Biocompatible Material-Based Flexible Biosensors: From Materials Design to Wearable/Implantable Devices and Integrated Sensing Systems.

Human beings have a greater need to pursue life and manage personal or family health in the context of the rapid growth of artificial intelligence, big data, the Internet of Things, and 5G/6G technologies. The application of micro biosensing devices is crucial in connecting technology and personalized medicine. Here, the progress and current status from biocompatible inorganic materials to organic materials and composites are reviewed and the material-to-device processing is described. Next, the operating principles of pressure, chemical, optical, and temperature sensors are dissected and the application of these flexible biosensors in wearable/implantable devices is discussed. Different biosensing systems acting in vivo and in vitro, including signal communication and energy supply are then illustrated. The potential of in-sensor computing for applications in sensing systems is also discussed. Finally, some essential needs for commercial translation are highlighted and future opportunities for flexible biosensors are considered.

Enhanced Electron Transfer Efficiency of Fructose Dehydrogenase onto Roll-to-Roll Thermal Stamped Laser-Patterned Reduced Graphene Oxide Films.

Herein, a strategy to stamp laser-produced reduced graphene oxide (rGO) onto flexible polymers using only office-grade tools, namely, roll-to-roll thermal stamping, is proposed, proving for the first time its effectiveness for direct bioelectrocatalysis. This straightforward, scalable, and low-cost approach allows us to overcome the limits of the integration of laser-induced rGO-films in bioanalytical devices. Laser-produced rGO has been thermally stamped (TS) onto different polymeric substrates (PET, PVC, and EVA) using a simple roll-laminator; the obtained TS-rGO films have been compared with the native rGO (untransferred) via morphochemical and electrochemical characterization. Particularly, the direct electron transfer (DET) reaction between fructose dehydrogenase (FDH) and TS-rGO transducers has been investigated, with respect to the influence of the amount of enzyme on the catalytic process. Remarkable differences have been observed among TS-rGO transducers; PET proved to be the elective substrate to support the transfer of the laser-induced rGO, allowing the preservation of the morphochemical features of the native material and returning a reduced capacitive current. Noteworthily, TS-rGOs ensure superior electrocatalysis using a very low amount of FDH units (15 mU). Eventually, TS-rGO-based third-generation complete enzymatic biosensors were fabricated via low-cost benchtop technologies. TS-rGOPET exhibited bioanalytical performances superior to the native rGO, allowing a sensitive (0.0289 µA cm-2 µM-1) and reproducible (RSD = 3%, n = 3) d-fructose determination at the nanomolar level (LOD = 0.2 µM). TS-rGO exploitability as a point-of-need device was proved via the monitoring of d-fructose during banana (Musa acuminata) postharvest ripening, returning accurate (recoveries 110-90%; relative error -13/+1%) and reproducible (RSD ≤ 7%; n = 3) data.

Electrochemical Wearable Biosensors and Bioelectronic Devices Based on Hydrogels: Mechanical Properties and Electrochemical Behavior.

Hydrogel-based wearable electrochemical biosensors (HWEBs) are emerging biomedical devices that have recently received immense interest. The exceptional properties of HWEBs include excellent biocompatibility with hydrophilic nature, high porosity, tailorable permeability, the capability of reliable and accurate detection of disease biomarkers, suitable device-human interface, facile adjustability, and stimuli responsive to the nanofiller materials. Although the biomimetic three-dimensional hydrogels can immobilize bioreceptors, such as enzymes and aptamers, without any loss in their activities. However, most HWEBs suffer from low mechanical strength and electrical conductivity. Many studies have been performed on emerging electroactive nanofillers, including biomacromolecules, carbon-based materials, and inorganic and organic nanomaterials, to tackle these issues. Non-conductive hydrogels and even conductive hydrogels may be modified by nanofillers, as well as redox species. All these modifications have led to the design and development of efficient nanocomposites as electrochemical biosensors. In this review, both conductive-based and non-conductive-based hydrogels derived from natural and synthetic polymers are systematically reviewed. The main synthesis methods and characterization techniques are addressed. The mechanical properties and electrochemical behavior of HWEBs are discussed in detail. Finally, the prospects and potential applications of HWEBs in biosensing, healthcare monitoring, and clinical diagnostics are highlighted.

Optical flexible biosensors: From detection principles to biomedical applications.

Optical flexible biosensors are novel sensors fabricated on flexible or ductile materials that are used for the detection of analytes. Compared to traditional sensors, these biosensors offer greater flexibility, which allows them to adapt to different working environments, to meet the deformation requirements of humans. Flexible devices can not only detect alterations in analytes in vitro, but can also realize real-time and non-invasive monitoring of the variation of physical conditions or metabolites in vivo. Flexible devices are earning increasing attention from researchers and clinicians. In the present review, we summarize and introduce the detection principles, key analytes, and applications of optical flexible biosensors in the diagnosis/treatment of diseases as well as health detection. Moreover, the remaining challenges of flexible devices and their perspectives have also been addressed. We hope that this review will pave ways for the development of more feasible and multifunctional flexible devices.

Flexible electrochemical uric acid and glucose biosensor.

Fully integrated uric acid (UA) and glucose biosensors were fabricated on polydimethylsiloxane/polyimide platform by facile one step laser scribed technique. The laser scribed graphene (LSG) on the thin polyimide film was functionalized using pyrenebutanoic acid, succinimide ester (PBSE) to improve the electrochemical activity of the biosensors. The LSG was further decorated with platinum nanoparticles (PtNPs) to promote the electrocatalytic activity towards the oxidation of UA. Glucose oxidase was immobilized on the PtNPs modified surface for selective detection of glucose. The fabricated biosensors were characterized via scanning electron microscopy (SEM), Energy dispersive X-ray (EDX), X-ray photoelectron spectroscopy (XPS), and electrochemical methods (cyclic voltammetry and amperometry measurements). Outstanding electrocatalytic activities toward oxidation of UA and glucose were demonstrated. A wide detection range of 5 µM to 480 µM UA with a high sensitivity of 156.56 µA/mMcm2 and a calculated detection limit (LOD) of 0.018 µM (S/N = 3) were achieved for the UA biosensor. The glucose biosensor exhibited a detection range of 5 µM to 3200 µM with a sensitivity of 12.64 µA/mMcm2 and an LOD of 2.57 µM (S/N = 3). These integrated biosensors offer great promise for potential applications in wearable UA and glucose sensing due to their good sensitivity, selectivity, and stability properties.

Recent Advances in the Construction of Flexible Sensors for Biomedical Applications.

The fabrication of flexible sensors is a potential way to promote the progress of modern social science and technology due to their wide applications in high-performance electronic equipment and devices. Flexible sensors based on organic materials combine the unique advantages of flexibility and low cost, increasing interest in healthcare monitoring, treatment, and human-machine interfaces. Advances in materials science and biotechnology have rapidly accelerated the development of bio-integrated multifunctional sensors and devices. Due to their excellent mechanical and electrical properties, many types of functional materials provided benefits for the construction of various sensors with improved flexibility and stretchability. In this review, recent advance in the fabrication of flexible sensors by using functional nanomaterials including nanoparticles, carbon materials, metal-organic materials, and polymers is presented. In addition, the potential biomedical applications of the fabricated flexible sensors for detecting gas molecules signals, small molecules, DNA/RNA, proteins, others are introduced and discussed.

Fabrication of a Flexible Biosensor Based on an Organic Field-effect Transistor for Lactate Detection.

A novel flexible lactate sensor based on organic field-effect transistors (OFETs) is demonstrated. Because lactate is known as a biomarker for assessing our physical performance, wearable lactate sensors could contribute to the monitoring of human health conditions. The flexible and low-voltage operatable OFET possesses an extended-gate modified with enzymes and an osmium-redox polymer for the lactate detection, meaning that the continuous measurement of lactate levels (0 - 10 mM) has been successfully achieved. We believe that insight obtained will open up opportunities for applying OFETs in wearable biosensors.

A Fully Integrated and Self-Powered Smartwatch for Continuous Sweat Glucose Monitoring.

Wearable devices for health monitoring and fitness management have foreseen a rapidly expanding market, especially those for noninvasive and continuous measurements with real-time display that provide practical convenience and eliminated safety/infection risks. Herein, a self-powered and fully integrated smartwatch that consists of flexible photovoltaic cells and rechargeable batteries in the forms of a "watch strap", electrochemical glucose sensors, customized circuits, and display units integrated into a "dial" platform is successfully fabricated for real-time and continuous monitoring of sweat glucose levels. The functionality of the smartwatch, including sweat glucose sensing, signal processing, and display, can be supported with the harvested/converted solar energy without external charging devices. The Zn-MnO2 batteries serve as intermediate energy storage units and the utilization of aqueous electrolytes eliminated safety concerns for batteries, which is critical for wearable devices. Such a wearable system in a smartwatch fashion realizes integration of energy modules with self-powered capability, electrochemical sensors for noninvasive glucose monitoring, and in situ and real-time signal processing/display in a single platform for the first time. The as-fabricated fully integrated and self-powered smartwatch also provides a promising protocol for statistical study and clinical investigation to reveal correlations between sweat compositions and human body dynamics.

A flexible and highly sensitive nonenzymatic glucose sensor based on DVD-laser scribed graphene substrate.

Flexible and implantable glucose biosensors are emerging technologies for continuous monitoring of blood-glucose of diabetes. Developing a flexible conductive substrates with high active surface area is critical for advancing the technology. Here, we successfully fabricate a flexible and highly sensitive nonenzymatic glucose by using DVD-laser scribed graphene (LSG) as a flexible conductively substrate. Copper nanoparticles (Cu-NPs) are electrodeposited as the catalyst. The LSG/Cu-NPs sensor demonstrates excellent catalytic activity toward glucose oxidation and exhibits a linear glucose detection range from 1 µM to 4.54 mM with high sensitivity (1.518 mA mM-1 cm-2) and low limit of detection (0.35 µM). Moreover, the LSG/Cu-NPs sensor shows excellent reproducibility and long-term stability. It is also highly selective toward glucose oxidation under the presence of various interfering species. Excellent flexing stability is also demonstrated by the LSG/Cu-NPs sensor, which is capable of maintaining 83.9% of its initial current after being bent against a 4-mm diameter rod for 180 times. The LSG/Cu-NPs sensor shows great potential for practical application as a nonenzymatic glucose biosensor. Meanwhile, the LSG conductive substrate provides a platform for the developing next-generation flexible and potentially implantable bioelectronics and biosensors.

Hydrodynamic Layer-by-Layer Assembly of Transferable Enzymatic Conductive Nanonetworks for Enzyme-Sticker-Based Contact Printing of Electrochemical Biosensors.

Realizing high-performance electrochemical biosensors in a simple contact-printing-based approach significantly increases the applicability of integrated flexible biosensors. Herein, an enzyme-sticker-based approach that enables flexible and multielectrochemical sensors via simple contact-transfer printing is reported. The enzyme sticker consists of an enzymatic conductive network film and a polymeric support. The enzyme-incorporated nanostructured conductive network showing an efficient electrical coupling was assembled via the hydrodynamic layer-by-layer assembly of redox enzymes, polyelectrolytes, single-walled carbon nanotubes, and a biological glue material, M13 phage. The enzymatic conductive network on a polymeric membrane support was facilely wet contact-transfer printed onto integrated electrode systems by exploiting varying degrees of hydrophilicity displayed by the enzymatic electronic film, polymeric support, and receiving electrodes of the sensor system. The glucose sensors fabricated using the enzyme sticker detected glucose at a concentration of as low as 35 µM and showed high selectivity and stability. Furthermore, a flexible dual-sensor array capable of detecting both glucose and lactate was demonstrated using the versatile enzyme sticker concept. This work presents a new route toward assembling and integrating hybrid nanomaterials with efficient electrochemical coupling for high-performance biosensors and health-monitoring devices as well as for emerging bioelectronics and electrochemical devices.

Approaches to label-free flexible DNA biosensors using low-temperature solution-processed InZnO thin-film transistors.

Low-temperature solution-processed In-Zn-O (IZO) thin-film transistors (TFTs) exhibiting a favorable microenvironment for electron transfer by adsorbed artificial deoxyribonucleic acid (DNA) have extraordinary potential for emerging flexible biosensor applications. Superb sensing ability to differentiate even 0.5 µL of 50 nM DNA target solution was achieved through using IZO TFTs fabricated at 280 °C. Our IZO TFT had a turn-on voltage (V(on)) of -0.8 V, on/off ratio of 6.94 × 10(5), and on-current (I(on)) value of 2.32 × 10(-6)A in pristine condition. A dry-wet method was applied to immobilize two dimensional double crossover tile based DNA nanostructures on the IZO surface, after which we observed a negative shift of the transfer curve accompanied by a significant increase in the Ion and degradation of the Von and on/off ratio. As the concentration of DNA target solution increased, variances in these parameters became increasingly apparent. The sensing mechanism based on the current evolution was attributed to the oxidation of DNA, in which the guanine nucleobase plays a key role. The sensing behavior obtained from flexible biosensors on a polymeric substrate fabricated under the identical conditions was exactly analogous. These results compare favorably with the conventional field-effect transistor based DNA sensors by demonstrating remarkable sensitivity and feasibility of flexible devices that arose from a different sensing mechanism and a low-temperature process, respectively.

Freestanding graphene paper decorated with 2D-assembly of Au@Pt nanoparticles as flexible biosensors to monitor live cell secretion of nitric oxide.

We report the development of a new type of flexible electrochemical biosensors based on graphene paper loaded with closely-packed Au@Pt core-shell nanoparticles as a freestanding cell culture substrate for real-time monitoring cell secretion of nitric oxide. The hybrid electrode was fabricated through a modular approach in which 2D-assembly of nanoparticles formed at the oil-water interface was transferred onto graphene paper by dip-coating. We have shown that the independently optimized metal nanostructures and graphene paper were integrated into functional electrodes with high electrocatalytic activity. When used for the detection of nitric oxide, the flexible electrodes have demonstrated high sensitivity, a wide linear range, and a low detection limit, which, in combination with its biocompatibility, offer unique opportunities for the real-time monitoring of nitric oxide secretion by human endothelial vein cells grown on the electrode. These interesting findings collectively demonstrate the potential of our modular approach for designing high-performance flexible electrodes with tailored surface properties.