There is a need for blood glucose monitoring techniques that eliminate the painful and invasive nature of current methods, while maintaining the reliability and accuracy of established medical technology. This research aims to ultimately address these shortcomings in critically ill pediatric patients. Presented in this work is an alternative, minimally invasive technique that uses microneedles (MN) for the collection of transdermal glucose (TG). Due to their comparable skin properties, diffusion studies were performed on full thickness Yucatan miniature pig skin mounted to an in-line diffusion flow cell and on different skin sites of human subjects. Collected TG samples were measured with a L255C mutant of the E. coli glucose-binding protein (GBP) with an attached fluorescent probe. The binding constant (K = 0.67 μM) revealed the micromolar sensitivity and high selectivity of the his-tagged GBP biosensor for glucose, making it suitable for TG measurements. In both the animal and human models, skin permeability and TG diffusion across the skin increased with MN application. For intact and MN-treated human skin, a significant positive linear correlation (r > 0.95, p < 0.01) existed between TG and BG. The micromolar sensitivity of GBP minimized the volume required for interstitial fluid glucose analysis allowing MN application time (30 s) to be shortened compared to other studies. This time reduction can help in eliminating skin irritation issues and improving practical use of the technique by caregivers in the hospital. In addition, the his-tagged optical biosensor used in this work can be immobilized and used with a portable sensing fluorometer device at the point of care (POC) making this minimally invasive technology more ideal for use in the pediatric intensive care unit. Graphical abstract ᅟ.
Due to high variability during clinical pharmacokinetic (PK) evaluation, the prediction of in vivo exposure from in vitro absorption testing of topical semisolid and liquid dermal products has historically proven di cult. Since absorption from unoccluded formulations can be in uenced by environmental factors such as temperature and humidity, maximal effort must be placed on the harmonization of experimental parameters between in vitro and in vivo testing conditions to establish accurate in vitro/in vivo correlations (IVIVC). Using four different sunscreen formulations as a model, we performed in vitro permeation testing (IVPT) studies with excised human skin and maintained strict harmonization techniques to control application time, occlusion, temperature and humidity during in vivo human serum PK evaluation. The goal was to investigate if increased control over experimental parameters would result in decreased intersubject variability of common topical formulations leading to acceptable IVIVC establishment. Using a deconvolution-based approach, excellent point-to-point (Level A correlation) IVIVC for the entire 12 h study duration was achieved for all four sunscreen formulations with < 10% prediction error of both area under the curve (AUC) and peak concentration (C max ) estimation. The low variability of in vivo absorption data presents a proof-of-concept protocol design for testing of complex semisolid and liquid topical formulations applied over a large surface area with reapplication in a reliable manner. This work also presents the opportunity for expanded development of testing for the impact of altered temperature and humidity conditions on product absorption in vivo with a high degree of precision.
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