Eyeglasses-based tear biosensing system: Non-invasive detection of alcohol, vitamins and glucose

Highlights

• Wearable fluidic tears biosensor and wireless circuitry integrated into eyeglasses for non-invasive biomarker monitoring.

• Wearable tear sensing platform placed outside the eye region mitigates drawbacks of systems requiring direct eye contact.

• Real-time collection and direct measurements of stimulated tears allow the first wearable tear alcohol monitoring platform.

Abstract

We report on a wearable tear bioelectronic platform, integrating a microfluidic electrochemical detector into an eyeglasses nose-bridge pad, for non-invasive monitoring of key tear biomarkers. The alcohol-oxidase (AOx) biosensing fluidic system allowed real-time tear collection and direct alcohol measurements in stimulated tears, leading to the first wearable platform for tear alcohol monitoring. Placed outside the eye region this fully wearable tear-sensing platform addresses drawbacks of sensor systems involving direct contact with the eye as the contact lenses platform. Integrating the wireless electronic circuitry into the eyeglasses frame thus yielded a fully portable, convenient-to-use fashionable sensing device. The tear alcohol sensing concept was demonstrated for monitoring of alcohol intake in human subjects over multiple drinking courses, displaying good correlation to parallel BAC measurements. We also demonstrate for the first time the ability to monitor tear glucose outside the eye and the utility of wearable devices for monitoring vitamin nutrients in connection to enzymatic flow detector and rapid voltammetric scanning, respectively. These developments pave the way to build an effective eyeglasses system capable of chemical tear analysis.

Introduction

Wearable electronics have become commonplace in our daily life and have generated a tremendous commercial interest. Such interest has stimulated considerable efforts towards the development of wearable and mobile sensing systems. (Bandodkar et al., 2016; Kim et al., 2018a; Liu et al., 2017). While early attention was given primarily to wearable mobility and physical sensors, recent efforts have shifted to the development of systems capable of non-invasive monitoring of (bio)chemical markers. (Bariya et al., 2018; Heikenfeld et al., 2018; Yang and Gao, 2019). Wearable (bio)chemical sensors have thus been designed to be conveniently incorporated into a wearer's daily routine, providing useful insights into the wearer's health and fitness levels, or its surroundings. (Sempionatto et al., 2017b). Non-invasive wearable chemical sensing platforms, operating in readily sampled biofluids, such as sweat, saliva or tears, have thus garnered considerable interest due to their potential to provide useful real-time insights into changes in biomarkers concentrations without necessitating blood sampling. Wearable chemical sensors have thus been integrated into a variety of body conformable platforms ranging from wristbands (Gao et al., 2016) and temporary tattoos (Bandodkar et al., 2015) to textiles (Jeerapan et al., 2016) and from mouthguard (Kim et al., 2015) to contact lenses (Park et al., 2018), with target analytes including key metabolites (such as glucose, lactate or alcohol) and electrolytes (e.g., Na⁺, Cl⁻, K⁺, etc.) (Campbell et al., 2018; Roh et al., 2016). As this exciting field and the available technologies advance rapidly, it is necessary to develop new, easy-to-use and fashionable platforms that enhance the user's comfort and acceptance, such as eyeglasses, and to explore new target biomarkers in different non-invasive biofluids, such as tears, towards fostering even greater acceptance, versatility and scope of wearable chemical sensors.

Tears, also known as lachrymal fluid, are generated through the lachrymal gland to coat and protect the eyes. Tears are less complex than blood, but they contain a variety of biomarkers present through either intracellular biomolecule secretion or via passive leakage of low-weight compounds from blood plasma (Farandos et al., 2015; Pankratov et al., 2016; Thaysen and Thorn, 1954). In the latter case, the concentrations of various metabolites in tears reflect concurrent blood levels, making the tears an attractive medium for non-invasive monitoring of important physiological parameters. Wearable sensing systems based on the tear biofluid have been reported for several analytes, particularly glucose and lactate (Senior, 2014; Taormina et al., 2007; Thomas et al., 2012; Yao et al., 2012). These systems have focused primarily on the incorporation of electrochemical sensors into contact lens-based platforms with integrated electronic components for direct measurements in basal tears. (Falk et al., 2013; Senior, 2014; Thomas et al., 2012; Yao et al., 2012). Efforts for improving such tear sensing systems have continued toward integration of appropriate power sources and wireless data transmission, along with advanced sensor designs (Kim et al., 2017; Kownacka et al., 2018; Park et al., 2018). Nevertheless, major challenges remain for reliable operation of fully integrated wireless tears-based wearable chemical sensing platforms.

Here we describe, for the first time, a non-invasive wearable tear biosensor system mounted on eyeglasses and demonstrate its robust and attractive analytical performance for real-time monitoring of different target analytes such as alcohol, vitamins, and glucose in tears. Recently, we described an eyeglasses-based sensing platform for monitoring sweat metabolites and electrolytes using nose-bridge pad electrodes contacting the skin. (Sempionatto et al., 2017b). In the present work, we mounted an on-line fluidic device onto the eyeglasses nose-bridge pad to allow direct collection of stimulated tears (Fig. 1), along with the flow of the sampled tears over an alcohol oxidase (AOx)-based electrochemical detector and rapid fluid replenishment from the device. Eyeglasses represent a commonly used lifestyle accessory with close proximity to tear fluid, hence providing convenient access to the nearby stimulated tears while addressing drawbacks associated with contact-lens based sensing platforms (Badugu et al., 2018; Jiang et al., 2018; Park et al., 2018). These drawbacks relate to placing the lenses directly on the eye, limited user compliance (particularly in younger subjects) and potential vision impairment due to the embedded sensor system (Farandos et al., 2015). To address these crucial issues, the present eyeglasses platform relies on placing the electrochemical detection system and its wireless electronic backbone outside the eye area, while collecting stimulated tears on the external miniaturized flow detector mounted on the eyeglasses pad. Integration of wireless electronic circuitry into the eyeglasses frame (for the amperometric and voltammetric operations and data transmission) thus leads to a fully portable, convenient-to-use, yet fashionable wearable sensing platform.

Alcohol represents an extremely important target opportunity for wearable sensing devices as it is the most widely used substance of abuse worldwide which leads annually to hundreds of billions of dollars in related costs (associated with lost productivity, crime, health care, etc.) in the United States alone (Grant et al., 2017). Thus, the continuous real-time monitoring of alcohol intake and assessment of an individual's level of intoxication have been the subject of tremendous research efforts (Campbell et al., 2018; Thungon et al., 2017). However, the reported devices have downsides, such as limited specificity and time delay after the alcohol intake (Campbell et al., 2018; Karns-Wright et al., 2017). Recent reports have demonstrated wearable alcohol biosensors capable of greater specificity and near real-time monitoring through amperometric detection in sweat (Gamella et al., 2014; Hauke et al., 2018; Kim et al., 2016) and interstitial fluid (Mohan et al., 2017). Despite of these advances, new and improved non-invasive alcohol monitoring platforms are greatly desired. The detection of alcohol in tears has been reported first by Giles et al. in the 1980s (Giles et al., 1987, 1988) with measurements carried out using a thermal resistivity sensor in vapors above the eyes. Since then, no wearable sensing system has focused on the detection of alcohol in tears.

The tear alcohol monitoring method described in this paper utilizes a wearable eyeglasses-based platform with an alcohol biosensor flow detector mounted onto the nose-bridge pad for alcohol measurements in stimulated tears (Fig. 1A). Such wearable non-invasive alcohol bioelectronic platform is shown to be extremely useful for measuring tear alcohol levels in real-life scenarios with good correlation to concurrent blood alcohol concentration (BAC). We demonstrate that the wearable tear alcohol biosensor, along with the integrated on-board wireless electronics, reliably detects alcohol intake in human subjects, as validated by parallel BAC monitoring. By placing the sensing system outside the eye region, the new system obviates the problems associated with wearable sensors placed directly in the eye. The microfluidic design of this system, along with the chemical tear stimulation method, minimizes common errors associated with tear sampling, such as low sample volume, tear evaporation, and changing tear composition upon mechanical stimulation (Mishima et al., 1966; Stuchell et al., 1984; Yan et al., 2011). We also demonstrate the utility of the eyeglasses-based sensing platform for non-invasive monitoring of tear glucose and vitamins. To the best of our knowledge, this represents the first example of non-invasive monitoring of vitamins toward potential personal nutrition applications. Such multi-vitamin sensing has been carried out using rapid square-wave voltammetry (SWV). Despite its multi-analyte capability, sensitivity and speed, SWV has rarely been explored for wearable sensing applications. Considering the importance of alcohol, glucose and vitamins target analytes, and the versatility and comfort of the eyeglasses platform, the new tear bioelectronic system represents a major step toward the non-invasive monitoring of biomarkers.