title: Cobalt-alloy implant debris induce HIF-1α hypoxia associated responses: a mechanism for metal-specific orthopedic implant failure.
abstract: 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-1α 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-1α, VEGF and TNF-α) 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-1α 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-1α with a maximal response at 0.3 mM. Cobalt-alloy particles (1 um-diameter, 10 particles/cell) induced significantly elevated HIF-1α, VEGF, TNF-α and ROS expression in human primary macrophages whereas Titanium-alloy particles did not. Elevated expression of HIF-1α 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.
authors.affiliation: Department of Orthopedic Surgery, Rush University Medical Center, Chicago, Illinois, USA.
authors.forename: Lauryn
authors.initials: L
authors.lastname: Samelko
authors.forename: Marco S
authors.initials: MS
authors.lastname: Caicedo
authors.forename: Seung-Jae
authors.initials: SJ
authors.lastname: Lim
authors.forename: Craig
authors.initials: C
authors.lastname: Della-Valle
authors.forename: Joshua
authors.initials: J
authors.lastname: Jacobs
authors.forename: Nadim J
authors.initials: NJ
authors.lastname: Hallab
mesh_terms: D015687:Cell Hypoxia / Q000187:drug effects; D002460:Cell Line; D006621:Hip Joint / Q000276:immunology / Q000378:metabolism; D006622:Hip Prosthesis; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics* / Q000378:metabolism; D061825:Metal-on-Metal Joint Prostheses; D052638:Particulate Matter / Q000494:pharmacology*; D011475:Prosthesis Failure; D017382:Reactive Oxygen Species / Q000378:metabolism; D013582:Synovial Fluid / Q000378:metabolism; D015533:Transcriptional Activation / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D014800:Vitallium / Q000494:pharmacology*
chemical_list: C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D052638:Particulate Matter; D017382:Reactive Oxygen Species; D014409:Tumor Necrosis Factor-alpha; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D014800:Vitallium