VR-enabled portable brain-computer interfaces via wireless soft bioelectronics.

Noninvasive, wearable brain-computer interfaces (BCI) find limited use due to their obtrusive nature and low information. Currently available portable BCI systems are limited by device rigidity, bulky form factors, and gel-based skin-contact electrodes - and therefore more prone to noise and motion artifacts. Here, we introduce virtual reality (VR)-enabled split-eye asynchronous stimulus (SEAS) allowing a target to present different stimuli to either eye. This results in unique asynchronous stimulus patterns measurable with as few as four EEG electrodes, as demonstrated with improved wireless soft electronics for portable BCI. This VR-embedded SEAS paradigm demonstrates potential for improved throughput with a greater number of unique stimuli. A wearable soft platform featuring dry needle electrodes and shielded stretchable interconnects enables high throughput decoding of steady-state visually evoked potentials (SSVEP) for a text spelling interface. A combination of skin-conformal electrodes and soft materials offers high-quality recordings of SSVEP with minimal motion artifacts, validated by comparing the performance with a conventional wearable system. A deep-learning algorithm provides real-time classification, with an accuracy of 78.93% for 0.8 s and 91.73% for 2 s with 33 classes from nine human subjects, allowing for a successful demonstration of VR text spelling and navigation of a real-world environment. With as few as only four data recording channels, the system demonstrates a highly competitive information transfer rate (243.6 bit/min). Collectively, the VR-enabled soft system offers unique advantages in wireless, real-time monitoring of brain signals for portable BCI, neurological rehabilitation, and disease diagnosis.

Smart bioelectronic pacifier for real-time continuous monitoring of salivary electrolytes.

Monitoring electrolytes is critical for newborns and babies in the intensive care unit. However, the gold standard methods use a blood draw, which is painful and only offers discrete measures. Although salivary-based detection offers promise as an alternative, existing devices are ineffective for real-time, continuous monitoring of electrolytes due to their rigidity, bulky form factors, and lack of salivary accumulation. Here, we introduce a smart, wireless, bioelectronic pacifier for salivary electrolyte monitoring of neonates, which can detect real-time continuous sodium and potassium levels without a blood draw. The miniature system facilitates the seamless integration of the ultralight and low-profile device with a commercial pacifier without additional fixtures or structural modifications. The portable device includes ion-selective sensors, flexible circuits, and microfluidic channels, allowing simplified measurement protocols in non-invasive electrolyte monitoring. The flexible microfluidic channel enables continuous and efficient saliva collection from a mouth. By modifying the surface properties of the channels and the structure of the capillary reservoir, we achieve reliable pumping of the viscous medium for quick calibration and measurement. Embedded sensors in the system show good stability and sensitivity: 52 and 57 mV/decade for the sodium and potassium sensor, respectively. In vivo study with neonates in the intensive care unit captures the device's feasibility and performance in the natural saliva-based detection of the critical electrolytes without induced stimulation.

Fully portable continuous real-time auscultation with a soft wearable stethoscope designed for automated disease diagnosis.

Modern auscultation, using digital stethoscopes, provides a better solution than conventional methods in sound recording and visualization. However, current digital stethoscopes are too bulky and nonconformal to the skin for continuous auscultation. Moreover, motion artifacts from the rigidity cause friction noise, leading to inaccurate diagnoses. Here, we report a class of technologies that offers real-time, wireless, continuous auscultation using a soft wearable system as a quantitative disease diagnosis tool for various diseases. The soft device can detect continuous cardiopulmonary sounds with minimal noise and classify real-time signal abnormalities. A clinical study with multiple patients and control subjects captures the unique advantage of the wearable auscultation method with embedded machine learning for automated diagnoses of four types of lung diseases: crackle, wheeze, stridor, and rhonchi, with a 95% accuracy. The soft system also demonstrates the potential for a sleep study by detecting disordered breathing for home sleep and apnea detection.

At-home wireless monitoring of acute hemodynamic disturbances to detect sleep apnea and sleep stages via a soft sternal patch.

Obstructive sleep apnea (OSA) affects more than 900 million adults globally and can create serious health complications when untreated; however, 80% of cases remain undiagnosed. Critically, current diagnostic techniques are fundamentally limited by low throughputs and high failure rates. Here, we report a wireless, fully integrated, soft patch with skin-like mechanics optimized through analytical and computational studies to capture seismocardiograms, electrocardiograms, and photoplethysmograms from the sternum, allowing clinicians to investigate the cardiovascular response to OSA during home sleep tests. In preliminary trials with symptomatic and control subjects, the soft device demonstrated excellent ability to detect blood-oxygen saturation, respiratory effort, respiration rate, heart rate, cardiac pre-ejection period and ejection timing, aortic opening mechanics, heart rate variability, and sleep staging. Last, machine learning is used to autodetect apneas and hypopneas with 100% sensitivity and 95% precision in preliminary at-home trials with symptomatic patients, compared to data scored by professionally certified sleep clinicians.

Wireless Soft Scalp Electronics and Virtual Reality System for Motor Imagery-Based Brain-Machine Interfaces.

Motor imagery offers an excellent opportunity as a stimulus-free paradigm for brain-machine interfaces. Conventional electroencephalography (EEG) for motor imagery requires a hair cap with multiple wired electrodes and messy gels, causing motion artifacts. Here, a wireless scalp electronic system with virtual reality for real-time, continuous classification of motor imagery brain signals is introduced. This low-profile, portable system integrates imperceptible microneedle electrodes and soft wireless circuits. Virtual reality addresses subject variance in detectable EEG response to motor imagery by providing clear, consistent visuals and instant biofeedback. The wearable soft system offers advantageous contact surface area and reduced electrode impedance density, resulting in significantly enhanced EEG signals and classification accuracy. The combination with convolutional neural network-machine learning provides a real-time, continuous motor imagery-based brain-machine interface. With four human subjects, the scalp electronic system offers a high classification accuracy (93.22 ± 1.33% for four classes), allowing wireless, real-time control of a virtual reality game.

Development of Flexible Ion-Selective Electrodes for Saliva Sodium Detection.

Saliva can be used for health monitoring with non-invasive wearable systems. Such devices, including electrochemical sensors, may provide a safe, fast, and cost-efficient way of detecting target ions. Although salivary ions are known to reflect those in blood, no available clinical device can detect essential ions directly from saliva. Here, we introduce an all-solid-state, flexible film sensor that allows highly accurate detection of sodium levels in saliva, comparable to those in blood. The wireless film sensor system can successfully measure sodium ions from a small volume of infants' saliva (<400 µL), demonstrating its potential as a continuous health monitor. This study includes the structural characterization and error analysis of a carbon/elastomer-based ion-selective electrode and a reference electrode to confirm the signal reliability. The sensor, composed of a pair of the electrodes, shows good sensitivity (58.9 mV/decade) and selectivity (log K = -2.68 for potassium), along with a broad detection range of 5 × 10-5 ≈ 1 M with a low detection limit of 4.27 × 10-5 M. The simultaneous comparison between the film sensor and a commercial electrochemical sensor demonstrates the accuracy of the flexible sensor and a positive correlation in saliva-to-blood sodium levels. Collectively, the presented study shows the potential of the wireless ion-selective sensor system for a non-invasive, early disease diagnosis with saliva.

Wireless, continuous monitoring of daily stress and management practice via soft bioelectronics.

Stress has become a significant factor, directly affecting human health. Due to the numerous sources of stress that are inevitable in daily life, effective management of stress is essential to maintain a healthy life. Recent advancements in wearable devices allow monitoring stress levels via the detection of galvanic skin response on the skin. Some of these devices show the capability of assessing stress relief methods. However, prior works have been limited in a controlled laboratory setting with a short period assessment (<1 h) of stress intervention. The existing systems' main issues include motion artifacts and discomfort caused by rigid and bulky electronics and mandatory device connection on active fingers. Here, we introduce soft, wireless, skin-like electronics (SKINTRONICS) that offers continuous, portable daily stress and management practice monitoring. The ultrathin, lightweight, all-in-one device captures the change of a subject's stress over six continuous hours during everyday activities, including desk work, cleaning, and resting. At the same time, the SKINTRONICS proves that typical stress alleviation methods (mindfulness and meditation) can reduce stress levels, even in the middle of the day, which is supported by statistical analysis. The low-profile, wireless, gel-free device shows enhanced breathability and minimized motion artifacts compared to a commercial stress monitor. Collectively, this study shows the first demonstration of soft, nanomembrane bioelectronics for long-term, continuous assessment of stress and intervention effectiveness throughout daily life.

Printed, Wireless, Soft Bioelectronics and Deep Learning Algorithm for Smart Human-Machine Interfaces.

Recent advances in flexible materials and wearable electronics offer a noninvasive, high-fidelity recording of biopotentials for portable healthcare, disease diagnosis, and machine interfaces. Current device-manufacturing methods, however, still heavily rely on the conventional cleanroom microfabrication that requires expensive, time-consuming, and complicated processes. Here, we introduce an additive nanomanufacturing technology that explores a contactless direct printing of aerosol nanomaterials and polymers to fabricate stretchable sensors and multilayered wearable electronics. Computational and experimental studies prove the mechanical flexibility and reliability of soft electronics, considering direct mounting to the deformable human skin with a curvilinear surface. The dry, skin-conformal graphene biosensor, without the use of conductive gels and aggressive tapes, offers an enhanced biopotential recording on the skin and multiple uses (over ten times) with consistent measurement of electromyograms. The combination of soft bioelectronics and deep learning algorithm allows classifying six classes of muscle activities with an accuracy of over 97%, which enables wireless, real-time, continuous control of external machines such as a robotic hand and a robotic arm. Collectively, the comprehensive study of nanomaterials, flexible mechanics, system integration, and machine learning shows the potential of the printed bioelectronics for portable, smart, and persistent human-machine interfaces.

Stretchable Nanocomposite Sensors, Nanomembrane Interconnectors, and Wireless Electronics toward Feedback-Loop Control of a Soft Earthworm Robot.

Sensors that can detect external stimuli and perceive the surrounding areas could offer an ability for soft biomimetic robots to use the sensory feedback for closed-loop control of locomotion. Although various types of biomimetic robots have been developed, few systems have included integrated stretchable sensors and interconnectors with miniaturized electronics. Here, we introduce a soft, stretchable nanocomposite system with built-in wireless electronics with an aim for feedback-loop motion control of a robotic earthworm. The nanostructured strain sensor, based on a carbon nanomaterial and a low-modulus silicone elastomer, allows for seamless integration with the body of the soft robot that can accommodate large strains caused by bending, stretching, and physical interactions with obstacles. A scalable, cost-effective, and screen-printing method manufactures an array of the strain sensors that are conductive and stretchable over 100% with a gauge factor over 38. An array of nanomembrane interconnectors enables a reliable connection between soft sensors and wireless electronics while tolerating the robot's multimodal movements. A set of computational and experimental studies of soft materials, stretchable mechanics, and hybrid packaging provides the key design factors for a reliable, nanocomposite sensor system. The miniaturized wireless circuit, embedded in the robot joint, offers real-time monitoring of strain changes during the motions of a robotic segment. Collectively, the soft sensor system presented in this work shows great potential to be integrated with other flexible, stretchable electronics for applications in soft robotics, wearable devices, and human-machine interfaces.

Fully Integrated, Stretchable, Wireless Skin-Conformal Bioelectronics for Continuous Stress Monitoring in Daily Life.

Stress is one of the main causes that increase the risk of serious health problems. Recent wearable devices have been used to monitor stress levels via electrodermal activities on the skin. Although many biosensors provide adequate sensing performance, they still rely on uncomfortable, partially flexible systems with rigid electronics. These devices are mounted on either fingers or palms, which hinders a continuous signal monitoring. A fully-integrated, stretchable, wireless skin-conformal bioelectronic (referred to as "SKINTRONICS") is introduced here that integrates soft, multi-layered, nanomembrane sensors and electronics for continuous and portable stress monitoring in daily life. The all-in-one SKINTRONICS is ultrathin, highly soft, and lightweight, which overall offers an ergonomic and conformal lamination on the skin. Stretchable nanomembrane electrodes and a digital temperature sensor enable highly sensitive monitoring of galvanic skin response (GSR) and temperature. A set of comprehensive signal processing, computational modeling, and experimental study provides key aspects of device design, fabrication, and optimal placing location. Simultaneous comparison with two commercial stress monitors captures the enhanced performance of SKINTRONICS in long-term wearability, minimal noise, and skin compatibility. In vivo demonstration of continuous stress monitoring in daily life reveals the unique capability of the soft device as a real-world applicable stress monitor.

All-printed nanomembrane wireless bioelectronics using a biocompatible solderable graphene for multimodal human-machine interfaces.

Recent advances in nanomaterials and nano-microfabrication have enabled the development of flexible wearable electronics. However, existing manufacturing methods still rely on a multi-step, error-prone complex process that requires a costly cleanroom facility. Here, we report a new class of additive nanomanufacturing of functional materials that enables a wireless, multilayered, seamlessly interconnected, and flexible hybrid electronic system. All-printed electronics, incorporating machine learning, offers multi-class and versatile human-machine interfaces. One of the key technological advancements is the use of a functionalized conductive graphene with enhanced biocompatibility, anti-oxidation, and solderability, which allows a wireless flexible circuit. The high-aspect ratio graphene offers gel-free, high-fidelity recording of muscle activities. The performance of the printed electronics is demonstrated by using real-time control of external systems via electromyograms. Anatomical study with deep learning-embedded electrophysiology mapping allows for an optimal selection of three channels to capture all finger motions with an accuracy of about 99% for seven classes.

Wireless, Flexible, Ion-Selective Electrode System for Selective and Repeatable Detection of Sodium.

Wireless, flexible, ion-selective electrodes (ISEs) are of great interest in the development of wearable health monitors and clinical systems. Existing film-based electrochemical sensors, however, still have practical limitations due to poor electrical contact and material-interfacial leakage. Here, we introduce a wireless, flexible film-based system with a highly selective, stable, and reliable sodium sensor. A flexible and hydrophobic composite with carbon black and soft elastomer serves as an ion-to-electron transducer offering cost efficiency, design simplicity, and long-term stability. The sensor package demonstrates repeatable analysis of selective sodium detection in saliva with good sensitivity (56.1 mV/decade), stability (0.53 mV/h), and selectivity coefficient of sodium against potassium (-3.0). The film ISEs have an additional membrane coating that provides reinforced stability for the sensor upon mechanical bending. Collectively, the comprehensive study of materials, surface chemistry, and sensor design in this work shows the potential of the wireless flexible sensor system for low-profile wearable applications.

Soft, wireless periocular wearable electronics for real-time detection of eye vergence in a virtual reality toward mobile eye therapies.

Recent advancements in electronic packaging and image processing techniques have opened the possibility for optics-based portable eye tracking approaches, but technical and safety hurdles limit safe implementation toward wearable applications. Here, we introduce a fully wearable, wireless soft electronic system that offers a portable, highly sensitive tracking of eye movements (vergence) via the combination of skin-conformal sensors and a virtual reality system. Advancement of material processing and printing technologies based on aerosol jet printing enables reliable manufacturing of skin-like sensors, while the flexible hybrid circuit based on elastomer and chip integration allows comfortable integration with a user's head. Analytical and computational study of a data classification algorithm provides a highly accurate tool for real-time detection and classification of ocular motions. In vivo demonstration with 14 human subjects captures the potential of the wearable electronics as a portable therapy system, whose minimized form factor facilitates seamless interplay with traditional wearable hardware.

Soft Nanomembrane Sensors and Flexible Hybrid Bioelectronics for Wireless Quantification of Blepharospasm.

Blepharospasm (BL) is characterized by involuntary closures of the eyelids due to spasms of the orbicularis oculi muscle. The gold standard for clinical evaluation of BL involves visual inspection for manual rating scales. This approach is highly subjective and error prone. Unfortunately, there are currently no simple quantitative systems for accurate and objective diagnostics of BL. Here, we introduce a soft, flexible hybrid bioelectronic system that offers highly conformal, gentle lamination on the skin, while enabling wireless, quantitative detection of electrophysiological signals. Computational and experimental studies of soft materials and flexible mechanics provide a set of key fundamental design factors for a low-profile bioelectronic system. The nanomembrane soft electrodes, mounted around the eyes, are capable of accurately measuring clinical symptoms, including the frequency of blinking, the duration of eye closures during spasms, as well as combinations of blinking and spasms. The use of a deep-learning, convolutional neural network, with the bioelectronics offers objective, real-time classification of key pathological features in BL. The wearable bioelectronics outperform the conventional manual clinical rating, as shown by a pilot study with 13 patients. In vivo demonstration of the bioelectronics with these patients indicates the device as an easy-to-use solution for objective quantification of BL.

Skin-conformal, soft material-enabled bioelectronic system with minimized motion artifacts for reliable health and performance monitoring of athletes.

Recent advances in biosensors, bioelectronics, and system integration allow the development of wristband-type devices for health and performance monitoring of athletes. Although these devices provide adequate sensing outputs, they suffer from signal loss due to improper contact of a rigid sensor with the skin. In addition, when a rubber band tightly secures the sensor to the skin, the gap between sensor and skin causes inevitable motion artifacts, resulting in corrupted data. Consequently, the rigidity and bulky form factor of the existing devices are not suitable for a practical use since athletes typically go through strenuous activities during training and matches. Here, we introduce a soft, wearable flexible hybrid electronics (WFHE) with integrated flexible sensors and circuits in an ultrathin, low-modulus elastomer. The thin-film bioelectronic system avoids the use of bulky, rigid sensors, while providing negligible mechanical and thermal burdens to the wearer. Enabling conformal contact between sensor and skin minimizes undesired motion artifacts. A set of computational and experimental studies of soft materials, flexible mechanics, and system packaging provides key fundamental design factors for a comfortable, reliable, waterproof bioelectronic system. Skin conformal WFHE with sparse signal reconstruction enables reliable, continuous monitoring of photoplethysmogram, heart rate, and activities of athletes. Development of a quantitative analysis between impact force and impact velocity extracted from motion acceleration provides an objective assessment of an athletic punching force. Collectively, this study shows the first demonstration of a wireless, soft, thin-film electronics for a real-time, reliable assessment of athletic health and performance.

Wireless, Skin-Like Membrane Electronics With Multifunctional Ergonomic Sensors for Enhanced Pediatric Care.

Continuous cardiac monitoring using electrocardiograms (ECG) provides a range of patient information, essential for making clinical decisions, to healthcare providers. Unfortunately, the clinical standard of ECG recording requires the use of rigid metal electrodes, conductive gels, and wired electronic devices, which often cause skin injuries and health risks for pediatric patients with underdeveloped, fragile skin. Here, we introduce a wireless, soft, comfortable electronic system that obviates the need for skin preparation, electrolyte gels, or aggressive tapes. The low-profile device incorporates a thin-film circuit and nanomembrane sensors, encapsulated in a hyperelastic elastomer. The soft elastomeric membrane offers an optimized adhesion that ensures a conformal lamination of stretchable electrodes on the skin for recording of high-fidelity biopotentials. The combined set of on-board Bluetooth module, front-end amplifier, and voltage regulator enables a real-time, long-range, wireless monitoring of physiological data, including ECG, heart rate (HR) and respiratory rate (RR). A pilot study with pediatric patients demonstrates the clinical feasibility of the device as a comfortable, reliable biopotential monitor, suggesting a new standard for safe and effective pediatric care.

All-in-One, Wireless, Stretchable Hybrid Electronics for Smart, Connected, and Ambulatory Physiological Monitoring.

Commercially available health monitors rely on rigid electronic housing coupled with aggressive adhesives and conductive gels, causing discomfort and inducing skin damage. Also, research-level skin-wearable devices, while excelling in some aspects, fall short as concept-only presentations due to the fundamental challenges of active wireless communication and integration as a single device platform. Here, an all-in-one, wireless, stretchable hybrid electronics with key capabilities for real-time physiological monitoring, automatic detection of signal abnormality via deep-learning, and a long-range wireless connectivity (up to 15 m) is introduced. The strategic integration of thin-film electronic layers with hyperelastic elastomers allows the overall device to adhere and deform naturally with the human body while maintaining the functionalities of the on-board electronics. The stretchable electrodes with optimized structures for intimate skin contact are capable of generating clinical-grade electrocardiograms and accurate analysis of heart and respiratory rates while the motion sensor assesses physical activities. Implementation of convolutional neural networks for real-time physiological classifications demonstrates the feasibility of multifaceted analysis with a high clinical relevance. Finally, in vivo demonstrations with animals and human subjects in various scenarios reveal the versatility of the device as both a health monitor and a viable research tool.

Wireless, intraoral hybrid electronics for real-time quantification of sodium intake toward hypertension management.

Recent wearable devices offer portable monitoring of biopotentials, heart rate, or physical activity, allowing for active management of human health and wellness. Such systems can be inserted in the oral cavity for measuring food intake in regard to controlling eating behavior, directly related to diseases such as hypertension, diabetes, and obesity. However, existing devices using plastic circuit boards and rigid sensors are not ideal for oral insertion. A user-comfortable system for the oral cavity requires an ultrathin, low-profile, and soft electronic platform along with miniaturized sensors. Here, we introduce a stretchable hybrid electronic system that has an exceptionally small form factor, enabling a long-range wireless monitoring of sodium intake. Computational study of flexible mechanics and soft materials provides fundamental aspects of key design factors for a tissue-friendly configuration, incorporating a stretchable circuit and sensor. Analytical calculation and experimental study enables reliable wireless circuitry that accommodates dynamic mechanical stress. Systematic in vitro modeling characterizes the functionality of a sodium sensor in the electronics. In vivo demonstration with human subjects captures the device feasibility for real-time quantification of sodium intake, which can be used to manage hypertension.

Dynamical System Modeling to Simulate Donor T Cell Response to Whole Exome Sequencing-Derived Recipient Peptides Demonstrates Different Alloreactivity Potential in HLA-Matched and -Mismatched Donor-Recipient Pairs.

Immune reconstitution kinetics and subsequent clinical outcomes in HLA-matched recipients of allogeneic stem cell transplantation (SCT) are variable and difficult to predict. Considering SCT as a dynamical system may allow sequence differences across the exomes of the transplant donors and recipients to be used to simulate an alloreactive T cell response, which may allow better clinical outcome prediction. To accomplish this, whole exome sequencing was performed on 34 HLA-matched SCT donor-recipient pairs (DRPs) and the nucleotide sequence differences translated to peptides. The binding affinity of the peptides to the relevant HLA in each DRP was determined. The resulting array of peptide-HLA binding affinity values in each patient was considered as an operator modifying a hypothetical T cell repertoire vector, in which each T cell clone proliferates in accordance with the logistic equation of growth. Using an iterating system of matrices, each simulated T cell clone's growth was calculated with the steady-state population being proportional to the magnitude of the binding affinity of the driving HLA-peptide complex. Incorporating competition between T cell clones responding to different HLA-peptide complexes reproduces a number of features of clinically observed T cell clonal repertoire in the simulated repertoire, including sigmoidal growth kinetics of individual T cell clones and overall repertoire, Power Law clonal frequency distribution, increase in repertoire complexity over time with increasing clonal diversity, and alteration of clonal dominance when a different antigen array is encountered, such as in SCT. The simulated, alloreactive T cell repertoire was markedly different in HLA-matched DRPs. The patterns were differentiated by rate of growth and steady-state magnitude of the simulated T cell repertoire and demonstrate a possible correlation with survival. In conclusion, exome wide sequence differences in DRPs may allow simulation of donor alloreactive T cell response to recipient antigens and may provide a quantitative basis for refining donor selection and titration of immunosuppression after SCT.