytes from each subject were cultured with 11 autologous molecular weight based serum fractions either with or without added metal. Two molecular weight ranges of human serum proteins were associated with the binding of Cr and Ti from Co‐Cr‐Mo and Ti implant alloy degradation (at < 30 and 180–330 kDa). High molecular weight serum proteins (≈ 180 kDa) demonstrated greater lymphocyte reactivity when complexed with metal released from Co‐Cr‐Mo alloy and Ti alloy than with low (5–30 kDa) and midrange (30–77 kDa) serum proteins. When the amount of lymphocyte stimulation was normalized to both the moles of metal and the moles of protein within each fraction (Metal‐Protein Complex Reactivity Index, MPCRI), Cr from Co‐Cr‐Mo alloy degradation demonstrated approximately 10 fold greater reactivity than Ti in the higher molecular weight serum proteins (≈ 180–250 kDa). This in vitro study demonstrated a lymphocyte proliferative response to both Co‐Cr‐Mo and Ti alloy metalloprotein degradation products. This response was greatest when the metals were complexed with high molecular weight proteins, and with metal‐protein complexes formed from Co‐Cr‐Mo alloy degradation.
Similar content being viewed by others
References
Jacobs JJ, Gilbert JL, Urban RM: Corrosion of metallic implants. In: M. Stauffer (ed). Total Revision Hip Arthroplasty. R.N. Mosby, St. Louis, 1994, p 279
Black J: Systemic effects of biomaterials. Biomaterials 5: 12, 1984
Jacobs JJ, Skipor AK, Black J, Hastings MC, Schavocky J, Urban RM, Galante JO: Metal release and excretion from cementless titanium total knee replacements. Trans Orthoped Res Soc New Orleans, LA: 558, 1991
Jacobs JJ, Skipor AK, Black J, Manion L, Urban RM, Galante JO: Metal release in patients with loose titanium alloy total hip replacements. Trans Fourth World Biomaterials Conference Berlin: 266, 1992
Jacobs JJ, Skipor AK, Black J, Urban RM, Galante GO: Release and excretion of metal in patients who have a total hip-replacement component made of titanium-base alloy. Am J Bone Joint Surg 73-A: 1475, 1991
Jacobs JJ, Skipor AK, Black J, Urban RM, Galante JO: Metal release and excretion in patients with titanium base alloy total hip replacement components. Am J Bone Joint Surg 73A:1475, 1991
Stulberg BN, Merritt K, Bauer T: Metallic wear debris in metal-backed patellar failure. J Biomed Mat Res Appl Biomat 5: 9, 1994
Stulberg BN, Watson JT, Shull SL, Merritt K, Crowe TD, Stulberg SD, Guidry CH: Metal ion release after porous total knee arthroplasty: A prospective controlled assessment. Trans Orthoped Res Soc 12: 314, 1987
Dorr LD, Bloebaum R, Emmanual J, Meldrum R: Histologic, biochemical and ion analysis of tissue and fluids retrieved during total hip arthroplasty. Clin Orthoped Rel Res 261: 82, 1990
Jacobs JJ, Skipor AK, Urban RM, Black J, Manion LM, Starr A, Talbert LF, Galante JO: Systemic distribution of metal degradation products from titanium alloy total hip replacements: An autopsy study. Trans Orthoped Res Soc New Orleans: 838, 1994
Michel R, Hoffman J, Loer F, Zilkens J: Trace element burdening of human tissue due to corrosion of hip-joint prostheses made of cobalt-chromium alloys. Arch Orthoped Trauma Surg 103: 85, 1984
Michel R, Nolte M, Reich M, Loer F: Systemic effects of implanted prostheses made of cobalt-chromium alloys. Arch Orthoped Trauma Surg 110: 61, 1991
Hallab NJ, Jacobs JJ, Skipor A, Black J, Mikecz K, Galante JO: Systemic metal-protein binding associated with total joint replacement arthroplasty. J Biomed Mat Res 49: 353, 2000
Griem P, Gleichmann E: Metal ion induced autoimmunity. Curr Opin Immunol 7: 831, 1995
Silvennoinen-Kassinen S, Ikaheimo I, Karvonen J, Kauppinen M, Kallioinen M: Mononuclear cell subsets in the nickel-allergic reaction in vitro and in vivo. J Allergy Clin Immunol 89: 794, 1992
Silvennoinen-Kassinen S, Poikonen K, Ikaheimo I: Characterization of nickel-specific T cell clones. Scand J Immunol 33: 429, 1991
Warner GL, Lawrence DA: The effect of metals on IL-2-related lymphocyte proliferation. Int J Immunopharmacol 10: 629, 1988
Warner GL, Lawrence DA: Cell surface and cell cycle analysis of metal-induced murine T cell proliferation. Eur J Immunol 16: 1337, 1986
Griem P, von Vultee C, Panthel K, Best SL, Sadler PJ, Shaw CF: T cell cross-reactivity to heavy metals: Identical cryptic peptides may be presented from protein exposed to different metals. Eur J Immunol 28: 1941, 1998
Jacobs J, Goodman S, Sumner DR, Hallab N: Biologic response to orthopedic implants. In: AnonymousOrthopedic Basic Science. American Academy of Orthopedic Surgeons, Chicago, 1999, p 402
Yang J, Merritt K: Detection of antibodies against corrosion products in patients after Co-Cr total joint replacements. J Biomed Mat Res 28: 1249, 1994
Yang J, Merritt K: Production of monoclonal antibodies to study corrosion of Co-Cr biomaterials. J Biomed Mat Res 31: 71, 1996
Wang JY, Wickland BH, Gustilo RB, Tsukayama DT: Prosthetic metals impair immune response and cytokine release in vivo and in vitro. J Orthoped Res 15: 688, 1997
Merritt K, Rodrigo JJ: Immune response to synthetic materials. Sensitization of patients receiving orthopaedic implants. Clin Orthoped Rel Res 326: 71, 1996
Merritt K, Brown S: Metal sensitivity reactions to orthopedic implants. Int J Dermatol 20: 89, 1981
Silvennoinen-Kassinen S, Ikaheimo I, Karvonen J, Kauppinen M, Kallioinen M: Mononuclear cell subsets in the nickel-allergic reaction in vitro and in vivo. J Allergy Clin Immunol 89: 794, 1992
Moulon C, Vollmer J, Weltzien HU: Characterization of processing requirements and metal cross-reactivities in T cell clones from patients with allergic contact dermatitis to nickel. Eur J Immunol 25: 3308, 1995
Vollmer J, Fritz M, Dormoy A, Weltzien HU, Moulon C: Dominance of the BV17 element in nickel-specific human T cell receptors relates to severity of contact sensitivity. Eur J Immunol 27: 1865, 1997
Vollmer J, Weltzien HU, Moulon C: TCR reactivity in human nickel allergy indicates contacts with complementarity-determining region 3 but excludes superantigen-like recognition. J Immunol 163: 2723, 1999
Saito K: Analysis of a genetic factor of metal allergy - polymorphism of HLA-DR,-DQ gene. Kokubyo Gakkai Zasshi 63: 53, 1996
Nakashima I, Pu MY, Nishizaki A, Rosila I, Ma L, Katano Y, Ohkusu K, Rahman SM, Isobe K, Hamaguchi M: Redox mechanism as alternative to ligand binding for receptor activation delivering disregulated cellular signals. J Immunol 152: 1064, 1994
Kubicka-Muranyi M, Griem P, Lubben B, Rottmann N, Luhrmann R, Gleichmann E: Mercuric-chloride-induced autoimmunity in mice involves up-regulated presentation by spleen cells of altered and unaltered nucleolar self antigen. Int Arch Allergy Immunol 108: 1, 1995
Bravo I, Carvalho GS, Barbosa MA, deSousa M: Differential effects of eight metal ions on lymphocyte differentiation antigens in vitro. J Biomed Mat Res 24: 1059, 1990
Gillespie WJ, Frampton CM, Henderson RJ, Ryan PM: The incidence of cancer following total hip replacement (published erratum appears in Br J Bone Joint Surg 78: 680, 1996 July). Br J Bone Joint Surg 70: 539, 1988
Merritt K, Brown SA: Biological Effects of Corrosion Products from Metal. American Society for Testing and Materials, Philadelphia, 1985
Poss R, Thornhill TS, Ewald FC, Thomas WH, Batte NJ, Sledge CB: Factors influencing the incidence and outcome of infection following total joint arthoplasty. Clin Orthoped 182: 1984
Wang JY, Wicklund BH, Gustilo RB, Tsukayama DT: Prosthetic metals interfere with the functions of human osteoblast cells in vitro. Clin Orthoped 216: 1997
Kubicka-Muranyi M, Goebels R, Goebel C, Uetrecht J, Gleichmann E: T lymphocytes ignore procainamide, but respond to its reactive metabolites in peritoneal cells: Demonstration by the adoptive transfer popliteal lymph node assay. Toxicol Appl Pharmacol 122: 88, 1993
Kubicka-Muranyi M, Kremer J, Rottmann N, Lubben B, Albers R, Bloksma N, Luhrmann R, Gleichmann E: Murine systemic autoimmune disease induced by mercuric chloride: T helper cells reacting to self proteins. Int Arch Allergy Immunol 109: 11, 1996
Saoudi A, Castedo M, Nochy D, Mandet C, Pasquier R, Druet P, Pelletier L: Self-reactive anti-class II T helper type 2 cell lines derived from gold salt-injected rats trigger B cell polycolonal activation and transfer autoimmunity in CD8-depleted normal syngeneic recipients. Eur J Immunol 25: 1972, 1995
Kubicka-Muranyi M, Behmer O, Uhrberg M, Klonowski H, Bister J, Gleichmann E: Murine systemic autoimmune disease induced by mercuric chloride (HgCl2): Hg-specific helper T-cells react to antigen stored in macrophages. Int J Immunopharmacol 15: 151, 1993
Merle C, Vigan M, Devred D, Girardin P, Adessi B, Laurent R: Generalized eczema from vitallium osteosynthesis material. Contact Dermatitis 27: 257, 1992
King J, Fransway A, Adkins RB: Chronic urticaria due to surgical clips. New Engl J Med 329: 1583, 1993
Barranco VP, Solloman H: Eczematous dermatitis from nickel. J Am Med Assoc 220: 1244, 1972
Thomas RH, Rademaker M, Goddard NJ, Munro DD: Severe eczema of the hands due to an orthopaedic plate made of Vitallium. Br Med J 294: 106, 1987
Abdallah HI, Balsara RK, O'Riordan AC: Pacemaker contact sensitivity: Clinical recognition and management. Annals Thoracic Surg 57: 1017, 1994
Halpin DS: An unusual reaction in muscle in association with a vitallium plate: A report of possible metal hypersensitivity. J Bone Joint Surg 57-B: 451, 1975
Gillespie WJ, Frampton CM, Henderson RJ, Ryan PM: The incidence of cancer following total hip replacement. Am J Bone Joint Surg 70-B: 539, 1988
Benson MK, Goodwin PG, Brostoff J: Metal sensitivity in patients with joint replacement arthroplasties. Br Med J 4: 374, 1975
Brown GC, Lockshin MD, Salvati EA, Bullough PG: Sensitivity to metal as a possible cause of sterile loosening after cobalt-chromium total hip-replacement arthroplasty. J Bone Joint Surg 59-A: 164, 1977
Deutman R, Mulder TH, Brian R, Nater JP: Metal sensitivity before and after total hip arthroplasty. Am J Bone Joint Surg 59-A: 862, 1977
Kubba R, Taylor JS, Marks KE: Cutaneous complications of orthopedic implants. A two-year prospective study. Arch Dermatol 117: 554, 1981
Mayor MB, Merritt K, Brown SA: Metal allergy and the surgical patient. Am J Surg 139: 477, 1980
Merritt K, Brown S: Tissue reaction and metal sensitivity. Acta Orthoped Scand 51: 403, 1980
Merritt K: Role of medical materials, both in implant and surface applications, in immune response and in resistance to infection. Biomaterials 5: 53, 1984
Pinkston JA, Finch SC: A method for the differentiation of T and B lymphocytes and monocytes migrating under agarose. Stain Technol 54: 233, 1979
Rooker GD, Wilkinson JD: Metal sensitivity in patients undergoing hip replacement. A prospective study. J Bone Joint Surg 62-B: 502, 1980
Carlsson AS, Macnusson B, Moller H: Metal sensitivity in patients with metal-to-plastic total hip arthroplasties. Acta Orthoped Scand 51: 57, 1980
Cramers M, Lucht U: Metal sensitivity in patients treated for tibial fractures with plates of stainless steel. Acta Orthoped Scand 48: 245, 1977
Fischer T, Rystedt I, Safwenberg J, Egle I: HLA-A,-B,-C and-DR antigens in individuals with sensitivity to cobalt. Acta Derm Venereol (Stockh) 64: 121, 1984
Hensten-Pettersen A: In: Allergy and Hypersensitivity. Raven Press, New York, 1993
Boyan BD: In: Discussion of Toxicity and Allergy. Raven Press, New York, 1993
Black J: In: Prosthetic Materials. VCH Publishers, Inc., New York, 1996
Jacobs JJ, Skipor AK, Doorn PF, Campbell P, Schmalzried TP, Black J, Amstutz HC: Cobalt and chromium concentrations in patients with metal on metal total hip replacements. Clin Orthoped Rel Res S329: S256, 1996
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Hallab, N.J., Mikecz, K., Vermes, C. et al. Orthopaedic implant related metal toxicity in terms of human lymphocyte reactivity to metal‐protein complexes produced from cobalt‐base and titanium‐base implant alloy degradation. Mol Cell Biochem 222, 127–136 (2001). https://doi.org/10.1023/A:1017979710992
Issue Date:
DOI: https://doi.org/10.1023/A:1017979710992