The Blood–Brain Barrier as a Target in Traumatic Brain Injury Treatment

Critical role of TRPP2 and TRPC1 channels in stretch-induced injury of blood-brain barrier endothelial cells.

Aims Monitors of transdermal alcohol concentration (TAC) provide an objective measurement of alcohol consumption that is less invasive than measurements in blood, breath or urine; however, there is a substantial time delay in the onset of TAC compared to blood or breath alcohol concentrations (BrACs). The current study examined the characteristics of the delay between peak TAC and peak BrAC.

Methods Data was aggregated from three experimental laboratory studies ( N  = 61; 32 men, 29 women) in which participants wore a TAC monitor and BrAC was monitored while drinking one, two, three, four and five beers in the laboratory. Analyses examined the sex- and dose-related differences in peak BrAC and TAC, the time-to-peak BrAC and TAC, and time lag between the peak BrAC and TAC values.

Results The times-to-peak were an increasing function of the number of beers consumed. At each level of beer consumption the peak TAC averaged lower than peak BrAC and times-to-peak TAC were longer than for BrAC. The time-to-peak BrAC and TAC was longer for women than men. The congruence between peak TAC and BrAC increased as a function of the beers consumed. No sex difference in the time lag between peak BrAC and TAC was detected.

Conclusions The congruence between TAC and BrAC and time lags between TAC and BrAC are related to the number of beers consumed. Peak values of TAC and BrAC became more congruent with higher doses but the time lag increased as a function of the amount of alcohol consumed.

Short summary The time delay (or lag) and congruence between transdermal vs. BrACs increases as the number of beers increases. Though sex differences are evident in peak transdermal and BrACs, no sex differences were evident in the time lag and the congruence between transdermal and breath alcohol concentrations.

/pdf/time-delays-in-transdermal-alcohol-concentrations-relative-za218owbsw.pdf

Time Delays in Transdermal Alcohol Concentrations Relative to Breath Alcohol Concentrations.

Transdermal alcohol biosensors have the ability to detect the alcohol that emanates from the bloodstream and diffuses through the skin. However, previous biosensors have suffered from long-term fouling of the sensor element and drift in the resulting sensor readings over time. Here, we report a wearable alcohol sensor platform that solves the problem of sensor fouling by enabling drift-free signals in vivo for up to 24 h and an interchangeable cartridge connection that enables consecutive days of measurement. We demonstrate how alcohol oxidase enzyme and Prussian Blue can be combined to prevent baseline drift above 25 nA, enabling sensitive detection of transdermal alcohol. Laboratory characterization of the enzymatic alcohol sensor demonstrates that the sensor is mass-transfer-limited by a diffusion-limiting membrane of lower permeability than human skin and a linear sensor range between 0 mM and 50 mM. Further, we show continuous transdermal alcohol data recorded with a human subject for two consecutive days. The non-invasive sensor presented here is an objective alternative to the self-reports used commonly to quantify alcohol consumption in research studies.

Wearable Enzymatic Alcohol Biosensor

This chapter provides biochemical and physiological research on the disposition and fate of ethanol in the body. Few if any drugs have been studied as extensively and over so many years as ethanol or ethyl alcohol, the principal psychoactive substance in all alcoholic beverages. Much has already been written and published about the absorption, distribution and metabolism of man's favorite drug, both from the viewpoint of forensic science and legal medicine as well as substance abuse and biomedical alcohol research. The present chapter combines and updates two separate chapters that were published in the fourth edition. One chapter dealt with biochemistry and physiology of ethanol metabolism and the other covered the basic principles and concepts underlying studies on the disposition and fate of ethanol in the body.

Biochemical and Physiological Research on the Disposition and Fate of Ethanol in the Body

Transdermal ethanol detection is a promising method that could prevent drunk driving if integrated into an ignition interlock system. However, experimental data from previous research has shown significant time delays between alcohol ingestion and detection at the skin which makes real time estimation of blood alcohol concentration via skin measurement difficult. Using a validated model we studied the effects that body weight, metabolic rate and ethanol dose had on the time lag between the blood alcohol concentration and transdermal alcohol concentration. The dose of alcohol ingested was found to have the most significant effect on the skin alcohol lag time; a dose of 15 ml of ethanol resulted in a peak lag time of approximately 33 minutes, while a dose of 60 ml of ethanol resulted in a peak time lag of 53 minutes. The time lag was found to be insensitive to body mass and only moderately sensitive to changes in metabolic rates.

Feasibility of transdermal ethanol sensing for the detection of intoxicated drivers

TThis paper investigates the effect that body weight and gender have on the transdermal transport of ethanol observed after the ingestion of an alcohol beverage. The approach is to use a computational model which combines a multi-compartment ethanol metabolism model with a transdermal transport model. Males have a larger proportion of alcohol soluble body mass when compared to females of the same weight allowing for greater dilution of the same dose of alcohol, and lower resultant blood alcohol concentrations. In addition, liver size increases with body mass and males have larger livers than females. Examination of these factors has shown that transdermal alcohol concentration lag time is insensitive to body mass and gender because these factors do not significantly affect the alcohol elimination rate.

/pdf/modeling-of-transdermal-transport-of-alcohol-effect-of-body-2ehroicvdj.pdf

Modeling of transdermal transport of alcohol effect of body mass and gender.

This paper discusses methods that will be used to experimentally determine the limitations of transdermal ethanol alcohol sensors when used on human subjects. Transdermal ethanol sensors are used to measure the concentration of ethanol emitted by the surface of the skin. The maximum concentration of ethanol in the skin is proportional to the concentration of ethanol in the blood stream but is offset temporally because of the diffusion delay intrinsic to body tissue. Methods to evaluate different model ethanol sensors are discussed as well as the development and function of a portable, transdermal ethanol sensing device suitable for measuring ethanol concentration on the palm of a test subject's hand. In addition, the designs of several experiments are described to test the functional limitations of transdermal ethanol sensors in practical use settings. These experiments include tests to correlate a subject's peak blood and skin ethanol concentrations and experimental determination of different false positive sources.

Assessment of dermal ethanol emission sensors: experimental design.

A wide body of existing research on cellular injury has been conducted using cell cultures grown on flexible elastomer membranes deformed by a transient pressure pulse. However, there has been little published information on the material properties of these elastic membranes. In order to facilitate the development of a finite element model of cellular injury, the material properties of the underlying membrane must first be known. A series of static tests of an elastomer yielded a set of pressure-deflection data for applied pressures of 2.5, 5.0, 7.5, 10, 12 and 14 PSIG. Using an optimization technique, the material properties for an elastic finite element model were iteratively changed and compared to these experimental results in order to minimize the difference between experiment and simulation. The final material properties were found to be quite different from the initial guess, with a final modulus of 950,000 Pa, a Poisson's ratio of 0.499, and a density of 5.5*10-4 g/mm3. The comparison between the experimental and finite element models was conducted using a sum of squares difference for each of the six pressures, yielding an average sum of squares difference of 0.271 mm. The average percent error of the deflection measurements was 3.57%, with errors measured at each pressure ranging between 0% and 12%. Parameter sensitivity was examined and the most influential property was the modulus of elasticity. The least influential parameter was the density, having almost no effect on the maximum deflection.

/pdf/mechanical-properties-of-polytetraflouroethylene-elastomer-35jxnqq2uw.pdf

Mechanical properties of polytetraflouroethylene elastomer membrane for dynamic cell culture testing.

Traumatic Brain Injury is hypothesized to occur as a function of the strain and strain rate experienced by neural tissues during a traumatic event. In vitro studies of TBI at the cellular level have used a variety of methods to subject neural cell cultures to potentially injurious strains and strain rates. The Advanced Cell Deformation System (ACDS) has been developed which has the ability to independently control strain and strain rate and can strain cell cultures grown on a stretchable membrane from 0.1 to 0.60 at rates up to 25 s-1. The ability to control strain and strain rate independently or to simulate quick repetitive loading was not available in previous devices. Here we present the experiments testing the ability of the ACDS to replicate the results of in vitro experiments of neural cell deformation conducted by earlier researchers. This is a first step toward future experiments which will use the more advanced capabilities of the ACDS.

/pdf/validation-of-an-improved-injury-device-for-in-vitro-study-4j5tlga1dr.pdf

Validation of an improved injury device for in vitro study of neural cell deformation - biomed 2009.

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