Catalytic effects of magnetic and conductive nanoparticles on immobilized glucose oxidase in skin sensors.

Wearable skin sensors is a promising technology for real-time health care monitoring. They are of particular interest for monitoring glucose in diabetic patients. The concentration of glucose in sweat can be more than two orders of magnitude lower than in blood. In consequence, the scientific and technological efforts are focused in developing new concepts to enhance the sensitivity, decrease the limit of detection (LOD) and reduce the response time (RT) of glucose skin sensors. This work explores the effect of adsorbed superparamagnetic magnetite nanoparticles (MNPs) and conductive nanoparticles (CNPs) on carbon nanotube substrates (CNTs) used to immobilize glucose oxidase enzyme in the working electrode of skin sensors. MNPs and CNPs are made of magnetite and gold, respectively. The performance of the sensors was tested in standard buffer solution, artificial sweat, fresh sweat and on the skin of a healthy volunteer during an exercise session. In the case of artificial sweat, the presence of MNPs accelerated the RT from 7 to 5 s at the expense of increasing the LOD from 0.017 to 0.022 mM with slight increase of the sensitivity from 4.90 to 5.09µAm M-1cm-2. The presence of CNPs greatly accelerated the RT from 7 to 2 s and lowered the LOD from 0.017 to 0.014 mM at the expense of a great diminution of the sensitivity from 4.90 to 4.09µAm M-1cm-2. These effects were explained mechanistically by analyzing the changes in the concentration of free oxygen and electrons promoted by MNPs and CNPs in the CNTs and its consequences on the the glucose oxidation process.

Bio-Integrated Wearable Systems: A Comprehensive Review.

Bio-integrated wearable systems can measure a broad range of biophysical, biochemical, and environmental signals to provide critical insights into overall health status and to quantify human performance. Recent advances in material science, chemical analysis techniques, device designs, and assembly methods form the foundations for a uniquely differentiated type of wearable technology, characterized by noninvasive, intimate integration with the soft, curved, time-dynamic surfaces of the body. This review summarizes the latest advances in this emerging field of "bio-integrated" technologies in a comprehensive manner that connects fundamental developments in chemistry, material science, and engineering with sensing technologies that have the potential for widespread deployment and societal benefit in human health care. An introduction to the chemistries and materials for the active components of these systems contextualizes essential design considerations for sensors and associated platforms that appear in following sections. The subsequent content highlights the most advanced biosensors, classified according to their ability to capture biophysical, biochemical, and environmental information. Additional sections feature schemes for electrically powering these sensors and strategies for achieving fully integrated, wireless systems. The review concludes with an overview of key remaining challenges and a summary of opportunities where advances in materials chemistry will be critically important for continued progress.

Soft, Skin-Interfaced Microfluidic Systems with Wireless, Battery-Free Electronics for Digital, Real-Time Tracking of Sweat Loss and Electrolyte Composition.

Sweat excretion is a dynamic physiological process that varies with body position, activity level, environmental factors, and health status. Conventional means for measuring the properties of sweat yield accurate results but their requirements for sampling and analytics do not allow for use in the field. Emerging wearable devices offer significant advantages over existing approaches, but each has significant drawbacks associated with bulk and weight, inability to quantify volumetric sweat rate and loss, robustness, and/or inadequate accuracy in biochemical analysis. This paper presents a thin, miniaturized, skin-interfaced microfluidic technology that includes a reusable, battery-free electronics module for measuring sweat conductivity and rate in real-time using wireless power from and data communication to electronic devices with capabilities in near field communications (NFC), including most smartphones. The platform exploits ultrathin electrodes integrated within a collection of microchannels as interfaces to circuits that leverage NFC protocols. The resulting capabilities are complementary to those of previously reported colorimetric strategies. Systematic studies of these combined microfluidic/electronic systems, accurate correlations of measurements performed with them to those of laboratory standard instrumentation, and field tests on human subjects exercising and at rest establish the key operational features and their utility in sweat analytics.

Super-Absorbent Polymer Valves and Colorimetric Chemistries for Time-Sequenced Discrete Sampling and Chloride Analysis of Sweat via Skin-Mounted Soft Microfluidics.

This paper introduces super absorbent polymer valves and colorimetric sensing reagents as enabling components of soft, skin-mounted microfluidic devices designed to capture, store, and chemically analyze sweat released from eccrine glands. The valving technology enables robust means for guiding the flow of sweat from an inlet location into a collection of isolated reservoirs, in a well-defined sequence. Analysis in these reservoirs involves a color responsive indicator of chloride concentration with a formulation tailored to offer stable operation with sensitivity optimized for the relevant physiological range. Evaluations on human subjects with comparisons against ex situ analysis illustrate the practical utility of these advances.

Highly Stretchable Fully-Printed CNT-Based Electrochemical Sensors and Biofuel Cells: Combining Intrinsic and Design-Induced Stretchability.

We present the first example of an all-printed, inexpensive, highly stretchable CNT-based electrochemical sensor and biofuel cell array. The synergistic effect of utilizing specially tailored screen printable stretchable inks that combine the attractive electrical and mechanical properties of CNTs with the elastomeric properties of polyurethane as a binder along with a judiciously designed free-standing serpentine pattern enables the printed device to possess two degrees of stretchability. Owing to these synergistic design and nanomaterial-based ink effects, the device withstands extremely large levels of strains (up to 500% strain) with negligible effect on its structural integrity and performance. This represents the highest stretchability offered by a printed device reported to date. Extensive electrochemical characterization of the printed device reveal that repeated stretching, torsional twisting, and indenting stress has negligible impact on its electrochemical properties. The wide-range applicability of this platform to realize highly stretchable CNT-based electrochemical sensors and biofuel cells has been demonstrated by fabricating and characterizing potentiometric ammonium sensor, amperometric enzyme-based glucose sensor, enzymatic glucose biofuel cell, and self-powered biosensor. Highly stretchable printable multianalyte sensor, multifuel biofuel cell, or any combination thereof can thus be realized using the printed CNT array. Such combination of intrinsically stretchable printed nanomaterial-based electrodes and strain-enduring design patterns holds considerable promise for creating an attractive class of inexpensive multifunctional, highly stretchable printed devices that satisfy the requirements of diverse healthcare and energy fields wherein resilience toward extreme mechanical deformations is mandatory.

Tattoo-based noninvasive glucose monitoring: a proof-of-concept study.

We present a proof-of-concept demonstration of an all-printed temporary tattoo-based glucose sensor for noninvasive glycemic monitoring. The sensor represents the first example of an easy-to-wear flexible tattoo-based epidermal diagnostic device combining reverse iontophoretic extraction of interstitial glucose and an enzyme-based amperometric biosensor. In-vitro studies reveal the tattoo sensor's linear response toward physiologically relevant glucose levels with negligible interferences from common coexisting electroactive species. The iontophoretic-biosensing tattoo platform is reduced to practice by applying the device on human subjects and monitoring variations in glycemic levels due to food consumption. Correlation of the sensor response with that of a commercial glucose meter underscores the promise of the tattoo sensor to detect glucose levels in a noninvasive fashion. Control on-body experiments demonstrate the importance of the reverse iontophoresis operation and validate the sensor specificity. This preliminary investigation indicates that the tattoo-based iontophoresis-sensor platform holds considerable promise for efficient diabetes management and can be extended toward noninvasive monitoring of other physiologically relevant analytes present in the interstitial fluid.

Non-invasive mouthguard biosensor for continuous salivary monitoring of metabolites.

The present work describes the first example of a wearable salivary metabolite biosensor based on the integration of a printable enzymatic electrode on a mouthguard. The new mouthguard enzymatic biosensor, based on an immobilized lactate oxidase and a low potential detection of the peroxide product, exhibits high sensitivity, selectivity and stability using whole human saliva samples. Such non-invasive mouthguard metabolite biosensors could tender useful real-time information regarding a wearer's health, performance and stress level, and thus hold considerable promise for diverse biomedical and fitness applications.

Soft, Long-Lived, Bioresorbable Electronic Surgical Mesh with Wireless Pressure Monitor and On-Demand Drug Delivery.

Current research in the area of surgical mesh implants is somewhat limited to traditional designs and synthesis of various mesh materials, whereas meshes with multiple functions may be an effective approach to address long-standing challenges including postoperative complications. Herein, a bioresorbable electronic surgical mesh is presented that offers high mechanical strength over extended timeframes, wireless post-operative pressure monitoring, and on-demand drug delivery for the restoration of tissue structure and function. The study of materials and mesh layouts provides a wide range of tunability of mechanical and biochemical properties. Dissolvable dielectric composite with porous structure in a pyramidal shape enhances sensitivity of a wireless capacitive pressure sensor, and resistive microheaters integrated with inductive coils provide thermo-responsive drug delivery system for an antibacterial agent. In vivo evaluations demonstrate reliable, long-lived operation, and effective treatment for abdominal hernia defects, by clear evidence of suppressed complications such as adhesion formation and infections.

Synthesis of shape-programmable elastomer for a bioresorbable, wireless nerve stimulator.

Materials that have the ability to manipulate shapes in response to stimuli such as heat, light, humidity and magnetism offer a means for versatile, sophisticated functions in soft robotics or biomedical implants, while such a reactive transformation has certain drawbacks including high operating temperatures, inherent rigidity and biological hazard. Herein, we introduce biodegradable, self-adhesive, shape-transformable poly (L-lactide-co-ε-caprolactone) (BSS-PLCL) that can be triggered via thermal stimulation near physiological temperature (∼38 °C). Chemical inspections confirm the fundamental properties of the synthetic materials in diverse aspects, and study on mechanical and biochemical characteristics validates exceptional stretchability up to 800 % and tunable dissolution behaviors under biological conditions. The integration of the functional polymer with a bioresorbable electronic system highlights potential for a wide range of biomedical applications.

Stretchable and biodegradable self-healing conductors for multifunctional electronics.

As the regenerative mechanisms of biological organisms, self-healing provides useful functions for soft electronics or associated systems. However, there have been few examples of soft electronics where all components have self-healing properties while also ensuring compatibility between components to achieve multifunctional and resilient bio-integrated electronics. Here, we introduce a stretchable, biodegradable, self-healing conductor constructed by combination of two layers: (i) synthetic self-healing elastomer and (ii) self-healing conductive composite with additives. Abundant dynamic disulfide and hydrogen bonds of the elastomer and conductive composite enable rapid and complete recovery of electrical conductivity (~1000 siemens per centimeter) and stretchability (~500%) in response to repetitive damages, and chemical interactions of interpenetrated polymer chains of these components facilitate robust adhesion strength, even under extreme mechanical stress. System-level demonstration of soft, self-healing electronics with diagnostic/therapeutic functions for the urinary bladder validates the possibility for versatile, practical uses in biomedical research areas.

Water-powered, electronics-free dressings that electrically stimulate wounds for rapid wound closure.

Chronic wounds affect ~2% of the U.S. population and increase risks of amputation and mortality. Unfortunately, treatments for such wounds are often expensive, complex, and only moderately effective. Electrotherapy represents a cost-effective treatment; however, its reliance on bulky equipment limits its clinical use. Here, we introduce water-powered, electronics-free dressings (WPEDs) that offer a unique solution to this issue. The WPED performs even under harsh conditions-situations wherein many present treatments fail. It uses a flexible, biocompatible magnesium-silver/silver chloride battery and a pair of stimulation electrodes; upon the addition of water, the battery creates a radial electric field. Experiments in diabetic mice confirm the WPED's ability to accelerate wound closure and promote healing by increasing epidermal thickness, modulating inflammation, and promoting angiogenesis. Across preclinical wound models, the WPED-treated group heals faster than the control with wound closure rates comparable to treatments requiring expensive biologics and/or complex electronics. The results demonstrate the WPED's potential as an effective and more practical wound treatment dressing.

Highly Elastic, Bioresorbable Polymeric Materials for Stretchable, Transient Electronic Systems.

Substrates or encapsulants in soft and stretchable formats are key components for transient, bioresorbable electronic systems; however, elastomeric polymers with desired mechanical and biochemical properties are very limited compared to non-transient counterparts. Here, we introduce a bioresorbable elastomer, poly(glycolide-co-ε-caprolactone) (PGCL), that contains excellent material properties including high elongation-at-break (< 1300%), resilience and toughness, and tunable dissolution behaviors. Exploitation of PGCLs as polymer matrices, in combination with conducing polymers, yields stretchable, conductive composites for degradable interconnects, sensors, and actuators, which can reliably function under external strains. Integration of device components with wireless modules demonstrates elastic, transient electronic suture system with on-demand drug delivery for rapid recovery of post-surgical wounds in soft, time-dynamic tissues.

Electrochemical tattoo biosensors for real-time noninvasive lactate monitoring in human perspiration.

The present work describes the first example of real-time noninvasive lactate sensing in human perspiration during exercise events using a flexible printed temporary-transfer tattoo electrochemical biosensor that conforms to the wearer's skin. The new skin-worn enzymatic biosensor exhibits chemical selectivity toward lactate with linearity up to 20 mM and demonstrates resiliency against continuous mechanical deformation expected from epidermal wear. The device was applied successfully to human subjects for real-time continuous monitoring of sweat lactate dynamics during prolonged cycling exercise. The resulting temporal lactate profiles reflect changes in the production of sweat lactate upon varying the exercise intensity. Such skin-worn metabolite biosensors could lead to useful insights into physical performance and overall physiological status, hence offering considerable promise for diverse sport, military, and biomedical applications.

A potentiometric tattoo sensor for monitoring ammonium in sweat.

The development and analytical characterization of a novel ion-selective potentiometric cell in a temporary-transfer tattoo platform for monitoring ammonium levels in sweat is presented. The fabrication of this skin-worn sensor, which is based on a screen-printed design, incorporates all-solid-state potentiometric sensor technology for both the working and reference electrodes, in connection to ammonium-selective polymeric membrane based on the nonactin ionophore. The resulting tattooed potentiometric sensor exhibits a working range between 10(-4) M to 0.1 M, well within the physiological levels of ammonium in sweat. Testing under stringent mechanical stress expected on the epidermis shows that the analytical performance is not affected by factors such as stretching or bending. Since the levels of ammonium are related to the breakdown of proteins, the new wearable potentiometric tattoo sensor offers considerable promise for monitoring sport performance or detecting metabolic disorders in healthcare. Such combination of the epidermal integration, screen-printed technology and potentiometric sensing represents an attractive path towards non-invasive monitoring of a variety of electrolytes in human perspiration.

Solid-state Forensic Finger sensor for integrated sampling and detection of gunshot residue and explosives: towards 'Lab-on-a-finger'.

Increasing security needs require field-deployable, on-the-spot detection tools for the rapid and reliable identification of gunshot residue (GSR) and nitroaromatic explosive compounds. This manuscript presents a simple, all-solid-state, wearable fingertip sensor for the rapid on-site voltammetric screening of GSR and explosive surface residues. To fabricate the new Forensic Fingers, we screen-print a three-electrode setup onto a nitrile finger cot, and coat another finger cot with an ionogel electrolyte layer. The new integrated sampling/detection methodology relies on 'voltammetry of microparticles' (VMP) and involves an initial mechanical transfer of trace amounts of surface-confined analytes directly onto the fingertip-based electrode contingent. Voltammetric measurements of the sample residues are carried out upon bringing the working electrode (printed on the index finger cot) in direct contact with a second finger cot coated with an ionogel electrolyte (worn on the thumb), thus completing the solid-state electrochemical cell. Sampling and screening are performed in less than four minutes and generate distinct voltammetric fingerprints which are specific to both GSR and explosives. The use of the solid, flexible ionogel electrolyte eliminates any liquid handling which can resolve problems associated with leakage, portability and contamination. A detailed study reveals that the fingertip detection system can rapidly identify residues of GSR and nitroaromatic compounds with high specificity, without compromising its attractive behavior even after undergoing repeated mechanical stress. This new integrated sampling/detection fingertip strategy holds considerable promise as a rapid, effective and low-cost approach for on-site crime scene investigations in various forensic scenarios.

Tattoo-based potentiometric ion-selective sensors for epidermal pH monitoring.

This article presents the fabrication and characterization of novel tattoo-based solid-contact ion-selective electrodes (ISEs) for non-invasive potentiometric monitoring of epidermal pH levels. The new fabrication approach combines commercially available temporary transfer tattoo paper with conventional screen printing and solid-contact polymer ISE methodologies. The resulting tattoo-based potentiometric sensors exhibit rapid and sensitive response to a wide range of pH changes with no carry-over effects. Furthermore, the tattoo ISE sensors endure repetitive mechanical deformation, which is a key requirement of wearable and epidermal sensors. The flexible and conformal nature of the tattoo sensors enable them to be mounted on nearly any exposed skin surface for real-time pH monitoring of the human perspiration, as illustrated from the response during a strenuous physical activity. The resulting tattoo-based ISE sensors offer considerable promise as wearable potentiometric sensors suitable for diverse applications.

Biofluid-Activated Biofuel Cells, Batteries, and Supercapacitors: A Comprehensive Review.

Recent developments in wearable and implanted devices have resulted in numerous, unprecedented capabilities that generate increasingly detailed information about a user's health or provide targeted therapy. However, options for powering such systems remain limited to conventional batteries which are large and have toxic components and as such are not suitable for close integration with the human body. This work provides an in-depth overview of biofluid-activated electrochemical energy devices, an emerging class of energy sources judiciously designed for biomedical applications. These unconventional energy devices are composed of biocompatible materials that harness the inherent chemistries of various biofluids to produce useable electrical energy. This work covers examples of such biofluid-activated energy devices in the form of biofuel cells, batteries, and supercapacitors. Advances in materials, design engineering, and biotechnology that form the basis for high-performance, biofluid-activated energy devices are discussed. Innovations in hybrid manufacturing and heterogeneous integration of device components to maximize power output are also included. Finally, key challenges and future scopes of this nascent field are provided.

Emerging technologies in wearable sensors.

This Editorial highlights some current challenges and emerging solutions in wearable sensors, a maturing field where interdisciplinary crosstalk is of paramount importance. Currently, investigation efforts are aimed at expanding the application scenarios and at translating early developments from basic research to widespread adoption in personal health monitoring for diagnostic and therapeutic purposes. This translation requires addressing several old and new challenges that are summarized in this editorial. The special issue "Emerging technologies in wearable sensors" includes four selected contributions from leading researchers, exploring the topic from different perspectives. The aim is to provide the APL Bioengineering readers with a solid and timely overall vision of the field and with some recent examples of wearable sensors, exploring new research avenues.

Wireless, Battery-Free Implants for Electrochemical Catecholamine Sensing and Optogenetic Stimulation.

Neurotransmitters and neuromodulators mediate communication between neurons and other cell types; knowledge of release dynamics is critical to understanding their physiological role in normal and pathological brain function. Investigation into transient neurotransmitter dynamics has largely been hindered due to electrical and material requirements for electrochemical stimulation and recording. Current systems require complex electronics for biasing and amplification and rely on materials that offer limited sensor selectivity and sensitivity. These restrictions result in bulky, tethered, or battery-powered systems impacting behavior and that require constant care of subjects. To overcome these challenges, we demonstrate a fully implantable, wireless, and battery-free platform that enables optogenetic stimulation and electrochemical recording of catecholamine dynamics in real time. The device is nearly 1/10th the size of previously reported examples and includes a probe that relies on a multilayer electrode architecture featuring a microscale light emitting diode (µ-LED) and a carbon nanotube (CNT)-based sensor with sensitivities among the highest recorded in the literature (1264.1 nA µM-1 cm-2). High sensitivity of the probe combined with a center tapped antenna design enables the realization of miniaturized, low power circuits suitable for subdermal implantation even in small animal models such as mice. A series of in vitro and in vivo experiments highlight the sensitivity and selectivity of the platform and demonstrate its capabilities in freely moving, untethered subjects. Specifically, a demonstration of changes in dopamine concentration after optogenetic stimulation of the nucleus accumbens and real-time readout of dopamine levels after opioid and naloxone exposure in freely behaving subjects highlight the experimental paradigms enabled by the platform.

A Miniaturized, Battery-Free, Wireless Wound Monitor That Predicts Wound Closure Rate Early.

Diabetic foot ulcers are chronic wounds that affect millions and increase the risk of amputation and mortality, highlighting the critical need for their early detection. Recent demonstrations of wearable sensors enable real-time wound assessment, but they rely on bulky electronics, making them difficult to interface with wounds. Herein, a miniaturized, wireless, battery-free wound monitor that measures lactate in real-time and seamlessly integrates with bandages for conformal attachment to the wound bed is introduced. Lactate is selected due to its multifaceted role in initiating healing. Studies in healthy and diabetic mice reveal distinct lactate profiles for normal and impaired healing wounds. A mathematical model based on the sensor data predicts wound closure rate within the first 3 days post-injury with ≈76% accuracy, which increases to ≈83% when pH is included. These studies underscore the significance of monitoring biomarkers during the inflammation phase, which can offer several benefits, including short-term use of wound monitors and their easy removal, resulting in lower risks of injury and infection at the wound site. Improvements in prediction accuracy can be achieved by designing mathematical models that build on multiple wound parameters such as pro-inflammatory and metabolic markers. Achieving this goal will require designing multi-analyte wound monitors.