Degenerative disc disease is a painful, disabling condition. In the 1960s, total disc replacement (TDR) was conceived as an alternative treatment to spinal fusion and the resulting complications. Now, after two decades of clinical use in Europe, and FDA approval in the US, the outcomes of TDR and implant design can be assessed. A fundamental objective of device retrieval research is to understand successful implants and assess failures through explant analysis. Failure mechanisms of TDRs may be design-related and/or result from material degradation. Potential mechanisms of device failure come from studies on total joint replacements (TJR). Many TJR failures are due to component degradation, wear debris generation and the stimulation of an inflammatory response. In contrast to TJRs, little is known about in vivo degradation or the contribution of wear debris to biologically-mediated failure mechanisms of artificial discs. We provide evidence here that TDRs exhibit surface damage such as rim fracture, delamination, polyethylene (PE) penetration and in-vivo oxidation. We have established methods to quantify linear wear and volumetric wear in TDR components using microCT analysis. Moreover, we have a method to evaluate the volume, shape and size of wear particles in periprosthetic tissues using environmental scanning electron microscopy and have shown a positive correlation between the amount of debris and the extent of the inflammatory and histopathologic changes, which { may contribute to the major reasons for TDR failure, e.g. heterotopic ossification (HO) and intractable pain. } To investigate the potential failure modes of TDRs, we propose to elucidate mechanisms of in vivo degradation and the contribution of wear debris to biologically-mediated failure mechanisms. First, we will evaluate physical changes of TDR implants to determine if there are significant differences in wear and wear rate among three TDR designs (two contemporary designs and a historical control). The physical changes that are significant with respect to implant wear will be established for the three TDR designs. Second, we will evaluate the volume, shape and size distribution of wear particles in periprosthetic tissue of retrieved TDRs and determine if these findings are significantly correlated to TDR design. Lastly, we will evaluate the inflammatory { (osteo- and neuro-inflammatory mediators) } and histological responses in periprosthetic tissues and correlate these changes to the presence of PE wear debris { and clinical TDR failure. } Successful achievement of the proposed specific aims will provide essential information about implant performance and design, { and potential biological mediators that can be targeted to prevent the loss of implant mobility and the need for revision surgery due to pain. In addition, it } will provide essential information needed for informed health care decisions.