Brain implantation of tissue-level-soft bioelectronics via embryonic development.

The design of bioelectronics capable of stably tracking brain-wide, single-cell, and millisecond-resolved neural activities in the developing brain is critical to the study of neuroscience and neurodevelopmental disorders. During development, the three-dimensional (3D) structure of the vertebrate brain arises from a 2D neural plate 1,2 . These large morphological changes previously posed a challenge for implantable bioelectronics to track neural activity throughout brain development 3-9 . Here, we present a tissue-level-soft, sub-micrometer-thick, stretchable mesh microelectrode array capable of integrating into the embryonic neural plate of vertebrates by leveraging the 2D-to-3D reconfiguration process of the tissue itself. Driven by the expansion and folding processes of organogenesis, the stretchable mesh electrode array deforms, stretches, and distributes throughout the entire brain, fully integrating into the 3D tissue structure. Immunostaining, gene expression analysis, and behavioral testing show no discernible impact on brain development or function. The embedded electrode array enables long-term, stable, brain-wide, single-unit-single-spike-resolved electrical mapping throughout brain development, illustrating how neural electrical activities and population dynamics emerge and evolve during brain development.

E-Tattoos: Toward Functional but Imperceptible Interfacing with Human Skin.

The human body continuously emits physiological and psychological information from head to toe. Wearable electronics capable of noninvasively and accurately digitizing this information without compromising user comfort or mobility have the potential to revolutionize telemedicine, mobile health, and both human-machine or human-metaverse interactions. However, state-of-the-art wearable electronics face limitations regarding wearability and functionality due to the mechanical incompatibility between conventional rigid, planar electronics and soft, curvy human skin surfaces. E-Tattoos, a unique type of wearable electronics, are defined by their ultrathin and skin-soft characteristics, which enable noninvasive and comfortable lamination on human skin surfaces without causing obstruction or even mechanical perception. This review article offers an exhaustive exploration of e-tattoos, accounting for their materials, structures, manufacturing processes, properties, functionalities, applications, and remaining challenges. We begin by summarizing the properties of human skin and their effects on signal transmission across the e-tattoo-skin interface. Following this is a discussion of the materials, structural designs, manufacturing, and skin attachment processes of e-tattoos. We classify e-tattoo functionalities into electrical, mechanical, optical, thermal, and chemical sensing, as well as wound healing and other treatments. After discussing energy harvesting and storage capabilities, we outline strategies for the system integration of wireless e-tattoos. In the end, we offer personal perspectives on the remaining challenges and future opportunities in the field.

3D spatiotemporally scalable in vivo neural probes based on fluorinated elastomers.

Electronic devices for recording neural activity in the nervous system need to be scalable across large spatial and temporal scales while also providing millisecond and single-cell spatiotemporal resolution. However, existing high-resolution neural recording devices cannot achieve simultaneous scalability on both spatial and temporal levels due to a trade-off between sensor density and mechanical flexibility. Here we introduce a three-dimensional (3D) stacking implantable electronic platform, based on perfluorinated dielectric elastomers and tissue-level soft multilayer electrodes, that enables spatiotemporally scalable single-cell neural electrophysiology in the nervous system. Our elastomers exhibit stable dielectric performance for over a year in physiological solutions and are 10,000 times softer than conventional plastic dielectrics. By leveraging these unique characteristics we develop the packaging of lithographed nanometre-thick electrode arrays in a 3D configuration with a cross-sectional density of 7.6 electrodes per 100 µm2. The resulting 3D integrated multilayer soft electrode array retains tissue-level flexibility, reducing chronic immune responses in mouse neural tissues, and demonstrates the ability to reliably track electrical activity in the mouse brain or spinal cord over months without disrupting animal behaviour.

A Multi-Day Wearable Surface EMG E-Tattoo for Fatigue Monitoring.

Surface electromyography (sEMG) is a commonly used technique for the non-invasive measurement of muscle activity. However, the traditional electrodes used for sEMG often have limitations regarding their long-term wearability. This study explored the feasibility of a wearable platform using a tattoo-like epidermal electrode (e-tattoo) for multi-day sEMG monitoring. Our sEMG e-tattoo provided stable and reliable sEMG signals over three days of application comparable to conventional gel electrodes. In addition, the e-tattoo has great resistance to motion artifacts and, therefore, maintains a high signal-to-noise ratio (SNR) and signal-to-motion ratio (SMR) during dynamic activities such as cycling. This robust wearable platform opens up new avenues for developing future wearable sEMG devices and advancing dynamic muscle fatigue research.Clinical relevance- The proposed wearable sEMG system can provide continuous and non-invasive monitoring of muscle activity, providing insights for improving rehabilitation and EMG-based prosthesis development for patients.

Towards Simultaneous Noninvasive Arterial and Venous Oxygenation Monitoring with Wearable E-Tattoo.

While noninvasive arterial blood oxygenation is easily estimated using peripheral pulse oximeters, noninvasive venous blood oxygenation monitoring is still a critical unmet need. Critical conditions that lead to inefficient extraction of oxygen from the blood, such as sepsis or shock, can only be detected by analyzing the oxygen content of the venous blood. In this work, we introduce a soft wearable e-tattoo sensor that simultaneously measures the arterial and venous pulses from the wrist. First, we prove that the origin of the signal is venous pulsatility. We hypothesize that a significant obstacle for simultaneous SaO2 and SvO2 extraction is the close proximity of the artery and vein, thus leading to crosstalk. We characterize this crosstalk with simulation, in vitro, and in vivo experiments. Finally, we offer a potential solution for minimizing the crosstalk through spatial filtering.Clinical Relevance- This lays foundational work for a novel method of noninvasively and simultaneously measuring arterial and venous blood oxygenation to improve clinical diagnoses of sepsis, shock, and metabolic abnormalities.

Conformability of flexible sheets on spherical surfaces.

Three-dimensional surface-conformable electronics is a burgeoning technology with potential applications in curved displays, bioelectronics, and biomimetics. Flexible electronics are notoriously difficult to fully conform to nondevelopable surfaces such as spheres. Although stretchable electronics can well conform to nondevelopable surfaces, they need to sacrifice pixel density for stretchability. Various empirical designs have been explored to improve the conformability of flexible electronics on spherical surfaces. However, no rational design guidelines exist. This study uses a combination of experimental, analytical, and numerical approaches to systematically investigate the conformability of both intact and partially cut circular sheets on spherical surfaces. Through the analysis of thin film buckling on curved surfaces, we identify a scaling law that predicts the conformability of flexible sheets on spherical surfaces. We also quantify the effects of radial slits on enhancing conformability and provide a practical guideline for using these slits to improve conformability from 40% to more than 90%.

Graphene e-tattoos for unobstructive ambulatory electrodermal activity sensing on the palm enabled by heterogeneous serpentine ribbons.

Electrodermal activity (EDA) is a popular index of mental stress. State-of-the-art EDA sensors suffer from obstructiveness on the palm or low signal fidelity off the palm. Our previous invention of sub-micron-thin imperceptible graphene e-tattoos (GET) is ideal for unobstructive EDA sensing on the palm. However, robust electrical connection between ultrathin devices and rigid circuit boards is a long missing component for ambulatory use. To minimize the well-known strain concentration at their interfaces, we propose heterogeneous serpentine ribbons (HSPR), which refer to a GET serpentine partially overlapping with a gold serpentine without added adhesive. A fifty-fold strain reduction in HSPR vs. heterogeneous straight ribbons (HSTR) has been discovered and understood. The combination of HSPR and a soft interlayer between the GET and an EDA wristband enabled ambulatory EDA monitoring on the palm in free-living conditions. A newly developed EDA event selection policy leveraging unbiased selection of phasic events validated our GET EDA sensor against gold standards.

Effects of AC frequency on the capacitance measurement of hybrid response pressure sensors.

E-skins consisting of soft pressure sensors are enabling technology for soft robots, bio-integrated devices, and deformable touch panels. A well-known bottleneck of capacitive pressure sensors (CPS) is the drastic decay in sensitivity with increasing pressure. To overcome this challenge, we have invented a hybrid-response pressure sensor (HRPS) that exhibits both the piezoresistive and piezocapacitive effects intrinsic to a highly porous nanocomposite (PNC) with carbon nanotube (CNT) dopants. The HRPS is constructed with two conductive electrodes sandwiching a laminated PNC and a stiff dielectric layer. We have simplified the hybrid response into a parallel resistor-capacitor circuit, whose output depends on the AC (alternating current) frequency used for the capacitance measurement. Herein, through theoretical analysis, we discover a dimensionless parameter that governs the frequency responses of the HRPS. The master curve is validated through experiments on the HRPS with various doping ratios, subject to different compressive strains, under diverse AC frequencies. In addition, the relative contribution of piezoresistive and piezocapacitive mechanisms are also found to vary with the three parameters. Based on this experimentally validated theory, we establish a very practical guideline for selecting the optimal AC frequency for the capacitance measurement of HRPSs.

Seeing inside a body in motion.

Adhesive ultrasound patches can provide medical imaging for patients on the go.

Soft Capacitive Pressure Sensors: Trends, Challenges, and Perspectives.

Soft pressure sensors are critical components of e-skins, which are playing an increasingly significant role in two burgeoning fields: soft robotics and bioelectronics. Capacitive pressure sensors (CPS) are popular given their mechanical flexibility, high sensitivity, and signal stability. After two decades of rapid development, e-skins based on soft CPS are able to achieve human-skin-like softness and sensitivity. However, there remain two major roadblocks in the way for practical application of soft CPS: the decay of sensitivity with increased pressure and the coupled response between in-plane stretch and out-of-plane pressure. In addition to existing strategies of building porous and/or high dielectric constant soft dielectrics, are there any other promising methods to overcome those bottlenecks? Are there any further considerations for the widespread deployment of e-skins? This perspective aims to shed some light on those topics.

Highly Sensitive Capacitive Pressure Sensors over a Wide Pressure Range Enabled by the Hybrid Responses of a Highly Porous Nanocomposite.

Past research aimed at increasing the sensitivity of capacitive pressure sensors has mostly focused on developing dielectric layers with surface/porous structures or higher dielectric constants. However, such strategies have only been effective in improving sensitivities at low pressure ranges (e.g., up to 3 kPa). To overcome this well-known obstacle, herein, a flexible hybrid-response pressure sensor (HRPS) composed of an electrically conductive porous nanocomposite (PNC) laminated with an ultrathin dielectric layer is devised. Using a nickel foam template, the PNC is fabricated with carbon nanotubes (CNTs)-doped Ecoflex to be 86% porous and electrically conductive. The PNC exhibits hybrid piezoresistive and piezocapacitive responses, resulting in significantly enhanced sensitivities (i.e., more than 400%) over wide pressure ranges, from 3.13 kPa-1 within 0-1 kPa to 0.43 kPa-1 within 30-50 kPa. The effect of the hybrid responses is differentiated from the effect of porosity or high dielectric constants by comparing the HRPS with its purely piezocapacitive counterparts. Fundamental understanding of the HRPS and the prediction of optimal CNT doping are achieved through simplified analytical models. The HRPS is able to measure pressures from as subtle as the temporal arterial pulse to as large as footsteps.

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.

Fabrication, characterization and applications of graphene electronic tattoos.

Numerous fields of science and technology, including healthcare, robotics and bioelectronics, have begun to switch their research direction from developing 'high-end, high-cost' tools towards 'high-end, low-cost' solutions. Graphene electronic tattoos (GETs), whose fabrication protocol is discussed in this work, are ideal building blocks of future wearable technology due to their outstanding electromechanical properties. The GETs are composed of high-quality, large-scale graphene that is transferred onto tattoo paper, resulting in an electronic device that is applied onto skin like a temporary tattoo. Here, we provide a comprehensive GET fabrication protocol, starting from graphene growth and ending with integration onto human skin. The methodology presented is unique since it utilizes high-quality electronic-grade graphene, while the processing is done by using low-cost and off-the-shelf methods, such as a mechanical cutter plotter. The GETs can be either used in combination with advanced scientific equipment to perform precision experiments, or with low-cost electrophysiology boards, to conduct similar operations from home. In this protocol, we showcase how GETs can be applied onto the human body and how they can be used to obtain a variety of biopotentials, including electroencephalogram (brain waves), electrocardiogram (heart activity), electromyogram (muscle activity), as well as monitoring of body temperature and hydration. With graphene available from commercial sources, the whole protocol consumes ~3 h of labor and does not require highly trained personnel. The protocol described in this work can be readily replicated in simple laboratories, including high school facilities.

Soft implantable drug delivery device integrated wirelessly with wearable devices to treat fatal seizures.

Personalized biomedical devices have enormous potential to solve clinical challenges in urgent medical situations. Despite this potential, a device for in situ treatment of fatal seizures using pharmaceutical methods has not been developed yet. Here, we present a novel treatment system for neurological medical emergencies, such as status epilepticus, a fatal epileptic condition that requires immediate treatment, using a soft implantable drug delivery device (SID). The SID is integrated wirelessly with wearable devices for monitoring electroencephalography signals and triggering subcutaneous drug release through wireless voltage induction. Because of the wireless integration, bulky rigid components such as sensors, batteries, and electronic circuits can be moved from the SID to wearables, and thus, the mechanical softness and miniaturization of the SID are achieved. The efficacy of the prompt treatment could be demonstrated with animal experiments in vivo, in which brain damages were reduced and survival rates were increased.

A Wrist-worn Respiration Monitoring Device using Bio-Impedance.

In the US alone, 22 million individuals suffer from obstructive sleep apnea (OSA), with 80% of the cases symptoms undiagnosed. Hence, there is an unmet need to continuously and unobtrusively monitor respiration and detect possible occurrences of apnea. Recent advancements in wearable biomedical technology can enable the capture of the periodicity of the heart pressure pulse from a wrist-worn device. In this paper, we propose a bio-impedance (Bio-Z)-based respiration monitoring system. We establish close contact with the skin using gold e-tattoos with a 35 mm by 5 mm active sensing area. We extracted the respiration from the wrist Bio-Z signal leveraging three different techniques and showed that we can detect the start of each respiration beat with an average root mean square error (RMSE) less than 13% and mean error of 0.3% over five subjects.

Electrically compensated, tattoo-like electrodes for epidermal electrophysiology at scale.

Epidermal electrophysiology is widely carried out for disease diagnosis, performance monitoring, human-machine interaction, etc. Compared with thick, stiff, and irritating gel electrodes, emerging tattoo-like epidermal electrodes offer much better wearability and versatility. However, state-of-the-art tattoo-like electrodes are limited in size (e.g., centimeters) to perform electrophysiology at scale due to challenges including large-area fabrication, skin lamination, and electrical interference from long interconnects. Therefore, we report large-area, soft, breathable, substrate- and encapsulation-free electrodes designed into transformable filamentary serpentines that can be rapidly fabricated by cut-and-paste method. We propose a Cartan curve-inspired transfer process to minimize strain in the electrodes when laminated on nondevelopable skin surfaces. Unwanted signals picked up by the unencapsulated interconnects can be eliminated through a previously unexplored electrical compensation strategy. These tattoo-like electrodes can comfortably cover the whole chest, forearm, or neck for applications such as multichannel electrocardiography, sign language recognition, prosthetic control or mapping of neck activities.