Multimodal charting of molecular and functional cell states via in situ electro-sequencing.

Paired mapping of single-cell gene expression and electrophysiology is essential to understand gene-to-function relationships in electrogenic tissues. Here, we developed in situ electro-sequencing (electro-seq) that combines flexible bioelectronics with in situ RNA sequencing to stably map millisecond-timescale electrical activity and profile single-cell gene expression from the same cells across intact biological networks, including cardiac and neural patches. When applied to human-induced pluripotent stem-cell-derived cardiomyocyte patches, in situ electro-seq enabled multimodal in situ analysis of cardiomyocyte electrophysiology and gene expression at the cellular level, jointly defining cell states and developmental trajectories. Using machine-learning-based cross-modal analysis, in situ electro-seq identified gene-to-electrophysiology relationships throughout cardiomyocyte development and accurately reconstructed the evolution of gene expression profiles based on long-term stable electrical measurements. In situ electro-seq could be applicable to create spatiotemporal multimodal maps in electrogenic tissues, potentiating the discovery of cell types and gene programs responsible for electrophysiological function and dysfunction.

Ultrathin and Flexible Bioelectronic Arrays for Functional Measurement of iPSC-Cardiomyocytes under Cardiotropic Drug Administration and Controlled Microenvironments.

Emerging heart-on-a-chip technology is a promising tool to establish in vitro cardiac models for therapeutic testing and disease modeling. However, due to the technical complexity of integrating cell culture chambers, biosensors, and bioreactors into a single entity, a microphysiological system capable of reproducing controlled microenvironmental cues to regulate cell phenotypes, promote iPS-cardiomyocyte maturity, and simultaneously measure the dynamic changes of cardiomyocyte function in situ is not available. This paper reports an ultrathin and flexible bioelectronic array platform in 24-well format for higher-throughput contractility measurement under candidate drug administration or defined microenvironmental conditions. In the array, carbon black (CB)-PDMS flexible strain sensors were embedded for detecting iPSC-CM contractility signals. Carbon fiber electrodes and pneumatic air channels were integrated to provide electrical and mechanical stimulation to improve iPSC-CM maturation. Performed experiments validate that the bioelectronic array accurately reveals the effects of cardiotropic drugs and identifies mechanical/electrical stimulation strategies for promoting iPSC-CM maturation.

Organic Electrochemical Transistors (OECTs) Toward Flexible and Wearable Bioelectronics.

Organic electronics have emerged as a fascinating area of research and technology in the past two decades and are anticipated to replace classic inorganic semiconductors in many applications. Research on organic light-emitting diodes, organic photovoltaics, and organic thin-film transistors is already in an advanced stage, and the derived devices are commercially available. A more recent case is the organic electrochemical transistors (OECTs), whose core component is a conductive polymer in contact with ions and solvent molecules of an electrolyte, thus allowing it to simultaneously regulate electron and ion transport. OECTs are very effective in ion-to-electron transduction and sensor signal amplification. The use of synthetically tunable, biocompatible, and depositable organic materials in OECTs makes them specially interesting for biological applications and printable devices. In this review, we provide an overview of the history of OECTs, their physical characterization, and their operation mechanism. We analyze OECT performance improvements obtained by geometry design and active material selection (i.e., conductive polymers and small molecules) and conclude with their broad range of applications from biological sensors to wearable devices.

Flexible self-powered bioelectronics enables personalized health management from diagnosis to therapy.

Flexible self-powered bioelectronics (FSPBs), incorporating flexible electronic features in biomedical applications, have revolutionized the human-machine interface since they hold the potential to offer natural and seamless human interactions while overcoming the limitations of battery-dependent power sources. Furthermore, as biosensors or actuators, FSPBs can dynamically monitor physiological signals to reveal real-time health abnormalities and provide timely and precise treatments. Therefore, FSPBs are increasingly shaping the landscape of health monitoring and disease treatment, weaving a sophisticated and personalized bond between humans and health management. Here, we examine the recent advanced progress of FSPBs in developing working mechanisms, design strategies, and structural configurations toward personalized health management, emphasizing its role in clinical medical scenarios from biophysical/biochemical sensors for sensing diagnosis to robust/biodegradable actuators for intervention therapy. Future perspectives on the challenges and opportunities in emerging multifunctional FSPBs for the next-generation health management systems are also forecasted.

Temperature Self-Compensating Intelligent Wireless Measuring Contact Lens for Quantitative Intraocular Pressure Monitoring.

Flexible bioelectronic devices that can perform real-time and accurate intraocular pressure (IOP) monitoring in both clinical and home settings hold significant implications for the diagnosis and treatment of glaucoma, yet they face challenges due to the open physiological environment of the ocular. Herein, we develop an intelligent wireless measuring contact lens (WMCL) incorporating a dual inductor-capacitor-resistor (LCR) resonant system to achieve temperature self-compensation for quantitative IOP monitoring in different application environments. The WMCL utilizes a compact circuitry design, which enables the integration of low-frequency and high-frequency resonators within a single layer of a sensing circuit without causing visual impairment. Mechanically guided microscale 3D encapsulation strategy combined with flexible circuit printing techniques achieves the surface-adaptive fabrication of the WMCL. The specific design of frequency separation imparts distinct temperature response characteristics to the dual resonators, and the linear combination of the dual resonators can eliminate the impact of temperature variations on measurement accuracy. The WMCL demonstrates outstanding sensitivity and linearity in monitoring the IOP of porcine eyes in vitro while maintaining satisfactory measurement accuracy even with internal temperature variations exceeding 10 °C. Overcoming the impact of temperature variations on IOP monitoring from the system level, the WMCL showcases immense potential as the next generation of all-weather IOP monitoring devices.

Skin-interfaced electronics: A promising and intelligent paradigm for personalized healthcare.

Skin-interfaced electronics (skintronics) have received considerable attention due to their thinness, skin-like mechanical softness, excellent conformability, and multifunctional integration. Current advancements in skintronics have enabled health monitoring and digital medicine. Particularly, skintronics offer a personalized platform for early-stage disease diagnosis and treatment. In this comprehensive review, we discuss (1) the state-of-the-art skintronic devices, (2) material selections and platform considerations of future skintronics toward intelligent healthcare, (3) device fabrication and system integrations of skintronics, (4) an overview of the skintronic platform for personalized healthcare applications, including biosensing as well as wound healing, sleep monitoring, the assessment of SARS-CoV-2, and the augmented reality-/virtual reality-enhanced human-machine interfaces, and (5) current challenges and future opportunities of skintronics and their potentials in clinical translation and commercialization. The field of skintronics will not only minimize physical and physiological mismatches with the skin but also shift the paradigm in intelligent and personalized healthcare and offer unprecedented promise to revolutionize conventional medical practices.

Flexible Electrodes for Brain-Computer Interface System.

Brain-computer interface (BCI) has been the subject of extensive research recently. Governments and companies have substantially invested in relevant research and applications. The restoration of communication and motor function, the treatment of psychological disorders, gaming, and other daily and therapeutic applications all benefit from BCI. The electrodes hold the key to the essential, fundamental BCI precondition of electrical brain activity detection and delivery. However, the traditional rigid electrodes are limited due to their mismatch in Young's modulus, potential damages to the human body, and a decline in signal quality with time. These factors make the development of flexible electrodes vital and urgent. Flexible electrodes made of soft materials have grown in popularity in recent years as an alternative to conventional rigid electrodes because they offer greater conformance, the potential for higher signal-to-noise ratio (SNR) signals, and a wider range of applications. Therefore, the latest classifications and future developmental directions of fabricating these flexible electrodes are explored in this paper to further encourage the speedy advent of flexible electrodes for BCI. In summary, the perspectives and future outlook for this developing discipline are provided.

Screen-Printable Functional Nanomaterials for Flexible and Wearable Single-Enzyme-Based Energy-Harvesting and Self-Powered Biosensing Devices.

Developing flexible bioelectronics is essential to the realization of artificial intelligence devices and biomedical applications, such as wearables, but their potential is limited by sustainable energy supply. An enzymatic biofuel cell (BFC) is promising for power supply, but its use is limited by the challenges of incorporating multiple enzymes and rigid platforms. This paper shows the first example of screen-printable nanocomposite inks engineered for a single-enzyme-based energy-harvesting device and a self-powered biosensor driven by glucose on bioanode and biocathode. The anode ink is modified with naphthoquinone and multiwalled carbon nanotubes (MWCNTs), whereas the cathode ink is modified with Prussian blue/MWCNT hybrid before immobilizing with glucose oxidase. The flexible bioanode and the biocathode consume glucose. This BFC yields an open circuit voltage of 0.45 V and a maximum power density of 266 µW cm-2. The wearable device coupled with a wireless portable system can convert chemical energy into electric energy and detect glucose in artificial sweat. The self-powered sensor can detect glucose concentrations up to 10 mM. Common interfering substances, including lactate, uric acid, ascorbic acid, and creatinine, have no effect on this self-powered biosensor. Additionally, the device can endure multiple mechanical deformations. New advances in ink development and flexible platforms enable a wide range of applications, including on-body electronics, self-sustainable applications, and smart fabrics.

Developing cellulosic functional materials from multi-scale strategy and applications in flexible bioelectronic devices.

With the forthcoming of the post-COVID-19 and the ageing era, the novel biomaterials and bioelectronic devices are attracting more and more attention and favor. Cellulose as one of the most globe-abundant natural macromolecules has multiple merits of biocompatibility, processability, carbon neutral feature and mechanical designability. Due to its progressive advancement of multi-scale design from macro to micro followed by new cognitions, cellulose shows a promising application prospect in developing bio-functional materials. In this review, we briefly discuss the role of cellulose from the "top-down" perspective of macro-scale fibers, micro-scale nanofibers, and molecular-scale macromolecular chains for the design of advanced cellulose-based functional materials. The focus then turns to the construction and development of emerging cellulose-based flexible bioelectronic devices including biosensors, biomimetic electronic skins, and biological detection devices. Finally, the dilemma and challenge of cellulose-based bioelectronic materials and their application prospects in basic biology and medical care have been prospected.

Recent Progress in Materials Chemistry to Advance Flexible Bioelectronics in Medicine.

Designing bioelectronic devices that seamlessly integrate with the human body is a technological pursuit of great importance. Bioelectronic medical devices that reliably and chronically interface with the body can advance neuroscience, health monitoring, diagnostics, and therapeutics. Recent major efforts focus on investigating strategies to fabricate flexible, stretchable, and soft electronic devices, and advances in materials chemistry have emerged as fundamental to the creation of the next generation of bioelectronics. This review summarizes contemporary advances and forthcoming technical challenges related to three principal components of bioelectronic devices: i) substrates and structural materials, ii) barrier and encapsulation materials, and iii) conductive materials. Through notable illustrations from the literature, integration and device fabrication strategies and associated challenges for each material class are highlighted.

Flexible Strain-Sensitive Silicone-CNT Sensor for Human Motion Detection.

This article describes the manufacturing technology of biocompatible flexible strain-sensitive sensor based on Ecoflex silicone and multi-walled carbon nanotubes (MWCNT). The sensor demonstrates resistive behavior. Structural, electrical, and mechanical characteristics are compared. It is shown that laser radiation significantly reduces the resistance of the material. Through laser radiation, electrically conductive networks of MWCNT are formed in a silicone matrix. The developed sensor demonstrates highly sensitive characteristics: gauge factor at 100% elongation -4.9, gauge factor at 90° bending -0.9%/deg, stretchability up to 725%, tensile strength 0.7 MPa, modulus of elasticity at 100% 46 kPa, and the temperature coefficient of resistance in the range of 30-40 °C is -2 × 10-3. There is a linear sensor response (with 1 ms response time) with a low hysteresis of ≤3%. An electronic unit for reading and processing sensor signals based on the ATXMEGA8E5-AU microcontroller has been developed. The unit was set to operate the sensor in the range of electrical resistance 5-150 kOhm. The Bluetooth module made it possible to transfer the received data to a personal computer. Currently, in the field of wearable technologies and health monitoring, a vital need is the development of flexible sensors attached to the human body to track various indicators. By integrating the sensor with the joints of the human hand, effective movement sensing has been demonstrated.

Recent Advances in Encapsulation of Flexible Bioelectronic Implants: Materials, Technologies, and Characterization Methods.

Bioelectronic implantable systems (BIS) targeting biomedical and clinical research should combine long-term performance and biointegration in vivo. Here, recent advances in novel encapsulations to protect flexible versions of such systems from the surrounding biological environment are reviewed, focusing on material strategies and synthesis techniques. Considerable effort is put on thin-film encapsulation (TFE), and specifically organic-inorganic multilayer architectures as a flexible and conformal alternative to conventional rigid cans. TFE is in direct contact with the biological medium and thus must exhibit not only biocompatibility, inertness, and hermeticity but also mechanical robustness, conformability, and compatibility with the manufacturing of microfabricated devices. Quantitative characterization methods of the barrier and mechanical performance of the TFE are reviewed with a particular emphasis on water-vapor transmission rate through electrical, optical, or electrochemical principles. The integrability and functionalization of TFE into functional bioelectronic interfaces are also discussed. TFE represents a must-have component for the next-generation bioelectronic implants with diagnostic or therapeutic functions in human healthcare and precision medicine.

Thin Film Encapsulation for LCP-Based Flexible Bioelectronic Implants: Comparison of Different Coating Materials Using Test Methodologies for Life-Time Estimation.

Liquid crystal polymer (LCP) has gained wide interest in the electronics industry largely due to its flexibility, stable insulation and dielectric properties and chip integration capabilities. Recently, LCP has also been investigated as a biocompatible substrate for the fabrication of multielectrode arrays. Realizing a fully implantable LCP-based bioelectronic device, however, still necessitates a low form factor packaging solution to protect the electronics in the body. In this work, we investigate two promising encapsulation coatings based on thin-film technology as the main packaging for LCP-based electronics. Specifically, a HfO2-based nanolaminate ceramic (TFE1) deposited via atomic layer deposition (ALD), and a hybrid Parylene C-ALD multilayer stack (TFE2), both with a silicone finish, were investigated and compared to a reference LCP coating. T-peel, water-vapour transmission rate (WVTR) and long-term electrochemical impedance spectrometry (EIS) tests were performed to evaluate adhesion, barrier properties and overall encapsulation performance of the coatings. Both TFE materials showed stable impedance characteristics while submerged in 60 °C saline, with TFE1-silicone lasting more than 16 months under a continuous 14V DC bias (experiment is ongoing). The results presented in this work show that WVTR is not the main factor in determining lifetime, but the adhesion of the coating to the substrate materials plays a key role in maintaining a stable interface and thus longer lifetimes.

Recent Advances in High-Throughput Nanomaterial Manufacturing for Hybrid Flexible Bioelectronics.

Hybrid flexible bioelectronic systems refer to integrated soft biosensing platforms with tremendous clinical impact. In this new paradigm, electrical systems can stretch and deform with the skin while previously hidden physiological signals can be continuously recorded. However, hybrid flexible bioelectronics will not receive wide clinical adoption until these systems can be manufactured at industrial scales cost-effectively. Therefore, new manufacturing approaches must be discovered and studied under the same innovative spirit that led to the adoption of novel materials and soft structures. Recent works have taken mature manufacturing approaches from the graphics industry, such as gravure, flexography, screen, and inkjet printing, and applied them to fully printed bioelectronics. These applications require the cohesive study of many disparate parts. For instance, nanomaterials with optimal properties for each specific application must be dispersed in printable inks with rheology suited to each printing method. This review summarizes recent advances in printing technologies, key nanomaterials, and applications of the manufactured hybrid bioelectronics. We also discuss the existing challenges of the available nanomanufacturing methods and the areas that need immediate technological improvements.

Skin-inspired gelatin-based flexible bio-electronic hydrogel for wound healing promotion and motion sensing.

Next generation tissue-engineered skin scaffolds promise to provide sensory restoration through electrical stimulation in addition to effectively rebuilding and repairing skin. The integration of real-time monitoring of the injury motion activities can fundamentally improve the therapeutic efficacy by providing detailed data to guide the clinical practice. Herein, a mechanically-flexible, electroactive, and self-healable hydrogels (MESGel) was engineered for the combinational function of electrically-stimulated accelerated wound healing and motion sensing. MESGel shows outstanding biocompatibility and multifunctional therapeutic properties including flexibility, self-healing characteristics, biodegradability, and bioelectroactivity. Moreover, MESGel shows its potential of being a novel flexible electronic skin sensor to record the injury motion activities. Comprehensive in vitro and in vivo experiments prove that MESGel can facilitate effective electrical stimulation, actively promoting proliferation in Chinese hamster lung epithelial cells and therefore can accelerate favorable epithelial biology during skin wound healing, demonstrating an effective therapeutic strategy for a full-thickness skin defect model and leading to new-type flexible bioelectronics.

Stretchable, Fully Polymeric Electrode Arrays for Peripheral Nerve Stimulation.

There is a critical need to transition research level flexible polymer bioelectronics toward the clinic by demonstrating both reliability in fabrication and stable device performance. Conductive elastomers (CEs) are composites of conductive polymers in elastomeric matrices that provide both flexibility and enhanced electrochemical properties compared to conventional metallic electrodes. This work focuses on the development of nerve cuff devices and the assessment of the device functionality at each development stage, from CE material to fully polymeric electrode arrays. Two device types are fabricated by laser machining of a thick and thin CE sheet variant on an insulative polydimethylsiloxane substrate and lamination into tubing to produce pre-curled cuffs. Device performance and stability following sterilization and mechanical loading are compared to a state-of-the-art stretchable metallic nerve cuff. The CE cuffs are found to be electrically and mechanically stable with improved charge transfer properties compared to the commercial cuff. All devices are applied to an ex vivo whole sciatic nerve and shown to be functional, with the CE cuffs demonstrating superior charge transfer and electrochemical safety in the biological environment.

Nature-derived materials for the fabrication of functional biodevices.

Nature provides an incredible source of inspiration, structural concepts, and materials toward applications to improve the lives of people around the world, while preserving ecosystems, and addressing environmental sustainability. In particular, materials derived from animal and plant sources can provide low-cost, renewable building blocks for such applications. Nature-derived materials are of interest for their properties of biodegradability, bioconformability, biorecognition, self-repair, and stimuli response. While long used in tissue engineering and regenerative medicine, their use in functional devices such as (bio)electronics, sensors, and optical systems for healthcare and biomonitoring is finding increasing attention. The objective of this review is to cover the varied nature derived and sourced materials currently used in active biodevices and components that possess electrical or electronic behavior. We discuss materials ranging from proteins and polypeptides such as silk and collagen, polysaccharides including chitin and cellulose, to seaweed derived biomaterials, and DNA. These materials may be used as passive substrates or support architectures and often, as the functional elements either by themselves or as biocomposites. We further discuss natural pigments such as melanin and indigo that serve as active elements in devices. Increasingly, combinations of different biomaterials are being used to address the challenges of fabrication and performance in human monitoring or medicine. Finally, this review gives perspectives on the sourcing, processing, degradation, and biocompatibility of these materials. This rapidly growing multidisciplinary area of research will be advanced by a systematic understanding of nature-inspired materials and design concepts in (bio)electronic devices.

Highly Stretchable and Conductive Self-Healing Hydrogels for Temperature and Strain Sensing and Chronic Wound Treatment.

Flexible bioelectronics for biomedical applications requires a stretchable, conductive, self-healable, and biocompatible material that can be obtained by cost-effective chemicals and strategies. Herein, we synthesized polypyrrole or Zn-functionalized chitosan molecules, which are cross-linked with poly(vinyl alcohol) to form a hydrogel through dynamic di-diol complexations, hydrogen bonding, and zinc-based coordination bonds. These multiple dynamic interactions endow the material with excellent stretchability and autonomous self-healing ability. The choice of Food and Drug Administration (FDA)-approved materials (poly(vinyl alcohol) and chitosan) as the matrix materials ensures the good biocompatibility of the hydrogel. The conductivity contributed by the polypyrrole allowed the hydrogel to sense strain and temperature, and the coordinated Zn significantly enhanced the antibacterial activity of the hydrogel. Moreover, using a diabetic rat model, we have proved that this hydrogel is capable of promoting the healing of the infected chronic wounds with electrical stimulation.

Highly Flexible Transistor Threads for All-Thread Based Integrated Circuits and Multiplexed Diagnostics.

Physically intimate, real-time monitoring of human biomarkers is becoming increasingly important to modern medicine and patient wellness. Such monitoring is possible due to advances in soft and flexible materials, devices and bioelectronics systems. Compared to other flexible platforms, multifilament textile fibers or threads offer superior flexibility, material diversity, and simple ambient processing to realize a wide range of flexible devices such as sensors, electronics, and microfluidics. In this paper, we realize unique flexible transistors on threads and interconnect them to realize logic gates and small-scale integrated circuits. Compared to prior textile-based transistors, the proposed thread-based transistors (TBTs) are realized with a readily shaped, colloidally dispersed gel consisting of silica nanoparticles and 1-ethyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide (EMI TFSI) ionic liquid for all-around electrolyte gating of a carbon nanotube (CNT) semiconducting network assembled on the thread. We interconnect TBTs with thread-based electrochemical sensors (TBEs) to realize an all-thread based multiplexed diagnostic device. All-thread based platforms are thin, highly flexible and conformal, allowing them to be worn directly on the skin without any polymeric substrate, or sutured transdermally using a needle.

Blending Electronics with the Human Body: A Pathway toward a Cybernetic Future.

At the crossroads of chemistry, electronics, mechanical engineering, polymer science, biology, tissue engineering, computer science, and materials science, electrical devices are currently being engineered that blend directly within organs and tissues. These sophisticated devices are mediators, recorders, and stimulators of electricity with the capacity to monitor important electrophysiological events, replace disabled body parts, or even stimulate tissues to overcome their current limitations. They are therefore capable of leading humanity forward into the age of cyborgs, a time in which human biology can be hacked at will to yield beings with abilities beyond their natural capabilities. The resulting advances have been made possible by the emergence of conformal and soft electronic materials that can readily integrate with the curvilinear, dynamic, delicate, and flexible human body. This article discusses the recent rapid pace of development in the field of cybernetics with special emphasis on the important role that flexible and electrically active materials have played therein.