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.

Clinical role of radiofrequency ablation for early-stage hepatocellular carcinoma in an advanced aging society.

AIM: It is unclear whether prognosis differs by age for early-stage hepatocellular carcinoma (HCC). We aimed to examine prognosis and recurrence after radiofrequency ablation (RFA) for early-stage HCC and to determine its prognostic factors for different age groups. METHODS: This retrospective study enrolled 1079 patients with initial early-stage HCC treated with RFA at two institutions. All patients in this study were divided into four groups: <70 years old (group1, n = 483), 70-74 years old (group2, n = 198), 75-79 years old (group3, n = 201), and ≥80 years old (group4, n = 197). Prognostic factors were evaluated by comparing survival and recurrence rates between each group. RESULTS: The median survival time and 5-year survival rates for each group were 113 months and 70.8% in group1, 99.2 months and 71.5% in group2, 91.3 months and 66.5% in group3, and 71 months and 52.6% in group 4, respectively. Group4 had a significantly shorter survival than the other groups (p < 0.05). There were no significant differences in recurrence-free survival among the groups. In group4, the most common cause of death was nonliver-related disease (69.4%). In all groups, modified albumin-bilirubin index grade was a factor contributing to prolonged prognosis, but only in group4 performance status (PS) was a significant factor (hazard ratio, 2.46; 95% confidence interval, 1.16-3.00; p = 0.009). CONCLUSION: For early-stage HCC in the elderly, preoperative evaluation of PS and management of other diseases could contribute to a prolonged prognosis.

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.

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.

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%.

Ultraflexible, large-area, physiological temperature sensors for multipoint measurements.

We report a fabrication method for flexible and printable thermal sensors based on composites of semicrystalline acrylate polymers and graphite with a high sensitivity of 20 mK and a high-speed response time of less than 100 ms. These devices exhibit large resistance changes near body temperature under physiological conditions with high repeatability (1,800 times). Device performance is largely unaffected by bending to radii below 700 µm, which allows for conformal application to the surface of living tissue. The sensing temperature can be tuned between 25 °C and 50 °C, which covers all relevant physiological temperatures. Furthermore, we demonstrate flexible active-matrix thermal sensors which can resolve spatial temperature gradients over a large area. With this flexible ultrasensitive temperature sensor we succeeded in the in vivo measurement of cyclic temperatures changes of 0.1 °C in a rat lung during breathing, without interference from constant tissue motion. This result conclusively shows that the lung of a warm-blooded animal maintains surprising temperature stability despite the large difference between core temperature and inhaled air temperature.

Multicenter prospective evaluation study of endoscopic ultrasound-guided hepaticogastrostomy combined with antegrade stenting (with video).

BACKGROUND AND AIM: Endoscopic ultrasonography-guided hepaticogastrostomy (EUS-HGS) is often indicated for advanced stage patients. Therefore it is important to prevent adverse events associated with EUS-HGS procedures and obtain long stent patency. EUS-guided antegrade stenting (AS) has been developed as an advanced technique. Thus, to prevent adverse events and achieve long stent patency, EUS-AS combined with EUS-HGS (EUS-HGAS) has been reported. The aim of the present study was to evaluate the technical feasibility and efficacy of EUS-HGAS in a multicenter, prospective study. METHODS: This prospective study was carried out at each hospital of the Therapeutic Endoscopic Ultrasound Group. Primary endpoint of this multicenter prospective study was stent patency of EUS-HGAS. RESULTS: A total of 49 patients were enrolled. Technical success rate of EUS-HGS was 95.9% (47/49). EUS-AS failed in five patients because the guidewire could not be advanced into the intestine across the bile duct obstruction site. Therefore, EUS-HGAS was successfully carried out in 40 patients (technical success rate: 85.7%). Median overall survival was 114 days. Median stent patency including stent dysfunction and patient death was 114 days. In contrast, mean stent patency was 320 days. Adverse events were seen in 10.2% (5/49) of cases. Hyperamylasemia was seen in four patients, and bleeding was seen in one patient. CONCLUSIONS: The present study is the first to evaluate EUS-HGAS. EUS-HGAS has clinical benefit for obtaining long stent patency and avoiding adverse events, although the possibility of acute pancreatitis as a result of obstruction of the orifice of the pancreatic duct must be considered.

Efficacy of chemotherapy in elderly patients with unresectable pancreatic cancer: a multicenter review of 895 patients.

BACKGROUND: The efficacy of chemotherapy for unresectable pancreatic cancer has improved. However, it is occasionally difficult to make treatment decisions for elderly patients. We reviewed the outcomes of elderly patients with unresectable pancreatic cancer by using a large cohort and evaluated whether they had received chemotherapy and the reason why. METHODS: Data for 895 pancreatic cancer patients who were treated using chemotherapy or best supportive care were analyzed considering demographics, clinical stage, treatment, and outcome. Data were analyzed using the chi-square test, Student t-test, or Mann-Whitney U-test, as appropriate. Outcomes were analyzed using the Kaplan-Meier method. Differences in survival were analyzed using the log-rank test. RESULTS: The median survival time was significantly shorter in elderly patients (≥65 years) than in younger patients (<65 years) (181 vs. 263 days, P = 0.0001). The median survival time of patients treated with chemotherapy was not significantly different between the elderly and the younger group (274 days vs. 333 days, P = 0.09), and nor was that of patients choosing best supportive care (84 days vs. 78 days, P = 0.83). These results held true even when the age cut-off between younger and elder patients was increased to 70, 75, and 80 years. Elderly patients treated with chemotherapy had a significantly longer median survival time than those choosing best supportive care (274 vs. 86 days, P < 0.0001); a significantly greater proportion of elderly patients chose best supportive care compared to younger patients (47.8 vs. 25.8%, P < 0.0001). The reason for choosing best supportive care was established in 261 elderly patients (82.9%); 133 (51.0%) met the eligibility criteria for chemotherapy, but of these, 78 (58.6%) were not informed about their disease. The treatment preferences of elderly patients were not always considered; they often received only best supportive care per family members preference (N = 65, 48.8%) or because the physician based their treatment decision only on the patient's age (N = 68, 51.1%). CONCLUSIONS: Chemotherapy appears effective for elderly pancreatic cancer patients with unresectable disease, but treatment needs to be optimized to improve prognosis.