Minimally Invasive Extraction of Dermal Interstitial Fluid for Glucose Monitoring Using Microneedles

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Abstract
Compliance with glucose monitoring by patients with diabetes is poor because of the pain and inconvenience of conventional blood collection using lancets. To improve compliance, and thereby reduce morbidity and mortality associated with poor glucose control, this study sought to develop and test minimally invasive microneedles to extract dermal interstitial fluid (ISF) for glucose monitoring. We used a thermal puller to fabricate individual or multi-needle arrays of glass microneedles with tip radii of 15-40 microm to penetrate 700-1,500 microm deep into the skin of anesthetized hairless rats or conscious, normal, adult, human subjects. After applying a vacuum of 200-500 mm Hg for 2-10 min, we extracted ISF and measured glucose concentration. These measurements were compared with glucose levels in blood collected from the tail vein of rats or finger stick on humans. Using this procedure, 1-10 microL of ISF was extracted out of holes punctured in the skin using microneedles. Human subjects generally reported the procedure as painless. ISF glucose concentration correlated well with blood levels based on 140 measurements on 15 rats and six measurements on six human subjects, where 95% of rat data and 100% of human data fell within the clinically acceptable A + B region in Clarke Error Grid analysis. A linear calibration factor was needed to correlate ISF and blood glucose concentrations using our standard procedure. Modifying the procedure to prevent ISF evaporation during extraction provided a one-to-one correlation that eliminated the need for calibration. ISF glucose measurements tracked rapidly changing blood glucose levels following insulin injection with a time lag of less than 20 min. These results suggest that microneedle devices can be used to extract ISF for painless glucose monitoring.