Clinical significance Several groups have reported glucose sensors that have functioned successfully for weeks to months in vivo; however, none of these sensors appear capable of reliable surviving long-term implantation. Our global hypothesis is that membrane modifications and local release strategies that resist biofouling, attenuate inflammation, and reduce the fibrosity and avascularity of the surrounding wound healing tissue will minimize impediments to glucose transport across the sensor membrane. The short term strategy is to examine the effect of anti-inflammatory steroids and/or angiogenic growth factor release on glucose transport to the sensor. Although likely to be effective mediators, we further hypothesize that these approaches are monolithic and prophylactic in their action. In the long term, the highest level of wound healing intervention would be to directly manipulate the macrophages residing in the wound healing tissue surrounding implanted sensor. Currently, the information base necessary to propose a macrophage-centered strategy does not exist. This project therefore takes the first step in this direction: determining the temporal profile of key inflammatory and reparative macrophage-derived cytokines in the sensor implant site. Experimental approach Microdialysis probes implanted in dorsal rat subcutis will be used as a real time method to (1) characterize the transport of glucose across implanted sensor membranes that have been treated to resist biofouling and increase vascularity of the tissue surrounding the implanted probe; and (2) collect cytokines &om the wound healing tissue surrounding the implanted probes. The collected glucose and cytokines will be analyzed by a commercial enzyme-linked microanalyzer and a custom-made antibody array, respectively. The target cytokines are basic-FGF, PDGF, TNF-a, TGF-P, IL-1 receptor antagonist, and IL-1 P, IL-4, IL-6, IL-8 and IL-10, all of which are macrophage-derived mediators of wound healing and inflammation. Correlation between the temporal composition of the cytokine profile, the acquisition of glucose, and the histology of the wound healing tissue under various membrane treatments will be used to: (1) develop a cause- and-effect understandings of sensor membrane modifications on access to blood borne analytes, and (2) assess the participation of macrophages in the wound healing-related decay of implanted sensor performance
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