Wearable Electrochemical Glucose Sensors in Diabetes Management: A Comprehensive Review.

With the rising diabetic population, the demand for glucose sensing devices has also been on an increasing trend. Accordingly, the field of glucose biosensors for diabetes management has witnessed tremendous scientific and technological advancements since the introduction of the first enzymatic glucose biosensor in the 1960s. Among these, electrochemical biosensors hold considerable potential for tracking dynamic glucose profiles in real time. The recent evolution of wearable devices has opened opportunities to use alternative body fluids in a pain-free, noninvasive or minimally invasive manner. This review aims to present a comprehensive report about the status and promise of wearable electrochemical sensors for on-body glucose monitoring. We start by highlighting the importance of diabetes management and how sensors can contribute toward its effective monitoring. We then discuss the electrochemical glucose sensing mechanisms, evolution of such glucose sensors over time, different versions of wearable glucose biosensors targeting various biofluids, and multiplexed wearable sensors toward optimal diabetes management. Finally, we focus on the commercial aspects of wearable glucose biosensors, starting with existing continuous glucose monitors, followed by other emerging sensing technologies, and concluding with highlighting the key prospects toward personalized diabetes management in connection to an autonomous closed-loop artificial pancreas.

Wearable soft electrochemical microfluidic device integrated with iontophoresis for sweat biosensing.

A soft and flexible wearable sweat epidermal microfluidic device capable of simultaneously stimulating, collecting, and electrochemically analyzing sweat is demonstrated. The device represents the first system integrating an iontophoretic pilocarpine delivery system around the inlet channels of epidermal polydimethylsiloxane (PDMS) microfluidic device for sweat collection and analysis. The freshly generated sweat is naturally pumped into the fluidic inlet without the need of exercising. Soft skin-mounted systems, incorporating non-invasive, on-demand sweat sampling/analysis interfaces for tracking target biomarkers, are in urgent need. Existing skin conformal microfluidic-based sensors for continuous monitoring of target sweat biomarkers rely on assays during intense physical exercising. This work demonstrates the first example of combining sweat stimulation, through transdermal pilocarpine delivery, with sample collection through a microfluidic channel for real-time electrochemical monitoring of sweat glucose, in a fully integrated soft and flexible multiplexed device which eliminates the need of exercising. The on-body operational performance and layout of the device were optimized considering the fluid dynamics and evaluated for detecting sweat glucose in several volunteers. Furthermore, the microfluidic monitoring device was integrated with a real-time wireless data transmission system using a flexible electronic board PCB conformal with the body. The new microfluidic platform paves the way to real-time non-invasive monitoring of biomarkers in stimulated sweat samples for diverse healthcare and wellness applications.

Extended Noninvasive Glucose Monitoring in the Interstitial Fluid Using an Epidermal Biosensing Patch.

An effective, noninvasive glucose monitoring technology could be a pivotal factor for addressing the major unmet needs for managing diabetes mellitus (DM). Here, we describe a skin-worn, disposable, wireless electrochemical biosensor for extended noninvasive monitoring of glucose in the interstitial fluid (ISF). The wearable platform integrates three components: a screen-printed iontophoretic electrode system for ISF extraction by reverse iontophoresis (RI), a printed three-electrode amperometric glucose biosensor, and an electronic interface for control and wireless communication. Prolonged on-body glucose monitoring of up to 8 h, including clinical trials conducted in individuals with and without DM, demonstrated good correlation between glucose blood and ISF concentrations and the ability to monitor dynamically changing glucose levels upon food consumption, with no evidence of skin irritation or discomfort. Such successful extended operation addresses the challenges reported for the GlucoWatch platform by using a lower RI current density at shorter extraction times, along with a lower measurement frequency. Such a noninvasive skin-worn platform could address long-standing challenges with existing glucose monitoring platforms.

Non-Invasive Sweat-Based Tracking of L-Dopa Pharmacokinetic Profiles Following an Oral Tablet Administration.

Levodopa (L-Dopa) is the "gold-standard" medication for symptomatic therapy of Parkinson disease (PD). However, L-Dopa long-term use is associated with the development of motor and non-motor complications, primarily due to its fluctuating plasma levels in combination with the disease progression. Herein, we present the first example of individualized therapeutic drug monitoring for subjects upon intake of standard L-Dopa oral pill, centered on dynamic tracking of the drug concentration in naturally secreted fingertip sweat. The touch-based non-invasive detection method relies on instantaneous collection of fingertip sweat on a highly permeable hydrogel that transports the sweat to a biocatalytic tyrosinase-modified electrode, where sweat L-Dopa is measured by reduction of the dopaquinone enzymatic product. Personalized dose-response relationship is demonstrated within a group of human subjects, along with close pharmacokinetic correlation between the finger touch-based fingertip sweat and capillary blood samples.

Non-invasive monitoring of interstitial fluid lactate through an epidermal iontophoretic device.

The development of a non-invasive sensing technology that allows collection of interstitial fluid (ISF) lactate and its subsequent analysis without exertion requirement, could enable lactate monitoring from rested individuals. Here, we describe a wearable, soft epidermal adhesive patch that integrates a reverse iontophoretic (RI) system, and an amperometric lactate biosensor placed on the anodic electrode with a porous hydrogel reservoir, for simultaneous ISF lactate extraction and quantification via electrochemical sensing, respectively. The iontophoretic system includes agarose hydrogels for preventing skin electrocution, while a porous polyvinyl alcohol-based hydrogel facilitates the effective transport of lactate from skin to the biosensor. The flexible skin-worn device tested on healthy individuals at rest showed rapid lactate collection from the ISF after 10 min of reverse iontophoresis with no evidence of discomfort or irritation to the skin. Detailed characterization of the enzymatic biosensor before and during on-body trials along with relevant control experiments confirmed the efficient extraction and selective detection of ISF lactate. Such an epidermal technology represents the first demonstration of an all-in-one platform that integrates non-invasive collection and subsequent analysis of lactate from iontophoretically extracted ISF toward point-of-care operation.

Disposable screen-printed electrochemical sensing strips for rapid decentralized measurements of salivary ketone bodies: Towards therapeutic and wellness applications.

The interest in ketone bodies (KBs) has intensified recently as they play significant roles in healthcare, nutrition, and wellness applications. We present a disposable electrochemical sensing strip for rapid decentralized detection of ß-hydroxybutyrate (HB), one of the dominant physiological KBs, in saliva. The new salivary enzymatic HB sensor strip relies on a gold-coated screen-printed carbon electrode modified with a reagent layer containing toluidine blue O (TBO mediator), ß-hydroxybutyrate dehydrogenase (HBD enzyme), and the HBD cofactor nicotinamide adenine dinucleotide (NAD+ coenzyme), along with carbon nanotubes (CNTs) and chitosan (Chit) for enhancing the sensor's sensitivity and for encapsulating the enzyme and its cofactor, respectively. The systematic optimization resulted in an attractive analytical performance, with a rapid response time within 60 s, a wide HB dynamic detection range from 0.1 to 3.0 mM along with a low limit of detection (50 µM HB) in an artificial saliva medium. The strip displays high selectivity for HB over acetoacetate (AcAc) and other interferences (i.e., acetaminophen, ascorbic acid, glucose, lactic acid, and uric acid), good reproducibility, and high stability towards temperature or pH effects. The new disposable sensing strip system, coupled with a hand-held electrochemical analyzer, showed rapid HB monitoring in human saliva samples collected from healthy volunteers, with similar temporal profiles to those obtained in parallel capillary blood measurements in response to the intake of keto supplements. This strip enables efficient, reliable, and near real-time salivary HB detection to track non-invasively the dynamics of HB concentrations after intaking commercial supplements towards diverse healthcare and nutrition applications.

Non-invasive in-vivo glucose-based stress monitoring in plants.

Plant stress responses involve a suite of genetically encoded mechanisms triggered by real-time interactions with their surrounding environment. Although sophisticated regulatory networks maintain proper homeostasis to prevent damage, the tolerance thresholds to these stresses vary significantly among organisms. Current plant phenotyping techniques and observables must be better suited to characterize the real-time metabolic response to stresses. This impedes practical agronomic intervention to avoid irreversible damage and limits our ability to breed improved plant organisms. Here, we introduce a sensitive, wearable electrochemical glucose-selective sensing platform that addresses these problems. Glucose is a primary plant metabolite, a source of energy produced during photosynthesis, and a critical molecular modulator of various cellular processes ranging from germination to senescence. The wearable-like technology integrates a reverse iontophoresis glucose extraction capability with an enzymatic glucose biosensor that offers a sensitivity of 22.7 nA/(µM·cm2), a limit of detection (LOD) of 9.4 µM, and a limit of quantification (LOQ) of 28.5 µM. The system's performance was validated by subjecting three different plant models (sweet pepper, gerbera, and romaine lettuce) to low-light and low-high temperature stresses and demonstrating critical differential physiological responses associated with their glucose metabolism. This technology enables non-invasive, non-destructive, real-time, in-situ, and in-vivo identification of early stress response in plants and provides a unique tool for timely agronomic management of crops and improving breeding strategies based on the dynamics of genome-metabolome-phenome relationships.

In-ear integrated sensor array for the continuous monitoring of brain activity and of lactate in sweat.

Owing to the proximity of the ear canal to the central nervous system, in-ear electrophysiological systems can be used to unobtrusively monitor brain states. Here, by taking advantage of the ear's exocrine sweat glands, we describe an in-ear integrated array of electrochemical and electrophysiological sensors placed on a flexible substrate surrounding a user-generic earphone for the simultaneous monitoring of lactate concentration and brain states via electroencephalography, electrooculography and electrodermal activity. In volunteers performing an acute bout of exercise, the device detected elevated lactate levels in sweat concurrently with the modulation of brain activity across all electroencephalography frequency bands. Simultaneous and continuous unobtrusive in-ear monitoring of metabolic biomarkers and brain electrophysiology may allow for the discovery of dynamic and synergetic interactions between brain and body biomarkers in real-world settings for long-term health monitoring or for the detection or monitoring of neurodegenerative diseases.

A self-powered ingestible wireless biosensing system for real-time in situ monitoring of gastrointestinal tract metabolites.

Information related to the diverse and dynamic metabolite composition of the small intestine is crucial for the diagnosis and treatment of various diseases. However, our current understanding of the physiochemical dynamics of metabolic processes within the small intestine is limited due to the lack of in situ access to the intestinal environment. Here, we report a demonstration of a battery-free ingestible biosensing system for monitoring metabolites in the small intestine. As a proof of concept, we monitor the intestinal glucose dynamics on a porcine model. Battery-free operation is achieved through a self-powered glucose biofuel cell/biosensor integrated into a circuit that performs energy harvesting, biosensing, and wireless telemetry via a power-to-frequency conversion scheme using magnetic human body communication. Such long-term biochemical analysis could potentially provide critical information regarding the complex and dynamic small intestine metabolic profiles.

An epidermal patch for the simultaneous monitoring of haemodynamic and metabolic biomarkers.

Monitoring the effects of daily activities on the physiological responses of the body calls for wearable devices that can simultaneously track metabolic and haemodynamic parameters. Here we describe a non-invasive skin-worn device for the simultaneous monitoring of blood pressure and heart rate via ultrasonic transducers and of multiple biomarkers via electrochemical sensors. We optimized the integrated device so that it provides mechanical resiliency and flexibility while conforming to curved skin surfaces, and to ensure reliable sensing of glucose in interstitial fluid and of lactate, caffeine and alcohol in sweat, without crosstalk between the individual sensors. In human volunteers, the device captured physiological effects of food intake and exercise, in particular the production of glucose after food digestion, the consumption of glucose via glycolysis, and increases in blood pressure and heart rate compensating for oxygen depletion and lactate generation. Continuous and simultaneous acoustic and electrochemical sensing via integrated wearable devices should enrich the understanding of the body's response to daily activities, and could facilitate the early prediction of abnormal physiological changes.