Tear-Based Ocular Wearable Biosensors for Human Health Monitoring

Abstract

Wearable tear-based biosensors have garnered substantial interest for real time monitoring with an emphasis on personalized health care. These biosensors utilize major tear biomarkers such as proteins, lipids, metabolites, and electrolytes for the detection and recording of stable biological signals in a non-invasive manner. The present comprehensive review delves deep into the tear composition along with potential biomarkers that can identify, monitor, and predict certain ocular diseases such as dry eye disease, conjunctivitis, eye-related infections, as well as diabetes mellitus. Recent technologies in tear-based wearable point-of-care medical devices, specifically the state-of-the-art and prospects of glucose, pH, lactate, protein, lipid, and electrolyte sensing from tear are discussed. Finally, the review addresses the existing challenges associated with the widespread application of tear-based sensors, which will pave the way for advanced scientific research and development of such non-invasive health monitoring devices.

Keywords: biomarkers; biosensors; healthcare; ocular; tear; wearable.

Figure 3

(a) Preclinical evaluation of NovioSense tear glucose sensor in sheep, (b) clinical trial–phase II evaluation in human eye using tear glucose sensor, (c) NovioSense device relative response to physiological interferences and glucose at varying concentration (reprinted with permission from [119]), (d) digital image of the sensor layer transferred onto a dome-shaped PDMS substrate, (e) image of the sensor placed on an artificial eye, (f) schematic representation of optical transmittance testing, (g) optical images (upper) and fluorescent images (lower) of in vitro cytotoxicity evaluation of contact lenses using human umbilical vein endothelial cells at different days (green and red fluorescence shows live and dead cells respectively), (h) average cell viability (percentage of live cells remain similar for 7 days), and (i) number of cells present (increasing number of live cells indicates cell culture reliability) (reprinted with permission from [125].

Figure 1

Schematic illustration of tear-based biosensors showing contact lens, flexible eye patch, and eye glass-based biosensors coupled with the real time data acquisition through a smartphone camera.

Figure 2

(i) Structure of three layered tear film constituting of inside mucin, intermediate aqueous, and exterior lipid layer (Reprinted with permission from [52]), tear fluid collection steps using (ii) Schirmer’s test strip and (iii) microcapillary tube methods (Reprinted with permission from [53]).

Figure 4

(a) Photograph of the microfluidic contact lens with colorimetric sensor (scale bar—5 mm), (b) smartphone camera imaging the color variation of sensor (scale bar—1 cm), (c) colorimetric characterization of pH sensor ranging from dark yellow at pH 6 to blue at pH 8 (reprinted with permission from [147]), (d–g) mechanically flexible eye patch sensor depicting tensile, torsional, and bending nature, (h) assay process to trigger the chromogenic reaction using the flowing tear stimulated by dacryagogue followed by the removal of eye patch sensor after 30 s for data collection and analysis (reprinted with permission from [151]), and (i) multilayered structure of crescent shaped PDMS microfluidic colorimetric sensing patch attached under the right eye of the human face followed by color data acquisition with the aid of a smartphone camera assisted by deep learning artificial intelligence (reprinted with permission from [17]).

Figure 5

(a) Fabrication process of l-lactate sensor on PET substrate molded into a contact-lens shape, (b) flat substrate comprising of sensing unit, interconnects, and electrodes connected to external potentiostat (CE—counter electrode, WE—working electrode, and RE—reference electrode), (c) fabricated contact lens sensor, (d) current response over time for dual sensor setup (S—functionalized sensor, C—control sensor, and D—differential signal), (e) optical image of a lens with the dual sensors configuration, (f) temperature stability of l-lactate sensor where current measurement was performed against l-lactate concentration for a varying temperature of 20–45 °C (reprinted with permission from [100]), and (g) tear lactate sensor fabrication and assembly. Tear lactate test strip inserts to a pen-like meter collects tear in contact with conjunctiva using a filter paper. Sensor comprised of carbon working electrode (WE), carbon counter electrode (CE), and silver/silver chloride (Ag/AgCl) reference electrode (RE) (Reprinted with permission from [158]).