Bio-inspired flexible electronics for smart E-skin.

"Learning from nature" provides endless inspiration for scientists to invent new materials and devices. Here, we review state-of-the-art technologies in flexible electronics, with a focus on bio-inspired smart skins. This review focuses on the development of E-skin for sensing a variety of parameters such as mechanical loads, temperature, light, and biochemical cues, with a trend of increased integration of multiple functions. It highlights the most recent advances in flexible electronics inspired by animals such as chameleons, squids, and octopi whose bodies have remarkable camouflage, mimicry, or self-healing attributes. Implantable devices, being overlapped with smart E-skin in a broad sense, are included in this review. This review outlines the remaining challenges in flexible electronics and the prospects for future development for biomedical applications. STATEMENT OF SIGNIFICANCE: This article reviews the state-of-the-art technologies of bio-inspired smart electronic skin (E-skin) developed in a "learning-mimicking-creating" (LMC) cycle. We emphasize the most recent innovations in the development of E-skin for sensing physical changes and biochemical cues, and for integrating multiple sensing modalities. We discuss the achievements in implantable materials, wireless communication, and device design pertaining to implantable flexible electronics. This review will provide prospective insights integrating material, electronics, and mechanical engineering viewpoints to foster new ideas for next-generation smart E-skin.

Sensing arbitrary contact forces with a flexible porous dielectric elastomer.

Artificial tactile sensing in next-generation robots requires the development of flexible sensors for complicated tactile force measurements in both normal and tangential directions. A variety of microstructures have been proposed to be integrated with material development for the enhanced performance of the devices. However, there remains a great challenge in this field on how to decouple contact forces in spatially arbitrary directions with the electric signal readouts. The fundamental correlation between contact force sensing and the microstructure deformations is still largely unknown. Here, we report a new method of arbitrary force deconvolution and sensitive detection of flexible contacts by a porous dielectric elastomer-based force (PDiF) sensor. Decoupling the complicated nonlinear mathematic problem reveals a critical synergy in the porous elastomer between the electrical property enhancement and the geometrical deformations induced by arbitrary contact forces. Proof-of-concept applications in flexible tactile sensing have been demonstrated with the PDiF sensors, including surface roughness discrimination, slippage detection, and real-time force mapping in handwriting. It creates an avenue for flexible sensing of the complicated contact forces with microstructure-embedded elastomeric materials.

Integrating Cycled Enzymatic DNA Amplification and Surface-Enhanced Raman Scattering for Sensitive Detection of Circulating Tumor DNA.

Circulating tumor DNA (ctDNA) represents an emerging biomarker of liquid biopsies for the development of precision cancer diagnostics and therapeutics. However, sensitive detection of ctDNA remains challenging, due to their short half-life and low concentrations in blood samples. In this study, we report a new method to address this challenge by integrating cycled enzymatic DNA amplification technique and Au nanoparticle@silicon-assisted surface-enhanced Raman scattering (SERS) technique. We have demonstrated a reproducible identification of a single-base-mutated ctDNA sequence of diffuse intrinsic pontine gliomas (DIPGs), with the limit of detection (LOD) as low as 9.1 fM in the spiked blood samples. This approach can be used to analyze trace amounts of ctDNA in translational medicine for early diagnosis, therapeutic effect monitoring, and prognosis of patients with cancer.

The sensitive detection of single-cell secreted lactic acid for glycolytic inhibitor screening with a microdroplet biosensor.

Lactic acid (LA) plays an important role in the tumor metabolism and malignant progression of various cancers. Herein, we have developed a one-step, wash-free microfluidic approach with droplet biosensors for the sensitive detection of LA secreted by a single tumor cell. Our assay integrates the enzyme-assisted chemical conversion of LA in small-volume (4.2 nL) droplets for fluorescence signal readout. The microdroplet assay achieved a limit of detection of 1.02 µM and was more sensitive than the commercial ELISA kit by nearly two orders of magnitude. A good specificity has been demonstrated for this assay by testing various ions and biomolecules from the culture medium. This droplet assay allows us to acquire the profiles of the lactic acid secretion of tumor cells under the influence of glycolytic inhibitors at the single-cell level. It offers a useful research tool to study the cell-to-cell differences of LA secretion and glycolytic inhibitor screening for cancer research.

Highly Stretchable and Sensitive Pressure Sensor Array Based on Icicle-Shaped Liquid Metal Film Electrodes.

Flexible pressure sensors emerge for important applications in wearable electronics, with increasing requirements for high sensitivity, fast response, and low detection limit. However, there is still a challenge in this field, that is, how to maximize both the electrical performance and mechanical stretchability simultaneously. Here, we report a straightforward and cost-effective method to fabricate highly stretchable and sensitive capacitive pressure sensor arrays. It features a unique design of integrating the icicle-shaped liquid metal film electrode and reliable processing of the liquid metal and elastomer. Under an external load, the deformation of the elastic bump structure dramatically results in an increase in the overlapping area of the electrodes and a decrease in the separation distance, offering a new capacitive sensing scheme with an enhanced sensitivity. Our sensor has been demonstrated with a high sensitivity of 39% kPa-1 in the range of 0-1 kPa, limit of detection as low as 12 Pa, hysteresis error of 8.46% at a maximum pressure of 25 kPa, and stretchability up to 94% strain without any failure. The arrayed sensor has been successfully applied to force measurements on a curved surface, contour mapping of external loads, and monitoring of contact pressures under various cervical postures.

Aptamer Conformation-Cooperated Enzyme-Assisted Surface-Enhanced Raman Scattering Enabling Ultrasensitive Detection of Cell Surface Protein Biomarkers in Blood Samples.

Developing novel strategies for sensitive and specific detection of protein biomarkers is a field of active research. Here, we report an ultrasensitive biosensor to detect protein tyrosine kinase-7 (PTK7), an important protein biomarker on the cell surface, by aptamer conformation-cooperated enzyme-assisted surface-enhanced Raman scattering (SERS) (ACCESS) technology. Our approach features a synergistic combination of the conformational alteration of the anglerfish aptamer triggered by the recognition of the membrane protein (PTK7) and Exo III enzyme-assisted nucleic acid amplification. It transduces the specific binding events between the aptamer and PTK7 protein into dramatically improved SERS signals. Sensitive and specific detection of PTK7 protein has been demonstrated both in the solution and directly on the surface of live CCRF-CEM cells, with a limit of detection better than the commercial enzyme-linked immunosorbent assay method by nearly 5 orders of magnitude. As a flexible, ultrasensitive, and specific approach, ACCESS promises important applications in clinical diagnostics, where only a very limited amount of the biological sample is available.

A Flexible and Highly Sensitive Inductive Pressure Sensor Array Based on Ferrite Films.

There is a rapid growing demand for highly sensitive, easy adaptive and low-cost pressure sensing solutions in the fields of health monitoring, wearable electronics and home care. Here, we report a novel flexible inductive pressure sensor array with ultrahigh sensitivity and a simple construction, for large-area contact pressure measurements. In general, the device consists of three layers: a planar spiral inductor layer and ferrite film units attached on a polyethylene terephthalate (PET) membrane, which are separated by an array of elastic pillars. Importantly, by introducing the ferrite film with an excellent magnetic permeability, the effective permeability around the inductor is greatly influenced by the separation distance between the inductor and the ferrite film. As a result, the value of the inductance changes largely as the separation distance varies as an external load applies. Our device has achieved an ultrahigh sensitivity of 1.60 kPa-1 with a resolution of 13.61 Pa in the pressure range of 0-0.18 kPa, which is comparable to the current state-of-the-art flexible pressure sensors. More remarkably, our device shows an outstanding stability when exposed to environmental interferences, e.g., electrical noises from skin surfaces (within 0.08% variations) and a constant pressure load for more than 32 h (within 0.3% variations). In addition, the device exhibits a fast response time of 111 ms and a good repeatability under cyclic pressures varying from 38.45 to 177.82 Pa. To demonstrate its practical usage, we have successfully developed a 4 × 4 inductive pressure sensor array into a wearable keyboard for a smart electronic calendar application.

Sensitive Detection of Single-Cell Secreted H2O2 by Integrating a Microfluidic Droplet Sensor and Au Nanoclusters.

As an important signaling molecule, hydrogen peroxide (H2O2) secreted externally by the cells influences cell migration, immunity generation, and cellular communications. Herein, we have developed a microfluidic approach with droplets in combination with Au nanoclusters for the sensitive detection of H2O2 secreted by a single cell. Isolated in the ultrasmall volume (4.2 nL) of a microdroplet, single-cell secreted H2O2 can initiate dramatic fluorescence changes of horseradish peroxidase-Au nanoclusters. We have demonstrated an ultrahigh sensitivity (200-400 attomole H2O2 directly measured from a single cell) with good specificity. It offers a useful research tool to study the cell-to-cell differences of H2O2 secretion at the single-cell level.

Telemedical Wearable Sensing Platform for Management of Chronic Venous Disorder.

Enabled by emerging wearable sensors, telemedicine can potentially offer personalized medical services to long-term home care or remote clinics in the future, which can be particularly helpful in the management of chronic diseases. The wireless wearable pressure sensing system reported in this article provides an excellent example of such an innovation, whereby periodic or continuous monitoring of interface pressure can be obtained to guide routine compression therapy, the cornerstone of chronic venous disorder management. By applying a novel capacitive, iontronic sensing technology, a flexible, ultrathin, and highly sensitive pressure sensing array is seamlessly incorporated into compression garments for the monitoring of interface pressure. The linear pressure sensing array assesses pressure distribution along the limb in a real-time manner (up to a scanning rate of 5 kHz), and the measurement data can be processed and displayed on a mobile device locally, as well as transmitted through a Bluetooth communication module to a remote clinical service. The proposed interface pressure measuring system provides real-time interface pressure distribution data and can be utilized for both clinical and self-management of compression therapy, where both treatment efficacy and quality assurance can be ascertained.

Flexible transparent iontronic film for interfacial capacitive pressure sensing.

A flexible, transparent iontronic film is introduced as a thin-film capacitive sensing material for emerging wearable and health-monitoring applications. Utilizing the capacitive interface at the ionic-electronic contact, the iontronic film sensor offers a large unit-area capacitance (of 5.4 µF cm(-2) ) and an ultrahigh sensitivity (of 3.1 nF kPa(-1) ), which is a thousand times greater than that of traditional solid-state counterparts.

Microfluidic tactile sensors for three-dimensional contact force measurements.

A microfluidic tactile sensing device has been first reported for three-dimensional contact force measurement utilizing the microfluidic interfacial capacitive sensing (MICS) principle. Consisting of common and differential microfluidic sensing elements and topologically micro-textured surfaces, the microfluidic sensing devices are intended not only to resolve normal mechanical loads but also to measure forces tangent to the surface upon contact. In response to normal or shear loads, the membrane surface deforms the underlying sensing elements uniformly or differentially. The corresponding variation in interfacial capacitance can be detected from each sensing unit, from which the direction and magnitude of the original load can be determined. Benefiting from the highly sensitive and adaptive MICS principle, the microfluidic sensor is capable of detecting normal forces with a device sensitivity of 29.8 nF N(-1) in a 7 mm × 7 mm × 0.52 mm package, which is at least a thousand times higher than its solid-state counterparts to our best knowledge. In addition, the microfluidic sensing elements enable facilitated relaxation response/time in the millisecond range (up to 12 ms). To demonstrate the utility and flexibility of the three-dimensional microfluidic sensor, it has been successfully configured into a fingertip-amounted setting for continuous tracing of the fingertip movement and contact force measurement.

Iontronic microdroplet array for flexible ultrasensitive tactile sensing.

An iontronic microdroplet array (IMA) device, using an ultra-large interfacial capacitance at the highly elastic droplet-electrode contact, has been proposed for flexible tactile sensing applications. The transparent IMA sensors consist of an array of nanoliter droplets sandwiched between two polymeric membranes with patterned transparent electrodes, forming the electrical double layers with remarkable unit-area capacitance. Under external loading, the membrane deformation results in the circumferential expansion at the highly elastic droplet-electrode contact, which offers a completely new capacitive sensing scheme with a dramatic increase in sensitivity. Under the simple device architecture, the IMA has achieved device sensitivity of 0.43 nF kPa(-1) and a minimal detectable pressure of 33 Pa, the highest reported values for its dimension. In addition, the hysteresis of the droplet deformation has been reduced by introducing a layer of hydrophobic coating to the conductive electrode surface, ensuring a fast mechanical response (on the order of several milliseconds). To demonstrate the utility of the transparent flexible IMA sensor, it has been successfully mounted onto a fingertip setting to map different surface topologies and embedded into a wristband to resolve dynamic pressure waves throughout cardiovascular cycles.

Droplet-based interfacial capacitive sensing.

This paper presented a novel droplet-based pressure sensor using elastic and capacitive electrode-electrolyte interfaces to achieve ultrahigh mechanical-to-electrical sensitivity (1.58 µF kPa(-1)) and resolution (1.8 Pa) with a simple device architecture. The miniature transparent droplet sensors, fabricated by one-step laser micromachining, consisted of two flexible polymer membranes with conductive coating and a separation layer hosting a sensing chamber for an electrolyte droplet. The sensing principle primarily relied on high elasticity of the sensing droplet and large capacitance presented at the electrode-electrolyte interface. A simple surface modification scheme was introduced to the conductive coating, which reduced hysteresis of the droplet deformation without substantially compromising the interfacial capacitance. Moreover, the major concern of liquid evaporation was addressed by a mixture of glycerol and electrolyte with long-term stability in a laboratory environment. Theoretical analyses and experimental investigations on several design parameters (i.e., the dimensions of the sensing chamber and the droplet size) were thoroughly conducted to characterize and optimize the overall sensitivity of the device. Moreover, the environmental influences (e.g., temperature and humidity) on the capacitive measurement were further investigated. Finally, the simply constructed and mechanically flexible droplet sensor was successfully applied to detect minute blood pressure variations on the skin surface (with the maximum value less than 100 Pa) throughout cardiovascular cycles.

Capillary-driven automatic packaging.

Packaging continues to be one of the most challenging steps in micro-nanofabrication, as many emerging techniques (e.g., soft lithography) are incompatible with the standard high-precision alignment and bonding equipment. In this paper, we present a simple-to-operate, easy-to-adapt packaging strategy, referred to as Capillary-driven Automatic Packaging (CAP), to achieve automatic packaging process, including the desired features of spontaneous alignment and bonding, wide applicability to various materials, potential scalability, and direct incorporation in the layout. Specifically, self-alignment and self-engagement of the CAP process induced by the interfacial capillary interactions between a liquid capillary bridge and the top and bottom substrates have been experimentally characterized and theoretically analyzed with scalable implications. High-precision alignment (of less than 10 µm) and outstanding bonding performance (up to 300 kPa) has been reliably obtained. In addition, a 3D microfluidic network, aligned and bonded by the CAP technique, has been devised to demonstrate the applicability of this facile yet robust packaging technique for emerging microfluidic and bioengineering applications.