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Funding: William Demant Foundation

In this paper we would like to clarify a essential question: "Why is impedance or dielectric spectroscopy sensitive to changes in glucose concentration in blood and why can this be done over a very broad frequency band, including microwaves?" Medical diagnostics would greatly benefit from an answer. Towards this, we want to summarize the underlying physics and base directions towards exploiting this direction. It is our impression that current worldview on the dielectric response of glucose in solution, as outlined below, will support the further evolution of practical noninvasive glucose monitoring solutions.

With diabetes set to become the number 3 killer in the Western hemisphere and proportionally growing in other parts of the world, the subject of noninvasive monitoring of glucose dynamics in blood remains a "hot" topic, with the involvement of many groups worldwide. There is a plethora of techniques involved in this academic push, but the so-called multisensor system with an impedance-based core seems to feature increasingly strongly. However, the symmetrical structure of the glucose molecule and its shielding by the smaller dipoles of water would suggest that this option should be less enticing. Yet there is enough phenomenological evidence to suggest that impedance-based methods are truly sensitive to the biophysical effects of glucose variations in the blood. We have been trying to answer this very fundamental conundrum: "Why is impedance or dielectric spectroscopy sensitive to glucose concentration changes in the blood and why can this be done over a very broad frequency band, including microwaves?" The vistas for medical diagnostics are very enticing. There have been a significant number of papers published that look seriously at this problem. In this review, we want to summarize this body of research and the underlying mechanisms and propose a perspective toward utilizing the phenomena. It is our impression that the current world view on the dielectric response of glucose in solution, as outlined below, will support the further evolution and implementation toward practical noninvasive glucose monitoring solutions.

Ecological validity is a relatively new concept in hearing science. It has been cited as relevant with increasing frequency in publications over the past 20 years, but without any formal conceptual basis or clear motive. The sixth Eriksholm Workshop was convened to develop a deeper understanding of the concept for the purpose of applying it in hearing research in a consistent and productive manner. Inspired by relevant debate within the field of psychology, and taking into account the World Health Organization's International Classification of Functioning, Disability, and Health framework, the attendees at the workshop reached a consensus on the following definition: "In hearing science, ecological validity refers to the degree to which research findings reflect real-life hearing-related function, activity, or participation." Four broad purposes for striving for greater ecological validity in hearing research were determined: A (Understanding) better understanding the role of hearing in everyday life; B (Development) supporting the development of improved procedures and interventions; C (Assessment) facilitating improved methods for assessing and predicting ability to accomplish real-world tasks; and D (Integration and Individualization) enabling more integrated and individualized care. Discussions considered the effects of variables and phenomena commonly present in hearing-related research on the level of ecological validity of outcomes, supported by examples from a few selected outcome domains and for different types of studies. Illustrated with examples, potential strategies were offered for promoting a high level of ecological validity in a study and for how to evaluate the level of ecological validity of a study. Areas in particular that could benefit from more research to advance ecological validity in hearing science include: (1) understanding the processes of hearing and communication in everyday listening situations, and specifically the factors that make listening difficult in everyday situations; (2) developing new test paradigms that include more than one person (e.g., to encompass the interactive nature of everyday communication) and that are integrative of other factors that interact with hearing in real-life function; (3) integrating new and emerging technologies (e.g., virtual reality) with established test methods; and (4) identifying the key variables and phenomena affecting the level of ecological validity to develop verifiable ways to increase ecological validity and derive a set of benchmarks to strive for.

With an ongoing shift from managing disease toward the inclusion of maintaining health and preventing disease, the world has seen the rise of increasingly sophisticated physiological monitoring and analytics. Innovations range from wearables, smartphone-based spot monitoring to highly complex noncontact, remote monitoring, utilizing different mechanisms. These tools empower the individual to better navigate their own health. They also generate powerful insights towards the detection of subclinical symptoms or processes via existing and novel digital biomarkers. In that context, a topic that is receiving increasing interest is the modulation of human physiology around an individual "baseline" in everyday life and the impact thereof on other sensorineural body functions such as hearing. More and more fully contextualized and truly long-term physiological data are becoming available that allows deeper insights into the response of the human body to our behavior, immediate environment and the understanding of how chronic conditions are evolving. Hearing loss often goes hand in hand with chronic conditions, such as diabetes, cognitive impairment, increased risk of fall, mental health, or cardiovascular risk factors. This inspires an interest to not only look at hearing impairment itself but to take a broader view, for example, to include contextualized vital signs. Interestingly, stress and its physiological implications have also been shown to be a relevant precursor to hearing loss and other chronic conditions. This article deduces the requirements for wearables and their ecosystems to detect relevant dynamics and connects that to the need for more ecologically valid data towards an integrated and more holistic mapping of hearing characteristics.

Even if still at an early stage of development, non-invasive continuous glucose monitoring (NI-CGM) sensors represent a promising technology for optimizing diabetes therapy. Recent studies showed that the Multisensor provides useful information about glucose dynamics with a mean absolute relative difference (MARD) of 35.4% in a fully prospective setting. Here we propose a method that, exploiting the same Multisensor measurements, but in a retrospective setting, achieves a much better accuracy. Data acquired by the Multisensor during a long-term study are retrospectively processed following a two-step procedure. First, the raw data are transformed to a blood glucose (BG) estimate by a multiple linear regression model. Then, an enhancing module is applied in cascade to the regression model to improve the accuracy of the glucose estimation by retrofitting available BG references through a time-varying linear model. MARD between the retrospectively reconstructed BG time-series and reference values is 20%. Here, 94% of values fall in zone A or B of the Clarke Error Grid. The proposed algorithm achieved a level of accuracy that could make this device a potential complementary tool for diabetes management and also for guiding prediabetic or nondiabetic users through life-style changes.

Background: Extensive past work showed that noninvasive continuous glucose monitoring with a wearable Multisensor device worn on the upper arm provides useful information about glucose trends to improve diabetes therapy in controlled and semicontrolled conditions. Methods: To test previous findings also in uncontrolled in-clinic and outpatient conditions, a long-term study has been conducted to collect Multisensor and reference glucose data in a population of 20 type 1 diabetes subjects. A total of 1072 study days were collected and a fully on-line compatible algorithmic routine linking Multisensor data to glucose applied to estimate glucose trends noninvasively. The operation of a digital log book, daily semiautomated data transfer and at least 10 daily SMBG values were requested from the patient. Results: Results showed that the Multisensor is capable of indicating glucose trends. It can do so in 9 out of 10 cases either correctly or with one level of discrepancy. This means that in 90% of all cases the Multisensor shows the glucose dynamic to rapidly increase or at least increase. Conclusions: The Multisensor and the algorithmic routine used in controlled conditions can track glucose trends in all patients, also in uncontrolled conditions. Training of the patient proved to be essential. The workload imposed on patients was significant and should be reduced in the next step with further automation. The feature of glucose trend indication was welcomed and very much appreciated by patients; this value creation makes a strong case for the justification of wearing a wearable.

Background: Extensive past work showed that noninvasive continuous glucose monitoring with a wearable multisensor device worn on the upper arm provides useful information about glucose trends to improve diabetes therapy in controlled and semicontrolled conditions. Method: To test previous findings also in uncontrolled conditions, a long term at home study has been organized to collect multisensor and reference glucose data in a population of 20 type 1 diabetes subjects. A total of 1072 study days were collected and a fully on-line compatible algorithmic routine linking multisensor data to glucose applied to estimate glucose levels noninvasively. Results: The algorithm used here calculates glucose values from sensor data and adds a constant obtained by a daily calibration. It provides point inaccuracy measured by a MARD of 35.4 mg/dL on test data. This is higher than current state-of-the-art minimally invasive devices, but still 86.9% of glucose rate points fall within the zone AR+BR. Conclusions: The multisensor device and the algorithmic routine used earlier in controlled conditions tracks glucose changes also in uncontrolled conditions, although with lower accuracy. The examination of learning curves suggests that obtaining more data would not improve the results. Therefore, further efforts would focus on the development of more complex algorithmic routines able to compensate for environmental and physiological confounders better.

In diabetes research, non-invasive continuous glucose monitoring (NI-CGM) devices represent a new and appealing frontier. In the last years, some multi-sensor devices for NI-CGM have been proposed, which exploit several sensors measuring phenomena of different nature, not only for measuring glucose related signals, but also signals reflecting some possible perturbing processes (temperature, blood perfusion). Estimation of glucose levels is then obtained combining these signals through a mathematical model which requires an initial calibration step exploiting one reference blood glucose (RBG) sample. Even if promising results have been obtained, especially in hospitalized volunteers, at present the temporal accuracy of NI-CGM sensors may suffer because of environmental and physiological interferences. The aim of this work is to develop a general methodology, based on Monte Carlo (MC) simulation, to assess the robustness of the calibration step used by NI-CGM devices against these disturbances. The proposed methodology is illustrated considering two examples: the first concerns the possible detrimental influence of sweat events, while the second deals with calibration scheduling. For implementing both examples, 45 datasets collected by the Solianis Multisensor system are considered. In the first example, the MC methodology suggests that no further calibration adjustments are needed after the occurrence of sweat events, because the “Multisensor+model” system is able to deal with the disturbance. The second case study shows how to identify the best time interval to update the model’s calibration for improving the accuracy of the estimated glucose. The methodology proposed in this work is of general applicability and can be helpful in making those incremental steps in NI-CGM devices development needed to further improve their performance.

Recent work has demonstrated that the reflection coefficient of human skin in the frequency range from 95 to 110 GHz (W band) mirrors the temporal relaxation of stress induced by physical exercise. In this work, we extend these findings to show that in the event of a subtle trigger to stress, such as mental activity, a similar picture of response emerges. Furthermore, the findings are extended to cover not only the W band (75-110 GHz), but also the frequency band from 110 to 170 GHz (D band). We demonstrate that mental stress, induced by the Stroop effect and recorded by the galvanic skin response (GSR), can be correlated to the reflection coefficient in the aforementioned frequency bands. Intriguingly, a light physical stress caused by repeated hand gripping clearly showed an elevated stress level in the GSR signal, but was largely unnoted in the reflection coefficient in the D band. The implication of this observation requires further validation.

Hyperglycaemia is well known to cause reductions in plasma Na(+) levels or even hyponatraemia due to an osmotically induced dilution of the interstitium and blood. It is, however, unclear whether this dilution is significantly counteracted by ion regulatory homeostatic mechanism(s) or not. Furthermore, the effects of moderate hyperglycaemia on other major ions are less well known. To further clarify these questions, we measured the changes in blood osmolarity and concentrations of Na(+), K(+), Cl(-), Mg(2+) and Ca(2+) during a 4-h-long experimental hyperglycaemia in healthy subjects rendered temporarily insulin deficient using the hyperglycaemic clamp. Hyperglycaemia, 16.8 mM, was rapidly imposed from a baseline of 4.4 mM by intravenous somatostatin and glucose infusions in 19 healthy subjects (10 m, 9 f; age 36 ± 5 years (mean ± SD); BMI 22.7 ± 2.9 kg/m(2)). Subsequently, glycaemia was returned to basal and measurements continued until all dynamic changes had stopped (at ~8 h). Osmolarity increased from 281.8 ± 0.7 to 287.9 ± 0.7, while Na(+) decreased from 143.9 ± 0.3 to 138.7 ± 0.2, Cl(-) from 101.7 ± 0.2 to 99.5 ± 0.1, Ca(2+) from 1.98 ± 0.04 to 1.89 ± 0.02 and Mg(2+) from 0.84 ± 0.01 to 0.80 ± 0.00 mM. All these changes were rapidly reaching stable levels. K(+) increased from 4.02 ± 0.02 to 4.59 ± 0.02 mM (P0.0001) also reaching stable levels but with some delay. Na(+), Cl(-), Mg(2+) and Ca(2+) are essentially determined by blood dilution, and their values will remain diminished as long as the hyperglycaemia lasts. Partial suppression of insulin-stimulated Na(+)/K(+) pumping lead to increased K(+) levels. The combination of elevated K(+) and decreased Mg(2+) and Ca(2+) levels may lead to an altered excitability, which is particularly relevant for diabetic patients with heart disease.

Background: Impedance spectroscopy has been shown to be a candidate for noninvasive continuous glucose monitoring in humans. However, in addition to glucose, other factors also have effects on impedance characteristics of the skin and underlying tissue. Method: Impedance spectra were summarized through a principal component analysis and relevant variables were identified with Akaike’s information criterion. In order to model blood glucose, a linear least-squares model was used. A Monte Carlo simulation was applied to examine the effects of personalizing models. Results: The principal component analysis was able to identify two major effects in the impedance spectra: a blood glucose-related process and an equilibration process related to moisturization of the skin and underlying tissue. With a global linear least-squares model, a coefficient of determination ( R 2 ) of 0.60 was achieved, whereas the personalized model reached an R 2 of 0.71. The Monte Carlo simulation proved a significant advantage of personalized models over global models. Conclusion: A principal component analysis is useful for extracting glucose-related effects in the impedance spectra of human skin. A linear global model based on Solianis Multisensor data yields a good predictive power for blood glucose estimation. However, a personalized linear model still has greater predictive power.

The Multisensor Glucose Monitoring System (MGMS) features non invasive sensors for dielectric characterisation of the skin and underlying tissue in a wide frequency range (1 kHz–100 MHz, 1 and 2 GHz) as well as optical characterisation. In this paper we describe the results of using an MGMS in a miniaturised housing with fully integrated sensors and battery. Six patients with Type I Diabetes Mellitus (age 44 ± 16 y; BMI 24.1 ± 1.3 kg/m2, duration of diabetes 27 ± 12 y; HbA1c 7.3 ± 1.0%) wore a single Multisensor at the upper arm position and performed a total of 45 in-clinic study days with 7 study days per patient on average (min. 5 and max. 10). Glucose changes were induced either orally or by i.v. glucose administration and the blood glucose was measured routinely. Several prospective data evaluation routines were applied to evaluate the data. The results are shown using one of the restrictive data evaluation routines, where measurements from the first 22 study days were used to train a linear regression model. The global model was then prospectively applied to the data of the remaining 23 study days to allow for an external validation of glucose prediction. The model application yielded a Mean Absolute Relative Difference of 40.8%, a Mean Absolute Difference of 51.9 mg dL−1, and a correlation of 0.84 on average per study day. The Clarke error grid analyses showed 89.0% in A + B, 4.5% in C, 4.6% in D and 1.9% in the E region. Prospective application of a global, purely statistical model, demonstrates that glucose variations can be tracked non invasively by the MGMS in most cases under these conditions.

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.

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.

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.

We propose a key role for the glucose transporter 1 (GLUT1) in mediating the observed changes in the dielectric properties of human erythrocyte membranes as determined by dielectric spectroscopy. Cytochalasin B, a GLUT1 transport inhibitor, abolished the membrane capacitance changes in glucose-exposed red cells. Surprisingly, D-fructose, known to be transported primarily by GLUT5, exerted similar membrane capacitance changes at increasing D-fructose concentrations. In order to evaluate whether the glucose-mediated membrane capacitance changes originated directly from intracellularly bound adenosine triphosphate (ATP) or other components of the glycolysis process, we studied the dielectric responses of swollen erythrocytes with a decreased ATP content and of nucleotide-filled ghosts. Resealed ghosts containing physiological concentrations of ATP yielded the same glucose-dependent capacitance changes as biconcave intact red blood cells, further supporting the finding that ATP is the effector of the glucose-mediated dielectric response where the ATP concentration is also the mediating factor in swollen red blood cells. The results suggest that ATP binding to GLUT1 elicits a membrane capacitance change that increases with the applied concentration gradient of D-glucose. A simplified model of the membrane capacitance alteration with glucose uptake is proposed.

Impedance spectroscopy has been shown to provide a great potential as a measuring technique for monitoring human blood glucose. The two major potential benefits are the ability to perform non-invasive and continuous measurements. Previous work has outlined the range of challenges of such an impedance based technique. Our impedance sensor is composed of several capacitive fringing field electrodes with various characteristic geometries to achieve the desired penetration depths in human skin and the underlying tissue. A comparison of the measurements made on reference materials of known dielectric properties with the results of electromagnetic field simulations allows sensor characterization to be achieved and provides the ability to optimize the sensor geometry. Such comparisons reveal that the measurements and simulations are in qualitative agreement with the expected impedance behavior, i.e. there is a larger sensitivity to changes in the dielectric properties of the deeper layer for electrodes with a deeper penetration of the electromagnetic field (EMF). Another conclusion is that, despite the approximations made in the simulation process, the measured and simulated quantities agree. This opens the possibility to use simulations to define the functional relation between the measured impedances and the layers dielectric parameters in order to correlate impedance changes with glucose concentration changes.

Background: We study here the influence of different patients and the influence of different devices with the same patients on the signals and modeling of data from measurements from a noninvasive Multisensor glucose monitoring system in patients with type 1 diabetes. The Multisensor includes several sensors for biophysical monitoring of skin and underlying tissue integrated on a single substrate. Method: Two Multisensors were worn simultaneously, 1 on the upper left and 1 on the upper right arm by 4 patients during 16 study visits. Glucose was administered orally to induce 2 consecutive hyperglycemic excursions. For the analysis, global (valid for a population of patients), personal (tailored to a specific patient), and device-specific multiple linear regression models were derived. Results: We find that adjustments of the model to the patients improves the performance of the glucose estimation with an MARD of 17.8% for personalized model versus a MARD of 21.1% for the global model. At the same time the effect of the measurement side is negligible. The device can equally well measure on the left or right arm. We also see that devices are equal in the linear modeling. Thus hardware calibration of the sensors is seen to be sufficient to eliminate interdevice differences in the measured signals. Conclusions: We demonstrate that the hardware of the 2 devices worn on the left and right arms are consistent yielding similar measured signals and thus glucose estimation results with a global model. The 2 devices also return similar values of glucose errors. These errors are mainly due to nonstationarities in the measured signals that are not solved by the linear model, thus suggesting for more sophisticated modeling approaches.

In this paper, we report on the influence of D- and L-glucose on the dielectric properties of native shaped (biconcave) human erythrocytes using time domain dielectric spectroscopy. The dielectric spectra of biconcave cells were analysed using a modified form of the model originally reported for spheroid particle suspensions (Asami and Yonezawa 1995 Biochim. Biophys. Acta. 1245 317–24) The observed increase in the specific membrane capacitance of the biconcave erythrocytes was correlated with an increase in the concentration of D-glucose. In contrast, no associated correlation was found to changes in the membrane capacitance with increasing concentrations of L-glucose. A similar analysis of the dielectric response of osmotically swollen erythrocytes to changes in D-glucose concentration revealed a significantly different calculated specific cell membrane capacitance at elevated (>12 mM) D-glucose concentrations. The paper outlines and discusses the possible biochemical mechanisms that could be responsible for the measured dielectric properties of the erythrocyte membrane capacitances.

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.

There is a requirement for the development of non-invasive continuous blood glucose monitoring devices to meet the clinical demands of the rapidly increasing number of people currently developing diabetes mellitus. Impedance spectroscopy is a technology that meets the requirements of such devices. An NI CGMD is being developed as a device that couples a sensor to the skin to form an RCL sensor. The reliability of such an RCL sensor model has been investigated by comparing electrodynamical simulations to in-vitro measurements of dielectrically "lossy" materials. The sensor has been modeled and simulated in FEMLAB (finite element modeling laboratory). In-vitro measurements are performed on hydrogels, representing the lossy material, by the aid of a Rohde & Schwarz VNA (vector network analyzer). From the quantitative agreement of the results we conclude, that the proposed qualitative model is appropriate for the characterization of the RCL sensor and suggests that more detailed models can be used to elucidate the behavior of human skin tissue.

The kinetics of d-glucose influence on spherical human erythrocyte and ghost suspensions, which were prepared from fresh blood provided by healthy donors, was studied by time domain dielectric spectroscopy (TDDS) in a wide physiologic range of glucose concentrations. The dielectric response of cell membranes was found to demonstrate a nonmonotonic behavior in the vicinity of 12 mM concentration of d-glucose in both cell and ghost suspensions. In contrast to spherical cells, where the membrane effect after exposure to d-glucose was reduced after 15−30 min, no reaction was detected in the case of ghosts. The possible mechanisms of glucose transport through the membrane and metabolism are discussed in this paper.

Impedance spectroscopy allows for the assessment of changes in the permittivity and conductivity of erythrocyte cell membranes, induced by blood glucose variations. This study was performed to evaluate the potential influence of motion-induced microvascular blood flow variations from different forearm postures on the PENDRA (Pendragon Medical AG, Zürich, Switzerland) signal. Fifteen volunteers without diabetes were included (seven female, eight male, mean +/- SD age 33.3 +/- 9.9 years, body mass index 24.8 +/- 3.0 kg/m(2)). PENDRA devices were fixed at both upper extremities with different fixation techniques (bracelet and adhesive tape). Standardized position changes of the upper extremities were performed to induce variations in cutaneous microcirculation, which were assessed by laser-Doppler-fluxmetry with different probe temperatures on the forearm. Changes in microcirculation were seen in some of the different motion procedures: supine to hanging, 61.1 +/- 29.9 arbitrary units (AU) to 46.2 +/- 24.8 AU at 37 degrees C and 15.9 +/- 13.0 AU to 13.4 +/- 10.1 at skin temperature (P0.01 for both probes); supine to upright, 80.5 +/- 55.4 AU to 74.9 +/- 43.8 AU (not significant) at 37 degrees C and 18.7 +/- 16.8 AU to 20.9 +/- 16.1 AU at skin temperature (P0.01). An initially observed subtle influence of microcirculation variations on the impedance signal was minimized when the device was fixed by both bracelet and tape. Other influencing factors (such as temperature, local anatomy, etc.) are addressed in the complex calibration procedure. Well-educated patients might be the best candidates for first using the device for continuous glucose monitoring. They may especially benefit from the trend indication and the hypoglycemia/hyperglycemia threshold and alarm functions.

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.

Time domain dielectric spectroscopy has been used to study spherical erythrocytes, suspended in diluted phosphate buffered saline (PBS) buffers at varying concentrations of D- and L-glucose at 25°C. The osmolarity for each glucose solution was adapted, equalling that of a 63% PBS (183 mOsm). The strong effect of the electrode polarization was corrected using the fractal approach in time domain. For analysis of the dielectric properties of suspensions of erythrocytes, the Maxwell–Wagner model is used for small volume fractions. Values of the permittivity and conductivity of the cell membrane were obtained from a fitting procedure according to the one-shell model. The non-monotonic and specific response of membrane electric properties on D-glucose concentrations were observed, with a dramatic decrease around 12 mM. No changes of membrane properties have been observed in the presence of increasing concentrations of L-glucose, the biologically inactive enantiomer of D-glucose. The effect is thus specific to D-glucose. The possible mechanism of specific cell reaction to D-glucose is discussed in this paper.

Previous developments of dielectric spectroscopy based non-invasive continuous monitoring devices have indicated that the measured impedances of the skin and underlying tissue can be influenced by a number of perturbing parameters such as changes in humidity, sweating and blood perfusion. Therefore successful glucose monitoring requires a range of sensors to be developed and combined in a multisensor concept to measure changes in such perturbing parameters. This work evaluates the feasibility of using the developed components of such a multisensor system to make corrections to the impedance measurements.

Continuous glucose monitoring (CGM) by suitable portable sensors plays a central role in the treatment of diabetes, a disease currently affecting more than 350 million people worldwide. Noninvasive CGM (NI-CGM), in particular, is appealing for reasons related to patient comfort (no needles are used) but challenging. NI-CGM prototypes exploiting multisensor approaches have been recently proposed to deal with physiological and environmental disturbances. In these prototypes, signals measured noninvasively (e.g., skin impedance, temperature, optical skin properties, etc.) are combined through a static multivariate linear model for estimating glucose levels. In this work, by exploiting a dataset of 45 experimental sessions acquired in diabetic subjects, we show that regularisation-based techniques for the identification of the model, such as the least absolute shrinkage and selection operator (better known as LASSO), Ridge regression, and Elastic-Net regression, improve the accuracy of glucose estimates with respect to techniques, such as partial least squares regression, previously used in the literature. More specifically, the Elastic-Net model (i.e., the model identified using a combination of ${l}_{1}$ and ${l}_{2}$ norms) has the best results, according to the metrics widely accepted in the diabetes community. This model represents an important incremental step toward the development of NI-CGM devices effectively usable by patients.

Recent studies of the minute morphology of the skin by optical coherence tomography showed that the sweat ducts in human skin become helically shaped tubes in the Epidermis and are filled with an aqueous solution. When considered as entities embedded in a dielectric media, they resemble helical antennas. The spectral response obtained by our computer simulations coincides with the analytical prediction of antenna theory and support this hypothesis, if a fast enough current mechanism exists in the duct. In particular the strongest spectral response of the simulation was noted around the predicted frequencies (240 GHz and 380 GHz) for the respective normal and axial modes of the helical structure. Furthermore, circular dichroism of the reflected electromagnetic field is a characteristic property of such helical antennas and it was shown that it is indeed a characteristic of the simulation model. Fast proton hopping is posited as the current mechanism. Consequently experimental evidence is presented that the spectral response of the skin in the sub-Terahertz region is governed by the level of activity of the perspiration system. This in turn is moderated by the Sympathetic Nerve Response and is demonstrated by the correlation to physiological stress as manifested by the pulse rate and the systolic blood pressure. These physical relaxations are tonic in nature (lasting more than a minute). Could the phasic characteristic of emotional excitation also be evident in the reflection coefficient? By applying techniques borrowed from psychiatric science we hope to answer this point in our paper.

Non-invasive continuous glucose monitoring (NI-CGM) sensors are still at an early stage of development, but, in the near future, they could become particularly appealing in diabetes management. Solianis Monitoring AG (Zurich, Switzerland) has proposed an approach for NI-CGM based on a multi-sensor concept, embedding primarily dielectric spectroscopy and optical sensors. This concept requires a mathematical model able to estimate glucose levels from the 150 channels directly measured through the Multisensor. A static multivariate linear regression model (with order and parameters common to the entire population of subjects) was proposed for such a scope (Caduff et al., Biosens Bioelectron 26:3794–3800, 2011). The aim of this work is to evaluate the accuracy in the estimation of glucose levels and trends that the NI-CGM Multisensor platform can achieve by exploiting different techniques for model identification, namely, ordinary least squares, subset variable selection, partial least squares and least absolute shrinkage and selection operator (LASSO). Data collected in human beings monitored for a total of 45 study days were used for model identification and model test. Several metrics of standard use in the diabetes scientific community to measure point and clinical accuracy of glucose sensors were used to assess the models. Results indicate that the LASSO technique is superior to the others shrinking many channel weights to zero thus leading to smoother glucose profiles and resulting in a more robust model to possible artifacts in the Multisensor data. Although, as expected, the performance of the NI-CGM system with the LASSO model is not yet comparable with that of enzyme-based needle glucose sensors, glucose trends are satisfactorily estimated. Considering the non-invasive nature of the multi-sensor platform, this result can have an immediate impact in the current clinical practice, e.g., to integrate sparse self-monitoring of blood glucose data with an indication of the glucose trend to aid the diabetic patient in dealing with, or even preventing in the short time scale, the threats of critical events such as hypoglycaemia.

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.

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. 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). Blood osmolarity increased during hyperglycaemia and was unaffected by hypoglycaemia. Hyperglycaemia induced decreases in plasma Na+ Cl− and Ca2+ 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 Ca2+. 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. 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. Clinicaltrial.gov NCT01060917. Pendragon Medical AG, Solianis Monitoring AG

The sub-coetaneous structures of human skin have been revealed to contain elements that demonstrate electromagnetic behavior in the sub-THz frequency range, reminiscent of low Q helical antennas. The structure in question is the coiled human sweat duct inside the epidermis. It was shown that the temporal behavior of the reflected spectral response mirrored physiological parameters such as blood pressure to a high degree of correlation. The current paper presents the experimental evidence of such and explores its parameters in terms of stress imposed on the subject.

It is widely accepted that noninvasive glucose monitoring (NIGM) has the potential to revolutionize diabetes therapy. However, current approaches to NIGM studied to date have not yet demonstrated a level of acceptable functionality to allow real-time use, beyond restricted fields of application. A number of reviews have been devoted to the subject of NIGM with different focuses related to challenges and a description of the respective underlying problems. This review is aimed at addressing a fundamental topic in the application of NIGM that seems to have received less attention, by describing the perturbations that result in a reduced functionality of NIGM in daily use. Here we provide a short general introduction to glucose monitoring and a basic illustration of the electromagnetic spectrum with a description of the respective physical mechanisms underlying the measurement techniques. This allows for a better understanding of how these perturbing factors affect the measured properties. Cutaneous blood perfusion is one of the major perturbing factors to NIGM, along with variations in temperature, migration of water, and the effect of attachment of the sensor to the skin. An understanding of the mechanisms underlying perfusion variation over time and within the measured human skin tissue matrix is required to enable a discrimination between glucose-induced effects within the tissue and various biophysical impacts to be made. It is suggested that a plurality of probing frequencies is required to discriminate glucose-related changes from the perturbations. A system designed to perform the measurements in different regions of the electromagnetic spectrum with dedicated sensors (multisensor approach) has the potential to more efficiently and reliably discriminate glucose-related information from perturbations. This can be achieved by combining signals related to measurements with different physical underlying mechanisms of the interaction between the probing field propagation and the tissue to help account for the different sources of perturbations.

Recent studies of the minute morphology of the skin by optical coherence tomography revealed that the sweat ducts in human skin are helically shaped tubes, filled with a conductive aqueous solution. This, together with the fact that the dielectric permittivity of the dermis is higher than that of the epidermis, brings forward the supposition that as electromagnetic entities, the sweat ducts could be regarded as low Q helical antennas. The implications of this statement were further investigated by electromagnetic simulation and experiment of the in vivo reflectivity of the skin of subjects under varying physiological conditions (Feldman et al 2008 Phys. Rev. Lett. 100 128102). The simulation and experimental results are in a good agreement and both demonstrate that sweat ducts in the skin could indeed behave as low Q antennas. Thus, the skin spectral response in the sub-Terahertz region is governed by the level of activity of the perspiration system and shows the minimum of reflectivity at some frequencies in the frequency band of 75-110 GHz. It is also correlated to physiological stress as manifested by the pulse rate and the systolic blood pressure. As such, it has the potential to become the underlying principle for remote sensing of the physiological parameters and the mental state of the examined subject.

In vivo variations of blood glucose (BG) are affecting the biophysical characteristics (e.g. dielectric and optical) of skin and underlying tissue (SAUT) at various frequencies. However, the skin impedance spectra for instance can also be affected by other factors, perturbing the glucose related information, factors such as temperature, skin moisture and sweat, blood perfusion as well as body movements affecting the sensor-skin contact. In order to be able to correct for such perturbing factors, a Multisensor system was developed including sensors to measure the identified factors. To evaluate the quality of glucose monitoring, the Multisensor was applied in 10 patients with Type 1 diabetes. Glucose was administered orally to induce hyperglycaemic excursions at two different study visits. For analysis of the sensor signals, a global multiple linear regression model was derived. The respective coefficients of the variables were determined from the sensor signals of this first study visit (R(2)=0.74, MARD=18.0%--mean absolute relative difference). The identical set of modelling coefficients of the first study visit was re-applied to the test data of the second study visit to evaluate the predictive power of the model (R(2)=0.68, MARD=27.3%). It appears as if the Multisensor together with the global linear regression model applied, allows for tracking glucose changes non-invasively in patients with diabetes without requiring new model coefficients for each visit. Confirmation of these findings in a larger study group and under less experimentally controlled conditions is required for understanding whether a global parameterisation routine is feasible.

The phenomena of non thermal effects of extremely high frequency electromagnetic radiation on biological systems is explored. It is demonstrated that the effect is existent on human beings and is correlated to their physiological state via a measurement of the reflection coefficient of the palm. Possible sources of transient currents in biological systems ,needed to elicit a response are proposed and discussed.

Recent studies of the minute morphology of the skin by optical coherence tomography showed that the sweat ducts in human skin are helically shaped tubes, filled with a conductive aqueous solution. A computer simulation study of these structures in millimeter and submillimeter wave bands show that the human skin functions as an array of low-Q helical antennas. Experimental evidence is presented that the spectral response in the sub-Terahertz region is governed by the level of activity of the perspiration system. It is also correlated to physiological stress as manifested by the pulse rate and the systolic blood pressure.

Summary form only given. For more than 50 years a number of phenomena of nonthermal effects (high Q factor resonances) of extremely high frequency microwaves (MMW) on biological systems have been reported. Intriguingly the reported resonant frequencies are virtually absent in natural biological surroundings, making these effect all the more unusual. While some insight has been gained their interpretation has remained controversial. Theoretical ideas discussed in earlier papers in connection with experimental observations have largely proved to be inconclusive, with poor reproducibility and several confounding results. Furthermore there is ample experimental evidence of the beneficiary effects of low power (less than 20 mW/cm2) MMW electromagnetic radiation in a number of therapeutic avenues such as coronary artery disease, various cancers, pain relief, wound regeneration and hyper tension. In short, while there has been extensive documentation and some serious theoretical consideration, the true cause of these phenomena remain a mystery. Clearly a more solid indication of the main biophysical mechanism(s) of the observed effects would offer the possibility to truly exploit these beneficial aspects, in a systematic fashion. In current presentation the other possible mechanisms are proposed and there validity is illustrated by experimental data.

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.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.Our study revealed a significantly reduced skin thickness (P0.05) and microvascular blood flow (P0.05) 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; P0.05) and microvascular blood flow (with diabetes, -41+/-49 arbitrary units; without diabetes, -46+/-51 arbitrary units; P0.05) could be observed in both groups without significant differences between the two.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.

Standard HDP technologies such as COB can be involved early in the development stage. They help to form the development process and to meet size requirements without exhausting the development budget. Higher HDP production costs are negligible compared with the total development, field test and regulatory approval costs. Using HDP for miniaturisation, it is possible to make applications of previously lab-scale equipment for WMDs and for implants.

In this review, we present an overview of the state of the art concerning the fundamental properties of electrode polarization (EP) of interest in the measurement of high conductivity samples and its implications for both dielectric (DS) and impedance spectroscopy (IS). Initially a detailed description of what constitutes EP is provided and the problems that it induces. Then, we review some of the more popular models that have been used to describe the physical phenomena behind the formation of the ionic double layer. Following this we shall enumerate the common strategies used historically to correct its influence on the measured signals in DS or in IS. Finally we also review recent attempts to employ fractal electrodes to bypass the effects of EP and to offer some physical explanation as to the limitations of their use.