Permeable Bioelectronics toward Biointegrated Systems.

Bioelectronics integrates electronics with biological organs, sustaining the natural functions of the organs. Organs dynamically interact with the external environment, managing internal equilibrium and responding to external stimuli. These interactions are crucial for maintaining homeostasis. Additionally, biological organs possess a soft and stretchable nature; encountering objects with differing properties can disrupt their function. Therefore, when electronic devices come into contact with biological objects, the permeability of these devices, enabling interactions and substance exchanges with the external environment, and the mechanical compliance are crucial for maintaining the inherent functionality of biological organs. This review discusses recent advancements in soft and permeable bioelectronics, emphasizing materials, structures, and a wide range of applications. The review also addresses current challenges and potential solutions, providing insights into the integration of electronics with biological organs.

Antimicrobial second skin using copper nanomesh.

The functional support and advancement of our body while preserving inherent naturalness is one of the ultimate goals of bioengineering. Skin protection against infectious pathogens is an application that requires common and long-term wear without discomfort or distortion of the skin functions. However, no antimicrobial method has been introduced to prevent cross-infection while preserving intrinsic skin conditions. Here, we propose an antimicrobial skin protection platform copper nanomesh, which prevents cross-infectionmorphology, temperature change rate, and skin humidity. Copper nanomesh exhibited an inactivation rate of 99.99% for Escherichia coli bacteria and influenza virus A within 1 and 10 min, respectively. The thin and porous nanomesh allows for conformal coating on the fingertips, without significant interference with the rate of skin temperature change and humidity. Efficient cross-infection prevention and thermal transfer of copper nanomesh were demonstrated using direct on-hand experiments.

Self-powered ultra-flexible electronics via nano-grating-patterned organic photovoltaics.

Next-generation biomedical devices1-9 will need to be self-powered and conformable to human skin or other tissue. Such devices would enable the accurate and continuous detection of physiological signals without the need for an external power supply or bulky connecting wires. Self-powering functionality could be provided by flexible photovoltaics that can adhere to moveable and complex three-dimensional biological tissues1-4 and skin5-9. Ultra-flexible organic power sources10-13 that can be wrapped around an object have proven mechanical and thermal stability in long-term operation13, making them potentially useful in human-compatible electronics. However, the integration of these power sources with functional electric devices including sensors has not yet been demonstrated because of their unstable output power under mechanical deformation and angular change. Also, it will be necessary to minimize high-temperature and energy-intensive processes10,12 when fabricating an integrated power source and sensor, because such processes can damage the active material of the functional device and deform the few-micrometre-thick polymeric substrates. Here we realize self-powered ultra-flexible electronic devices that can measure biometric signals with very high signal-to-noise ratios when applied to skin or other tissue. We integrated organic electrochemical transistors used as sensors with organic photovoltaic power sources on a one-micrometre-thick ultra-flexible substrate. A high-throughput room-temperature moulding process was used to form nano-grating morphologies (with a periodicity of 760 nanometres) on the charge transporting layers. This substantially increased the efficiency of the organophotovoltaics, giving a high power-conversion efficiency that reached 10.5 per cent and resulted in a high power-per-weight value of 11.46 watts per gram. The organic electrochemical transistors exhibited a transconductance of 0.8 millisiemens and fast responsivity above one kilohertz under physiological conditions, which resulted in a maximum signal-to-noise ratio of 40.02 decibels for cardiac signal detection. Our findings offer a general platform for next-generation self-powered electronics.

An organic transistor matrix for multipoint intracellular action potential recording.

Electrode arrays are widely used for multipoint recording of electrophysiological activities, and organic electronics have been utilized to achieve both high performance and biocompatibility. However, extracellular electrode arrays record the field potential instead of the membrane potential itself, resulting in the loss of information and signal amplitude. Although much effort has been dedicated to developing intracellular access methods, their three-dimensional structures and advanced protocols prohibited implementation with organic electronics. Here, we show an organic electrochemical transistor (OECT) matrix for the intracellular action potential recording. The driving voltage of sensor matrix simultaneously causes electroporation so that intracellular action potentials are recorded with simple equipment. The amplitude of the recorded peaks was larger than that of an extracellular field potential recording, and it was further enhanced by tuning the driving voltage and geometry of OECTs. The capability of miniaturization and multiplexed recording was demonstrated through a 4 × 4 action potential mapping using a matrix of 5- × 5-µm2 OECTs. Those features are realized using a mild fabrication process and a simple circuit without limiting the potential applications of functional organic electronics.

Robust, self-adhesive, reinforced polymeric nanofilms enabling gas-permeable dry electrodes for long-term application.

Robust polymeric nanofilms can be used to construct gas-permeable soft electronics that can directly adhere to soft biological tissue for continuous, long-term biosignal monitoring. However, it is challenging to fabricate gas-permeable dry electrodes that can self-adhere to the human skin and retain their functionality for long-term (>1 d) health monitoring. We have succeeded in developing an extraordinarily robust, self-adhesive, gas-permeable nanofilm with a thickness of only 95 nm. It exhibits an extremely high skin adhesion energy per unit area of 159 µJ/cm2 The nanofilm can self-adhere to the human skin by van der Waals forces alone, for 1 wk, without any adhesive materials or tapes. The nanofilm is ultradurable, and it can support liquids that are 79,000 times heavier than its own weight with a tensile stress of 7.82 MPa. The advantageous features of its thinness, self-adhesiveness, and robustness enable a gas-permeable dry electrode comprising of a nanofilm and an Au layer, resulting in a continuous monitoring of electrocardiogram signals with a high signal-to-noise ratio (34 dB) for 1 wk.

Natural Biopolymer-Based Biocompatible Conductors for Stretchable Bioelectronics.

Biocompatible conductors are important components for soft and stretchable bioelectronics for digital healthcare, which have attracted extensive research efforts. Natural biopolymers, compared to other polymers, possess unique features that make them promising building blocks for biocompatible conductors, such as good biocompatibility/biodegradability, natural abundance, sustainability, and capability, can be processed into various functional formats with tunable material properties under benign conditions. In this comprehensive review, we focus on the recent advances in biocompatible conductors based on natural biopolymers for stretchable bioelectronics. We first give a brief introduction of conductive components and natural polymers and summarize the recent development of biocompatible conductors based on representative natural biopolymers including protein (silk), polypeptide (gelatin), and polysaccharide (alginate). The design and fabrication strategies for biocompatible conductors based on these representative biopolymers are outlined, after the chemical structure and properties of such biopolymers are presented. Then we discuss the electronic component-biopolymer interface and bioelectronic-biological tissue (skin and internal tissues) interface, highlight various fabrication techniques of biocompatible conductors for soft bioelectronics, and introduce representative examples of utilizing natural biopolymer-based biocompatible conductors for on-skin bioelectronics, textile-based wearable electronics, and implantable bioelectronics for digital healthcare. Finally, we present concluding remarks on challenges and prospects for designing natural biopolymers for soft biocompatible conductors and bioelectronics.

Ultraflexible organic light-emitting diodes for optogenetic nerve stimulation.

Organic electronic devices implemented on flexible thin films are attracting increased attention for biomedical applications because they possess extraordinary conformity to curved surfaces. A neuronal device equipped with an organic light-emitting diode (OLED), used in combination with animals that are genetically engineered to include a light-gated ion channel, would enable cell type-specific stimulation to neurons as well as conformal contact to brain tissue and peripheral soft tissue. This potential application of the OLEDs requires strong luminescence, well over the neuronal excitation threshold in addition to flexibility. Compatibility with neuroimaging techniques such as MRI provides a method to investigate the evoked activities in the whole brain. Here, we developed an ultrathin, flexible, MRI-compatible OLED device and demonstrated the activation of channelrhodopsin-2-expressing neurons in animals. Optical stimulation from the OLED attached to nerve fibers induced contractions in the innervated muscles. Mechanical damage to the tissues was significantly reduced because of the flexibility. Owing to the MRI compatibility, neuronal activities induced by direct optical stimulation of the brain were visualized using MRI. The OLED provides an optical interface for modulating the activity of soft neuronal tissues.

All-nanofiber-based, ultrasensitive, gas-permeable mechanoacoustic sensors for continuous long-term heart monitoring.

The prolonged and continuous monitoring of mechanoacoustic heart signals is essential for the early diagnosis of cardiovascular diseases. These bodily acoustics have low intensity and low frequency, and measuring them continuously for long periods requires ultrasensitive, lightweight, gas-permeable mechanoacoustic sensors. Here, we present an all-nanofiber mechanoacoustic sensor, which exhibits a sensitivity as high as 10,050.6 mV Pa-1 in the low-frequency region (<500 Hz). The high sensitivity is achieved by the use of durable and ultrathin (2.5 µm) nanofiber electrode layers enabling a large vibration of the sensor during the application of sound waves. The sensor is ultralightweight, and the overall weight is as small as 5 mg or less. The devices are mechanically robust against bending, and show no degradation in performance even after 1,000-cycle bending. Finally, we demonstrate a continuous long-term (10 h) measurement of heart signals with a signal-to-noise ratio as high as 40.9 decibels (dB).

Highly efficient organic photovoltaics with enhanced stability through the formation of doping-induced stable interfaces.

Flexible organic photovoltaics (OPVs) are promising power sources for wearable electronics. However, it is challenging to simultaneously achieve high efficiency as well as good stability under various stresses. Herein, we demonstrate the fabrication of highly efficient (efficiency, 13.2%) and stable OPVs based on nonfullerene blends by a single-step postannealing treatment. The device performance decreases dramatically after annealing at 90 °C and is fully recovered after annealing at 150 °C. Glass-encapsulated annealed OPVs show good environmental stability with 4.8% loss in efficiency after 4,736 h and an estimated T 80 lifetime (80% of the initial power conversion efficiency) of over 20,750 h in the dark under ambient condition and T 80 lifetime of 1,050 h at 85 °C and 30% relative humidity. This environmental stability is enabled by the synergetic effect of the stable morphology of donor/acceptor blends and thermally stabilized interfaces due to doping. Furthermore, the high efficiency and good stability are almost 100% retained in ultraflexible OPVs and minimodules which are mechanically robust and have long-term operation capability and thus are promising for future self-powered and wearable electronics.

Skin bioelectronics towards long-term, continuous health monitoring.

Skin bioelectronics are considered as an ideal platform for personalised healthcare because of their unique characteristics, such as thinness, light weight, good biocompatibility, excellent mechanical robustness, and great skin conformability. Recent advances in skin-interfaced bioelectronics have promoted various applications in healthcare and precision medicine. Particularly, skin bioelectronics for long-term, continuous health monitoring offer powerful analysis of a broad spectrum of health statuses, providing a route to early disease diagnosis and treatment. In this review, we discuss (1) representative healthcare sensing devices, (2) material and structure selection, device properties, and wireless technologies of skin bioelectronics towards long-term, continuous health monitoring, (3) healthcare applications: acquisition and analysis of electrophysiological, biophysical, and biochemical signals, and comprehensive monitoring, and (4) rational guidelines for the design of future skin bioelectronics for long-term, continuous health monitoring. Long-term, continuous health monitoring of advanced skin bioelectronics will open unprecedented opportunities for timely disease prevention, screening, diagnosis, and treatment, demonstrating great promise to revolutionise traditional medical practices.

Intelligent and Multifunctional Graphene Nanomesh Electronic Skin with High Comfort.

As the aging population increases in many countries, electronic skin (e-skin) for health monitoring has been attracting much attention. However, to realize the industrialization of e-skin, two factors must be optimized. The first is to achieve high comfort, which can significantly improve the user experience. The second is to make the e-skin intelligent, so it can detect and analyze physiological signals at the same time. In this article, intelligent and multifunctional e-skin consisting of laser-scribed graphene and polyurethane (PU) nanomesh is realized with high comfort. The e-skin can be used as a strain sensor with large measurement range (>60%), good sensitivity (GF≈40), high linearity range (60%), and excellent stability (>1000 cycles). By analyzing the morphology of e-skin, a parallel networks model is proposed to express the mechanism of the strain sensor. In addition, laser scribing is also applied to etch the insulating PU, which greatly decreases the impedance in detecting electrophysiology signals. Finally, the e-skin is applied to monitor the electrocardiogram, electroencephalogram (EEG), and electrooculogram signals. A time- and frequency-domain concatenated convolution neural network is built to analyze the EEG signal detected using the e-skin on the forehead and classify the attention level of testers.

The rise of plastic bioelectronics.

Plastic bioelectronics is a research field that takes advantage of the inherent properties of polymers and soft organic electronics for applications at the interface of biology and electronics. The resulting electronic materials and devices are soft, stretchable and mechanically conformable, which are important qualities for interacting with biological systems in both wearable and implantable devices. Work is currently aimed at improving these devices with a view to making the electronic-biological interface as seamless as possible.

Continuous measurement of surface electrical potentials from transplanted cardiomyocyte tissue derived from human-induced pluripotent stem cells under physiological conditions in vivo.

Recording the electrical potentials of bioengineered cardiac tissue after transplantation would help to monitor the maturation of the tissue and detect adverse events such as arrhythmia. However, a few studies have reported the measurement of myocardial tissue potentials in vivo under physiological conditions. In this study, human-induced pluripotent stem cell-derived cardiomyocyte (hiPSCM) sheets were stacked and ectopically transplanted into the subcutaneous tissue of rats for culture in vivo. Three months after transplantation, a flexible nanomesh sensor was implanted onto the hiPSCM tissue to record its surface electrical potentials under physiological conditions, i.e., without the need for anesthetic agents that might adversely affect cardiomyocyte function. The nanomesh sensor was able to record electrical potentials in non-sedated, ambulating animals for up to 48 h. When compared with recordings made with conventional needle electrodes in anesthetized animals, the waveforms obtained with the nanomesh sensor showed less dispersion of waveform interval and waveform duration. However, waveform amplitude tended to show greater dispersion for the nanomesh sensor than for the needle electrodes, possibly due to motion artifacts produced by movements of the animal or local tissue changes in response to surgical implantation of the sensor. The implantable nanomesh sensor utilized in this study potentially could be used for long-term monitoring of bioengineered myocardial tissue in vivo under physiological conditions.

Thermally stable, highly efficient, ultraflexible organic photovoltaics.

Flexible photovoltaics with extreme mechanical compliance present appealing possibilities to power Internet of Things (IoT) sensors and wearable electronic devices. Although improvement in thermal stability is essential, simultaneous achievement of high power conversion efficiency (PCE) and thermal stability in flexible organic photovoltaics (OPVs) remains challenging due to the difficulties in maintaining an optimal microstructure of the active layer under thermal stress. The insufficient thermal capability of a plastic substrate and the environmental influences cannot be fully expelled by ultrathin barrier coatings. Here, we have successfully fabricated ultraflexible OPVs with initial efficiencies of up to 10% that can endure temperatures of over 100 °C, maintaining 80% of the initial efficiency under accelerated testing conditions for over 500 hours in air. Particularly, we introduce a low-bandgap poly(benzodithiophene-cothieno[3,4-b]thiophene) (PBDTTT) donor polymer that forms a sturdy microstructure when blended with a fullerene acceptor. We demonstrate a feasible way to adhere ultraflexible OPVs onto textiles through a hot-melt process without causing severe performance degradation.

Transparent, conformable, active multielectrode array using organic electrochemical transistors.

Mechanically flexible active multielectrode arrays (MEA) have been developed for local signal amplification and high spatial resolution. However, their opaqueness limited optical observation and light stimulation during use. Here, we show a transparent, ultraflexible, and active MEA, which consists of transparent organic electrochemical transistors (OECTs) and transparent Au grid wirings. The transparent OECT is made of Au grid electrodes and has shown comparable performance with OECTs with nontransparent electrodes/wirings. The transparent active MEA realizes the spatial mapping of electrocorticogram electrical signals from an optogenetic rat with 1-mm spacing and shows lower light artifacts than noise level. Our active MEA would open up the possibility of precise investigation of a neural network system with direct light stimulation.

Materials and structural designs of stretchable conductors.

Stretchable conductors are essential building blocks for stretchable electronic devices used in next-generation wearables and soft robotics. Over 10 years of research in stretchable electronics has produced stretchable sensors, circuits, displays, and energy harvesters, mostly enabled by unique stretchable conductors. This review covers recent advances in stretchable conductors, which have been achieved by engineering their structures, materials, or both. Advantages, mechanisms, and limitations of the different classes of stretchable conductors are discussed to provide insight into which class of stretchable conductor is suitable for fabrication of various stretchable electronic devices. The significantly improved electronic performance and wide variety of stretchable conductors are creating a new paradigm in stretchable electronics.

An ultra-lightweight design for imperceptible plastic electronics.

Electronic devices have advanced from their heavy, bulky origins to become smart, mobile appliances. Nevertheless, they remain rigid, which precludes their intimate integration into everyday life. Flexible, textile and stretchable electronics are emerging research areas and may yield mainstream technologies. Rollable and unbreakable backplanes with amorphous silicon field-effect transistors on steel substrates only 3 µm thick have been demonstrated. On polymer substrates, bending radii of 0.1 mm have been achieved in flexible electronic devices. Concurrently, the need for compliant electronics that can not only be flexed but also conform to three-dimensional shapes has emerged. Approaches include the transfer of ultrathin polyimide layers encapsulating silicon CMOS circuits onto pre-stretched elastomers, the use of conductive elastomers integrated with organic field-effect transistors (OFETs) on polyimide islands, and fabrication of OFETs and gold interconnects on elastic substrates to realize pressure, temperature and optical sensors. Here we present a platform that makes electronics both virtually unbreakable and imperceptible. Fabricated directly on ultrathin (1 µm) polymer foils, our electronic circuits are light (3 g m(-2)) and ultraflexible and conform to their ambient, dynamic environment. Organic transistors with an ultra-dense oxide gate dielectric a few nanometres thick formed at room temperature enable sophisticated large-area electronic foils with unprecedented mechanical and environmental stability: they withstand repeated bending to radii of 5 µm and less, can be crumpled like paper, accommodate stretching up to 230% on prestrained elastomers, and can be operated at high temperatures and in aqueous environments. Because manufacturing costs of organic electronics are potentially low, imperceptible electronic foils may be as common in the future as plastic wrap is today. Applications include matrix-addressed tactile sensor foils for health care and monitoring, thin-film heaters, temperature and infrared sensors, displays, and organic solar cells.

A Highly Sensitive Capacitive-type Strain Sensor Using Wrinkled Ultrathin Gold Films.

Soft strain sensors are needed for a variety of applications including human motion and health monitoring, soft robotics, and human/machine interactions. Capacitive-type strain sensors are excellent candidates for practical applications due to their great linearity and low hysteresis; however, a big limitation of this sensor is its inherent property of low sensitivity when it comes to detecting various levels of applied strain. This limitation is due to the structural properties of the parallel plate capacitor structure during applied stretching operations. According to this model, at best the maximum gauge factor (sensitivity) that can be achieved is 1. Here, we report the highest gauge factor ever achieved in capacitive-type strain sensors utilizing an ultrathin wrinkled gold film electrode. Our strain sensor achieved a gauge factor slightly above 3 and exhibited high linearity with negligible hysteresis over a maximum applied strain of 140%. We further demonstrated this highly sensitive strain sensor in a wearable application. This work opens up the possibility of engineering even higher sensitivity in capacitive-type strain sensors for practical and reliable wearable applications.

Printable elastic conductors by in situ formation of silver nanoparticles from silver flakes.

Printable elastic conductors promise large-area stretchable sensor/actuator networks for healthcare, wearables and robotics. Elastomers with metal nanoparticles are one of the best approaches to achieve high performance, but large-area utilization is limited by difficulties in their processability. Here we report a printable elastic conductor containing Ag nanoparticles that are formed in situ, solely by mixing micrometre-sized Ag flakes, fluorine rubbers, and surfactant. Our printable elastic composites exhibit conductivity higher than 4,000 S cm-1 (highest value: 6,168 S cm-1) at 0% strain, and 935 S cm-1 when stretched up to 400%. Ag nanoparticle formation is influenced by the surfactant, heating processes, and elastomer molecular weight, resulting in a drastic improvement of conductivity. Fully printed sensor networks for stretchable robots are demonstrated, sensing pressure and temperature accurately, even when stretched over 250%.

Transparency-enhancing technology allows three-dimensional assessment of gastrointestinal mucosa: A porcine model.

Although high-resolution three-dimensional imaging of endoscopically resected gastrointestinal specimens can help elucidating morphological features of gastrointestinal mucosa or tumor, there are no established methods to achieve this without breaking specimens apart. We evaluated the utility of transparency-enhancing technology for three-dimensional assessment of gastrointestinal mucosa in porcine models. Esophagus, stomach, and colon mucosa samples obtained from a sacrificed swine were formalin-fixed and paraffin-embedded, and subsequently deparaffinized for analysis. The samples were fluorescently stained, optically cleared using transparency-enhancing technology: ilLUmination of Cleared organs to IDentify target molecules method (LUCID), and visualized using laser scanning microscopy. After observation, all specimens were paraffin-embedded again and evaluated by conventional histopathological assessment to measure the impact of transparency-enhancing procedures. As a result, microscopic observation revealed horizontal section views of mucosa at deeper levels and enabled the three-dimensional image reconstruction of glandular and vascular structures. Besides, paraffin-embedded specimens after transparency-enhancing procedures were all assessed appropriately by conventional histopathological staining. These results suggest that transparency-enhancing technology may be feasible for clinical application and enable the three-dimensional structural analysis of endoscopic resected specimen non-destructively. Although there remain many limitations or problems to be solved, this promising technology might represent a novel histopathological method for evaluating gastrointestinal cancers.