Soft Bioelectronics Based on Nanomaterials.

Recent advances in nanostructured materials and unconventional device designs have transformed the bioelectronics from a rigid and bulky form into a soft and ultrathin form and brought enormous advantages to the bioelectronics. For example, mechanical deformability of the soft bioelectronics and thus its conformal contact onto soft curved organs such as brain, heart, and skin have allowed researchers to measure high-quality biosignals, deliver real-time feedback treatments, and lower long-term side-effects in vivo. Here, we review various materials, fabrication methods, and device strategies for flexible and stretchable electronics, especially focusing on soft biointegrated electronics using nanomaterials and their composites. First, we summarize top-down material processing and bottom-up synthesis methods of various nanomaterials. Next, we discuss state-of-the-art technologies for intrinsically stretchable nanocomposites composed of nanostructured materials incorporated in elastomers or hydrogels. We also briefly discuss unconventional device design strategies for soft bioelectronics. Then individual device components for soft bioelectronics, such as biosensing, data storage, display, therapeutic stimulation, and power supply devices, are introduced. Afterward, representative application examples of the soft bioelectronics are described. A brief summary with a discussion on remaining challenges concludes the review.

Chronic and acute stress monitoring by electrophysiological signals from adrenal gland.

We present electrophysiological (EP) signals correlated with cellular cell activities in the adrenal cortex and medulla using an adrenal gland implantable flexible EP probe. With such a probe, we could observe the EP signals from the adrenal cortex and medulla in response to various stress stimuli, such as enhanced hormone activity with adrenocorticotropic hormone, a biomarker for chronic stress response, and an actual stress environment, like a forced swimming test. This technique could be useful to continuously monitor the elevation of cortisol level, a useful indicator of chronic stress that potentially causes various diseases.

Material Design and Fabrication Strategies for Stretchable Metallic Nanocomposites.

Stretchable conductive nanocomposites fabricated by integrating metallic nanomaterials with elastomers have become a vital component of human-friendly electronics, such as wearable and implantable devices, due to their unconventional electrical and mechanical characteristics. Understanding the detailed material design and fabrication strategies to improve the conductivity and stretchability of the nanocomposites is therefore important. This Review discusses the recent technological advances toward high performance stretchable metallic nanocomposites. First, the effect of the filler material design on the conductivity is briefly discussed, followed by various nanocomposite fabrication techniques to achieve high conductivity. Methods for maintaining the initial conductivity over a long period of time are also summarized. Then, strategies on controlled percolation of nanomaterials are highlighted, followed by a discussion regarding the effects of the morphology of the nanocomposite and postfabricated 3D structures on achieving high stretchability. Finally, representative examples of applications of such nanocomposites in biointegrated electronics are provided. A brief outlook concludes this Review.

Biosafe, Eco-Friendly Levan Polysaccharide toward Transient Electronics.

New options in the material context of transient electronics are essential to create or expand potential applications and to progress in the face of technological challenges. A soft, transparent, and cost-effective polymer of levan polysaccharide that is capable of complete, programmable dissolution is described when immersed in water and implanted in an animal model. The results include chemical analysis, the kinetics of hydrolysis, and adjustable dissolution rates of levan, and a simple theoretical model of reactive diffusion governed by temperature. In vivo experiments of the levan represent nontoxicity and biocompatibility without any adverse reactions. On-demand, selective control of dissolution behaviors with an animal model demonstrates an effective triggering strategy to program the system's lifetime, providing the possibility of potential applications in envisioned areas such as bioresorbable electronic implants and drug release systems.

Introductory Review of Soft Implantable Bioelectronics Using Conductive and Functional Hydrogels and Hydrogel Nanocomposites.

Interfaces between implantable bioelectrodes and tissues provide critical insights into the biological and pathological conditions of targeted organs, aiding diagnosis and treatment. While conventional bioelectronics, made from rigid materials like metals and silicon, have been essential for recording signals and delivering electric stimulation, they face limitations due to the mechanical mismatch between rigid devices and soft tissues. Recently, focus has shifted toward soft conductive materials, such as conductive hydrogels and hydrogel nanocomposites, known for their tissue-like softness, biocompatibility, and potential for functionalization. This review introduces these materials and provides an overview of recent advances in soft hydrogel nanocomposites for implantable electronics. It covers material strategies for conductive hydrogels, including both intrinsically conductive hydrogels and hydrogel nanocomposites, and explores key functionalization techniques like biodegradation, bioadhesiveness, injectability, and self-healing. Practical applications of these materials in implantable electronics are also highlighted, showcasing their effectiveness in real-world scenarios. Finally, we discuss emerging technologies and future needs for chronically implantable bioelectronics, offering insights into the evolving landscape of this field.

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.

Low-impedance tissue-device interface using homogeneously conductive hydrogels chemically bonded to stretchable bioelectronics.

Stretchable bioelectronics has notably contributed to the advancement of continuous health monitoring and point-of-care type health care. However, microscale nonconformal contact and locally dehydrated interface limit performance, especially in dynamic environments. Therefore, hydrogels can be a promising interfacial material for the stretchable bioelectronics due to their unique advantages including tissue-like softness, water-rich property, and biocompatibility. However, there are still practical challenges in terms of their electrical performance, material homogeneity, and monolithic integration with stretchable devices. Here, we report the synthesis of a homogeneously conductive polyacrylamide hydrogel with an exceptionally low impedance (~21 ohms) and a reasonably high conductivity (~24 S/cm) by incorporating polyaniline-decorated poly(3,4-ethylenedioxythiophene:polystyrene). We also establish robust adhesion (interfacial toughness: ~296.7 J/m2) and reliable integration between the conductive hydrogel and the stretchable device through on-device polymerization as well as covalent and hydrogen bonding. These strategies enable the fabrication of a stretchable multichannel sensor array for the high-quality on-skin impedance and pH measurements under in vitro and in vivo circumstances.

Needle-Like Multifunctional Biphasic Microfiber for Minimally Invasive Implantable Bioelectronics.

Implantable bioelectronics has attracted significant attention in electroceuticals and clinical medicine for precise diagnosis and efficient treatment of target diseases. However, conventional rigid implantable devices face challenges such as poor tissue-device interface and unavoidable tissue damage during surgical implantation. Despite continuous efforts to utilize various soft materials to address such issues, their practical applications remain limited. Here, a needle-like stretchable microfiber composed of a phase-convertible liquid metal (LM) core and a multifunctional nanocomposite shell for minimally invasive soft bioelectronics is reported. The sharp tapered microfiber can be stiffened by freezing akin to a conventional needle to penetrate soft tissue with minimal incision. Once implanted in vivo where the LM melts, unlike conventional stiff needles, it regains soft mechanical properties, which facilitate a seamless tissue-device interface. The nanocomposite incorporating with functional nanomaterials exhibits both low impedance and the ability to detect physiological pH, providing biosensing and stimulation capabilities. The fluidic LM embedded in the nanocomposite shell enables high stretchability and strain-insensitive electrical properties. This multifunctional biphasic microfiber conforms to the surfaces of the stomach, muscle, and heart, offering a promising approach for electrophysiological recording, pH sensing, electrical stimulation, and radiofrequency ablation in vivo.

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.

Floatable photocatalytic hydrogel nanocomposites for large-scale solar hydrogen production.

Storing solar energy in chemical bonds aided by heterogeneous photocatalysis is desirable for sustainable energy conversion. Despite recent progress in designing highly active photocatalysts, inefficient solar energy and mass transfer, the instability of catalysts and reverse reactions impede their practical large-scale applications. Here we tackle these challenges by designing a floatable photocatalytic platform constructed from porous elastomer-hydrogel nanocomposites. The nanocomposites at the air-water interface feature efficient light delivery, facile supply of water and instantaneous gas separation. Consequently, a high hydrogen evolution rate of 163 mmol h-1 m-2 can be achieved using Pt/TiO2 cryoaerogel, even without forced convection. When fabricated in an area of 1 m2 and incorporated with economically feasible single-atom Cu/TiO2 photocatalysts, the nanocomposites produce 79.2 ml of hydrogen per day under natural sunlight. Furthermore, long-term stable hydrogen production in seawater and highly turbid water and photoreforming of polyethylene terephthalate demonstrate the potential of the nanocomposites as a commercially viable photocatalytic system.

Stretchable Low-Impedance Conductor with Ag-Au-Pt Core-Shell-Shell Nanowires and in Situ Formed Pt Nanoparticles for Wearable and Implantable Device.

Mechanically soft metallic nanocomposites have gained much attention as a key material for intrinsically stretchable biointegrated devices. However, it has been challenging to develop a stretchable conductive nanocomposite with all the desired material characteristics including high conductivity, high stretchability, low cytotoxicity, and low impedance. Here, we present a material strategy for the stretchable conductive nanocomposite, particularly emphasizing low impedance, by combining silver-gold-platinum core-shell-shell nanowires and homogeneously dispersed in situ synthesized platinum nanoparticles (Pt NPs). The highly embossed structure of the outermost Pt shell, together with the intrinsic electrical property of Pt, contributes to minimizing the impedance. The gold-platinum double-layer sheath prevents leaching of cytotoxic Ag ions, thus improving biocompatibility. Homogeneously dispersed Pt NPs, synthesized in situ during fabrication of the nanocomposite, simultaneously enhance conductivity, reduce impedance, and improve stretchability by supporting the percolation network formation. This intrinsically stretchable nanocomposite conductor can be applied to wearable and implantable bioelectronics for recording biosignals and delivering electrical stimulations in vivo.

Minimally-Invasive and In-Vivo Hydrogel Patterning Method for In Situ Fabrication of Implantable Hydrogel Devices.

Despite advances in a wide range of device applications of hydrogels, including implantable ones, a method for deploying patterned hydrogel devices into the body in a minimally-invasive manner is not available yet. However, in situ patterning of the hydrogel in vivo has an obvious advantage, by which incision surgery for implantation of the hydrogel device can be avoided. Here, a minimally-invasive and in vivo hydrogel patterning method for in situ fabrication of implantable hydrogel devices is presented. The sequential application of injectable hydrogels and enzymes, with assistance of minimally-invasive surgical instruments, enables the in vivo and in situ hydrogel patterning. This patterning method can be achieved by adopting an appropriate combination of the sacrificial mold hydrogel and the frame hydrogel, in consideration of unique material properties of the hydrogels such as high softness, facile mass transfer, biocompatibility, and diverse crosslinking mechanisms. In vivo and in situ patterning of the hydrogels functionalized with nanomaterials is also demonstrated to fabricate the wireless heater and tissue scaffold, showcasing broad applicability of the patterning method.

Ventricular tachyarrhythmia treatment and prevention by subthreshold stimulation with stretchable epicardial multichannel electrode array.

The implantable cardioverter-defibrillator (ICD) is an effective method to prevent sudden cardiac death in high-risk patients. However, the transvenous lead is incompatible with large-area electrophysiological mapping and cannot accommodate selective multichannel precision stimulations. Moreover, it involves high-energy shocks, resulting in pain, myocardial damage, and recurrences of ventricular tachyarrhythmia (VTA). We present a method for VTA treatment based on subthreshold electrical stimulations using a stretchable epicardial multichannel electrode array, which does not disturb the normal contraction or electrical propagation of the ventricle. In rabbit models with myocardial infarction, the infarction was detected by mapping intracardiac electrograms with the stretchable epicardial multichannel electrode array. Then, VTAs could be terminated by sequential electrical stimuli from the epicardial multichannel electrode array beginning with low-energy subthreshold stimulations. Last, we used these subthreshold stimulations to prevent the occurrence of additional VTAs. The proposed protocol using the stretchable epicardial multichannel electrode array provides opportunities toward the development of innovative methods for painless ICD therapy.

Highly Efficient Nitrogen-Fixing Microbial Hydrogel Device for Sustainable Solar Hydrogen Production.

Conversion of sunlight and organic carbon substrates to sustainable energy sources through microbial metabolism has great potential for the renewable energy industry. Despite recent progress in microbial photosynthesis, the development of microbial platforms that warrant efficient and scalable fuel production remains in its infancy. Efficient transfer and retrieval of gaseous reactants and products to and from microbes are particular hurdles. Here, inspired by water lily leaves floating on water, a microbial device designed to operate at the air-water interface and facilitate concomitant supply of gaseous reactants, smooth capture of gaseous products, and efficient sunlight delivery is presented. The floatable device carrying Rhodopseudomonas parapalustris, of which nitrogen fixation activity is first determined through this study, exhibits a hydrogen production rate of 104 mmol h-1  m-2 , which is 53 times higher than that of a conventional device placed at a depth of 2 cm in the medium. Furthermore, a scaled-up device with an area of 144 cm2 generates hydrogen at a high rate of 1.52 L h-1  m-2 . Efficient nitrogen fixation and hydrogen generation, low fabrication cost, and mechanical durability corroborate the potential of the floatable microbial device toward practical and sustainable solar energy conversion.

Multifunctional Injectable Hydrogel for In Vivo Diagnostic and Therapeutic Applications.

Injectable hydrogels show high potential for in vivo biomedical applications owing to their distinctive mode of administration into the human body. In this study, we propose a material design strategy for developing a multifunctional injectable hydrogel with good adhesiveness, stretchability, and bioresorbability. Its multifunctionality, whereupon multiple reactions occur simultaneously during its injection into the body without requiring energy stimuli and/or additives, was realized through meticulous engineering of bioresorbable precursors based on hydrogel chemistry. The multifunctional injectable hydrogel can be administered through a minimally invasive procedure, form a conformal adhesive interface with the target tissue, dynamically stretch along with the organ motions with minimal mechanical constraints, and be resorbed in vivo after a specific period. Further, the incorporation of functional nanomaterials into the hydrogel allows for various in vivo diagnostic and therapeutic applications, without compromising the original multifunctionality of the hydrogel. These features are verified through theranostic case studies on representative organs, including the skin, liver, heart, and bladder.

Facile and Scalable Synthesis of Whiskered Gold Nanosheets for Stretchable, Conductive, and Biocompatible Nanocomposites.

Noble metal nanomaterials have been studied as conductive fillers for stretchable, conductive, and biocompatible nanocomposites. However, their performance as conductive filler materials is far from ideal because of their high percolation threshold and low intrinsic conductivity. Moreover, the difficulty in large-scale production is another critical hurdle in their practical applications. Here we report a method for the facile and scalable synthesis of whiskered gold nanosheets (W-AuNSs) for stretchable, conductive, and biocompatible nanocomposites and their application to stretchable bioelectrodes. W-AuNSs show a lower percolation threshold (1.56 vol %) than those of gold nanoparticles (5.02 vol %) and gold nanosheets (2.74 vol %), which enables the fabrication of W-AuNS-based stretchable nanocomposites with superior conductivity and high stretchability. Addition of platinum-coated W-AuNSs (W-AuNSs@Pt) to the prepared nanocomposite significantly reduces the impedance and improved charge storage capacity. Such enhanced performance of the stretchable nanocomposite enables us to fabricate stretchable bioelectrodes whose performance is demonstrated through animal experiments including electrophysiological recording and electrical stimulation in vivo.

Stretchable colour-sensitive quantum dot nanocomposites for shape-tunable multiplexed phototransistor arrays.

High-performance photodetecting materials with intrinsic stretchability and colour sensitivity are key requirements for the development of shape-tunable phototransistor arrays. Another challenge is the proper compensation of optical aberrations and noises generated by mechanical deformation and fatigue accumulation in a shape-tunable phototransistor array. Here we report rational material design and device fabrication strategies for an intrinsically stretchable, multispectral and multiplexed 5 × 5 × 3 phototransistor array. Specifically, a unique spatial distribution of size-tuned quantum dots, blended in a semiconducting polymer within an elastomeric matrix, was formed owing to surface energy mismatch, leading to highly efficient charge transfer. Such intrinsically stretchable quantum-dot-based semiconducting nanocomposites enable the shape-tunable and colour-sensitive capabilities of the phototransistor array. We use a deep neural network algorithm for compensating optical aberrations and noises, which aids the precise detection of specific colour patterns (for example, red, green and blue patterns) both under its flat state and hemispherically curved state (radius of curvature of 18.4 mm).

Wearable and Implantable Soft Bioelectronics: Device Designs and Material Strategies.

High-performance wearable and implantable devices capable of recording physiological signals and delivering appropriate therapeutics in real time are playing a pivotal role in revolutionizing personalized healthcare. However, the mechanical and biochemical mismatches between rigid, inorganic devices and soft, organic human tissues cause significant trouble, including skin irritation, tissue damage, compromised signal-to-noise ratios, and limited service time. As a result, profuse research efforts have been devoted to overcoming these issues by using flexible and stretchable device designs and soft materials. Here, we summarize recent representative research and technological advances for soft bioelectronics, including conformable and stretchable device designs, various types of soft electronic materials, and surface coating and treatment methods. We also highlight applications of these strategies to emerging soft wearable and implantable devices. We conclude with some current limitations and offer future prospects of this booming field.

Wireless Power Transfer and Telemetry for Implantable Bioelectronics.

Implantable bioelectronic devices are becoming useful and prospective solutions for various diseases owing to their ability to monitor or manipulate body functions. However, conventional implantable devices (e.g., pacemaker and neurostimulator) are still bulky and rigid, which is mostly due to the energy storage component. In addition to mechanical mismatch between the bulky and rigid implantable device and the soft human tissue, another significant drawback is that the entire device should be surgically replaced once the initially stored energy is exhausted. Besides, retrieving physiological information across a closed epidermis is a tricky procedure. However, wireless interfaces for power and data transfer utilizing radio frequency (RF) microwave offer a promising solution for resolving such issues. While the RF interfacing devices for power and data transfer are extensively investigated and developed using conventional electronics, their application to implantable bioelectronics is still a challenge owing to the constraints and requirements of in vivo environments, such as mechanical softness, small module size, tissue attenuation, and biocompatibility. This work elucidates the recent advances in RF-based power transfer and telemetry for implantable bioelectronics to tackle such challenges.

Functionalized Elastomers for Intrinsically Soft and Biointegrated Electronics.

Elastomers are suitable materials for constructing a conformal interface with soft and curvilinear biological tissue due to their intrinsically deformable mechanical properties. Intrinsically soft electronic devices whose mechanical properties are comparable to human tissue can be fabricated using suitably functionalized elastomers. This article reviews recent progress in functionalized elastomers and their application to intrinsically soft and biointegrated electronics. Elastomers can be functionalized by adding appropriate fillers, either nanoscale materials or polymers. Conducting or semiconducting elastomers synthesized and/or processed with these materials can be applied to the fabrication of soft biointegrated electronic devices. For facile integration of soft electronics with the human body, additional functionalization strategies can be employed to improve adhesive or autonomous healing properties. Recently, device components for intrinsically soft and biointegrated electronics, including sensors, stimulators, power supply devices, displays, and transistors, have been developed. Herein, representative examples of these fully elastomeric device components are discussed. Finally, the remaining challenges and future outlooks for the field are presented.