Problem: Biodegradable implants composed of poly(a-hydroxyesters) (PAEs) are being increasing used for fabricating biodegradable plates, screws, and membranes. Clinically significant morbidity has been reported including an unpredictable foreign body reaction which has necessitated surgical exploration, debridement, and removal of the implants. Purpose: The studies outlined in this application are designed to critically examine the degradation debris associated with the erosion of biodegradable implants and to study the oxidative stress reaction involving degradation debris from biodegradable implants.
Specific Aim I is designed to examine the effect of oxidative stress on degradation debris from biodegradable polymers. This is based on the hypothesis that reactive oxygen species cause alterations in the molecular structure of polymeric microparticles.
Specific Aim 2 is designed to examine protein interactions with free radical-treated polymeric microparticles. It is based on the hypothesis that free radicals produce intrinsic changes in biodegradable polymers which alter their protein binding and biophysical activity. Methods: Three compositions of PAEs will be used including: L-polylactic acid, 50:50 poly(D,L- lactide)-co-glycolide, and 70:30 poly(L-lactide)-co-glycolide. These materials have been used historically either to either deliver growth factors or cells, or as biodegradable plates, screws, and membranes. Degradation debris will be generated by degrading raw material via hydrolysis at 37 C. Particulate debris will be vacuum filtered and characterized using stereological analysis of scanning electron photomicrographs. Image analysis will be performed to examine for circularity, the aspect ratio, angularity, and the fractal dimension. Fenton reagents (Fe+2 and H2O2) in physiologic (IX) and 1OX concentrations and will then be incubated with the debris to generate oxidative stress. To examine the effect of free radicals on PAEs, gel permeation chromatography will be used to determine the weight average molecular weight and polydispersity changes. In order to examine free radical changes which may affect protein interactions, particulate debris will be incubated with Fenton reagents. Xanthine oxidase and alkaline phosphatase will then be incubated with the debris to assess protein activity, the degree of naturation, or denaturation of the bound protein, and the nature of the protein interactions (hydrophobic, ionic, covalent) with the material. Outcomes: ANOVA, confirmed by Student's t-tests, will be used to determine will be used to determine the differences between groups. Data will be considered significant if p less than 0.05. Benefit: Data derived from this study could provide information which would allow modifications to existing biomaterials to provide an enhanced cellular response.
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