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Title: DNA damage caused by cobalt chromium and ceramic orthopaedic wear debris across a model placental barrier : an in vitro study
Author: Bhabra, Gev
Awarding Body: University of Bristol
Current Institution: University of Bristol
Date of Award: 2013
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Metal-on-metal and ceramic-on-ceramic hip replacements generate low volumes of wear debris and have been used increasingly in younger, more physically demanding patients. Metal-on-metal implants generate micron-sized and nano-sized particles of cobalt chromium alloy (CoCr) and ions of cobalt (Co) and chromium (Cr). Ceramic-on-ceramic implants generate nanoparticles of alumina ceramic. There are concerns that the unique properties of metal nanoparticles may allow them access across cellular barriers to cause toxicity to privileged sites in the body. In 2010 the Medicines and Healthcare products Regulatory Agency published a report highlighting a specific concern regarding the potential toxicity of CoCr wear debris across a placenta to an unborn child in utero. Addressing this concern would not be possible using epidemiological studies, and differences in placental morphology prohibit simple extrapolation from animal models. We have therefore used an in vitro, dual chamber model to determine whether CoCr and ceramic wear debris can cause DNA damage to human fibroblasts separated from the debris by an intact cellular barrier. We have used a multilayered BeWo cell barrier that has similarities to the human placenta in vivo, and used the comet and y-H2AX assays to measure DNA damage. Co and Cr ions, CoCr micron-sized and nano-sized particles, and ceramic nanoparticles all caused DNA damage to human fibroblasts across the BeWo cell barrier. None of the exposures adversely affected the barrier permeability or integrity, and the metal was not transported across the barrier. Instead, these indirect effects were dependant on a mechanism involving intercellular and paracellular signalling through connexin 43 gap junctions and hemichannels. The threshold concentration at which Cr ions caused DNA damage was 5 parts per billion; a concentration equivalent to that found in the peripheral blood of some patients with well-functioning metal-on-metal hip replacements. The dose of CoCr and ceramic particles necessary to cause DNA damage across the barrier was high, and unlikely to be relevant in most patients with well-functioning implants.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (M.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available