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Continuous glucose monitoring (CGM) allows patients with diabetes to manage critical disease effectively and autonomously and prevent exacerbation. A painless, wireless, compact, and minimally invasive device that can provide CGM is essential for monitoring the health conditions of freely moving patients with diabetes. Here, we propose a glucose-responsive fluorescence-based highly sensitive biodegradable microneedle CGM system. These ultrathin and ultralight microneedle sensor arrays continuously and precisely monitored glucose concentration in the interstitial fluid with minimally invasive, pain-free, wound-free, and skin inflammation–free outcomes at various locations and thicknesses of the skin. Bioresorbability in the body without a need for device removal after use was a key characteristic of the microneedle glucose sensor. We demonstrated the potential long-term use of the bioresorbable device by applying the tether-free CGM system, thus confirming the successful detection of glucose levels based on changes in fluorescence intensity. In addition, this microneedle glucose sensor with a user-friendly designed home diagnosis system using mobile applications and portable accessories offers an advance in CGM and its applicability to other bioresorbable, wearable, and implantable monitoring device technology.

Large, distributed collections of miniaturized, wireless electronic devices1,2 may form the basis of future systems for environmental monitoring3, population surveillance4, disease management5 and other applications that demand coverage over expansive spatial scales. Aerial schemes to distribute the components for such networks are required, and—inspired by wind-dispersed seeds6—we examined passive structures designed for controlled, unpowered flight across natural environments or city settings. Techniques in mechanically guided assembly of three-dimensional (3D) mesostructures7–9 provide access to miniature, 3D fliers optimized for such purposes, in processes that align with the most sophisticated production techniques for electronic, optoelectronic, microfluidic and microelectromechanical technologies. Here we demonstrate a range of 3D macro-, meso- and microscale fliers produced in this manner, including those that incorporate active electronic and colorimetric payloads. Analytical, computational and experimental studies of the aerodynamics of high-performance structures of this type establish a set of fundamental considerations in bio-inspired design, with a focus on 3D fliers that exhibit controlled rotational kinematics and low terminal velocities. An approach that represents these complex 3D structures as discrete numbers of blades captures the essential physics in simple, analytical scaling forms, validated by computational and experimental results. Battery-free, wireless devices and colorimetric sensors for environmental measurements provide simple examples of a wide spectrum of applications of these unusual concepts. With a design inspired by wind-dispersed seeds, a series of three-dimensional passive fliers at the macro-, meso- and microscale are realized that can bear active electronic payloads.

Abnormal formation of solid thrombus inside a blood vessel can cause thrombotic morbidity and mortality. This necessitates early stage diagnosis, which requires quantitative assessment with a small volume, for effective therapy with low risk to unwanted development of various diseases. We propose a micro-ultrasonic diagnosis using an all-optical ultrasound-based spectral sensing (AOUSS) technique for sensitive and quantitative characterization of early stage and whole blood coagulation. The AOUSS technique detects and analyzes minute viscoelastic variations of blood at a micro-ultrasonic spot (100 μm) defined by laser-generated focused ultrasound (LGFU). This utilizes (1) a uniquely designed optical transducer configuration for frequency-spectral matching and wideband operation (6 dB widths: 7-32 MHz and d.c. ∼ 46 MHz, respectively) and (2) an empirical mode decomposition (EMD)-based signal process particularly adapted to nonstationary LGFU signals backscattered from the spot. An EMD-derived spectral analysis enables one to assess viscoelastic variations during the initiation of fibrin formation, which occurs at a very early stage of blood coagulation (1 min) with high sensitivity (frequency transition per storage modulus increment = 8.81 MHz/MPa). Our results exhibit strong agreement with those obtained by conventional rheometry (Pearson's

Evaluating the biomechanics of soft tissues at depths well below their surface, and at high precision and in real time, would open up diagnostic opportunities. Here, we report the development and application of miniaturized electromagnetic devices, each integrating a vibratory actuator and a soft strain-sensing sheet, for dynamically measuring the Young’s modulus of skin and of other soft tissues at depths of approximately 1–8 mm, depending on the particular design of the sensor. We experimentally and computationally established the operational principles of the devices and evaluated their performance with a range of synthetic and biological materials and with human skin in healthy volunteers. Arrays of devices can be used to spatially map elastic moduli and to profile the modulus depth-wise. As an example of practical medical utility, we show that the devices can be used to accurately locate lesions associated with psoriasis. Compact electronic devices for the rapid and precise mechanical characterization of living tissues could be used to monitor and diagnose a range of health disorders. Electromagnetic devices involving a vibratory actuator and a soft strain-sensing sheet can dynamically measure the Young’s modulus of skin and of other soft biological tissues at depths of millimetres.

The color filter required for manufacturing a CMOS image sensor was redeveloped to optimize its optical uniformity. An in-depth study of the three-dimensional (3D) coating process and how it gives rise to various radial-shaped striation patterns was conducted. These radial-shaped striation patterns were systematically investigated with reference to two types of patterns: the orthogonal type found only at the orthogonal edges of the wafer and the diagonal type found mostly at the corner of each quadrant. The formation of the orthogonal pattern was based on the wide standing wave created by the incident force of the spreading color photoresist (PR) and the reflective force from the bump pads acting as coating barriers. The diagonal pattern was found to be generated by the turbulent wakes created behind the bump pads by the drag force, which interfered with the coating flow. An in-depth study using Ansys CFX software and an in-line inspection tool revealed that lowering the viscosity of the color PR material is a key factor for improving the phenomenon whereby the 3D striation patterns of the orthogonal and diagonal types are formed. Based on this finding, it was possible to drastically reduce the formation of the 3D striation patterns by decreasing the viscosity of the material comprising each color PR. This study provides not only an empirical and theoretical understanding of the 3D color PR coating mechanism, but also guidelines for future color filter processes.

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.

Capabilities for continuous monitoring of pressures and temperatures at critical skin interfaces can help to guide care strategies that minimize the potential for pressure injuries in hospitalized patients or in individuals confined to the bed. This paper introduces a soft, skin-mountable class of sensor system for this purpose. The design includes a pressure-responsive element based on membrane deflection and a battery-free, wireless mode of operation capable of multi-site measurements at strategic locations across the body. Such devices yield continuous, simultaneous readings of pressure and temperature in a sequential readout scheme from a pair of primary antennas mounted under the bedding and connected to a wireless reader and a multiplexer located at the bedside. Experimental evaluation of the sensor and the complete system includes benchtop measurements and numerical simulations of the key features. Clinical trials involving two hemiplegic patients and a tetraplegic patient demonstrate the feasibility, functionality and long-term stability of this technology in operating hospital settings.

Soft grippers that incorporate functional materials are important in the development of mechanically compliant and multifunctional interfaces for both sensing and stimulating soft objects and organisms. In particular, the capability for firm and delicate grasping of soft cells and organs without mechanical damage is essential to identify the condition of and monitor meaningful biosignals from objects. Here, we report a millimeter-scale soft gripper based on a shape memory polymer that enables manipulating a heavy object (payload-to-weight ratio up to 6400) and grasping organisms at the micro/milliscale. The silver nanowires and crack-based strain sensor embedded in this soft gripper enable simultaneous measurement of the temperature and pressure on grasped objects and offer temperature and mechanical stimuli for the grasped object. We validate our miniaturized soft gripper by demonstrating that it can grasp a snail egg while simultaneously applying a moderate temperature stimulation to induce hatching process and monitor the heart rate of a newborn snail. The results present the potential for widespread utility of soft grippers in the area of biomedical engineering, especially in the development of conditional or closed-loop interfacing with microscale biotissues and organisms.

Capabilities for continuous monitoring of pressures and temperatures at critical skin interfaces can help to guide care strategies that minimize the potential for pressure injuries in hospitalized patients or in individuals confined to the bed. This paper introduces a soft, skin-mountable class of sensor system for this purpose. The design includes a pressure-responsive element based on membrane deflection and a battery-free, wireless mode of operation capable of multi-site measurements at strategic locations across the body. Such devices yield continuous, simultaneous readings of pressure and temperature in a sequential readout scheme from a pair of primary antennas mounted under the bedding and connected to a wireless reader and a multiplexer located at the bedside. Experimental evaluation of the sensor and the complete system includes benchtop measurements and numerical simulations of the key features. Clinical trials involving two hemiplegic patients and a tetraplegic patient demonstrate the feasibility, functionality and long-term stability of this technology in operating hospital settings., Uninterrupted monitoring of pressure and temperature at skin interfaces can help to minimize the potential for pressure injuries in hospitalized or bedridden patients. Here, the authors introduce a soft, skin-mountable sensor that can continuously provide readings via antennas mounted under bedding, and demonstrate the functionality and robustness of the devices on patients.

Flexible biocompatible electronic systems that leverage key materials and manufacturing techniques associated with the consumer electronics industry have potential for broad applications in biomedicine and biological research. This study reports scalable approaches to technologies of this type, where thin microscale device components integrate onto flexible polymer substrates in interconnected arrays to provide multimodal, high performance operational capabilities as intimately coupled biointerfaces. Specificially, the material options and engineering schemes summarized here serve as foundations for diverse, heterogeneously integrated systems. Scaled examples incorporate >32,000 silicon microdie and inorganic microscale light-emitting diodes derived from wafer sources distributed at variable pitch spacings and fill factors across large areas on polymer films, at full organ-scale dimensions such as human brain, over ∼150 cm(2). In vitro studies and accelerated testing in simulated biofluids, together with theoretical simulations of underlying processes, yield quantitative insights into the key materials aspects. The results suggest an ability of these systems to operate in a biologically safe, stable fashion with projected lifetimes of several decades without leakage currents or reductions in performance. The versatility of these combined concepts suggests applicability to many classes of biointegrated semiconductor devices.

The fast-growing field of bioelectronic medicine aims to develop engineered systems that can relieve clinical conditions by stimulating the peripheral nervous system1–5. This type of technology relies largely on electrical stimulation to provide neuromodulation of organ function or pain. One example is sacral nerve stimulation to treat overactive bladder, urinary incontinence and interstitial cystitis (also known as bladder pain syndrome)4,6,7. Conventional, continuous stimulation protocols, however, can cause discomfort and pain, particularly when treating symptoms that can be intermittent (for example, sudden urinary urgency)8. Direct physical coupling of electrodes to the nerve can lead to injury and inflammation9–11. Furthermore, typical therapeutic stimulators target large nerve bundles that innervate multiple structures, resulting in a lack of organ specificity. Here we introduce a miniaturized bio-optoelectronic implant that avoids these limitations by using (1) an optical stimulation interface that exploits microscale inorganic light-emitting diodes to activate opsins; (2) a soft, high-precision biophysical sensor system that allows continuous measurements of organ function; and (3) a control module and data analytics approach that enables coordinated, closed-loop operation of the system to eliminate pathological behaviours as they occur in real-time. In the example reported here, a soft strain gauge yields real-time information on bladder function in a rat model. Data algorithms identify pathological behaviour, and automated, closed-loop optogenetic neuromodulation of bladder sensory afferents normalizes bladder function. This all-optical scheme for neuromodulation offers chronic stability and the potential to stimulate specific cell types. A closed-loop implantable bioelectronic device that can modulate peripheral neuronal activity is used to improve bladder function in a rat model of cystitis.

3D multifunctional frameworks, as flexible as a single strand of silk, modulate and measure neural activity of brain spheroids., Three-dimensional (3D), submillimeter-scale constructs of neural cells, known as cortical spheroids, are of rapidly growing importance in biological research because these systems reproduce complex features of the brain in vitro. Despite their great potential for studies of neurodevelopment and neurological disease modeling, 3D living objects cannot be studied easily using conventional approaches to neuromodulation, sensing, and manipulation. Here, we introduce classes of microfabricated 3D frameworks as compliant, multifunctional neural interfaces to spheroids and to assembloids. Electrical, optical, chemical, and thermal interfaces to cortical spheroids demonstrate some of the capabilities. Complex architectures and high-resolution features highlight the design versatility. Detailed studies of the spreading of coordinated bursting events across the surface of an isolated cortical spheroid and of the cascade of processes associated with formation and regrowth of bridging tissues across a pair of such spheroids represent two of the many opportunities in basic neuroscience research enabled by these platforms.

Tethered optical, electrical and fluidic battery-powered devices that interface with neural tissue constrain or prevent subject motion, as well as social interactions, and prevent their long-term use in larger models, such as non-human primates, which inhabit complex environments, move over large distances and have high levels of manual dexterity. Here, we discuss recent advances in ultra-lightweight, miniaturized, wireless and battery-free devices that are fully implantable, with capabilities that match or exceed the performance of tethered and battery-powered alternatives, while bypassing their intrinsic limitations. These systems enable closed-loop applications that combine neural recordings and neurostimulation and include the long-lived delivery of therapeutic compounds and the real-time monitoring and treatment of abnormal physiological functions.

Large, distributed collections of miniaturized, wireless electronic devices

Objective and Impact Statement . Real-time monitoring of the temperatures of regional tissue microenvironments can serve as the diagnostic basis for treating various health conditions and diseases. Introduction . Traditional thermal sensors allow measurements at surfaces or at near-surface regions of the skin or of certain body cavities. Evaluations at depth require implanted devices connected to external readout electronics via physical interfaces that lead to risks for infection and movement constraints for the patient. Also, surgical extraction procedures after a period of need can introduce additional risks and costs. Methods . Here, we report a wireless, bioresorbable class of temperature sensor that exploits multilayer photonic cavities, for continuous optical measurements of regional, deep-tissue microenvironments over a timeframe of interest followed by complete clearance via natural body processes. Results . The designs decouple the influence of detection angle from temperature on the reflection spectra, to enable high accuracy in sensing, as supported by in vitro experiments and optical simulations. Studies with devices implanted into subcutaneous tissues of both awake, freely moving and asleep animal models illustrate the applicability of this technology for in vivo measurements. Conclusion . The results demonstrate the use of bioresorbable materials in advanced photonic structures with unique capabilities in tracking of thermal signatures of tissue microenvironments, with potential relevance to human healthcare.

Evaluating the biomechanics of soft tissues at depths well below their surface, and at high precision and in real time, would open up diagnostic opportunities. Here, we report the development and application of miniaturized electromagnetic devices, each integrating a vibratory actuator and a soft strain-sensing sheet, for dynamically measuring the Young's modulus of skin and of other soft tissues at depths of approximately 1-8 mm, depending on the particular design of the sensor. We experimentally and computationally established the operational principles of the devices and evaluated their performance with a range of synthetic and biological materials and with human skin in healthy volunteers. Arrays of devices can be used to spatially map elastic moduli and to profile the modulus depth-wise. As an example of practical medical utility, we show that the devices can be used to accurately locate lesions associated with psoriasis. Compact electronic devices for the rapid and precise mechanical characterization of living tissues could be used to monitor and diagnose a range of health disorders.

Soft, wireless sensors monitor the temperature and interface pressure of the patient’s skin for compression therapy., Therapeutic compression garments (TCGs) are key tools for the management of a wide range of vascular lower extremity conditions. Proper use of TCGs involves application of a minimum and consistent pressure across the lower extremities for extended periods of time. Slight changes in the characteristics of the fabric and the mechanical properties of the tissues lead to requirements for frequent measurements and corresponding adjustments of the applied pressure. Existing sensors are not sufficiently small, thin, or flexible for practical use in this context, and they also demand cumbersome, hard-wired interfaces for data acquisition. Here, we introduce a flexible, wireless monitoring system for tracking both temperature and pressure at the interface between the skin and the TCGs. Detailed studies of the materials and engineering aspects of these devices, together with clinical pilot trials on a range of patients with different pathologies, establish the technical foundations and measurement capabilities.

The nonvolatile and volatile memory characteristics of feedback field-effect transistors (FBFETs) with nitride charge storage layers were theoretically studied. Because of the electrons and holes stored in the nitride layer, the threshold voltage (V TH) window of 0.6 V was opened/observed. And, with the help of the formation of a positive feedback loop in the p+–n+–p–n+ doped silicon region in FBFET, it turned out that the read delay time of the FBFET for nonvolatile memory applications can be shorter than 1 ns. On the other hand, for the volatile memory applications, the FBFET can implement (a) non-destructive read operations owing to the self-sustaining feedback loop characteristic, and (b) a significantly long retention time which can suppress the power dissipation in refresh. Furthermore, the operation scheme of volatile memory mode can be simplified by setting gate voltage conditions for the hold and read operations to be identical to each other. The FBFET showed its on-state drive current of 6 × 10−5 A μm−1 and the on-/off-current ratio of 109. The potential of merging nonvolatile and volatile memory devices in a single cell is discussed and demonstrated in this work.

Junctionless complementary field effect transistor (JL-CFET) is an emerging device that needs a small layout area and low fabrication cost. However, in order for the JL-CFET to be adopted for low power applications, two main constraints need to be overcome: (a) a high work function of metal gate and (b) a low drain current. In this work, an optimal device design is proposed to overcome those problems, by analyzing various performance metrics, such as on-state drive current, subthreshold swing, drain induced barrier lowering, propagation delay time, and ring oscillator’s oscillation frequency, which are extracted from various structures of JL-CFET. In addition, the negative capacitance effect in JL-CFET is examined to address the limit from device structures.

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.

Noninvasive methods for precise characterization of the thermal properties of soft biological tissues such as the skin can yield vital details about physiological health status including at critical intervals during recovery following skin injury. Here, we introduce quantitative measurement and characterization methods that allow rapid, accurate determination of the thermal conductivity of soft materials using thin, skin-like resistive sensor platforms. Systematic evaluations of skin at eight different locations and of six different synthetic skin-mimicking materials across sensor sizes, measurement times, and surface geometries (planar, highly curvilinear) validate simple scaling laws for data interpretation and parameter extraction. As an example of the possibilities, changes in the thermal properties of skin (volar forearm) can be monitored during recovery from exposure to ultraviolet radiation (sunburn) and to stressors associated with localized heating and cooling. More generally, the results described here facilitate rapid, non-invasive thermal measurements on broad classes of biological and non-biological soft materials., GRAPHICAL ABSTRACT

We demonstrate a variable-focus optoacoustic lens (VFOL) by pneumatically controlling a flexible polymer nano-composite membrane, which can produce laser-generated focused ultrasound (LGFU) with a high peak amplitude (>30 MPa) and a tight focal dimension (several hundred μm) over a wide dynamic range of focus variation (>20 mm) together with a long focal length up to 60 mm, each of which is widest and longest among optoacoustic lenses developed so far. Two different designs in lens dimension have been fabricated and characterized: VFOL-L with a 40-mm diameter and VFOL-S with 10 mm. VFOL-L exhibits a wide dynamic range of focal length variation from 38.52 to 60.39 mm with a center frequency near ~ 10 MHz, which is proper for practical long-range applications with several-cm depth. In comparison, VFOL-S covers a focal variation range from 6.75 to 11.1 mm with ~ 14 MHz, producing a relatively higher-pressure amplitude, which allows the inception of acoustic cavitation at an impedance-mismatched boundary. The nano-composite membrane of VFOL is actuated from a planar to deeply curved shape by externally injecting liquid into the VFOL, resulting in a focal gain up to 255 and a positive peak pressure of > 30 MPa in the VFOL-L case. The minimum-geometrical f-number as low as 0.963 is achieved at the shortest focal length (38.52 mm) with 6-dB lateral and axial spot dimensions of 304 μm and 2.86 mm, respectively. We expect that the proposed VFOL-based LGFU with a high peak pressure, a wide dynamic axial range, and a tight focal dimension are suitably applied for depth-dependent characterization of tissues and shockwave treatment, taking advantages of optoacoustic pulses as input with inherent broadband high-frequency characteristics.

Flexible, large-area tactile sensors capable of simultaneously measuring in real time both the normal pressure and the tangential shear stress have many important applications, including those in artificial skin for uses in robotics, medicine and rehabilitation. Previously reported sensors exhibit responses to pressure and shear stress that are coupled, mainly due to nonlinearities, in ways that can be difficult to separate. A recently developed sensor based on techniques in mechanics-guided, deterministic three-dimensional (3D) assembly provides a route to decouple these responses such that the pressure and the shear stress can be determined explicitly and linearly from the change in resistance of multiple strain gauges integrated at carefully selected locations on the 3D structure. A clear understanding of the mechanics of this 3D structure-based sensor is essential for its optimization and application. Here analytic models, validated by finite element analysis, are presented for the deformation of such structures under pressure and shear stress. Analytic solutions in concise forms are derived for a buckled wavy ribbon encapsulated in a soft elastomer, which reveal the effect of the geometry and material parameters on the sensitivity, therefore establishing design guidelines for these devices.

Long-lasting, high-resolution neural interfaces that are ultrathin and flexible are essential for precise brain mapping and high-performance neuroprosthetic systems. Scaling to sample thousands of sites across large brain regions requires integrating powered electronics to multiplex many electrodes to a few external wires. However, existing multiplexed electrode arrays rely on encapsulation strategies that have limited implant lifetimes. Here, we developed a flexible, multiplexed electrode array, called "Neural Matrix," that provides stable in vivo neural recordings in rodents and nonhuman primates. Neural Matrix lasts over a year and samples a centimeter-scale brain region using over a thousand channels. The long-lasting encapsulation (projected to last at least 6 years), scalable device design, and iterative in vivo optimization described here are essential components to overcoming current hurdles facing next-generation neural technologies.