PubMed Health⌕ Search

Biomedical subjects

Gerald B Kasting

Publications and source records attributed to Gerald B Kasting.

13 recordsLinked to original sources
PubMed2006

Improvement of epidermal barrier properties in cultured skin substitutes after grafting onto athymic mice.

Barrier function in cultured skin substitutes (CSS) prepared from human cell sources was measured by noninvasive (surface hydration, transepidermal water loss) and invasive methods (water permeation, niacinamide flux) before and after grafting onto athymic mice. In vitro measurements were made on days 7 and 14. Although three of the four measures of barrier function improved markedly from day 7 to 14, the values obtained were still far from those obtained with native human skin controls. Additional CSS were grafted onto athymic mice on day 14, and skin was harvested 2 and 6 weeks after grafting. Grafting brought about a substantial decrease in all measurements by 2 weeks and almost complete normalization of barrier function after 6 weeks. The most sensitive measure of this recovery was niacinamide permeability, which decreased from (280 +/- 40) x 10(-4) cm/h in vitro to (17 +/- 30) x 10(-4) cm/h 2 weeks after grafting and (5 +/- 2) x 10(-4) cm/h 6 weeks after grafting, versus control values of (2 +/- 2) x 10(-4) cm/h in human cadaver skin and (0.6 +/- 0.4) x 10(-4) cm/h in human epidermal membrane prepared from freshly excised breast skin. These results demonstrate the reformation of epidermal barrier function after transplantation and provide insights for the development of a functional epidermal barrier in CSS in vitro.

Animals↗
PubMed2006

Glucose partition coefficient and diffusivity in the lower skin layers.

PURPOSE: This work aims to estimate the diffusivity and partitioning of glucose in the dermis and the viable epidermis of human skin. METHODS: The partition coefficient of glucose between phosphate-buffered saline and dermis, tape-stripped epidermis (TSE), stratum corneum (SC), and split-thickness skin, was measured in vitro using human cadaver skin. Glucose permeability across dermis and tape-stripped split-thickness skin (TSS) was measured using side-by-side diffusion cells. Glucose desorption from TSE and human epidermal membrane (HEM) was measured. All measurements were conducted at 32 degrees C. RESULTS: The partition coefficient for glucose [mean +/- SD (no. of samples)] was 0.65 +/- 0.09 (n = 25) for dermis, 0.81 +/- 0.06 (n = 10) for TSE, and 0.53 +/- 0.12 (n = 9) for SC. Glucose diffusivity in dermis was calculated to be 2.64 +/- 0.42 x 10(-6) cm2/s (n = 14). Glucose diffusivities in the viable epidermis estimated from TSS permeation, TSE desorption, and HEM desorption were 0.075 +/- 0.050 x 10(-6) cm2/s (n = 5), 0.037 +/- 0.018 x 10(-6) cm2/s (n = 4), and 1.0 +/- 0.6 x 10(-6) cm2/s (n = 4), respectively. CONCLUSION: The tissue/buffer partition coefficient of glucose in all skin layers was found to be less than unity, suggestive of excluded volumes in each layer. Glucose diffusivity in human dermis was found to be one third of its value in water, indicative of hindered diffusion related to the structural components of the tissue. A substantially lower value for glucose diffusivity in viable epidermis is suggested.

Buffers↗
PubMed2006

Kinetics of finite dose absorption through skin 2: volatile compounds.

A diffusion model to account for the disposition of an arbitrary dose of a (potentially) volatile compound applied to skin from a volatile vehicle is presented. In its most general form, the model allows for variable diffusivity of the permeant in the stratum corneum (SC) and must be solved numerically. However, for permeants having a constant diffusivity, absorption, and evaporation is characterized in terms of four dimensionless parameters-a reduced time tau, a fractional deposition depth in the SC f, a ratio of membrane capacity for the permeant to the applied dose beta, and a ratio of evaporative mass transfer coefficient to diffusive permeability chi. An important combination of these parameters arises as the reduced dose M(r) = (fbeta)(-1). Two cases are distinguished. In Case 1, corresponding to M(r) < or = 1, the dose is less than that required to saturate the upper layers of the SC, and the shape of the absorption and evaporation profiles is independent of the dose. Analytical solutions to Case 1 may be derived for arbitrary initial distributions of the permeant; the solution for a square wave is presented. In Case 2, corresponding to M(r) > 1, absorption and evaporation approach steady-state values as the dose is increased. Numerical evaluations of this behavior are shown. Limiting behavior for the case of a highly volatile solvent applied to skin is discussed. A companion paper discusses the application of the model to the absorption and evaporation of benzyl alcohol from human skin in vitro.

Administration, Cutaneous↗
PubMed2006

A multiphase microscopic diffusion model for stratum corneum permeability. I. Formulation, solution, and illustrative results for representative compounds.

A two-dimensional microscopic transport model of the stratum corneum (SC) incorporating corneocytes of varying hydration and permeability embedded in an anisotropic lipid matrix is presented. Results are expressed in terms of a dimensionless permeability (P(SC/w)(comp), which is a function of two dimensionless parameters, R and sigma. R is a ratio of transbilayer to lateral molecular flows within a lipid bilayer and sigma is the ratio of (lateral) permeability in the lipid phase, D(lip)K(lip/w), to that in the corneocyte phase, D(cor)K(cor/w.) The shape of the dimensionless permeability surface is also governed by the arrangement of the SC lipids, where Model 1 represents the extreme in which lipid-phase transport can occur with no transbilayer transport, whereas Model 2 entails maximum transbilayer transport. Model calculations are exemplified by characterizing the skin permeability of four representative permeants: water, ethanol, nicotinamide, and testosterone. A comparison with experimental steady state permeability and partition data supports that the transport properties of the SC lipids are highly anisotropic, with lateral diffusivities several orders of magnitude higher than the equivalent diffusivity calculated from transbilayer hopping. Nevertheless, the calculations suggest that corneocyte-phase transport plays a major role for all four permeants. These results confirm our previous calculations on water permeability and present a marked contrast to the commonly stated doctrine that the SC transport pathway is primarily intercellular.

Cell Membrane Permeability↗
PubMed2006

Dose and airflow dependence of benzyl alcohol disposition on skin.

The penetration of benzyl alcohol (BA) through split-thickness cadaver skin was measured in nonoccluded Franz cells placed in a fume hood. BA, dissolved in a small volume of ethanol and spiked with (14)C radiolabel, was applied to skin at nine doses ranging from 0.9 to 10600 microg/cm(2). The percentage of radioactivity penetrated after 24 h increased gradually with dose, ranging from 19.8 +/- 2.9% at the lowest dose to 29.2 +/- 3.0% at the highest. Less than 4% of the radioactivity was retained in the tissue at 24 h; the remainder was considered to be evaporated. These data and those from a previous study were analyzed in terms of a finite dose diffusion/evaporation model. The analysis showed that the increase in BA absorption with dose was consistent with a threefold increase in BA diffusivity in the stratum corneum, as its concentration increased from tracer levels to saturation. The variable diffusivity model was able to describe the combined observations from the two studies to within an rms error of 4.2% of dose. A method of estimating the diffusion model parameters independently of the experiment was found to yield good agreement with the experimentally-derived values at low and moderate doses.

Administration, Cutaneous↗
PubMed2006

A two-phase analysis of solute partitioning into the stratum corneum.

An analysis is presented of partition coefficients K(SC/w) describing solute distribution into fully hydrated stratum corneum (SC) from dilute aqueous solution (w). A comprehensive database is compiled from the experimental literature covering more than eight decades in the octanol/water partition coefficient K(o/w). It is analyzed according to a two-phase model following that of Anderson, Raykar, and coworkers (1988, 1989), which accounts for uptake by intercellular lipid and corneocyte (keratin plus water) phases having inherently different lipophilicities, as characterized by an SC lipid/water partition coefficient K(lip/w) and a partition coefficient PC(pro/w) quantifying cornoeocyte-phase binding. Regression of 72 data points yields useful best-fit recalibrations of power laws (or linear free energy relationships) giving K(lip/w) and PC(pro/w) as functions of K(o/w). The specific conclusions of the analysis are as follows: (i) The two-phase model offers substantial improvements over previously proposed analytical representations of K(SC/w), yielding an rms error in log(10)K(SC/w) of 0.30 limited by the scatter in the data. (ii) The best-fit description of the lipid phase is given by the power law K(lip/w) = 0.43 (K(o/w))(0.81), suggesting about half the absolute value of K(lip/w) relative to previous estimates. (iii) The best-fit description of corneocyte-phase binding differs negligibly from the correlation found by Anderson, Raykar, and coworkers for the more limited set of compounds studied by them. Explicit consideration of the two-phase nature of the SC also furnishes a rational basis for predicting the effects of varying hydration state upon K(SC/w).

1-Octanol↗
PubMed2005

Absorption and evaporation of N,N-diethyl-m-toluamide from human skin in vitro.

The penetration of DEET through split-thickness cadaver skin was measured in non-occluded Franz cells placed either in a fume hood or on a laboratory workbench. DEET, dissolved in a small volume of ethanol and spiked with (14)C radiolabel was applied to skin at doses from 0.02 to 11000 microg/cm(2). DEET penetration was greater for cells placed on the workbench, and the percentage of radioactivity penetrated after 72 h increased gradually with dose, for doses up to 680 microg/cm(2). At higher doses, it declined. Percent penetration ranged from 11.5 +/- 3.2% for a dose of 0.021 microg/cm(2) in the fume hood to 71.9 +/- 5.5% for a dose of 260 microg/cm(2) on the workbench. Results were interpreted in terms of a diffusion/evaporation model having three parameters-a solubility value for the chemical in the upper stratum corneum, M(sat); a mass transfer coefficient for evaporation, k(evap); and a characteristic time for diffusion, h(2)/D. The parameters obtained from fitting the model to the data (normalized to the fume hood environment) were M(sat) = 18 microg/cm(2) and k(evap) = 2.6 x 10(-5) cm/h. The value of h(2)/D decreased from 16 h at a DEET dose of 25 microg/cm(2) to 10 h at 1480 microg/cm(2), consistent with an increase in skin permeability of about 1.5-fold over this dose range. This effect was confirmed by means of an additional study in which skin samples pretreated with increasing amounts of unlabeled DEET were washed and redosed with (14)C-benzyl alcohol. A small (1.7-fold), but significant, increase in benzyl alcohol penetration with increasing amount of DEET was obtained. Thus, DEET enhanced its own skin permeation rate as well as that of another compound, but the effect was modest and not likely to be a major concern for compounds coadministered with DEET.

Abdomen↗
PubMed2004

In vivo evaporation rate of benzyl alcohol from human skin.

The evaporation rate of benzyl alcohol from the human volar forearm under controlled conditions in vivo shows a similar dependence on airflow and time to that seen in earlier in vitro studies. After an initial time lag associated with the apparatus, evaporation rate over a 2-h time period post-dose was satisfactorily described by a single exponential decay with a rate constant proportional to airflow over the skin, nu. The cumulative percentage of dose evaporated after 2 h ranged from 16% at nu = 20 mL min(-1) to 52% at nu = 100 mL min(-1). The absorption rate constant determined by an analysis of the in vivo data was equivalent to that determined in vitro, whereas the evaporation rate constants were related by the inverse ratio of the headspace volumes. The latter finding suggests that a simple laminar flow model can satisfactorily describe evaporation in both systems over the range of airflows used.

Administration, Topical↗
PubMed2004

Distributed diffusion-clearance model for transient drug distribution within the skin.

Quantitative predictions of molecular transport rates through the skin are key to the development of topically applied and transdermally delivered drugs, as well as risk assessment associated with dermal exposure. Most research to date has focused on correlations for the permeability of the stratum corneum, and transient diffusion models that oversimplify vascular clearance processes in terms of a perfect-removal boundary condition at an artificially introduced lower boundary. Considerations of the spatially distributed nature and action of blood vessels have usually been limited to the steady-state case. This article describes a more comprehensive transient model of percutaneous absorption formulated in terms of volumetric dispersion and clearance coefficients reflecting the spatial distribution of vascular processes. The model was implemented through an analysis of published experimental results on in vivo permeation of salicylic acid (SA) in de-epidermized rat skin. With regard to the characterization of SA in rat dermis ("de") in vivo, it was found that: (i) SA is likely to have a dermal effective partition coefficient (relative to pH 7.4 aqueous buffer "pH7.4") around unity (K(de/pH7.4) = 0.9 +/- 0.3); (ii) vascular processes seem not to increase drug dispersion significantly beyond molecular diffusion [D(de) approximately (D(de))(mol) = (8 +/- 3) . 10(-7) cm(2) s(-1)]; and (iii) vascular clearance is characterized by a rate coefficient k(de) = (7 +/- 2) . 10(-4) s(-1). Application of a whole-skin variant of the model (including the stratum corneum and viable epidermis) allowed realistic predictions to be made of transient subsurface concentration levels after application from a finite dose.

Animals↗
PubMed2003

Equilibrium water sorption in human stratum corneum.

The water content of the stratum corneum (SC) is a key factor in skin barrier homeostasis; it is intimately related to both skin condition and skin permeability. Studies of water uptake in excised human SC show strong similarities and allow characterization of the equilibrium SC water sorption isotherm in terms of widely used theoretical models. At low water activities, SC water sorption resembles that in other keratinized tissues (i.e., wool and horn), whereas at high water activities, it resembles that in polymeric hydrogels. In this paper, theoretical water sorption models [Brunauer-Emmett-Teller (BET), D'Arcy-Watt, and Frenkel-Halsey-Hill] are fit to the combined human SC water sorption data from our laboratories and others. Each of these models provides a satisfactory description of the equilibrium water content of human SC over the water activity range 0.03-1.0. An accompanying paper discusses the implications of SC water sorption on water mobility in corneocytes and on SC permeability.

Epidermis↗
PubMed2003

Disposition of benzyl alcohol after topical application to human skin in vitro.

Dissipation of a volatile compound or mixture from the skin surface after topical application involves both diffusion and evaporation. This report presents a detailed test of a previously described first-order kinetic approach to modeling this problem. Modified Franz diffusion cells fitted with a vapor trap were used to obtain absorption and evaporation data for benzyl alcohol (1% solution in ethanol) after application to human skin in vitro. Airflow over the skin surface (upsilon) was controlled in the experiment and accounted for in the model by allowing the evaporation rate constant(s) to vary as a function of upsilon. A linear dependence was found over the working range of the system, 10-100 mL/min. Three kinetic models were developed, all of which satisfactorily correlated cumulative absorption and evaporation results over the full range of upsilon (n = 120, s = 4-5%, r2 = 0.98-0.99). One of these was the model presented previously, in which all dissipation occurs from a single skin compartment. However, more details of the evaporation and absorption profiles could be accounted for by means of two-compartment models that explicitly consider the surface film present in the early stages post-application. The latter models seem to be better candidates for describing the time evolution of the volatile mixture evolving from the skin surface after topical application of, e.g., a complex fragrance or perfume.

Administration, Cutaneous↗
PubMed2003

Mobility of water in human stratum corneum.

At low water activities, stratum corneum (SC) water sorption resembles that in other keratinized tissues (i.e., wool and horn), whereas at high water activities, it resembles that in polymeric hydrogels. We propose that the concentration-dependent water diffusivity observed in these other systems applies to the corneocyte phase of the SC. An increase in SC hydration leads to increased water diffusivity in the corneocytes, in accordance with the predictions of both effective diffusion and free volume theories. Thus, theoretical results on effective diffusivity in a composite medium with random fiber obstacles and a free volume theory for water diffusivity in hydrogels (calibrated using data from wool and horn) have been applied to human SC water sorption data to estimate and establish theoretical limits on water diffusivity in corneocytes as a function of water activity. These results are used in conjunction with steady-state water permeability data to estimate the water permeability of both corneocyte and lipid phases of the SC under hydrated and partially hydrated conditions. The results of the analysis, when combined with previous spectroscopic analyses, strongly suggest that the lipids provide most of the SC water barrier in either case; thus, the diffusion pathway for water is primarily transcellular.

Algorithms↗