Intravital microscopy evaluation of angiogenesis and its effects on glucose sensor performance.

An optical window model for the rodent dorsum was used to perform chronic and quantitative intravital microscopy and laser Doppler flowmetry of microvascular networks adjacent to functional and non-functional glucose sensors. The one-sided configuration afforded direct, real-time observation of the tissue response to bare (unmodified, smooth surface) sensors and sensors coated with porous poly-L-lactic acid (PLLA). Microvessel length density and red blood cell flux (blood perfusion) within 1 mm of the sensors were measured bi-weekly over 2 weeks. When non-functional sensors were fully implanted beneath the windows, the porous coated sensors had two-fold more vasculature and significantly higher blood perfusion than bare sensors on Day 14. When functional sensors were implanted percutaneously, as in clinical use, no differences in baseline current, neovascularization, or tissue perfusion were observed between bare and porous coated sensors. However, percutaneously implanted bare sensors had two-fold more vascularity than fully implanted bare sensors by Day 14, indicating the other factors, such as micromotion, might be stimulating angiogenesis. Despite increased angiogenesis adjacent to percutaneous sensors, modest sensor current attenuation occurred over 14 days, suggesting that factors other than angiogenesis may play a dominant role in determining sensor function.

In vitro and in vivo characterization of porous poly-L-lactic acid coatings for subcutaneously implanted glucose sensors.

The purpose of this study was to test the hypothesis that porous poly-L-lactic acid (PLLA) sensor coatings reduce fibrosis and promote blood microvessel formation in tissue adjacent to the sensor surface. Porous PLLA coatings were produced using ammonium bicarbonate as the gas foaming/salt leaching agent, and deployed on functional and nonfunctional sensors. The porous coatings minimally affected sensor accuracy and response rate in vitro. Three-week subcutaneous rat studies of nonfunctional glucose sensors showed the anticipated effect of porous coatings enhancing vascularity and decreasing collagen deposition. In contrast, percutaneous functional sensors with and without porous coatings showed no significant difference in terms of histology or sensor response. In spite of the observation that texturing increases the vascularity of the tissue that surrounds implanted sensors, other factors such as the additional mechanical stresses imposed by percutaneous tethering may override the beneficial effects of the porous coatings.

Vascular endothelial growth factor and dexamethasone release from nonfouling sensor coatings affect the foreign body response.

Vascular endothelial growth factor (VEGF) and dexamethasone (DX) release from hydrogel coatings were examined as a means to modify tissue inflammation and induce angiogenesis. Antibiofouling hydrogels for implantable glucose sensor coatings were prepared from 2-hydroxyethyl methacrylate, N-vinyl pyrrolidinone, and polyethylene glycol. Microdialysis sampling was used to test the effect of the hydrogel coating on glucose recovery. VEGF-releasing hydrogel-coated fibers increased vascularity and inflammation in the surrounding tissue after 2 weeks of implantation compared to hydrogel-coated fibers. DX-releasing hydrogel-coated fibers reduced inflammation compared to hydrogel-coated fibers and had reduced capsule vascularity compared to VEGF-releasing hydrogel-coated fibers. Hydrogels that released both VEGF and DX simultaneously also showed reduced inflammation at 2 weeks implantation; however, no enhanced vessel formation was observed indicating that the DX diminished the VEGF effect. At 6 weeks, there were no detectable differences between drug-releasing hydrogel-coated fibers and control fibers. From this study, hydrogel drug release affected initial events of the foreign body response with DX inhibiting VEGF, but once the drug depot was exhausted these effects disappeared.