Date of Award

8-2007

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Legacy Department

Bioengineering

Advisor

LaBerge, Martine

Abstract

Chronic inflammation has been identified as a major contributor to many diseases including, atherosclerosis, osteoporosis, dementia, Alzheimer's disease and type 2 diabetes, to name a few. Many of the same markers of inflammation found in the diseases listed above, including IL-1, IL-6, TNF-α, NF-B and adhesion molecules, have also been found in wear debris induced osteolysis. While the local response to biomaterial wear debris has been characterized quite extensively, very little is known about the systemic effect of biomaterial wear debris on the inflammatory system. The objectives of this study were to evaluate the in vitro and in vivo inflammatory response to different biomaterial debris and to test the ability of the bisphosphonate, risedronate, in inhibiting the expected response. In a co-culture of macrophages and endothelial cells, treated with commercially pure titanium (cpTi) particles and high density polyethylene (HDPE) particles, there were no significant increase in intracellular adhesion molecule-1 (ICAM-1). Similarly, while not statistically significant, the addition of risedronate did lower the ICAM-1 values as compared to no treatment. The second portion of this study was to assess the trajectory of biomaterial particles after being injected into the tail vein of the rat and to determine the effect of particle injection on ICAM-1. Stainless steel (316L SS) and cpTi particles at a dose of 1 x 108 particles per 24 hours were injected into the tail vein of the rat. Two time points were studied: 24 hours after the first injection and 24 hours after the last of four injections (one injection per 24 hours) for a total exposure time of 96 hours. After four injections, particles were observed in the spleens of all animals using light microscopy and the composition of the particles was confirmed using energy dispersive x-ray. At 24 hours, there were no significant differences in ICAM-1 between SS, cpTi or the control groups. However, at 96 hours (or after four injections), the SS group exhibited a significantly higher ICAM-1 response than both the cpTi group and the control group. For the final phase of this project, SS particles were injected into the tail vein of the rat and pro-inflammatory markers, IL-6, TNF-α, ICAM-1 and C-reactive protein (CRP) were measured to see if risedronate could inhibit the inflammatory response. Three time points were analyzed: 1) 24 hours after one injection; 2) 96 hours after the fourth injections (one per day); and 3) 168 hours after the seventh injection. Histology was performed and particles were found in all spleens after one injection of particles as well as after seven injections. Particle injection elicited an increase in all measured parameters that varied over the course of duration. While risedronate did not lower the cytokine response, IL-6 and TNF-α, it did lower the ICAM-1 response (after 168 hours) as well as the CRP response (after 24 hours). This is the first study to describe the systemic inflammatory response to circulating biomaterial debris. As seen in the local response, there was an increase in pro-inflammatory cytokines as well as ICAM-1 and CRP. The bisphosphonate, risedronate, inhibited the ICAM-1 and CRP response and thus may have a potential role in mediating wear debris induced osteolysis and inflammation. Having a therapy that can not only prevent and treat bone loss, but may also inhibit chronic inflammation that may lead to atherosclerosis would be of significant importance.

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