A battery-less implantable glucose sensor based on electrical impedance spectroscopy.

The ability to perform accurate continuous glucose monitoring without blood sampling has revolutionised the management of diabetes. Newer methods that can allow measurements during longer periods are necessary to substantially improve patients' quality of life. This paper presents an alternative method for glucose monitoring which is based on electrical impedance spectroscopy. A battery-less implantable bioimpedance spectroscope was designed, built, and used in an in vivo study on pigs. After a recovery period of 14 days post surgery, a total of 236 subcutaneous bioimpedance measurements obtained from intravenous glucose tolerance tests, with glucose concentration ranges between 77.4 and 523.8 mg/dL, were analyzed. The results show that glucose concentrations estimated by subcutaneous bioimpedance measurements correlate very well to the blood glucose reference values. The pigs were clinically healthy throughout the study, and the postmortem examinations revealed no signs of adverse effects related to the sensor. The implantation of the sensor requires minor surgery. The implant, being externally powered, could in principle last indefinitely. These encouraging results demonstrate the potential of the bioimpedance method to be used in future continuous glucose monitoring systems.

Skin hydration dynamics investigated by electrical impedance techniques in vivo and in vitro.

Skin is easily accessible for transdermal drug delivery and also attractive for biomarker sampling. These applications are strongly influenced by hydration where elevated hydration generally leads to increased skin permeability. Thus, favorable transdermal delivery and extraction conditions can be easily obtained by exploiting elevated skin hydration. Here, we provide a detailed in vivo and in vitro investigation of the skin hydration dynamics using three techniques based on electrical impedance spectroscopy. Good correlation between in vivo and in vitro results is demonstrated, which implies that simple but realistic in vitro models can be used for further studies related to skin hydration (e.g., cosmetic testing). Importantly, the results show that hydration proceeds in two stages. Firstly, hydration between 5 and 10 min results in a drastic skin impedance change, which is interpreted as filling of superficial voids in skin with conducting electrolyte solution. Secondly, a subtle impedance change is observed over time, which is interpreted as leveling of the water gradient across skin leading to structural relaxation/changes of the macromolecular skin barrier components. With respect to transdermal drug delivery and extraction of biomarkers; 1 h of hydration is suggested to result in beneficial and stable conditions in terms of high skin permeability and extraction efficiency.

A Batteryless Sensor ASIC for Implantable Bio-Impedance Applications.

The measurement of the biological tissue's electrical impedance is an active research field that has attracted a lot of attention during the last decades. Bio-impedances are closely related to a large variety of physiological conditions; therefore, they are useful for diagnosis and monitoring in many medical applications. Measuring living tissues, however, is a challenging task that poses countless technical and practical problems, in particular if the tissues need to be measured under the skin. This paper presents a bio-impedance sensor ASIC targeting a battery-free, miniature size, implantable device, which performs accurate 4-point complex impedance extraction in the frequency range from 2 kHz to 2 MHz. The ASIC is fabricated in 150 nm CMOS, has a size of 1.22 mm × 1.22 mm and consumes 165 µA from a 1.8 V power supply. The ASIC is embedded in a prototype which communicates with, and is powered by an external reader device through inductive coupling. The prototype is validated by measuring the impedances of different combinations of discrete components, measuring the electrochemical impedance of physiological solution, and performing ex vivo measurements on animal organs. The proposed ASIC is able to extract complex impedances with around 1 Ω resolution; therefore enabling accurate wireless tissue measurements.

A methodology for extracting the electrical properties of human skin.

A methodology to determine dielectrical properties of human skin is presented and analyzed. In short, it is based on a mathematical model that considers the local transport of charge in the various layers of the skin, which is coupled with impedance measurements of both stripped and intact skin, an automated code generator, and an optimization algorithm. New resistivity and permittivity values for the stratum corneum soaked with physiological saline solution for 1 min and the viable skin beneath are obtained and expressed as easily accessible functions. The methodology can be extended to account for different electrode designs as well as more physical phenomena that are relevant to electrical impedance measurements of skin and their interpretation.

Electrical impedance spectroscopy and the diagnostic accuracy for malignant melanoma.

BACKGROUND: The accuracy of diagnosis of skin cancer and especially of early malignant melanoma is most important to reduce its morbidity and mortality. Previous pilot studies using electrical impedance measurements indicate statistically significant accuracies for the detection of skin cancer. OBJECTIVES: The aim of this study is to investigate the accuracy of electrical impedance spectra to distinguish between malignant melanoma and benign skin lesions using an automated classification algorithm. PATIENTS/METHODS: Electrical impedance spectra were measured in a multi-centre study at 12 clinics around Europe. Data from 285 histologically analysed lesions were used to train an algorithm to sort out lesions for automatic detection of melanoma. Another data cohort of 210 blinded lesions (148 various benign lesions and 62 malignant melanomas where 38 being from Breslow thickness ≤1 mm) from 183 patients was thereafter used to estimate the accuracy of the technique. RESULTS: Observed sensitivity to malignant melanoma is 95% (59/62) and observed specificity 49% (72/148). CONCLUSIONS: The results suggest that electrical impedance spectra can distinguish between malignant melanoma and benign skin lesions. Although it is indicated that the accuracy of the device is clinically promising, the overall performance, and the sensitivity to thin malignant melanomas, must be improved and thoroughly validated before the instrument can be used as a routine stand-alone diagnostic decision support tool. The technique is under revision to further improve the reproducibility, specificity and sensitivity.

Non-invasive bioimpedance of intact skin: mathematical modeling and experiments.

The functional integrity and pathology of the skin is reflected in its electrical impedance spectra. Non-invasive electrical impedance measurements of intact skin are dominated by the high impedic stratum corneum in low frequencies and with increasing frequency gradually comes to be dominated by viable skin. Models of this multi-layered organ can increase our understanding of the actual physical properties/dimensions and facilitate better diagnostics in certain applications. Therefore, a mathematical model considering conservation of charge in the various layers of the skin and adjacent electrodes is derived and validated with experimental findings; the latter was carried out on 60 young female subjects. The impact of the stratum corneum thickness, inundation, solvent and cohort size on the electrical properties is studied. Both model parameters and experimental conditions were adjusted for calibration and subsequent validation of the model with measurements. It is found that both the model's thickness of the stratum corneum as well as experimental soaking conditions (both time and saline concentration) affect the fit between the model and measurements. It is concluded that it is essential that the electrical properties of the skin are presented in the context of the ion concentration (if a moisturizer is employed) as well as the soaking time. Further refinements should be made to determine even more accurate dielectrical properties of the stratum corneum and viable skin layers by accounting for the true skin thickness and the heterogeneity of the skin layers-this would be useful in applications where subtle alterations in the skin are of interest.

Non-invasive and microinvasive electrical impedance spectra of skin cancer - a comparison between two techniques.

BACKGROUND/PURPOSE: Bio-electrical impedance spectra of skin cancer and other lesions can be assessed using both regular non-invasive probes and a novel type of microinvasive electrode system with a surface furnished with tiny spikes that penetrate stratum corneum. The aim of the study was to compare the accuracy of detection for various types of skin cancer using impedance spectra measured with these two different electrode systems in an objective way without optimising the power of discrimination. METHODS: Impedance spectra of 99 benign nevi, 28 basal cell carcinomas (BCC), and 13 malignant melanomas (MM) were measured using the two electrode systems. Classification of the lesions was made using Fisher's linear discriminant, and the sensitivities and specificities of the techniques were estimated using cross-validation. RESULTS: The best separation between nevi and BCC was achieved using the regular non-invasive probe (96% sensitivity and 86% specificity), whereas the best separation between nevi and MM was achieved using the microinvasive electrodes (92% sensitivity and 80% specificity). CONCLUSIONS: Our results indicate that the choice of electrode system is application dependent.

Skin cancer identification using multifrequency electrical impedance--a potential screening tool.

Electrical bio-impedance can be used to assess skin cancers and other cutaneous lesions. The aim of this study was to distinguish skin cancer from benign nevi using multifrequency impedance spectra. Electrical impedance spectra of about 100 skin cancers and 511 benign nevi were measured. Impedance of reference skin was measured ipsi-laterally to the lesions. The impedance relation between lesion and reference skin was used to distinguish the cancers from the nevi. It was found that it is possible to separate malignant melanoma from benign nevi with 75% specificity at 100% sensitivity, and to distinguish nonmelanoma skin cancer from benign nevi with 87% specificity at 100% sensitivity. The power of skin cancer detection using electrical impedance is as good as, or better than, conventional visual screening made by general practitioners.

Clinically normal atopic skin vs. non-atopic skin as seen through electrical impedance.

BACKGROUND/AIMS: In an earlier study, we have shown that the electrical impedance (IMP) is dependent on the lipid content of the stratum corneum as studied by lipid extraction. Therefore, we now employ the IMP technique to compare the properties of clinically normal atopic skin with that of non-atopic skin. We looked at the same time at concomitant alterations in transepidermal water loss (TEWL) and skin moisture results. METHODS: Twenty-two healthy participants and 26 patients with atopic dermatitis were recruited. One test site on each volar forearm was used in the test procedure, of cyclohexane swabbing, skin stripping, and lipid extraction using a mixture of hexane:isopropanol. Responses were evaluated by measuring TEWL, skin moisture using electrical capacitance, and finally IMP spectroscopy in the frequency range 1 kHz to 1 MHz before the start of the study, after each step of the test procedure, and also during a 2 weeks recovery period. RESULTS: Only the IMP results showed significant changes between baseline values of clinically normal atopic skin and healthy skin. Furthermore, IMP and TEWL showed significantly larger reactivity for the atopic group after the skin stripping procedure, and IMP after lipid extraction as well. CONCLUSION: Our results show that IMP is a useful method for detection of changes in the lipid content of the stratum corneum by discriminating healthy looking atopic skin from healthy control skin, and to detect changes in reactivity between the two groups.

Assessment of skin lesions and skin cancer using simple electrical impedance indices.

BACKGROUND/AIMS: Purpose of this investigation was to assess benign pigmented cellular nevus (BEN), basal cell carcinoma (BCC), dermatofibroma (DER), dysplastic nevus (DYS), and seborrheic keratoses (SEB) using in vivo non- invasive electrical impedance technique. METHODS: Electrical impedance was measured at 258 BEN, 34 BCC, 17 DER, 35 DYS, and 26 SEB lesions. Controls were measured at healthy skin close to the lesions. The impedance was measured between 1 kHz and 1 MHz at five depth settings. After the impedance measurements the lesions were histopathologically diagnosed. The impedance spectra were parameterized to four indices prior to the statistical analysis of the data. RESULTS: There were significant differences between the lesions and their controls for BEN (P < 0.001), BCC (P < 0.001), DYS (P < 0.01), and SEB (P < 0.01). CONCLUSIONS: There are clear statistical differences between impedance of common lesions and control skin. With some further developments, the impedance technique can be useful as a diagnostic decision support tool for skin cancer assessment.

The use of different concentrations of betaine as a reducing irritation agent in soaps monitored visually and non-invasively.

BACKGROUND/AIMS: Products containing detergents can damage the skin and give rise to irritant contact dermatitis. Therefore, attempts have been made to find less irritating detergents as well as substances decreasing undesired side-effects of detergents, and a novel approach is offered by betaine. The aim of the study has been to determine the irritating properties of some liquid soaps for personal hygiene and to map the effect of different concentrations of betaine using electrical impedance, trans-epidermal water loss and visual inspection. METHODS: Twenty-eight healthy subjects were patch tested with different commercial soaps with and without betaine and sodium lauryl sulphate on both volar forearms for 24 h. A site with distilled water and an unoccluded area were used as references. Responses of the skin reactions were evaluated by visual inspection and by measuring trans-epidermal water loss and electrical impedance before application and 24 h after removal of the chambers. RESULTS/CONCLUSIONS: Significant skin reactions were found for all soaps tested but the soaps containing betaine were the least irritating. However, the skin irritation did not decrease with increasing concentrations of betaine in the tested range. On the whole the differences between the products were not large. The non-invasive methods used were more sensitive than visual assessment for evaluation of invisible or barely visible skin responses.

The ability of betaine to reduce the irritating effects of detergents assessed visually, histologically and by bioengineering methods.

BACKGROUND/AIMS: A novel approach for reducing the undesired irritating properties of detergents on skin might be offered by betaine, which is a natural product derived from the sugar beet. The aim of the study was to explore the ability of betaine to reduce the irritating effects of two surfactants, sodium lauryl sulphate (SLS) and cocoamidopropylbetaine (CAPB). For evaluation of changes in skin reactions visual scoring, electrical impedance, transepidermal water loss and histology were used. METHODS: Twenty-one healthy subjects were patch tested for 24 h with SLS and CAPB alone and together with betaine, betaine alone, and the two controls distilled water and an unoccluded test site on both volar forearms. Responses were evaluated by measuring electrical impedance and transepidermal water loss before exposure and 24 h after the removal of the test substances, and also by visual inspection and histology. The electrical impedance device enables measurements at 31 frequencies and relevant information was extracted from the spectra using four indices. RESULTS: CAPB was found to be less irritating than SLS. The used detergents gave rise to distinctive impedance patterns also reflected by different types of histopathological skin responses. After the adding of betaine, the irritant reaction decreased for both detergents. CONCLUSIONS: Betaine is a promising ingredient to reduce the side effects of detergents and electrical impedance is a suitable tool both to quantify the degree of irritation as well as to differentiate between various types of reactions.

Betaine reduces the irritating effect of sodium lauryl sulfate on human oral mucosa in vivo.

Our aim was to evaluate whether betaine has a protective effect during exposure of the human oral mucosa in vivo to sodium lauryl sulfate (SLS) or cocoamidopropylbetaine (CAPB) as measured with a multifrequency electrical impedance spectrometer (EI). Both detergents were used at the concentration of 2.0% w/v with and without 4.0% w/v betaine in distilled water in 20 volunteers, and 0.5% and 1.0% w/v SLS combined with 4.0% w/v betaine in 5 volunteers. EI measurements were taken before application of the test solutions, after their removal, and every 15 min up to 45 min. Both 0.5% and 1% SLS solutions showed a significant reduction in 3 of the 4 indices, indicating mucosal irritation after the 15-min exposure (P < 0.05), whereas 2% SLS did so in all 4 indices (P < 0.001). Betaine had no effect on the detergent-induced decline with either the 2% or the 0.5% SLS solutions. However, when combined with the 1% SLS solution, betaine significantly (P < 0.05) reduced mucosal irritation by abolishing decreases in indices MIX (magnitude index) and IMIX (imaginary part index) and lowering it for PIX (phase index). The 2% CAPB solution showed a significant (P < 0.05) reduction in all 4 indices after the 15-min exposure, but the effect was significantly weaker than that of 2% SLS (P < 0.05). Betaine did not reduce the irritating effect of 2% CAPB. These findings can be used in the development of less irritating products for oral health care.

Variation of skin properties within human forearms demonstrated by non-invasive detection and multi-way analysis.

BACKGROUND/AIM: It is known that the properties of human skin vary locally. The purpose of this study was to investigate the properties of human volar forearms even further using advanced non-invasive techniques and numerical methods. METHODS: The skin properties of human volar forearms were investigated using measurements of trans epidermal water loss and multifrequency electrical impedance. Eight sites on the forearms of 27 healthy volunteers were measured. The sites were oriented as squares, four sites on both left and right forearm, approximately 40-50 mm apart. RESULTS: Analysis of variance showed significant differences for epidermal water loss (P < 0.01) and the skin impedance (P < 0.001) between the inner and outer sides of the arms. Additionally, parallel factor analysis of the full skin impedance spectra also showed that there are systematic differences between right and left arm (P < 0.01). CONCLUSION: It is crucial to design skin studies carefully in order to minimise the effects of the local skin properties of human skin.

Electrical impedance measurements at different skin sites related to seasonal variations.

BACKGROUND/AIMS: In a previous study we mapped differences in electrical impedance between different anatomical locations related to age and sex. Now we employ the electrical impedance technique for studying the seasonal variations for the same skin sites. METHOD: The investigation was performed on 48 healthy volunteers divided into two groups on the basis of sex. Readings of electrical impedance were taken from ten different body locations at each of the four seasons during one year. Electrical impedance spectra were measured in the frequency range 1 kHz to 1 MHz, and four impedance indices based on the complex impedance values at 20 kHz and 500 kHz were calculated. RESULTS: The baseline values varied from one site to another and increased significantly for most sites from the winter to the summer, while the changes from October to March were negligible. Using ANOVA, the seasonal variation was found to be a more important factor than sex. CONCLUSIONS: Our results suggest that seasonal variations for different skin sites should be taken into consideration when using the electrical impedance technique.