Soft, bioresorbable coolers for reversible conduction block of peripheral nerves.

Implantable devices capable of targeted and reversible blocking of peripheral nerve activity may provide alternatives to opioids for treating pain. Local cooling represents an attractive means for on-demand elimination of pain signals, but traditional technologies are limited by rigid, bulky form factors; imprecise cooling; and requirements for extraction surgeries. Here, we introduce soft, bioresorbable, microfluidic devices that enable delivery of focused, minimally invasive cooling power at arbitrary depths in living tissues with real-time temperature feedback control. Construction with water-soluble, biocompatible materials leads to dissolution and bioresorption as a mechanism to eliminate unnecessary device load and risk to the patient without additional surgeries. Multiweek in vivo trials demonstrate the ability to rapidly and precisely cool peripheral nerves to provide local, on-demand analgesia in rat models for neuropathic pain.

Soft, skin-interfaced sweat stickers for cystic fibrosis diagnosis and management.

The concentration of chloride in sweat remains the most robust biomarker for confirmatory diagnosis of cystic fibrosis (CF), a common life-shortening genetic disorder. Early diagnosis via quantitative assessment of sweat chloride allows prompt initiation of care and is critically important to extend life expectancy and improve quality of life. The collection and analysis of sweat using conventional wrist-strapped devices and iontophoresis can be cumbersome, particularly for infants with fragile skin, who often have insufficient sweat production. Here, we introduce a soft, epidermal microfluidic device ("sweat sticker") designed for the simple and rapid collection and analysis of sweat. Intimate, conformal coupling with the skin supports nearly perfect efficiency in sweat collection without leakage. Real-time image analysis of chloride reagents allows for quantitative assessment of chloride concentrations using a smartphone camera, without requiring extraction of sweat or external analysis. Clinical validation studies involving patients with CF and healthy subjects, across a spectrum of age groups, support clinical equivalence compared to existing device platforms in terms of accuracy and demonstrate meaningful reductions in rates of leakage. The wearable microfluidic technologies and smartphone-based analytics reported here establish the foundation for diagnosis of CF outside of clinical settings.

Bioresorbable Microdroplet Lasers as Injectable Systems for Transient Thermal Sensing and Modulation.

Minimally invasive methods for temperature sensing and thermal modulation in living tissues have extensive applications in biological research and clinical care. As alternatives to bioelectronic devices for this purpose, functional nanomaterials that self-assemble into optically active microstructures offer important features in remote sensing, injectability, and compact size. This paper introduces a transient, or bioresorbable, system based on injectable slurries of well-defined microparticles that serve as photopumped lasers with temperature-sensitive emission wavelengths (>4-300 nm °C-1). The resulting platforms can act as tissue-embedded thermal sensors and, simultaneously, as distributed vehicles for thermal modulation. Each particle consists of a spherical resonator formed by self-organized cholesteric liquid crystal molecules doped with fluorophores as gain media, encapsulated in thin shells of soft hydrogels that offer adjustable rates of bioresorption through chemical modification. Detailed studies highlight fundamental aspects of these systems including particle sensitivity, lasing threshold, and size. Additional experiments explore functionality as photothermal agents with active temperature feedback (ΔT = 1 °C) and potential routes in remote evaluation of thermal transport properties. Cytotoxicity evaluations support their biocompatibility, and ex vivo demonstrations in Casper fish illustrate their ability to measure temperature within biological tissues with resolution of 0.01 °C. This collective set of results demonstrates a range of multifunctional capabilities in thermal sensing and modulation.

Skin-Interfaced Microfluidic Systems that Combine Hard and Soft Materials for Demanding Applications in Sweat Capture and Analysis.

Eccrine sweat contains a rich blend of electrolytes, metabolites, proteins, metal ions, and other biomarkers. Changes in the concentrations of these chemical species can indicate alterations in hydration status and they can also reflect health conditions such as cystic fibrosis, schizophrenia, and depression. Recent advances in soft, skin-interfaced microfluidic systems enable real-time measurement of local sweat loss and sweat biomarker concentrations, with a wide range of applications in healthcare. Uses in certain contexts involve, however, physical impacts on the body that can dynamically deform these platforms, with adverse effects on measurement reliability. The work presented here overcomes this limitation through the use of microfluidic structures constructed in relatively high modulus polymers, and designed in geometries that offer soft, system level mechanics when embedded low modulus elastomers. Analytical models and finite element analysis quantitatively define the relevant mechanics of these systems, and serve as the basis for layouts optimized to allow robust operation in demanding, rugged scenarios such as those encountered in football, while preserving mechanical stretchability for comfortable, water-tight bonding to the skin. Benchtop testing and on-body field studies of measurements of sweat loss and chloride concentration under imposed mechanical stresses and impacts demonstrate the key features of these platforms.

Skin-interfaced microfluidic system with personalized sweating rate and sweat chloride analytics for sports science applications.

Advanced capabilities in noninvasive, in situ monitoring of sweating rate and sweat electrolyte losses could enable real-time personalized fluid-electrolyte intake recommendations. Established sweat analysis techniques using absorbent patches require post-collection harvesting and benchtop analysis of sweat and are thus impractical for ambulatory use. Here, we introduce a skin-interfaced wearable microfluidic device and smartphone image processing platform that enable analysis of regional sweating rate and sweat chloride concentration ([Cl-]). Systematic studies (n = 312 athletes) establish significant correlations for regional sweating rate and sweat [Cl-] in a controlled environment and during competitive sports under varying environmental conditions. The regional sweating rate and sweat [Cl-] results serve as inputs to algorithms implemented on a smartphone software application that predicts whole-body sweating rate and sweat [Cl-]. This low-cost wearable sensing approach could improve the accessibility of physiological insights available to sports scientists, practitioners, and athletes to inform hydration strategies in real-world ambulatory settings.

Soft, skin-interfaced microfluidic systems with integrated immunoassays, fluorometric sensors, and impedance measurement capabilities.

Soft microfluidic systems that capture, store, and perform biomarker analysis of microliter volumes of sweat, in situ, as it emerges from the surface of the skin, represent an emerging class of wearable technology with powerful capabilities that complement those of traditional biophysical sensing devices. Recent work establishes applications in the real-time characterization of sweat dynamics and sweat chemistry in the context of sports performance and healthcare diagnostics. This paper presents a collection of advances in biochemical sensors and microfluidic designs that support multimodal operation in the monitoring of physiological signatures directly correlated to physical and mental stresses. These wireless, battery-free, skin-interfaced devices combine lateral flow immunoassays for cortisol, fluorometric assays for glucose and ascorbic acid (vitamin C), and digital tracking of skin galvanic responses. Systematic benchtop evaluations and field studies on human subjects highlight the key features of this platform for the continuous, noninvasive monitoring of biochemical and biophysical correlates of the stress state.

Continuous, noninvasive wireless monitoring of flow of cerebrospinal fluid through shunts in patients with hydrocephalus.

Hydrocephalus is a common disorder caused by the buildup of cerebrospinal fluid (CSF) in the brain. Treatment typically involves the surgical implantation of a pressure-regulated silicone tube assembly, known as a shunt. Unfortunately, shunts have extremely high failure rates and diagnosing shunt malfunction is challenging due to a combination of vague symptoms and a lack of a convenient means to monitor flow. Here, we introduce a wireless, wearable device that enables precise measurements of CSF flow, continuously or intermittently, in hospitals, laboratories or even in home settings. The technology exploits measurements of thermal transport through near-surface layers of skin to assess flow, with a soft, flexible, and skin-conformal device that can be constructed using commercially available components. Systematic benchtop studies and numerical simulations highlight all of the key considerations. Measurements on 7 patients establish high levels of functionality, with data that reveal time dependent changes in flow associated with positional and inertial effects on the body. Taken together, the results suggest a significant advance in monitoring capabilities for patients with shunted hydrocephalus, with potential for practical use across a range of settings and circumstances, and additional utility for research purposes in studies of CSF hydrodynamics.

Emerging Modalities and Implantable Technologies for Neuromodulation.

Techniques for neuromodulation serve as effective routes to care of patients with many types of challenging conditions. Continued progress in this field of medicine will require (1) improvements in our understanding of the mechanisms of neural control over organ function and (2) advances in technologies for precisely modulating these functions in a programmable manner. This review presents recent research on devices that are relevant to both of these goals, with an emphasis on multimodal operation, miniaturized dimensions, biocompatible designs, advanced neural interface schemes, and battery-free, wireless capabilities. A future that involves recording and modulating neural activity with such systems, including those that exploit closed-loop strategies and/or bioresorbable designs, seems increasingly within reach.

Mechano-acoustic sensing of physiological processes and body motions via a soft wireless device placed at the suprasternal notch.

Skin-mounted soft electronics that incorporate high-bandwidth triaxial accelerometers can capture broad classes of physiologically relevant information, including mechano-acoustic signatures of underlying body processes (such as those measured by a stethoscope) and precision kinematics of core-body motions. Here, we describe a wireless device designed to be conformally placed on the suprasternal notch for the continuous measurement of mechano-acoustic signals, from subtle vibrations of the skin at accelerations of around 10-3 m s-2 to large motions of the entire body at about 10 m s-2, and at frequencies up to around 800 Hz. Because the measurements are a complex superposition of signals that arise from locomotion, body orientation, swallowing, respiration, cardiac activity, vocal-fold vibrations and other sources, we exploited frequency-domain analysis and machine learning to obtain-from human subjects during natural daily activities and exercise-real-time recordings of heart rate, respiration rate, energy intensity and other essential vital signs, as well as talking time and cadence, swallow counts and patterns, and other unconventional biomarkers. We also used the device in sleep laboratories and validated the measurements using polysomnography.

Resettable skin interfaced microfluidic sweat collection devices with chemesthetic hydration feedback.

Recently introduced classes of thin, soft, skin-mounted microfluidic systems offer powerful capabilities for continuous, real-time monitoring of total sweat loss, sweat rate and sweat biomarkers. Although these technologies operate without the cost, complexity, size, and weight associated with active components or power sources, rehydration events can render previous measurements irrelevant and detection of anomalous physiological events, such as high sweat loss, requires user engagement to observe colorimetric responses. Here we address these limitations through monolithic systems of pinch valves and suction pumps for purging of sweat as a reset mechanism to coincide with hydration events, microstructural optics for reversible readout of sweat loss, and effervescent pumps and chemesthetic agents for automated delivery of sensory warnings of excessive sweat loss. Human subject trials demonstrate the ability of these systems to alert users to the potential for dehydration via skin sensations initiated by sweat-triggered ejection of menthol and capsaicin.

Battery-free, fully implantable optofluidic cuff system for wireless optogenetic and pharmacological neuromodulation of peripheral nerves.

Studies of the peripheral nervous system rely on controlled manipulation of neuronal function with pharmacologic and/or optogenetic techniques. Traditional hardware for these purposes can cause notable damage to fragile nerve tissues, create irritation at the biotic/abiotic interface, and alter the natural behaviors of animals. Here, we present a wireless, battery-free device that integrates a microscale inorganic light-emitting diode and an ultralow-power microfluidic system with an electrochemical pumping mechanism in a soft platform that can be mounted onto target peripheral nerves for programmed delivery of light and/or pharmacological agents in freely moving animals. Biocompliant designs lead to minimal effects on overall nerve health and function, even with chronic use in vivo. The small size and light weight construction allow for deployment as fully implantable devices in mice. These features create opportunities for studies of the peripheral nervous system outside of the scope of those possible with existing technologies.

Soft, Skin-Interfaced Microfluidic Systems with Passive Galvanic Stopwatches for Precise Chronometric Sampling of Sweat.

Comprehensive analysis of sweat chemistry provides noninvasive health monitoring capabilities that complement established biophysical measurements such as heart rate, blood oxygenation, and body temperature. Recent developments in skin-integrated soft microfluidic systems address many challenges associated with standard technologies in sweat collection and analysis. However, recording of time-dependent variations in sweat composition requires bulky electronic systems and power sources, thereby constraining form factor, cost, and modes of use. Here, presented are unconventional design concepts, materials, and device operation principles that address this challenge. Flexible galvanic cells embedded within skin-interfaced microfluidics with passive valves serve as sweat-activated "stopwatches" that record temporal information associated with collection of discrete microliter volumes of sweat. The result allows for precise measurements of dynamic sweat composition fluctuations using in situ or ex situ analytical techniques. Integrated electronics based on near-field communication (NFC) protocols or docking stations equipped with standard electronic measurement tools provide means for extracting digital timing results from the stopwatches. Human subject studies of time-stamped sweat samples by in situ colorimetric methods and ex situ techniques based on inductively coupled plasma mass spectroscopy (ICP-MS) and chlorodimetry illustrate the ability to quantitatively capture time-dynamic sweat chemistry in scenarios compatible with field use.

Soft, Skin-Integrated Multifunctional Microfluidic Systems for Accurate Colorimetric Analysis of Sweat Biomarkers and Temperature.

Real-time measurements of the total loss of sweat, the rate of sweating, the temperature of sweat, and the concentrations of electrolytes and metabolites in sweat can provide important insights into human physiology. Conventional methods use manual collection processes (e.g., absorbent pads) to determine sweat loss and lab-based instrumentation to analyze its chemical composition. Although such schemes can yield accurate data, they cannot be used outside of laboratories or clinics. Recently reported wearable electrochemical devices for sweat sensing bypass these limitations, but they typically involve on-board electronics, electrodes, and/or batteries for measurement, signal processing, and wireless transmission, without direct means for measuring sweat loss or capturing and storing small volumes of sweat. Alternative approaches exploit soft, skin-integrated microfluidic systems for collection and colorimetric chemical techniques for analysis. Here, we present the most advanced platforms of this type, in which optimized chemistries, microfluidic designs, and device layouts enable accurate assessments not only of total loss of sweat and sweat rate but also of quantitatively accurate values of the pH and temperature of sweat, and of the concentrations of chloride, glucose, and lactate across physiologically relevant ranges. Color calibration markings integrated into a graphics overlayer allow precise readout by digital image analysis, applicable in various lighting conditions. Field studies conducted on healthy volunteers demonstrate the full capabilities in measuring sweat loss/rate and analyzing multiple sweat biomarkers and temperature, with performance that quantitatively matches that of conventional lab-based measurement systems.

Waterproof, electronics-enabled, epidermal microfluidic devices for sweat collection, biomarker analysis, and thermography in aquatic settings.

Noninvasive, in situ biochemical monitoring of physiological status, via the use of sweat, could enable new forms of health care diagnostics and personalized hydration strategies. Recent advances in sweat collection and sensing technologies offer powerful capabilities, but they are not effective for use in extreme situations such as aquatic or arid environments, because of unique challenges in eliminating interference/contamination from surrounding water, maintaining robust adhesion in the presence of viscous drag forces and/or vigorous motion, and preventing evaporation of collected sweat. This paper introduces materials and designs for waterproof, epidermal, microfluidic and electronic systems that adhere to the skin to enable capture, storage, and analysis of sweat, even while fully underwater. Field trials demonstrate the ability of these devices to collect quantitative in situ measurements of local sweat chloride concentration, local sweat loss (and sweat rate), and skin temperature during vigorous physical activity in controlled, indoor conditions and in open-ocean swimming.

Battery-free, skin-interfaced microfluidic/electronic systems for simultaneous electrochemical, colorimetric, and volumetric analysis of sweat.

Wearable sweat sensors rely either on electronics for electrochemical detection or on colorimetry for visual readout. Non-ideal form factors represent disadvantages of the former, while semiquantitative operation and narrow scope of measurable biomarkers characterize the latter. Here, we introduce a battery-free, wireless electronic sensing platform inspired by biofuel cells that integrates chronometric microfluidic platforms with embedded colorimetric assays. The resulting sensors combine advantages of electronic and microfluidic functionality in a platform that is significantly lighter, cheaper, and smaller than alternatives. A demonstration device simultaneously monitors sweat rate/loss, pH, lactate, glucose, and chloride. Systematic studies of the electronics, microfluidics, and integration schemes establish the key design considerations and performance attributes. Two-day human trials that compare concentrations of glucose and lactate in sweat and blood suggest a potential basis for noninvasive, semi-quantitative tracking of physiological status.

Soft, Skin-Interfaced Microfluidic Systems with Wireless, Battery-Free Electronics for Digital, Real-Time Tracking of Sweat Loss and Electrolyte Composition.

Sweat excretion is a dynamic physiological process that varies with body position, activity level, environmental factors, and health status. Conventional means for measuring the properties of sweat yield accurate results but their requirements for sampling and analytics do not allow for use in the field. Emerging wearable devices offer significant advantages over existing approaches, but each has significant drawbacks associated with bulk and weight, inability to quantify volumetric sweat rate and loss, robustness, and/or inadequate accuracy in biochemical analysis. This paper presents a thin, miniaturized, skin-interfaced microfluidic technology that includes a reusable, battery-free electronics module for measuring sweat conductivity and rate in real-time using wireless power from and data communication to electronic devices with capabilities in near field communications (NFC), including most smartphones. The platform exploits ultrathin electrodes integrated within a collection of microchannels as interfaces to circuits that leverage NFC protocols. The resulting capabilities are complementary to those of previously reported colorimetric strategies. Systematic studies of these combined microfluidic/electronic systems, accurate correlations of measurements performed with them to those of laboratory standard instrumentation, and field tests on human subjects exercising and at rest establish the key operational features and their utility in sweat analytics.

3D, Reconfigurable, Multimodal Electronic Whiskers via Directed Air Assembly.

A batch-assembly technique for forming 3D electronics on shape memory polymer substrates is demonstrated and is used to create dense, highly sensitive, multimodal arrays of electronic whiskers. Directed air flow at temperatures above the substrate's glass transition temperature transforms planar photolithographically defined resistive sensors from 2D precursors into shape-tunable, deterministic 3D assemblies. Reversible 3D assembly and flattening is achieved by exploiting the shape memory properties of the substrate, enabling context-driven shape reconfiguration to isolate/enhance specific sensing modes. In particular, measurement schemes and device configurations are introduced that allow for the sensing of temperature, stiffness, contact force, proximity, and surface texture and roughness. The assemblies offer highly spatiotemporally resolved, wide-range measurements of surface topology (50 nm to 500 µm), material stiffness (200 kPa to 7.5 GPa), and temperature (0-100 °C), with response times of <250 µs. The development of a scalable process for 3D assembly of reconfigurable electronic sensors, as well as the large breadth and sensitivity of complex sensing modes demonstrated, has applications in the growing fields of 3D assembly, electronic skin, and human-machine interfaces.

Soft, skin-mounted microfluidic systems for measuring secretory fluidic pressures generated at the surface of the skin by eccrine sweat glands.

During periods of activity, sweat glands produce pressures associated with osmotic effects to drive liquid to the surface of the skin. The magnitudes of these pressures may provide insights into physiological health, the intensity of physical exertion, psychological stress factors and/other information of interest, yet they are currently unknown due to absence of means for non-invasive measurement. This paper introduces a thin, soft wearable microfluidic system that mounts onto the surface of the skin to enable precise and routine measurements of secretory fluidic pressures generated at the surface of the skin by eccrine sweat glands (surface SPSG, or s-SPSG) at nearly any location on the body. These platforms incorporate an arrayed collection of unit cells each of which includes an opening to the skin, an inlet through which sweat can flow, a capillary bursting valve (CBV) with a unique bursting pressure (BP), a corresponding microreservoir to receive sweat and an outlet to the surrounding ambient to allow release of backpressure. The BPs systematically span the physiologically relevant range, to enable a measurement precision approximately defined by the ratio of the range to the number of unit cells. Human studies demonstrate measurements of s-SPSG under different conditions, from various regions of the body. Average values in healthy young adults lie between 2.4 and 2.9 kPa. Sweat associated with vigorous exercise have s-SPSGs that are somewhat higher than those associated with sedentary activity. For all conditions, the forearm and lower back tend to yield the highest and lowest s-SPSGs, respectively.

Genome-wide analysis of KAP1, the 7SK snRNP complex, and RNA polymerase II.

The transition of RNA polymerase II (Pol II) from transcription initiation into productive elongation in eukaryotic cells is regulated by the P-TEFb kinase, which phosphorylates the C-terminal domain of paused Pol II at promoter-proximal regions. Our recent study found that P-TEFb (in an inhibited state bound to the 7SK snRNP complex) interacts with the KAP1/TRIM28 transcriptional regulator, and that KAP1 and the 7SK snRNP co-occupy most gene promoters containing paused Pol II. Here we provide a detailed experimental description and analysis of the ChIP-seq datasets that have been deposited into Gene Expression Omnibus (GEO): GS72622, so that independent groups can replicate and expand upon these findings. We propose these datasets would provide valuable information for researchers studying mechanisms of transcriptional regulation including Pol II pausing and pause release.

A transparent bending-insensitive pressure sensor.

Measuring small normal pressures is essential to accurately evaluate external stimuli in curvilinear and dynamic surfaces such as natural tissues. Usually, sensitive and spatially accurate pressure sensors are achieved through conformal contact with the surface; however, this also makes them sensitive to mechanical deformation (bending). Indeed, when a soft object is pressed by another soft object, the normal pressure cannot be measured independently from the mechanical stress. Here, we show a pressure sensor that measures only the normal pressure, even under extreme bending conditions. To reduce the bending sensitivity, we use composite nanofibres of carbon nanotubes and graphene. Our simulations show that these fibres change their relative alignment to accommodate bending deformation, thus reducing the strain in individual fibres. Pressure sensitivity is maintained down to a bending radius of 80 µm. To test the suitability of our sensor for soft robotics and medical applications, we fabricated an integrated sensor matrix that is only 2 µm thick. We show real-time (response time of ∼20 ms), large-area, normal pressure monitoring under different, complex bending conditions.