Cobalt-Alloy Implant Debris Induce HIF-1[alpha] Hypoxia Associated Responses: A Mechanism for Metal-Specific Orthopedic Implant Failure

• Published in: PloS one Vol. 8; no. 6; p. e67127
• Main Authors: Samelko, Lauryn, Caicedo, Marco S, Lim, Seung-Jae, Della-Valle, Craig, Jacobs, Joshua, Hallab, Nadim J
• Format: Journal Article
• Language: English
• Published: Public Library of Science 20.06.2013
• Subjects: Cobalt; Macrophages; Molybdenum alloys; Prostheses and implants; Specialty metals industry; Titanium alloys; Tumor necrosis factor; Vascular endothelial growth factor
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0067127

The historical success of orthopedic implants has been recently tempered by unexpected pathologies and early failures of some types of Cobalt-Chromium-Molybdenum alloy containing artificial hip implants. Hypoxia-associated responses to Cobalt-alloy metal debris were suspected as mediating this untoward reactivity at least in part. Hypoxia Inducible Factor-1[alpha] is a major transcription factor involved in hypoxia, and is a potent coping mechanism for cells to rapidly respond to changing metabolic demands. We measured signature hypoxia associated responses (i.e. HIF-1[alpha], VEGF and TNF-[alpha]) to Cobalt-alloy implant debris both in vitro (using a human THP-1 macrophage cell line and primary human monocytes/macrophages) and in vivo. HIF-1[alpha] in peri-implant tissues of failed metal-on-metal implants were compared to similar tissues from people with metal-on-polymer hip arthroplasties, immunohistochemically. Increasing concentrations of cobalt ions significantly up-regulated HIF-1[alpha] with a maximal response at 0.3 mM. Cobalt-alloy particles (1 um-diameter, 10 particles/cell) induced significantly elevated HIF-1[alpha], VEGF, TNF-[alpha] and ROS expression in human primary macrophages whereas Titanium-alloy particles did not. Elevated expression of HIF-1[alpha] was found in peri-implant tissues and synovial fluid of people with failing Metal-on-Metal hips (n = 5) compared to failed Metal-on-Polymer articulating hip arthroplasties (n = 10). This evidence suggests that Cobalt-alloy, more than other metal implant debris (e.g. Titanium alloy), can elicit hypoxia-like responses that if unchecked can lead to unusual peri-implant pathologies, such as lymphocyte infiltration, necrosis and excessive fibrous tissue growths.