A wireless and battery-less implant for multimodal closed-loop neuromodulation in small animals.

Fully implantable wireless systems for the recording and modulation of neural circuits that do not require physical tethers or batteries allow for studies that demand the use of unconstrained and freely behaving animals in isolation or in social groups. Moreover, feedback-control algorithms that can be executed within such devices without the need for remote computing eliminate virtual tethers and any associated latencies. Here we report a wireless and battery-less technology of this type, implanted subdermally along the back of freely moving small animals, for the autonomous recording of electroencephalograms, electromyograms and body temperature, and for closed-loop neuromodulation via optogenetics and pharmacology. The device incorporates a system-on-a-chip with Bluetooth Low Energy for data transmission and a compressed deep-learning module for autonomous operation, that offers neurorecording capabilities matching those of gold-standard wired systems. We also show the use of the implant in studies of sleep-wake regulation and for the programmable closed-loop pharmacological suppression of epileptic seizures via feedback from electroencephalography. The technology can support a broader range of applications in neuroscience and in biomedical research with small animals.

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.

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.

Skin-interfaced soft microfluidic systems with modular and reusable electronics for in situ capacitive sensing of sweat loss, rate and conductivity.

Important insights into human health can be obtained through the non-invasive collection and detailed analysis of sweat, a biofluid that contains a wide range of essential biomarkers. Skin-interfaced microfluidic platforms, characterized by soft materials and thin geometries, offer a collection of capabilities for in situ capture, storage, and analysis of sweat and its constituents. In ambulatory uses cases, the ability to provide real-time feedback on sweat loss, rate and content, without visual inspection of the device, can be important. This paper introduces a low-profile skin-interfaced system that couples disposable microfluidic sampling devices with reusable 'stick-on' electrodes and wireless readout electronics that remain isolated from the sweat. An ultra-thin capping layer on the microfluidic platform permits high-sensitivity, contactless capacitive measurements of both sweat loss and sweat conductivity. This architecture avoids the potential for corrosion of the sensing components and eliminates the need for cleaning/sterilizing the electronics, thereby resulting in a cost-effective platform that is simple to use. Optimized electrode designs follow from a combination of extensive benchtop testing, analytical calculations and FEA simulations for two sensing configurations: (1) sweat rate and loss, and (2) sweat conductivity, which contains information about electrolyte content. Both configurations couple to a flexible, wireless electronics platform that digitizes and transmits information to Bluetooth-enabled devices. On-body field testing during physical exercise validates the performance of the system in scenarios of practical relevance to human health and performance.

Successful venoplasty of superior vena cava stenosis in a patient with a total artificial heart after orthotopic heart transplantation due to primary graft failure.

BACKGROUND: With the limited number of available suitable donor hearts resulting in plateaued numbers of heart transplantations, short- and long-term mechanical circulatory support devices, including the implantation of total artificial hearts (TAHs) are modalities that are increasingly being used as treatment options for patients with end-stage heart failure. The superior vena cava syndrome has been described in this context in various disease processes. We report successful venoplasty for superior vena cava syndrome in a patient with a TAH. CASE PRESENTATION: A 65-year-old man with a history of nonischemic cardiomyopathy had received a left ventricular assist device, and then 2 years later, underwent orthotopic heart transplantation using the bicaval anastomosis technique. The postprocedural course was complicated by primary graft failure, resulting in the need for implantation of a TAH. About 5 months after TAH implantation, he started to develop complications such as volume retention, swelling of the upper extremities, and was diagnosed to have a superior vena cava syndrome. The patient underwent a successful venoplasty of his superior vena cava by interventional radiology with resolution of upper body edema, normalization of renal, and liver function. CONCLUSION: Potential fatal complications caused by catheter or wire entrapment in the right-sided mechanical valve of a TAH have been reported. We describe a safe method for the treatment of superior vena cava syndrome in patients with TAH.

Soft, skin-interfaced microfluidic systems with integrated enzymatic assays for measuring the concentration of ammonia and ethanol in sweat.

Eccrine sweat is a rich and largely unexplored biofluid that contains a range of important biomarkers, from electrolytes, metabolites, micronutrients and hormones to exogenous agents, each of which can change in concentration with diet, stress level, hydration status and physiologic or metabolic state. Traditionally, clinicians and researchers have used absorbent pads and benchtop analyzers to collect and analyze the biochemical constituents of sweat in controlled, laboratory settings. Recently reported wearable microfluidic and electrochemical sensing devices represent significant advances in this context, with capabilities for rapid, in situ evaluations, in many cases with improved repeatability and accuracy. A limitation is that assays performed in these platforms offer limited control of reaction kinetics and mixing of different reagents and samples. Here, we present a multi-layered microfluidic device platform with designs that eliminate these constraints, to enable integrated enzymatic assays with demonstrations of in situ analysis of the concentrations of ammonia and ethanol in microliter volumes of sweat. Careful characterization of the reaction kinetics and their optimization using statistical techniques yield robust analysis protocols. Human subject studies with sweat initiated by warm-water bathing highlight the operational features of these systems.

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.

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.

Highly flexible, wearable, and disposable cardiac biosensors for remote and ambulatory monitoring.

Contemporary cardiac and heart rate monitoring devices capture physiological signals using optical and electrode-based sensors. However, these devices generally lack the form factor and mechanical flexibility necessary for use in ambulatory and home environments. Here, we report an ultrathin (~1 mm average thickness) and highly flexible wearable cardiac sensor (WiSP) designed to be minimal in cost (disposable), light weight (1.2 g), water resistant, and capable of wireless energy harvesting. Theoretical analyses of system-level bending mechanics show the advantages of WiSP's flexible electronics, soft encapsulation layers and bioadhesives, enabling intimate skin coupling. A clinical feasibility study conducted in atrial fibrillation patients demonstrates that the WiSP device effectively measures cardiac signals matching the Holter monitor, and is more comfortable. WiSP's physical attributes and performance results demonstrate its utility for monitoring cardiac signals during daily activity, exertion and sleep, with implications for home-based care.

Electronic sensor and actuator webs for large-area complex geometry cardiac mapping and therapy.

Curved surfaces, complex geometries, and time-dynamic deformations of the heart create challenges in establishing intimate, nonconstraining interfaces between cardiac structures and medical devices or surgical tools, particularly over large areas. We constructed large area designs for diagnostic and therapeutic stretchable sensor and actuator webs that conformally wrap the epicardium, establishing robust contact without sutures, mechanical fixtures, tapes, or surgical adhesives. These multifunctional web devices exploit open, mesh layouts and mount on thin, bio-resorbable sheets of silk to facilitate handling in a way that yields, after dissolution, exceptionally low mechanical moduli and thicknesses. In vivo studies in rabbit and pig animal models demonstrate the effectiveness of these device webs for measuring and spatially mapping temperature, electrophysiological signals, strain, and physical contact in sheet and balloon-based systems that also have the potential to deliver energy to perform localized tissue ablation.

Materials for multifunctional balloon catheters with capabilities in cardiac electrophysiological mapping and ablation therapy.

Developing advanced surgical tools for minimally invasive procedures represents an activity of central importance to improving human health. A key challenge is in establishing biocompatible interfaces between the classes of semiconductor device and sensor technologies that might be most useful in this context and the soft, curvilinear surfaces of the body. This paper describes a solution based on materials that integrate directly with the thin elastic membranes of otherwise conventional balloon catheters, to provide diverse, multimodal functionality suitable for clinical use. As examples, we present sensors for measuring temperature, flow, tactile, optical and electrophysiological data, together with radiofrequency electrodes for controlled, local ablation of tissue. Use of such 'instrumented' balloon catheters in live animal models illustrates their operation, as well as their specific utility in cardiac ablation therapy. The same concepts can be applied to other substrates of interest, such as surgical gloves.

Isolation of high-quality RNA from white spruce tissue using a three-stage purification method and subsequent cloning of a transcript from the PR-10 gene family.

Isolation of PinmIII cDNA homologues from white spruce tissues required a rigorous RNA extraction protocol developed following assessment of three previously reported conifer RNA extraction protocols. Total RNA was extracted via several purification steps designed to minimize binding of phenolics to nucleic acids and was then subjected to caesium chloride ultra-centrifugation. This procedure produced consistently high-quality, intact RNA from both needles and roots with spectrophotometric ratios of approximately 2.0 for both 260/280 nm and 260/230 nm. Total RNA was obtained from the roots of cold-hardened white spruce seedlings for cDNA library construction. More than 2 million recombinant phage particles were generated from 5 microg of a poly(A)+RNA fraction, and ca. 1.3 million cDNA particles were amplified for storage. Approximately 500,000 primary recombinant clones were screened with an heterologous PinmIII cDNA sequence yielding a unique clone, picgl, that was very similar to members of the PR10 gene family.