DIABETES TECHNOLOGY & THERAPEUTICS Volume 10, Number 4, 2008 © Mary Ann Liebert, Inc. DOI: 10.1089/dia.2007.0290 Modeling Glucose and Water Dynamics in Human Skin W. Groenendaal, M.Sc., 1 K.A. Schmidt, Ph.D., 2 G. von Basum, Ph.D., 2 N.A.W. van Riel, Ph.D., 1 and P.A.J. Hilbers, Ph.D. 1 Abstract Background: Glucose is heterogeneously distributed in the different physiological compartments in the human skin. Therefore, for the development of a noninvasive measurement method, both a good quantification of the different compartments of human skin and an understanding of glucose transport processes are important. Methods: The composition of human skin was quantified by histology research. Based on this information a mathematical model was developed to simulate glucose dynamics in human skin. Results: The model predicts dynamically glucose concentrations in the different layers of the skin as a result of changes in blood glucose concentration. The model was validated with published time course data of blood and interstitial fluid glucose during a clamp study with three different set points for blood glucose, and model outcomes were compared to measurements for the lag time and gradient. According to the model, glucose in the interstitial fluid of the dermis best matches the amplitude and dynamics of blood glucose. Conclusions: The new data obtained from quantitative histology appeared crucial for the model. The proposed model was successfully validated. This result was obtained without tuning or fitting of any parameter. It was shown how the model can be used to set standards for measurements and to define the best measurement depth for noninvasive glucose monitoring. 283 Introduction T HE PREVALENCE OF DIABETES has reached enormous pro- portions. The disease is now affecting approximately 7% of the population in the United States. 1 The risk for compli- cations of diabetes can be reduced by good glycemic control. However, in diabetes care decisions for intervention are usu- ally based on self-monitored blood glucose (BG) by finger pricking. These measurements represent but a few minutes of the day, and therefore it is likely that substantial fluctua- tions are not detected. In order to achieve good glycemic con- trol, a continuous measurement system is preferred. In ad- dition, finger pricking is painful, and therefore a noninvasive method, such as spectroscopy of the skin, is more appealing. Currently no noninvasive continuous method has Food and Drug Administration approval. In recent reviews 2,3 the advances are considered. Khalil 2 stated that glucose in the interstitial fluid (ISF), or any other body fluid, can be used as a substitute for BG values only if changes in its magni- tude and duration of change in the blood vessels and tissue are identical. For this reason compartmentalization of glu- cose values (different physiological compartments in human skin are expected to show different glucose levels) has to be understood. It is thus essential to study glucose dynamics in the dif- ferent compartments of the skin. Consequently, two aspects are important: a good definition of the compartments and to understand the transport processes between compartments. Histology research was performed to quantify the compart- ments in human skin. These results were used as input for a new computational model that describes glucose and wa- ter dynamics in total human forearm skin. Human forearm was chosen, because this seems to be a good position for non- invasive continuous measurements. Model validation is an important aspect in model development. In this study the model output was compared to measurements of blood and ISF glucose profiles during a clamp study with three differ- ent setpoints for BG, 4 lag time, 4–8 and gradient values be- tween the blood compartment and the ISF compartments in the different skin layers. 9–13 In the literature no model was found that describes glu- cose and water transport in the different layers of the skin. Models in literature either described whole body glucose dy- namics, 14,15 (detailed) capillary transport, 16,17 or detailed cell 1 Department of Biomedical Engineering, Eindhoven University of Technology, Eindhoven, The Netherlands. 2 Care & Health Applications, Philips Research Eindhoven, Eindhoven, The Netherlands.