title: 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.
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 microm) 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 (approximately 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 (approximately 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.
authors.affiliation: Department of Orthopedic Surgery, Rush-Presbyterian-St. Lukes Medical Center, Chicago, IL, USA.
authors.forename: N J
authors.initials: NJ
authors.lastname: Hallab
authors.forename: K
authors.initials: K
authors.lastname: Mikecz
authors.forename: C
authors.initials: C
authors.lastname: Vermes
authors.forename: A
authors.initials: A
authors.lastname: Skipor
authors.forename: J J
authors.initials: JJ
authors.lastname: Jacobs
mesh_terms: D000328:Adult; D000497:Alloys; D001672:Biocompatible Materials / Q000633:toxicity; D001798:Blood Proteins / Q000378:metabolism; D002857:Chromium / Q000097:blood*; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D008213:Lymphocyte Activation / Q000187:drug effects*; D008297:Male; D008875:Middle Aged; D009985:Orthopedics; D019736:Prostheses and Implants / Q000009:adverse effects*; D014018:Tissue Distribution; D014025:Titanium / Q000097:blood* / Q000493:pharmacokinetics / Q000633:toxicity*; D014800:Vitallium / Q000493:pharmacokinetics / Q000633:toxicity*
chemical_list: D000497:Alloys; D001672:Biocompatible Materials; D001798:Blood Proteins; D002857:Chromium; D014800:Vitallium; C031462:titanium alloy (TiAl6V4); D014025:Titanium