Clinical Significance. The time course and in vivo concentrations of macrophage-derived inflammatory chemical mediators associated with modulating the foreign body response to implanted materials at the host interface are not fully known. The lack of this needed information for a macrophage-centered hypothesis of biocompatibility is a primary obstacle to developing a quantitative theory of biocompatibility. Our primary hypothesis is that biocompatibility can only become more quantitative with the ability to measure the real time concentrations of chemical interactions/mediators at the biomaterial/tissue interface. Only then can these concentrations be compared to material chemistry, protein adsorption, and the efficacy of bioengineering approaches to wound healing at biomaterial implant sites. Macrophages are important cells associated with the inflammatory response to implanted materials. To achieve our objective of measuring macrophage-derived chemical mediators, the non-selective nature of microdialysis sampling will be used as a means to collect a fraction of the extracellular fluid space surrounding the biomaterial implant. Knowledge of the concentration and temporal profiles of these mediators will provide a more quantitative approach to biocompatibility. This knowledge can be applied to bioengineering approaches for solving problems in biomaterials biocompatibility Experimental Approach. Cultured macrophages will be used to (1) validate and ensure sensitivity of the analytical techniques; and (2) develop an understanding of the potentially complex microdialysis calibration issues that may arise during in vivo studies. For in vivo studies, two microdialysis probes will be implanted into the dorsal subcutis of male Sprague-Dawley rats. One probe will serve as a control and the other probe will either be placed in the presence of the targeted biomaterial (polyurethanes, Nation, PVC, etc.). Zymosan (a product that creates an inflammatory response) will be used as a positive control. The collected dialysate will be analyzed by using specific analytical techniques directed towards the analysis of nitric oxide, oxidative burst, eicosanoids (LTB4 and PGE2), cytokines (TNF-oc, IL-4, and IL-6) and localized elastase activity. Additional animal experiments will explore how localized blood flow is altered during the progression of the foreign body response. The completion of these first time in vivo studies focused on gaining quantitative chemical mediator concentration at the biomaterials implant site will help guide future research focused on modulating macrophage cells at the biomaterial implant site.
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