Stretchable Functional Nanocomposites for Soft Implantable Bioelectronics.

Material advances in soft bioelectronics, particularly those based on stretchable nanocomposites─functional nanomaterials embedded in viscoelastic polymers with irreversible or reversible bonds─have driven significant progress in translational medical device research. The unique mechanical properties inherent in the stretchable nanocomposites enable stiffness matching between tissue and device, as well as its spontaneous mechanical adaptation to in vivo environments, minimizing undesired mechanical stress and inflammation responses. Furthermore, these properties allow percolative networks of conducting fillers in the nanocomposites to be sustained even under repetitive tensile/compressive stresses, leading to stable tissue-device interfacing. Here, we present an in-depth review of materials strategies, fabrication/integration techniques, device designs, applications, and translational opportunities of nanocomposite-based soft bioelectronics, which feature intrinsic stretchability, self-healability, tissue adhesion, and/or syringe injectability. Among many, applications to brain, heart, and peripheral nerves are predominantly discussed, and translational studies in certain domains such as neuromuscular and cardiovascular engineering are particularly highlighted.

Nanostructured Carbons: Towards Soft-Bioelectronics, Biosensing and Theraputic Applications.

Recently, nanostructured carbon-based soft bioelectronics and biosensors have received tremendous attention due to their outstanding physical and chemical properties. The ultrahigh specific surface area, high flexibility, lightweight, high electrical conductivity, and biocompatibility of 1D and 2D nanocarbons, such as carbon nanotubes (CNT) and graphene, are advantageous for bioelectronics applications. These materials improve human life by delivering therapeutic advancements in gene, tumor, chemo, photothermal, immune, radio, and precision therapies. They are also utilized in biosensing platforms, including optical and electrochemical biosensors to detect cholesterol, glucose, pathogenic bacteria (e. g., coronavirus), and avian leucosis virus. This review summarizes the most recent advancements in bioelectronics and biosensors by exploiting the outstanding characteristics of nanocarbon materials. The synthesis and biocompatibility of nanocarbon materials are briefly discussed. In the following sections, applications of graphene and CNTs for different therapies and biosensing are elaborated. Finally, the key challenges and future perspectives of nanocarbon materials for biomedical applications are highlighted.

Soft bioelectronics for diagnostic and therapeutic applications in neurological diseases.

Physical and chemical signals in the central nervous system yield crucial information that is clinically relevant under both physiological and pathological conditions. The emerging field of bioelectronics focuses on the monitoring and manipulation of neurophysiological signals with high spatiotemporal resolution and minimal invasiveness. Significant advances have been realized through innovations in materials and structural design, which have markedly enhanced mechanical and electrical properties, biocompatibility, and overall device performance. The diagnostic and therapeutic potential of soft bioelectronics has been corroborated across a diverse array of pre-clinical settings. This review summarizes recent studies that underscore the developments and applications of soft bioelectronics in neurological disorders, including neuromonitoring, neuromodulation, tumor treatment, and biosensing. Limitations and outlooks of soft devices are also discussed in terms of power supply, wireless control, biocompatibility, and the integration of artificial intelligence. This review highlights the potential of soft bioelectronics as a future platform to promote deciphering brain functions and clinical outcomes of neurological diseases.

A Soft Bioelectronic Patch for Simultaneous Respiratory and Cardiovascular Monitoring.

Sleep is critical to maintaining physical and mental health. Measuring physiological parameters to quantify sleep quality without uncomfortable user experience remains highly desired but a challenge. Here, this work develops a soft bioelectronic patch to perform simultaneous respiration and cardiovascular monitoring during sleep in a wearable and non-invasive manner. The soft bioelectronic patch system is mainly composed of a pressure sensor, a flexible printed circuit for signal processing, and a soft thermoplastic urethane mold for assembling different functional modules. The soft bioelectronic patch holds a sensitivity of >0.12 V kPa-1 and a remarkable low-frequency response from 0.5 to 15 Hz. It is demonstrated to continuously monitor respiration and heartbeat during the whole night, which could be harnessed for sleep monitoring and obstructive sleep apnea-hypopnea syndrome diagnosis. The reported soft bioelectronic patch represents a simple and convenient platform technology for sleep study.

Next-Generation Cardiac Interfacing Technologies Using Nanomaterial-Based Soft Bioelectronics.

Cardiac interfacing devices are essential components for the management of cardiovascular diseases, particularly in terms of electrophysiological monitoring and implementation of therapies. However, conventional cardiac devices are typically composed of rigid and bulky materials and thus pose significant challenges for effective long-term interfacing with the curvilinear surface of a dynamically beating heart. In this regard, the recent development of intrinsically soft bioelectronic devices using nanocomposites, which are fabricated by blending conductive nanofillers in polymeric and elastomeric matrices, has shown great promise. The intrinsically soft bioelectronics not only endure the dynamic beating motion of the heart and maintain stable performance but also enable conformal, reliable, and large-area interfacing with the target cardiac tissue, allowing for high-quality electrophysiological mapping, feedback electrical stimulations, and even mechanical assistance. Here, we explore next-generation cardiac interfacing strategies based on soft bioelectronic devices that utilize elastic conductive nanocomposites. We first discuss the conventional cardiac devices used to manage cardiovascular diseases and explain their undesired limitations. Then, we introduce intrinsically soft polymeric materials and mechanical restraint devices utilizing soft polymeric materials. After the discussion of the fabrication and functionalization of conductive nanomaterials, the introduction of intrinsically soft bioelectronics using nanocomposites and their application to cardiac monitoring and feedback therapy follow. Finally, comments on the future prospects of soft bioelectronics for cardiac interfacing technologies are discussed.

A soft, scalable and adaptable multi-contact cuff electrode for targeted peripheral nerve modulation.

BACKGROUND: Cuff electrodes target various nerves throughout the body, providing neuromodulation therapies for motor, sensory, or autonomic disorders. However, when using standard, thick silicone cuffs, fabricated in discrete circular sizes, complications may arise, namely cuff displacement or nerve compression, due to a poor adaptability to variable nerve shapes and sizes encountered in vivo. Improvements in cuff design, materials, closing mechanism and surgical approach are necessary to overcome these issues. METHODS: In this work, we propose a microfabricated multi-channel silicone-based soft cuff electrode with a novel easy-to-implant and size-adaptable design and evaluate a number of essential features such as nerve-cuff contact, nerve compression, cuff locking stability, long-term integration and stimulation selectivity. We also compared performance to that of standard fixed-size cuffs. RESULTS: The belt-like cuff made of 150 µm thick silicone membranes provides a stable and pressure-free conformal contact, independently of nerve size variability, combined with a straightforward implantation procedure. The adaptable design and use of soft materials lead to limited scarring and demyelination after 6-week implantation. In addition, multi-contact designs, ranging from 6 to 16 electrodes, allow for selective stimulation in models of rat and pig sciatic nerve, achieving targeted activation of up to 5 hindlimb muscles. CONCLUSION: These results suggest a promising alternative to classic fixed-diameter cuffs and may facilitate the adoption of soft, adaptable cuffs in clinical settings.

Highly Conductive and Stretchable Hydrogel Nanocomposite Using Whiskered Gold Nanosheets for Soft Bioelectronics.

The low electrical conductivity of conductive hydrogels limits their applications as soft conductors in bioelectronics. This low conductivity originates from the high water content of hydrogels, which impedes facile carrier transport between conductive fillers. This study presents a highly conductive and stretchable hydrogel nanocomposite comprising whiskered gold nanosheets. A dry network of whiskered gold nanosheets is fabricated and then incorporated into the wet hydrogel matrices. The whiskered gold nanosheets preserve their tight interconnection in hydrogels despite the high water content, providing a high-quality percolation network even under stretched states. Regardless of the type of hydrogel matrix, the gold-hydrogel nanocomposites exhibit a conductivity of ≈520 S cm-1 and a stretchability of ≈300% without requiring a dehydration process. The conductivity reaches a maximum of ≈3304 S cm-1 when the density of the dry gold network is controlled. A gold-adhesive hydrogel nanocomposite, which can achieve conformal adhesion to moving organ surfaces, is fabricated for bioelectronics demonstrations. The adhesive hydrogel electrode outperforms elastomer-based electrodes in in vivo epicardial electrogram recording, epicardial pacing, and sciatic nerve stimulation.

Tailor-Made Gold Nanomaterials for Applications in Soft Bioelectronics and Optoelectronics.

In modern nanoscience and nanotechnology, gold nanomaterials are indispensable building blocks that have demonstrated a plethora of applications in catalysis, biology, bioelectronics, and optoelectronics. Gold nanomaterials possess many appealing material properties, such as facile control over their size/shape and surface functionality, intrinsic chemical inertness yet with high biocompatibility, adjustable localized surface plasmon resonances, tunable conductivity, wide electrochemical window, etc. Such material attributes have been recently utilized for designing and fabricating soft bioelectronics and optoelectronics. This motivates to give a comprehensive overview of this burgeoning field. The discussion of representative tailor-made gold nanomaterials, including gold nanocrystals, ultrathin gold nanowires, vertically aligned gold nanowires, hard template-assisted gold nanowires/gold nanotubes, bimetallic/trimetallic gold nanowires, gold nanomeshes, and gold nanosheets, is begun. This is followed by the description of various fabrication methodologies for state-of-the-art applications such as strain sensors, pressure sensors, electrochemical sensors, electrophysiological devices, energy-storage devices, energy-harvesting devices, optoelectronics, and others. Finally, the remaining challenges and opportunities are discussed.

Scalable Layered Heterogeneous Hydrogel Fibers with Strain-Induced Crystallization for Tough, Resilient, and Highly Conductive Soft Bioelectronics.

The advancement of soft bioelectronics hinges critically on the electromechanical properties of hydrogels. Despite ongoing research into diverse material and structural strategies to enhance these properties, producing hydrogels that are simultaneously tough, resilient, and highly conductive for long-term, dynamic physiological monitoring remains a formidable challenge. Here, a strategy utilizing scalable layered heterogeneous hydrogel fibers (LHHFs) is introduced that enables synergistic electromechanical modulation of hydrogels. High toughness (1.4 MJ m-3) and resilience (over 92% recovery from 200% strain) of LHHFs are achieved through a damage-free toughening mechanism that involves dense long-chain entanglements and reversible strain-induced crystallization of sodium polyacrylate. The unique symmetrical layered structure of LHHFs, featuring distinct electrical and mechanical functional layers, facilitates the mixing of multi-walled carbon nanotubes to significantly enhance electrical conductivity (192.7 S m-1) without compromising toughness and resilience. Furthermore, high-performance LHHF capacitive iontronic strain/pressure sensors and epidermal electrodes are developed, capable of accurately and stably capturing biomechanical and bioelectrical signals from the human body under long-term, dynamic conditions. The LHHF offers a promising route for developing hydrogels with uniquely integrated electromechanical attributes, advancing practical wearable healthcare applications.

Sustainable Nanofibril Interfaces for Strain-Resilient and Multimodal Porous Bioelectronics.

Porous soft bioelectronics have attracted significant attention due to their high breathability, long-term biocompatibility, and other unique features inaccessible in nonporous counterparts. However, fabricating high-quality multimodal bioelectronic components that operate stably under strain on porous substrates, along with integrating microfluidics for sweat management, remains challenging. In this study, cellulose nanofibrils (CNF) are explored, biomass-derived sustainable biomaterials, as nanofibril interfaces with unprecedented interfacial robustness to enable high-quality printing of strain-resilient bioelectronics on porous substrates by reducing surface roughness and creating mechanical heterogeneity. Also, CNF-based microfluidics can provide continuous sweat collection and refreshment, crucial for accurate biochemical sensing. Building upon these advancements, a multimodal porous wearable bioelectronic system is further developed capable of simultaneously detecting electrocardiograms and glucose and beta-hydroxybutyrate in sweat for monitoring energy metabolism and consumption. This work introduces novel strategies for fabricating high-quality, strain-resilient porous bioelectronics with customizable multimodalities to meet arising personalized healthcare needs.

Soft Bioelectronics for Neuroengineering: New Horizons in the Treatment of Brain Tumor and Epilepsy.

Soft bioelectronic technologies for neuroengineering have shown remarkable progress, which include novel soft material technologies and device design strategies. Such technological advances that are initiated from fundamental brain science are applied to clinical neuroscience and provided meaningful promises for significant improvement in the diagnosis efficiency and therapeutic efficacy of various brain diseases recently. System-level integration strategies in consideration of specific disease circumstances can enhance treatment effects further. Here, recent advances in soft implantable bioelectronics for neuroengineering, focusing on materials and device designs optimized for the treatment of intracranial disease environments, are reviewed. Various types of soft bioelectronics for neuroengineering are categorized and exemplified first, and then details for the sensing and stimulating device components are explained. Next, application examples of soft implantable bioelectronics to clinical neuroscience, particularly focusing on the treatment of brain tumor and epilepsy are reviewed. Finally, an ideal system of soft intracranial bioelectronics such as closed-loop-type fully-integrated systems is presented, and the remaining challenges for their clinical translation are discussed.

Outdoor Worker Stress Monitoring Electronics with Nanofabric Radiative Cooler-Based Thermal Management.

Severe stress endangers outdoor workers who are in an exceedingly hot workplace. Although recent studies quantify stress levels on the human skin, they still rely on rigid, bulky sensor modules, causing data loss from motion artifacts and limited field-deployability for continuous health monitoring. Moreover, no prior work shows a wearable device that can endure heat exposure while showing continuous monitoring of a subject's stress under realistic working environments. Herein, a soft, field-deployable, wearable bioelectronic system is introduced for detecting outdoor workers' stress levels with negligible motion artifacts and controllable thermal management. A nanofabric radiative cooler (NFRC) and miniaturized sensors with a nanomembrane soft electronic platform are integrated to measure stable electrodermal activities and temperature in hot outdoor conditions. The NFRC exhibits outstanding cooling performance in sub-ambient air with high solar reflectivity and high thermal emissivity. The integrated wearable device with all embedded electronic components and the NFRC shows a lower temperature (41.1%) in sub-ambient air than the NFRC-less device while capturing improved operation time (18.2%). In vivo human study of the bioelectronics with agricultural activities demonstrates the device's capability for portable, continuous, real-time health monitoring of outdoor workers with field deployability.

Integration of hydrogels in microfabrication processes for bioelectronic medicine: Progress and outlook.

Recent research aiming at the development of electroceuticals for the treatment of medical conditions such as degenerative diseases, cardiac arrhythmia and chronic pain, has given rise to microfabricated implanted bioelectronic devices capable of interacting with host biological tissues in synergistic modalities. Owing to their multimodal affinity to biological tissues, hydrogels have emerged as promising interface materials for bioelectronic devices. Here, we review the state-of-the-art and forefront in the techniques used by research groups for the integration of hydrogels into the microfabrication processes of bioelectronic devices, and present the manufacturability challenges to unlock their further clinical deployment.

Soft Bioelectronics for Therapeutics.

Soft bioelectronics play an increasingly crucial role in high-precision therapeutics due to their softness, biocompatibility, clinical accuracy, long-term stability, and patient-friendliness. In this review, we provide a comprehensive overview of the latest representative therapeutic applications of advanced soft bioelectronics, ranging from wearable therapeutics for skin wounds, diabetes, ophthalmic diseases, muscle disorders, and other diseases to implantable therapeutics against complex diseases, such as cardiac arrhythmias, cancer, neurological diseases, and others. We also highlight key challenges and opportunities for future clinical translation and commercialization of soft therapeutic bioelectronics toward personalized medicine.

Carbon-Based Fiber Materials as Implantable Depth Neural Electrodes.

Implantable brain electrophysiology electrodes are valuable tools in both fundamental and applied neuroscience due to their ability to record neural activity with high spatiotemporal resolution from shallow and deep brain regions. Their use has been hindered, however, by the challenges in achieving chronically stable operations. Furthermore, implantable depth neural electrodes can only carry out limited data sampling within predefined anatomical regions, making it challenging to perform large-area brain mapping. Minimizing inflammatory responses and associated gliosis formation, and improving the durability and stability of the electrode insulation layers are critical to achieve long-term stable neural recording and stimulation. Combining electrophysiological measurements with simultaneous whole-brain imaging techniques, such as magnetic resonance imaging (MRI), provides a useful solution to alleviate the challenge in scalability of implantable depth electrodes. In recent years, various carbon-based materials have been used to fabricate flexible neural depth electrodes with reduced inflammatory responses and MRI-compatible electrodes, which allows structural and functional MRI mapping of the whole brain without obstructing any brain regions around the electrodes. Here, we conducted a systematic comparative evaluation on the electrochemical properties, mechanical properties, and MRI compatibility of different kinds of carbon-based fiber materials, including carbon nanotube fibers, graphene fibers, and carbon fibers. We also developed a strategy to improve the stability of the electrode insulation without sacrificing the flexibility of the implantable depth electrodes by sandwiching an inorganic barrier layer inside the polymer insulation film. These studies provide us with important insights into choosing the most suitable materials for next-generation implantable depth electrodes with unique capabilities for applications in both fundamental and translational neuroscience research.

Integrated contact lens sensor system based on multifunctional ultrathin MoS2 transistors.

Smart contact lenses attract extensive interests due to their capability of directly monitoring physiological and ambient information. However, previous demonstrations usually lacked efficient sensor modalities, facile fabrication process, mechanical stability, or biocompatibility. Here, we demonstrate a flexible approach for fabrication of multifunctional smart contact lenses with an ultrathin MoS2 transistors-based serpentine mesh sensor system. The integrated sensor systems contain a photodetector for receiving optical information, a glucose sensor for monitoring glucose level directly from tear fluid, and a temperature sensor for diagnosing potential corneal disease. Unlike traditional sensors and circuit chips sandwiched in the lens substrate, this serpentine mesh sensor system can be directly mounted onto the lenses and maintain direct contact with tears, delivering high detection sensitivity, while being mechanically robust and not interfering with either blinking or vision. Furthermore, the in vitro cytotoxicity tests reveal good biocompatibility, thus holding promise as next-generation soft electronics for healthcare and medical applications.

Mechanical Tolerance of Cascade Bioreactions via Adaptive Curvature Engineering for Epidermal Bioelectronics.

Epidermal bioelectronics that can monitor human health status non-invasively and in real time are core to wearable healthcare equipment. Achieving mechanically tolerant surface bioreactions that convert biochemical information to detectable signals is crucial for obtaining high sensing fidelity. In this work, by combining simulations and experiments, a typical epidermal biosensor system is investigated based on a redox enzyme cascade reaction (RECR) comprising glucose oxidase/lactate oxidase enzymes and Prussian blue nanoparticles. Simulations reveal that strain-induced change in surface reactant flux is the key to the performance drop in traditional flat bioelectrodes. In contrast, wavy bioelectrodes capable of curvature adaptation maintain the reactant flux under strain, which preserves sensing fidelity. This rationale is experimentally proven by bioelectrodes with flat/wavy geometry under both static strain and dynamic stretching. When exposed to 50% strain, the signal fluctuations for wavy bioelectrodes are only 7.0% (4.9%) in detecting glucose (lactate), which are significantly lower than the 40.3% (51.8%) in flat bioelectrodes. Based on this wavy bioelectrode, a stable human epidermal metabolite biosensor insensitive to human gestures is further demonstrated. This mechanically tolerant biosensor based on adaptive curvature engineering provides a reliable bio/chemical-information monitoring platform for soft healthcare bioelectronics.

Device-assisted transdermal drug delivery.

Transdermal drug delivery is a prospective drug delivery strategy to complement the limitations of conventional drug delivery systems including oral and injectable methods. This delivery route allows both convenient and painless drug delivery and a sustained release profile with reduced side effects. However, physiological barriers in the skin undermine the delivery efficiency of conventional patches, limiting drug candidates to small-molecules and lipophilic drugs. Recently, transdermal drug delivery technology has advanced from unsophisticated methods simply relying on natural diffusion to drug releasing systems that dynamically respond to external stimuli. Furthermore, physical barriers in the skin have been overcome using microneedles, and controlled delivery by wearable biosensors has been enabled ultimately. In this review, we classify the evolution of advanced drug delivery strategies based on generations and provide a comprehensive overview. Finally, the recent progress in advanced diagnosis and therapy through customized drug delivery systems based on real-time analysis of physiological cues is highlighted.

Materials, Devices and Systems of Soft Bioelectronics for Precision Therapy.

The potential applications of soft bioelectronics in biomedical research and clinical trials have inspired a great deal of research interest in the past decade. While there has been significant amount of work in the fabrication and characterization of soft and stretchable sensors for monitoring of physical conditions and vital signs of human body, the development of soft bioelectronics based medical treatment and intervention systems has just begun. In addition to health monitoring, active treatments are essential for disease control in the healthcare domain, and medical therapy and surgery realized by sophisticated soft bioelectronic systems are better demonstrations of their utility in healthcare. In this Research News, we summarize recent key research achievements in soft bioelectronics enabled precision therapy, with emphasis on drug delivery, therapeutic and surgical mechanisms and tools enabled by integrated systems. Challenges in technology development and prospects for commercialization are also discussed.