Physiological Skin Temperature Research Articles

Temperature Correction of Printed Na+, K+, and pH Sensors with PEDOT:PSS‐Based Thermistors toward Wearable Sweat Sensing

AbstractTemperature correction for sensors is a critical aspect of ensuring accurate measurements in wearable devices, because skin and sweat temperatures vary between 20 and 40 °C depending on individual and time. Here, this study reports on the temperature dependence and correction techniques of printed Na+, K+, and pH sensors toward wearable applications. The ion sensor array is fabricated using a cost‐effective printing method. To enable temperature correction, a printed thermistor of crosslinked poly(3,4‐ethylenedioxythiophene):poly(styrenesulfonate) (PEDOT:PSS) is monolithically integrated with the ion sensor array on a flexible plastic substrate. Temperature dependence of the potential response of the printed ion sensors exhibits a linear behavior with a slope of 1–2 mV °C−1 in the physiological skin temperature range of 20–40 °C. Applying temperature correction to the ion sensors, the maximum relative errors are reduced from 60% to 7.8% for the Na+ sensors and from 76% to 14.6% for the K+ sensors, while the maximum absolute error is reduced from 0.88 to 0.19 for the pH sensors, indicating the critical importance of temperature correction as a technology for wearable printed ion sensors.

The range of normative surface skin temperature changes in adolescents: prospective multicenter study.

We aimed to establish a normative range of surface skin temperature (SST) changes due to blood redistribution in adolescents and to register the time needed for complete postural change-related blood redistribution. The healthy volunteers (age 15-18, n = 500, M 217, F 283) were recruited for this prospective multicenter study. The volunteers were asked to keep one extremity down and another extremity up in supine rest, sitting with straight legs, and upright rest. We obtained temperature readings being taken from the tips of the middle fingers and temperature readings from the tips of the first toes at the ambient temperature of 25 °C and 30 °C. The control group consisted of a 100 of adult volunteers. The resting temperature of the middle fingers for a sitting participant was 28.6 ± 0.8 °C. The physiological change of this temperature during body position changes was 4.5 ± 1.1 °C and for most of the participants remained within the 26.5-31.5 °C range at 25 °C. For the toe, physiological skin temperature range was 25.5-33 °C. At 30 °C, these ranges were 27-33 °C for the fingers and 27-34 °C for the toes. On average, 2-3 min were needed for such temperature changes. At normal room temperature, the SST of thermoneutral adolescents may vary within a range of approximately 5 °C only due to the blood redistribution in the body. This range is specific for each person due to individual peculiarities of the vasomotor activity. This normative range of SSTs should be taken into account during investigations of thermoregulation.

Effect of Mild Hyperthermia on Transdermal Absorption of Nicotine from Patches.

Application of heat (hyperthermic conditions) on skin is known to enhance drug transfer and facilitate skin penetration of molecules. The aim of this work was to study the effect of hyperthermia on the drug release and skin permeation from nicotine transdermal patches. The drug release and skin permeation were characterized by in vitro release test and in vitro permeation test. The temperature was maintained at 32°C as control (simulating normal physiological skin temperature) and 42°C as hyperthermia condition. The in vitro release test was carried out using USP apparatus 5-Paddle over disk method for a transdermal patch. Skin permeation study was carried out across porcine skin using the flow through cells (PermeGear, Inc.) with an active diffusion area of 0.94cm2. Mechanistic studies (parameters such as partition coefficient, TEWL and electrical resistivity) were also performed to understand the mechanisms involved in determining the influence of hyperthermia on drug delivery from transdermal patches of nicotine. The rate and extent of drug release from nicotine patch was not significantly different at two temperatures (Cumulative release after 12h was 43.99 ± 3.29% at 32°C and 53.70 ± 5.14% at 42°C). Whereas, in case of in vitro permeation studies, the nicotine transdermal permeation flux for patch was threefold higher at 42°C (100.1 ± 14.83μg/cm2/h) than at 32°C (33.3 ± 14.83μg/cm2/h). The mechanistic studies revealed that the predominant mechanism of enhancement of drug permeation by hyperthermia condition is by the way of increasing the skin permeability. There is a potential concern of dumping of higher dose of nicotine via transdermal route.

Permeability and microstructure of cholesterol-depleted skin lipid membranes and human stratum corneum

Cholesterol (Chol) is one of the major skin barrier lipids. The physiological level of Chol in the stratum corneum (SC) appears to exceed its miscibility with other barrier lipids, as some Chol is phase separated. Chol synthesis is essential for epidermal homeostasis, yet the role of these Chol domains in SC permeability is unknown. We investigated the impact of Chol depletion on the permeability properties and microstructure of model membranes and human SC. X-ray powder diffraction of membranes constructed from isolated human skin ceramides or synthetic ceramides confirmed that only approximately half of the normal Chol amount can be incorporated in either long or short periodicity lamellar phases. The long periodicity lipid arrangement persisted even in the absence of Chol. Infrared spectroscopy suggested that Chol had negligible effects on the lipid chain order and packing at physiological skin temperature. Chol depletion of the model membranes or isolated human SC did not compromise the barrier function to water and two model permeants. On the contrary, the membrane with the Chol content reduced to 40% of the normal value, where no separated Chol was observed, was significantly less permeable than the control. Thus, a 0.4:1:1 M ratio of Chol/ceramides/fatty acids appears sufficient for skin lipids to limit water loss and prevent the entry of environmental substances. We speculate that the SC Chol domains may have roles in the skin other than barrier function.

Probing the role of ceramide hydroxylation in skin barrier lipid models by 2H solid-state NMR spectroscopy and X-ray powder diffraction

In this work, we studied model stratum corneum lipid mixtures composed of the hydroxylated skin ceramides N-lignoceroyl 6-hydroxysphingosine (Cer[NH]) and α-hydroxylignoceroyl phytosphingosine (Cer[AP]). Two model skin lipid mixtures of the composition Cer[NH] or Cer[AP], N-lignoceroyl sphingosine (Cer[NS]), lignoceric acid (C24:0) and cholesterol in a 0.5:0.5:1:1 molar ratio were compared. Model membranes were investigated by differential scanning calorimetry and 2H solid-state NMR spectroscopy at temperatures from 25 °C to 80 °C. Each component of the model mixture was specifically deuterated for selective detection by 2H NMR. Thus, the exact phase composition of the mixture at varying temperatures could be quantified. Moreover, using X-ray powder diffraction we investigated the lamellar phase formation. From the solid-state NMR and DSC studies, we found that both hydroxylated Cer[NH] and Cer[AP] exhibit a similar phase behavior. At physiological skin temperature of 32 °C, the lipids form a crystalline (orthorhombic) phase. With increasing temperature, most of the lipids become fluid and form a liquid-crystalline phase, which converts to the isotropic phase at higher temperatures (65–80 °C). Interestingly, lignoceric acid in the Cer[NH]-containing mixture has a tendency to form two types of fluid phases at 65 °C. This tendency was also observed in Cer[AP]-containing membranes at 80 °C. While Cer[AP]-containing lipid models formed a short periodicity phase featuring a repeat spacing of d = 5.4 nm, in the Cer[NH]-based model skin lipid membranes, the formation of unusual long periodicity phase with a repeat spacing of d = 10.7 nm was observed.

Influence of the penetration enhancer isopropyl myristate on stratum corneum lipid model membranes revealed by neutron diffraction and 2H NMR experiments

The stratum corneum (SC) provides the main barrier properties in native skin. The barrier function is attributed to the intercellular lipids, forming continuous multilamellar membranes. In this study, SC lipid membranes in model ratios were enriched with deuterated lipids in order to investigate structural and dynamical properties by neutron diffraction and 2H solid-state NMR spectroscopy. Further, the effect of the penetration enhancer isopropyl myristate (IPM) on the structure of a well-known SC lipid model membrane containing synthetically derived methyl-branched ceramide [EOS], ceramide [AP], behenic acid and cholesterol (23/10/33/33wt%) was investigated. IPM supported the formation of a single short-periodicity phase (SPP), in which we determined the molecular organization of CER[AP] and CER[EOS]-br for the first time. Furthermore, the thermotropic phase behavior of the lipid system was analyzed by additional neutron diffraction studies as well as by 2H solid-state NMR spectroscopy, covering temperatures of 32°C (physiological skin temperature), 50°C, and 70°C with a subsequent cooldown back to skin temperature. Both techniques revealed a phase transition and a hysteresis effect. During the cooldown, Bragg peaks corresponding to a long-periodicity phase (LPP) appeared. Additionally, 2H NMR revealed that the IPM molecules are isotopic mobile at all temperatures.

Phase separation in ceramide[NP] containing lipid model membranes: neutron diffraction and solid-state NMR.

The stratum corneum is the outermost layer of the skin and protects the organism against external influences as well as water loss. It consists of corneocytes embedded in a mixture of ceramides, fatty acids, and cholesterol in a molar ratio of roughly 1 : 1 : 1. The unique structural and compositional arrangement of these stratum corneum lipids is responsible for the skin barrier properties. Many studies investigated the organization of these barrier lipids and, in particular, the exact conformation of ceramides. However, so far no consensus has been reached. In this study, we investigate a model system comprised of N-(non-hydroxy-tetracosanoyl)-phytosphingosine/cholesterol/tetracosanoic acid (CER[NP]-C24/CHOL/TA) at a 1 : 1 : 1 molar ratio using neutron diffraction and 2H solid-state NMR spectroscopy at temperatures from 25 °C to 80 °C. Deuterated variants of all three lipid components of the model system were used to enable their separate investigation in the NMR spectra and quantification of the amount of molecules in each phase. Neutron scattering experiments show the coexistence of two lipid phases at low temperatures with repeat spacings of 54.2 Å and 43.0 Å at a physiological skin temperature of 32 °C. They appear to be indistinguishable in the 2H NMR spectra as both phases are crystalline and ceramide molecules do not rotate around their long axis on a microsecond timescale. The evolution of these phases upon heating is followed and with increasing temperature fluid and even isotropically mobile molecules are observed. A model of the organization of the lamellar phases is proposed in which the thicker phase consists of CER[NP]-C24 in a hairpin conformation mixed with CHOL and TA, while the phase with a repeat spacing of 43.0 Å contains CER[NP]-C24 in a V-shape conformation.

Development of Thermochromic Pigment Based Sportswear for Detection of Physical Exhaustion

Endurance athletes face a complex array of physiological changes as their skin temperature rises during vigorous exercise. Since endurance athletes do not typically have fiscally feasible and straightforward real-time physiological monitoring (outside of complex Bluetooth and wireless connectivity linking their heart rate, pulse oximetry, etc. to electronic databases), exercise reaching high levels of physical exhaustion is of great concern. To aid in easy and visual determination of physical exhaustion, thermochromic pigments were applied to Nylon/spandex fabric, using pigment activation temperature as an indication for exhaustion. Thermochromic pigments were chosen because these microcapsules contain leuco dyes capable of changing chemical structure to alter the dye molecule absorbance, leading to a visual tool for skin temperature indication. Each pigment was chosen to activate at a targeted physiological skin temperature range between 33 and 38̊C. Nylon/spandex was chosen for high wearer comfort and excellent garment/skin contact. This technology was coupled with conventional textiles to create smart apparel with satisfactory abrasion and color fastness capabilities. Using targeted placement of thermochromic panels in garment construction, a garment capable of serving as a “warning light” for physical exhaustion in athletes was created.

Importance of transient receptor potential vanilloid 4 (TRPV4) in epidermal barrier function in human skin keratinocytes

The state of the skin changes drastically depending on the ambient temperature. Skin epidermal keratinocytes express thermosensitive transient receptor potential vanilloid (TRPV) cation channels, TRPV3 and TRPV4. These multimodal receptors are activated by various kinds of chemical and physical stimuli, including warm temperatures (>30°C). It has been suggested that TRPV4 is involved in cell-cell junction maturation; however, the effect of temperature fluctuations on TRPV4-dependent barrier homeostasis is unclear. In the present study, we demonstrated that activation of TRPV4 was crucial for barrier formation and recovery, both of which were critical for the prevention of excess dehydration of human skin keratinocytes. TRPV4 activation by physiological skin temperature (33°C), GSK1016790A or 4α-PDD allowed influx of Ca(2+) from extracellular spaces which promoted cell-cell junction development. These changes resulted in augmentation of intercellular barrier integrity in vitro and ex vivo. TRPV4 disruption reduced the increase in trans-epidermal resistance and increased intercellular permeation after a Ca(2+) switch. Furthermore, barrier recovery after the disruption of the stratum corneum was accelerated by the activation of TRPV4 either by warm temperature or a chemical activator. Our results suggest that physiological skin temperatures play important roles in cell-cell junction and skin barrier homeostasis through TRPV4 activation.

The TRPV4 cation channel

The skin barrier function is indispensable for terrestrial animals to avoid dehydration. The function is achieved by a hydrophobic cornified layer consisting of dead keratinocytes and lipids, and by an intercellular junction barrier formed among differentiated keratinocytes. A recent report demonstrated that TRPV4, one of the temperature-sensitive cation channels, contributes to the formation and maintenance of the intercellular junction-dependent barrier in the skin. TRPV4 associates with the E-cadherin complex via β-catenin, and thereby participates in the promotion of cell-cell junction development. TRPV4 allows influx of Ca2+ ions from the extracellular space at physiological skin temperatures. The Ca2+ influx induces Rho activation and promotes actin fiber organization and junction formation, thereby augmenting barrier integrity. Indeed, the intercellular junction structures and the skin barrier function were impaired in TRPV4-deficeint mice. This novel role of TRPV4 in keratinocytes may explain the significant correlation between temperature and the condition of skin.

The TRPV4 Channel Contributes to Intercellular Junction Formation in Keratinocytes

Transient receptor potential vanilloid 4 (TRPV4) channel is a physiological sensor for hypo-osmolarity, mechanical deformation, and warm temperature. The channel activation leads to various cellular effects involving Ca(2+) dynamics. We found that TRPV4 interacts with beta-catenin, a crucial component linking adherens junctions and the actin cytoskeleton, thereby enhancing cell-cell junction development and formation of the tight barrier between skin keratinocytes. TRPV4-deficient mice displayed impairment of the intercellular junction-dependent barrier function in the skin. In TRPV4-deficient keratinocytes, extracellular Ca(2+)-induced actin rearrangement and stratification were delayed following significant reduction in cytosolic Ca(2+) increase and small GTPase Rho activation. TRPV4 protein located where the cell-cell junctions are formed, and the channel deficiency caused abnormal cell-cell junction structures, resulting in higher intercellular permeability in vitro. Our results suggest a novel role for TRPV4 in the development and maturation of cell-cell junctions in epithelia of the skin.

Stable expression of CD1a molecule in human epithelial cell lines shows temperature-dependent expression and affects cell morphology and growth.

The human CD1a molecule is a transmembrane protein which shares structural similarities with HLA class I molecules. It has restricted tissue distribution in normal individuals, and is a useful diagnostic marker for certain disease states such as Langerhans cell histiocytosis. In order to investigate the function of this molecule, a cDNA fragment encoding the CD1a molecule was cloned into several EUKARYOTIC expression vectors which were then used to establish human epithelial cell lines stably expressing the membrane-bound CD1a molecule. Human keratinocytes (HaCaT) and epithelial cells (HeLa) stably expressing CD1a were established by retroviral-mediated gene transfer and DNA transfection, respectively. Expression and localization of the CD1A molecule were then confirmed by Northern blot analysis and immunofluorescence methods. CD1a expression appears to have profound effects on cellular growth and morphology. Both stably CD1a-expressing HeLa and HaCaT cells showed increased doubling times, and up to 20% of CD1a-expressing cells showed altered cell morphology. Clonogenicity experiments demonstrated a reduction in colony size and plating efficiency was augmented in CD1a-positive cells when compared with vector-transfected/infected controls. Our findings suggest that CD1A expression may act as a negative growth regulator in these cells in vitro. Furthermore, lower temperatures greatly enhanced the expression of CD1a at both the protein and mRNA levels in a time-dependent fashion. Since the physiological skin temperatures lie well below the core temperature, this observation may have important implications in the study of Langerhans cells in vitro.

Ex vivo protocol for testing virus survival on human skin: experiments with herpesvirus 2.

We report an ex vivo method, which uses pieces of human skin excised during routine plastic surgery, for testing survival of hazardous pathogens. Using this procedure, we compared the survival of human herpesvirus 2 on human skin and on metal disks. At the physiological skin temperature of 32 degrees C, the half-life of the virus on skin was 1.44 h while on metal disks it was 0.36 h. Even at ambient temperature (22 degrees C), the virus lost infectivity faster (half-life = 0.96 h) on metal disks than on the skin at 32 degrees C. The method described could be used to assess the survival of other human pathogens on skin and to evaluate the germicidal activity of handwashing agents and other topicals.

The efficacy of orally applied terbinafine, itraconazole and fluconazole in models of experimental trichophytoses

The antimycotic efficacy of terbinafine, itraconazole and fluconazole was evaluated in guinea-pig trichophytoses (Trichophyton mentagrophytes, Trichophyton rubrum) by use of the hair root invasion test (HIT) and the auricular skin temperature test (STT). In the prophylactic HIT model using T. mentagrophytes as the infective agent, statistical evaluation of the ratios of protected/inoculated animals revealed ED50 values of 2.8 mg kg-1 for terbinafine, 10.7 mg kg-1 for itraconazole and 11.6 mg kg-1 for fluconazole. When T. rubrum was used in the same model the ED50 value of terbinafine was 7.3 mg kg-1 whereas only two of eight animals became protected by itraconazole and fluconazole at the highest dose of 16 mg kg-1. In the therapeutic HIT model carried out with T. mentagrophytes, the curative doses were increased for all test compounds, revealing an ED50 of 12.3 mg kg-1 for terbinafine and > 40 mg kg-1 for itraconazole and fluconazole. In the STT model, decline of temperature was quicker and more pronounced during therapy with terbinafine than during treatment with the triazole derivatives. Skin temperature was back to normal on day 8 (after seven treatments) with 20 mg kg-1 terbinafine, whereas a decline to, or almost to, physiological skin temperature was not observed until day 24 (5 days after the last treatment) in animals treated with 40 mg kg-1 itraconazole or fluconazole.

The physical properties of sebum in acne vulgaris.

1. Methods are described for the collection of scalp sebum, and for the determination of the density, viscosity, surface tension, and freezing-point of sebum samples from individual subjects. 2. Data are presented from ten acne patients and seven normal subjects, of whom three previously had acne. No significant difference was demonstrated between the sebum from acne patients and controls. The sebum viscosity increased with fall in temperature, but sebum did not solidify at physiological skin temperatures, and it is concluded that sebum viscosity is unlikely to be important in the pathogenesis of acne. 3. There was no relationship between sebum excretion rate and viscosity in individual subjects and sebum viscosity is unlikely to play a major role in the normal regulation of sebum production.