A dielectric inverse problem applied to human skin measurements during glucose excursions.

A fringing field capacitive sensor has been used to measure the dielectric properties of human skin and underlying tissue in the MHz frequency range. It has recently been shown in clinical experimental studies that these dielectric properties can be related to the effects of in vivo glucose variations of the test subject. Previously, the relationship between electrical impedance and the glucose level has been established via statistical methods, such as the regression method. In this work, we explored a different approach, namely the resolution of the so-called inverse problem. First we applied the method on an artificial two-layer lossy system in order to test the sensitivity of the solution to forced changes in the layer properties and its stability to a constant setting. After validation of this method on artificial systems, a similar inverse problem was set and solved for dielectric measurements on human skin during an induced glucose excursion, where the skin is also modelled as a double-layer system. The changes of the measured permittivity and conductivity of the second layer versus the glucose changes are calculated for 22 study days. The statistical distribution shows that the median slopes of both dielectric properties are negative. These results can be used to test our hypothesis and to continue building potential explanations for the phenomena induced by the glucose changes on the skin layer dielectric parameters.

Dynamics of blood electrolytes in repeated hyper- and/or hypoglycaemic events in patients with type 1 diabetes.

AIMS/HYPOTHESIS: Electrolyte disturbances are well-known consequences of the diabetic pathology. However, less is known about the cumulative effects of repeated changes in glycaemia, a characteristic of diabetes, on the electrolyte balance. We therefore investigated the ionic profiles of patients with type 1 diabetes during consecutive hyper- and/or hypoglycaemic events using the glucose clamp. METHODS: In protocol 1, two successive hyperglycaemic excursions to 18 mmol/l were induced; in protocol 2, a hypoglycaemic excursion (2.5 mmol/l) was followed by a hyperglycaemic excursion (12 mmol/l) and another hypoglycaemic episode (3.0 mmol/l). RESULTS: Blood osmolarity increased during hyperglycaemia and was unaffected by hypoglycaemia. Hyperglycaemia induced decreases in plasma Na(+) Cl(-) and Ca(2+) concentrations and increases in K(+) concentrations. These changes were faithfully reproduced during a second hyperglycaemia. Hypoglycaemia provoked rapid and rapidly reversible increases in Na(+), Cl(-) and Ca(2+). In sharp contrast, K(+) levels displayed a rapid and substantial fall from which they did not fully recover even 2 h after the re-establishment of euglycaemia. A second hypoglycaemia caused an additional fall. CONCLUSIONS/INTERPRETATION: Repeated hyperglycaemia events do not lead to any cumulative effects on blood electrolytes. However, repeated hypoglycaemias are cumulative with respect to K(+) levels due to a very slow recovery following hypoglycaemia. These results suggest that recurring hypoglycaemic events may lead to progressively lower K(+) levels despite rapid re-establishment of euglycaemia. This warrants close monitoring of plasma K(+) levels combined with continuous glucose monitoring particularly in patients under intensive insulin therapy who are subject to repeated hypoglycaemic episodes. TRIAL REGISTRATION: Clinicaltrial.gov NCT01060917.

The effect of blood content on the optical and dielectric skin properties.

A wearable system incorporating sensors for dielectric and optical spectroscopy was used to study skin properties and their dependence on the cutaneous blood content (CBC). Simultaneous measurements with both modalities were carried out on the upper arm during blood perfusion-provoking exercises performed by four subjects in four separate sets of experiments. By relating changes in the attenuation of green (central wavelength λ(c) = 568 nm) and infrared (λ(c) = 798 nm) light, the ratio of mean pathlengths travelled by photons in the skin blood plexus was obtained. The pathlength for infrared light is found to be 3.85 times larger than for green. Combining signals of two wavelengths and accounting for pathlength difference, we quantitatively characterize the CBC as a cumulative optical thickness of red blood cells in the skin plexus. The dielectric spectra of skin in the MHz range were fitted with the Cole-Cole model and the changes of parameters were quantitatively related to the optically derived changes in CBC using a linear regression analysis. The positive correlation with CBC is obtained for the dispersion exponent (R(2) = 0.68), and the negative-for the dispersion time (R(2) = 0.40). Thus dielectric dispersion of the skin gets broader and shifts towards lower frequencies with an increase of CBC.

Full-field optical coherence tomography for the rapid estimation of epidermal thickness: study of patients with diabetes mellitus type 1.

Changes in morphology of the skin are an important factor that can affect non-invasive measurements performed through this organ, in particular for glucose monitoring in e.g. patients with diabetes mellitus. A characterization technique for non-contact in vivo profiling of the superficial skin layers can be beneficial for evaluation of the performance of such measurement systems. We applied a full-field optical coherence tomography (OCT) system followed by the fully automatic processing for this task. With the developed procedure, non-invasive quantification of the skin morphology can be performed within a few minutes. The dorsal skin of the upper arm of 22 patients with Type 1 Diabetes Mellitus was investigated with an OCT system and with a commercially available dermatological laser scanning confocal microscope (CM) as a reference method. The estimates of epidermal thickness from OCT were compared with the results of expert-assisted analysis of confocal images. The highest correlation with the CM measurements has been obtained for the distance from the entrance peak to the first minimum of the OCT reflection profile (R2 = 0.657, p < 0.0001). In this specific patient group, we have observed a statistically significant correlation of the subjects' body mass index with the distance from the entrance peak to the dermal reflection peak in the OCT profile (p = 0.010). Furthermore, the same OCT parameter is negatively correlated with age with marginal statistical significance (p = 0.062). At the same time, no relation of diabetes-related parameters (duration of disease and concentration of glycated haemoglobin) to the skin morphology observed with the OCT and CM was found.

A wearable diffuse reflectance sensor for continuous monitoring of cutaneous blood content.

An optical diffuse reflectance sensor for characterization of cutaneous blood content and optimized for continuous monitoring has been developed as part of a non-invasive multisensor system for glucose monitoring. A Monte Carlo simulation of the light propagation in the multilayered skin model has been performed in order to estimate the optimal geometrical separation of the light source and detector for skin and underlying tissue. We have observed that the pathlength within the upper vascular plexus of the skin which defines the sensor sensitivity initially grows with increasing source-detector distance (SDD) before reaching a maximum at 3.5 mm and starts to decay with further increase. At the same time, for distances above 2.4 mm, the sensor becomes sensitive to muscle blood content, which decreases the specificity to skin perfusion monitoring. Thus, the SDDs in the range from 1.5 mm to 2.4 mm satisfy the requirements of sensor sensitivity and specificity. The hardware implementation of the system has been realized and tested in laboratory experiments with a venous occlusion procedure and in an outpatient clinical study in 16 patients with type 1 diabetes mellitus. For both testing procedures, the optical sensor demonstrated high sensitivity to perfusion change provoking events. The general build-up of cutaneous blood under the sensor has been observed which can be associated with pressure-induced vasodilation as a response to the sensor application.

Non-invasive glucose monitoring in patients with diabetes: a novel system based on impedance spectroscopy.

The aim of this work was to evaluate the performance of a novel non-invasive continuous glucose-monitoring system based on impedance spectroscopy (IS) in patients with diabetes. Ten patients with type 1 diabetes (mean+/-S.D., age 28+/-8 years, BMI 24.2+/-3.2 kg/m(2) and HbA(1C) 7.3+/-1.6%) and five with type 2 diabetes (age 61+/-8 years, BMI 27.5+/-3.2 kg/m(2) and HbA(1C) 8.3+/-1.8%) took part in this study, which comprised a glucose clamp experiment followed by a 7-day outpatient evaluation. The measurements obtained by the NI-CGMD and the reference blood glucose-measuring techniques were evaluated using retrospective data evaluation procedures. Under less controlled outpatient conditions a correlation coefficient of r=0.640 and a standard error of prediction (SEP) of 45 mg dl(-1) with a total of 590 paired glucose measurements was found (versus r=0.926 and a SEP of 26 mg dl(-1) under controlled conditions). Clark error grid analyses (EGA) showed 56% of all values in zone A, 37% in B and 7% in C-E. In conclusion, these results indicate that IS in the used technical setting allows retrospective, continuous and truly non-invasive glucose monitoring under defined conditions for patients with diabetes. Technical advances and developments are needed to expand on this concept to bring the results from the outpatient study closer to those in the experimental section of the study. Further studies will not only help to evaluate the performance and limitations of using such a technique for non non-invasive glucose monitoring but also help to verify technical extensions towards a IS-based concept that offers improved performance under real life operating conditions.

Impact of environmental temperature on skin thickness and microvascular blood flow in subjects with and without diabetes.

BACKGROUND: Glucose measurement from different skin areas might be influenced by changes in skin texture due to several environmental confounders. Our study was performed to investigate the effect of changes in ambient temperature on skin thickness and microvascular skin blood flow in subjects with and without diabetes at the lower forearm. METHODS: Thirteen subjects with diabetes and seven without diabetes participated in the study. The investigations were performed in a temperature- and humidity-controlled climatic chamber (EMPA, St. Gallen, Switzerland). Starting at 25 degrees C, the environmental temperature was changed in 4 degrees C steps every 40 min. Skin thickness was measured by an ultrasonic reflection technique, and microcirculation was measured by laser Doppler fluxmetry at the lower forearm. Study participants underwent the entire procedure on up to four separate study trials. RESULTS: Our study revealed a significantly reduced skin thickness (P<0.05) and microvascular blood flow (P<0.05) in patients with diabetes mellitus compared with controls without diabetes during the entire investigation. During declining ambient temperature a significant reduction in skin thickness (with diabetes, -0.09+/-0.13 mm; without diabetes, -0.06+/-0.11 mm; P<0.05) and microvascular blood flow (with diabetes, -41+/-49 arbitrary units; without diabetes, -46+/-51 arbitrary units; P<0.05) could be observed in both groups without significant differences between the two. CONCLUSIONS: Although skin thickness and microvascular skin blood flow at the lower forearm were found to be reduced in patients with diabetes compared with controls without diabetes, both groups revealed comparable dynamics in skin thickness and microvascular blood flow during changes in environmental temperature.

First human experiments with a novel non-invasive, non-optical continuous glucose monitoring system.

This paper describes a non-invasive continuous glucose monitoring system based on impedance spectroscopy. Changes in the glucose concentrations can be monitored by varying the frequency in the radio band over a range, optimised to measure the impact of glucose on the impedance pattern. A number of clinical-experimental studies (hyperglycaemic excursions) were performed with healthy subjects in order to prove the applicability of this approach. The sensor used in these experiments is the size of a wristwatch and holds an open resonant circuit coupled to the skin and a circuit, performing an impedance measurement. In most cases, the experiments showed a good correlation between changes in blood glucose and the sensor recordings. A detailed description of the trials is presented. The results of this first series of experiments can be considered as a proof of concept for this novel non-invasive monitoring approach. Nevertheless, partly due to the indirect measurement, a considerable number of questions remain to be clarified.