Enhancing glucose flux into sweat by increasing paracellular permeability of the sweat gland

Abstract

Non-invasive wearable biosensors provide real-time, continuous, and actionable health information. However, difficulties detecting diluted biomarkers in excreted biofluids limit practical applications. Most biomarkers of interest are transported paracellularly into excreted biofluids from biomarker-rich blood and interstitial fluid during normal modulation of cellular tight junctions. Calcium chelators are reversible tight junction modulators that have been shown to increase absorption across the intestinal epithelium. However, calcium chelators have not yet been shown to improve the extraction of biomarkers. Here we show that for glucose, a paracellularly transported biomarker, the flux into sweat can be increased by >10x using citrate, a calcium chelator, in combination with electroosmosis. Our results demonstrate a method of increasing glucose flux through the sweat gland epithelium, thereby increasing the concentration in sweat. Future work should examine if this method enhances flux for other paracellularly transported biomarkers to make it possible to detect more biomarkers with currently available biosensors.

A wearable freestanding electrochemical sensing system

“…The design methodology can be equivalently adopted to construct physical sensing interfaces in order to characterize the informative metrics related to the sweat secretion profile (e.g., the onset of sweating, secretion rate, and sweat loss volume). The inclusion of such interfaces can be particularly useful for devising correction mechanisms toward mitigating the confounding effect of inter-/intrasubject physiological variations and gland activity variability (in terms of metabolism and secretion rate), which have been reported to distort the physiological significance of the raw sweat readings (35,36,(42)(43)(44).…”

Physiological mechanisms determining eccrine sweat composition

“…There is significant interest in sweat glucose as a possible noninvasive alternative to blood glucose monitoring in diabetic patients. While glucose is present in sweat, as first demonstrated by Silvers et al (1928), its concentration is ~ 100 × lower than that of blood glucose (Boysen et al 1984;Jajack et al 2018;Katchman et al 2018;Lobitz and Mason 1948;Moyer et al 2012;Ono et al 2018). There is still speculation regarding the exact mechanism of glucose secretion into sweat.…”

“…There is still speculation regarding the exact mechanism of glucose secretion into sweat. Most studies suggest that blood glucose is the primary source of sweat glucose (Boysen et al 1984;Jajack et al 2018;Moyer et al 2012;Ono et al 2018) albeit its large size and polarity likely limit the passage of glucose into the lumen of the eccrine gland.…”

“…However, neither study investigated potential mechanisms of glucose secretion. Some recent papers have suggested a potential route of glucose transport that is paracellular in nature (Heikenfeld et al 2019;Jajack et al 2018;Katchman et al 2018). Paracellular transport is highly regulated via tight junctions that function to limit large molecule transport (Kutchai 1998).…”

“…Paracellular transport is highly regulated via tight junctions that function to limit large molecule transport (Kutchai 1998). Glucose flux in sweat has been shown to change with the modulation of tight junctions in the sweat gland epithelium (Jajack et al 2018). Using citrate, a calcium chelator, Jajack et al (2018) were able to modify paracellular pathways and found a > 10-fold increase in sweat glucose flux.…”