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.

Wireless Optofluidic Systems for Programmable In Vivo Pharmacology and Optogenetics.

In vivo pharmacology and optogenetics hold tremendous promise for dissection of neural circuits, cellular signaling, and manipulating neurophysiological systems in awake, behaving animals. Existing neural interface technologies, such as metal cannulas connected to external drug supplies for pharmacological infusions and tethered fiber optics for optogenetics, are not ideal for minimally invasive, untethered studies on freely behaving animals. Here, we introduce wireless optofluidic neural probes that combine ultrathin, soft microfluidic drug delivery with cellular-scale inorganic light-emitting diode (µ-ILED) arrays. These probes are orders of magnitude smaller than cannulas and allow wireless, programmed spatiotemporal control of fluid delivery and photostimulation. We demonstrate these devices in freely moving animals to modify gene expression, deliver peptide ligands, and provide concurrent photostimulation with antagonist drug delivery to manipulate mesoaccumbens reward-related behavior. The minimally invasive operation of these probes forecasts utility in other organ systems and species, with potential for broad application in biomedical science, engineering, and medicine.

A dynamically reprogrammable surface with self-evolving shape morphing.

Dynamic shape-morphing soft materials systems are ubiquitous in living organisms; they are also of rapidly increasing relevance to emerging technologies in soft machines1-3, flexible electronics4,5 and smart medicines6. Soft matter equipped with responsive components can switch between designed shapes or structures, but cannot support the types of dynamic morphing capabilities needed to reproduce natural, continuous processes of interest for many applications7-24. Challenges lie in the development of schemes to reprogram target shapes after fabrication, especially when complexities associated with the operating physics and disturbances from the environment can stop the use of deterministic theoretical models to guide inverse design and control strategies25-30. Here we present a mechanical metasurface constructed from a matrix of filamentary metal traces, driven by reprogrammable, distributed Lorentz forces that follow from the passage of electrical currents in the presence of a static magnetic field. The resulting system demonstrates complex, dynamic morphing capabilities with response times within 0.1 second. Implementing an in situ stereo-imaging feedback strategy with a digitally controlled actuation scheme guided by an optimization algorithm yields surfaces that can follow a self-evolving inverse design to morph into a wide range of three-dimensional target shapes with high precision, including an ability to morph against extrinsic or intrinsic perturbations. These concepts support a data-driven approach to the design of dynamic soft matter, with many unique characteristics.

Three-dimensional electronic microfliers inspired by wind-dispersed seeds.

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.

A wirelessly programmable, skin-integrated thermo-haptic stimulator system for virtual reality.

Sensations of heat and touch produced by receptors in the skin are of essential importance for perceptions of the physical environment, with a particularly powerful role in interpersonal interactions. Advances in technologies for replicating these sensations in a programmable manner have the potential not only to enhance virtual/augmented reality environments but they also hold promise in medical applications for individuals with amputations or impaired sensory function. Engineering challenges are in achieving interfaces with precise spatial resolution, power-efficient operation, wide dynamic range, and fast temporal responses in both thermal and in physical modulation, with forms that can extend over large regions of the body. This paper introduces a wireless, skin-compatible interface for thermo-haptic modulation designed to address some of these challenges, with the ability to deliver programmable patterns of enhanced vibrational displacement and high-speed thermal stimulation. Experimental and computational investigations quantify the thermal and mechanical efficiency of a vertically stacked design layout in the thermo-haptic stimulators that also supports real-time, closed-loop control mechanisms. The platform is effective in conveying thermal and physical information through the skin, as demonstrated in the control of robotic prosthetics and in interactions with pressure/temperature-sensitive touch displays.

A wireless, implantable bioelectronic system for monitoring urinary bladder function following surgical recovery.

Partial cystectomy procedures for urinary bladder-related dysfunction involve long recovery periods, during which urodynamic studies (UDS) intermittently assess lower urinary tract function. However, UDS are not patient-friendly, they exhibit user-to-user variability, and they amount to snapshots in time, limiting the ability to collect continuous, longitudinal data. These procedures also pose the risk of catheter-associated urinary tract infections, which can progress to ascending pyelonephritis due to prolonged lower tract manipulation in high-risk patients. Here, we introduce a fully bladder-implantable platform that allows for continuous, real-time measurements of changes in mechanical strain associated with bladder filling and emptying via wireless telemetry, including a wireless bioresorbable strain gauge validated in a benchtop partial cystectomy model. We demonstrate that this system can reproducibly measure real-time changes in a rodent model up to 30 d postimplantation with minimal foreign body response. Studies in a nonhuman primate partial cystectomy model demonstrate concordance of pressure measurements up to 8 wk compared with traditional UDS. These results suggest that our system can be used as a suitable alternative to UDS for long-term postoperative bladder recovery monitoring.

Self-powered, light-controlled, bioresorbable platforms for programmed drug delivery.

Degradable polymer matrices and porous scaffolds provide powerful mechanisms for passive, sustained release of drugs relevant to the treatment of a broad range of diseases and conditions. Growing interest is in active control of pharmacokinetics tailored to the needs of the patient via programmable engineering platforms that include power sources, delivery mechanisms, communication hardware, and associated electronics, most typically in forms that require surgical extraction after a period of use. Here we report a light-controlled, self-powered technology that bypasses key disadvantages of these systems, in an overall design that is bioresorbable. Programmability relies on the use of an external light source to illuminate an implanted, wavelength-sensitive phototransistor to trigger a short circuit in an electrochemical cell structure that includes a metal gate valve as its anode. Consequent electrochemical corrosion eliminates the gate, thereby opening an underlying reservoir to release a dose of drugs by passive diffusion into surrounding tissue. A wavelength-division multiplexing strategy allows release to be programmed from any one or any arbitrary combination of a collection of reservoirs built into an integrated device. Studies of various bioresorbable electrode materials define the key considerations and guide optimized choices in designs. In vivo demonstrations of programmed release of lidocaine adjacent the sciatic nerves in rat models illustrate the functionality in the context of pain management, an essential aspect of patient care that could benefit from the results presented here.

Closed-loop network of skin-interfaced wireless devices for quantifying vocal fatigue and providing user feedback.

Vocal fatigue is a measurable form of performance fatigue resulting from overuse of the voice and is characterized by negative vocal adaptation. Vocal dose refers to cumulative exposure of the vocal fold tissue to vibration. Professionals with high vocal demands, such as singers and teachers, are especially prone to vocal fatigue. Failure to adjust habits can lead to compensatory lapses in vocal technique and an increased risk of vocal fold injury. Quantifying and recording vocal dose to inform individuals about potential overuse is an important step toward mitigating vocal fatigue. Previous work establishes vocal dosimetry methods, that is, processes to quantify vocal fold vibration dose but with bulky, wired devices that are not amenable to continuous use during natural daily activities; these previously reported systems also provide limited mechanisms for real-time user feedback. This study introduces a soft, wireless, skin-conformal technology that gently mounts on the upper chest to capture vibratory responses associated with vocalization in a manner that is immune to ambient noises. Pairing with a separate, wirelessly linked device supports haptic feedback to the user based on quantitative thresholds in vocal usage. A machine learning-based approach enables precise vocal dosimetry from the recorded data, to support personalized, real-time quantitation and feedback. These systems have strong potential to guide healthy behaviors in vocal use.

Skin-integrated systems for power efficient, programmable thermal sensations across large body areas.

Thermal sensations contribute to our ability to perceive and explore the physical world. Reproducing these sensations in a spatiotemporally programmable manner through wireless computer control could enhance virtual experiences beyond those supported by video, audio and, increasingly, haptic inputs. Flexible, lightweight and thin devices that deliver patterns of thermal stimulation across large areas of the skin at any location of the body are of great interest in this context. Applications range from those in gaming and remote socioemotional communications, to medical therapies and physical rehabilitation. Here, we present a set of ideas that form the foundations of a skin-integrated technology for power-efficient generation of thermal sensations across the skin, with real-time, closed-loop control. The systems exploit passive cooling mechanisms, actively switchable thermal barrier interfaces, thin resistive heaters and flexible electronics configured in a pixelated layout with wireless interfaces to portable devices, the internet and cloud data infrastructure. Systematic experimental studies and simulation results explore the essential mechanisms and guide the selection of optimized choices in design. Demonstration examples with human subjects feature active thermoregulation, virtual social interactions, and sensory expansion.

Advances in Bioresorbable Materials and Electronics.

Transient electronic systems represent an emerging class of technology that is defined by an ability to fully or partially dissolve, disintegrate, or otherwise disappear at controlled rates or triggered times through engineered chemical or physical processes after a required period of operation. This review highlights recent advances in materials chemistry that serve as the foundations for a subclass of transient electronics, bioresorbable electronics, that is characterized by an ability to resorb (or, equivalently, to absorb) in a biological environment. The primary use cases are in systems designed to insert into the human body, to provide sensing and/or therapeutic functions for timeframes aligned with natural biological processes. Mechanisms of bioresorption then harmlessly eliminate the devices, and their associated load on and risk to the patient, without the need of secondary removal surgeries. The core content focuses on the chemistry of the enabling electronic materials, spanning organic and inorganic compounds to hybrids and composites, along with their mechanisms of chemical reaction in biological environments. Following discussions highlight the use of these materials in bioresorbable electronic components, sensors, power supplies, and in integrated diagnostic and therapeutic systems formed using specialized methods for fabrication and assembly. A concluding section summarizes opportunities for future research.

Skin-integrated wireless haptic interfaces for virtual and augmented reality.

Traditional technologies for virtual reality (VR) and augmented reality (AR) create human experiences through visual and auditory stimuli that replicate sensations associated with the physical world. The most widespread VR and AR systems use head-mounted displays, accelerometers and loudspeakers as the basis for three-dimensional, computer-generated environments that can exist in isolation or as overlays on actual scenery. In comparison to the eyes and the ears, the skin is a relatively underexplored sensory interface for VR and AR technology that could, nevertheless, greatly enhance experiences at a qualitative level, with direct relevance in areas such as communications, entertainment and medicine1,2. Here we present a wireless, battery-free platform of electronic systems and haptic (that is, touch-based) interfaces capable of softly laminating onto the curved surfaces of the skin to communicate information via spatio-temporally programmable patterns of localized mechanical vibrations. We describe the materials, device structures, power delivery strategies and communication schemes that serve as the foundations for such platforms. The resulting technology creates many opportunities for use where the skin provides an electronically programmable communication and sensory input channel to the body, as demonstrated through applications in social media and personal engagement, prosthetic control and feedback, and gaming and entertainment.

A wireless closed-loop system for optogenetic peripheral neuromodulation.

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.

Dynamics of plosive consonants via imaging, computations, and soft electronics.

A quantitative understanding of the coupled dynamics of flow and particles in aerosol and droplet transmission associated with speech remains elusive. Here, we summarize an effort that integrates insights into flow-particle dynamics induced by the production plosive sounds during speech with skin-integrated electronic systems for monitoring the production of these sounds. In particular, we uncover diffusive and ballistic regimes separated by a threshold particle size and characterize the Lagrangian acceleration and pair dispersion. Lagrangian dynamics of the particles in the diffusive regime exhibit features of isotropic turbulence. These fundamental findings highlight the value in skin-interfaced wireless sensors for continuously measuring critical speech patterns in clinical settings, work environments, and the home, based on unique neck biomechanics associated with the generation of plosive sounds. We introduce a wireless, soft device that captures these motions to enable detection of plosive sounds in multiple languages through a convolutional neural network approach. This work spans fundamental flow-particle physics to soft electronic technology, with implications in monitoring and studying critical speech patterns associated with aerosol and droplet transmissions relevant to the spread of infectious diseases.

Utilization of remote reprogramming to manage insertable cardiac monitor arrhythmia alert burden.

INTRODUCTION: The increasing use of insertable cardiac monitors (ICMs) for long-term continuous arrhythmia monitoring creates a high volume of transmissions and a significant workload for clinics. The ability to remotely reprogram device alert settings without in-office patient visits was recently introduced, but its impact on clinic workflow compared to the previous ICM iteration is unknown. METHODS: The aim of this real-world study was to evaluate the impact of device reprogramming capabilities on ICM alert burden and on clinic workflow. Deidentified data was obtained from US patients and a total of 19 525 receiving a LINQ II were propensity score-matched with 19 525 implanted with LINQ TruRhythm (TR) ICM based on age and reason for monitoring. RESULTS: After reprogramming, ICM alerts reduced by 20.5% (p < .001). Compared with patients monitored with LINQ TR, patients with LINQ II had their device reprogrammed sooner after implant and more frequently during follow-up. Adoption of remote programming was projected to lead to an annual total clinic time savings of 211 h per 100 ICM patients managed. CONCLUSION: These data suggest that utilization of ICM alert reprogramming has increased with remote capabilities, which may reduce clinic and patient burden for ICM follow-up and free clinician time for other valuable patient care activities.

Antinociceptive and adverse effects of morphine:ketamine mixtures in rats.

Prescription opioids are the gold standard for treating moderate to severe pain despite their well-documented adverse effects. Of all prescription medications, opioids are abused most widely, and fatal overdoses have reached epidemic levels. One strategy for improving the margin of safety of opioids is combining them with non-opioid drugs to decrease the opioid dose needed for pain relief, thereby reducing adverse effects that occur with larger doses. The N-methyl-D-aspartate receptor antagonist ketamine has been used safely as an analgesic but only under a very limited range of conditions. The current studies characterized the antinociceptive, behavioral suppressant, and gastrointestinal effects of morphine and ketamine alone and in mixtures to determine their interaction in 24 adult male Sprague-Dawley rats (n = 8 per assay). Given alone, both morphine and ketamine produced antinociception, decreased responding for food, and reduced gastrointestinal transit (i.e. produced constipation). The effects of morphine:ketamine mixtures generally were additive, except for the antinociceptive effects of 1:1 mixtures for which the difference in slope (i.e. non-parallel shift) between the observed and predicted effects suggested synergy at smaller doses and additivity at larger doses. The potency of morphine to produce constipation was not enhanced by administration of morphine:ketamine mixtures with antinociceptive effects. The nature of the interaction between morphine and ketamine for adverse effects such as dependence, withdrawal, abuse, or respiratory depression remains unknown but also might be related to the ratio of each drug in mixtures. It will be important to identify conditions that produce the largest potential therapeutic window in humans.

Factors Associated with Having both Male and Female Recent Sexual Partnerships Among Men Who Have Sex with Men in Harare and Bulawayo, Zimbabwe.

To better understand male and female sexual partnerships among men who have sex with men (MSM), we used data from a 2019 biobehavioral survey among MSM in Harare and Bulawayo, Zimbabwe to conduct bivariate analyses and multivariable logistic regression to determine whether sociodemographic characteristics and HIV-related factors were associated with having both male and female sexual partnerships within the last 6 months. Of included MSM (N = 1143), 31% reported both male and female partnerships in the last 6 months. Being married/cohabiting (adjusted odds ratio (aOR) = 8.58, 95% confidence interval (CI) = 4.92-14.95) or separated/divorced/widowed (aOR = 1.96, 95% CI = 1.24-3.08) vs. being single, and hazardous alcohol consumption (aOR = 1.58, 95% CI 1.19-2.09) were associated with higher odds of having both male and female recent partnerships. Being aged 35 + vs. 18-24 (aOR = 0.50, 95% CI = 0.31-0.81), condomless receptive anal intercourse at last sex with the main male partner (aOR = 0.43, 95% CI = 0.26-0.74), and positive HIV status (aOR = 0.46, 95% CI = 0.31-0.67) were associated with lower odds of recent male and female partnerships. MSM in Harare who reported harassment/abuse (aOR = 3.16, 95% CI = 1.72-5.79) had higher odds of both male and female partnerships than MSM in Bulawayo reporting harassment/abuse. The prevalence of both male and female recent partnerships (31%) was lower among MSM in this survey than in other biobehavioral surveys of MSM in sub-Saharan Africa. Findings suggest that MSM with recent male and female partnerships compared to MSM with only male recent partners have lower odds of positive HIV status and participate in behaviors that lower HIV risk; however, the direction of these relationships cannot be determined due to the cross-sectional nature of the data. The findings also suggest a possible connection between experiences of stigma of MSM behavior and not having both male and female partnerships that warrants further exploration. Accessible, stigma-free HIV testing and education programming that considers the potential overlap between the MSM and general populations via both male and female partnerships and the associated behaviors could be a key component of HIV elimination in Zimbabwe.

Materials Chemistry of Neural Interface Technologies and Recent Advances in Three-Dimensional Systems.

Advances in materials chemistry and engineering serve as the basis for multifunctional neural interfaces that span length scales from individual neurons to neural networks, neural tissues, and complete neural systems. Such technologies exploit electrical, electrochemical, optical, and/or pharmacological modalities in sensing and neuromodulation for fundamental studies in neuroscience research, with additional potential to serve as routes for monitoring and treating neurodegenerative diseases and for rehabilitating patients. This review summarizes the essential role of chemistry in this field of research, with an emphasis on recently published results and developing trends. The focus is on enabling materials in diverse device constructs, including their latest utilization in 3D bioelectronic frameworks formed by 3D printing, self-folding, and mechanically guided assembly. A concluding section highlights key challenges and future directions.

Modeling programmable drug delivery in bioelectronics with electrochemical actuation.

Drug delivery systems featuring electrochemical actuation represent an emerging class of biomedical technology with programmable volume/flowrate capabilities for localized delivery. Recent work establishes applications in neuroscience experiments involving small animals in the context of pharmacological response. However, for programmable delivery, the available flowrate control and delivery time models fail to consider key variables of the drug delivery system--microfluidic resistance and membrane stiffness. Here we establish an analytical model that accounts for the missing variables and provides a scalable understanding of each variable influence in the physics of delivery process (i.e., maximum flowrate, delivery time). This analytical model accounts for the key parameters--initial environmental pressure, initial volume, microfluidic resistance, flexible membrane, current, and temperature--to control the delivery and bypasses numerical simulations allowing faster system optimization for different in vivo experiments. We show that the delivery process is controlled by three nondimensional parameters, and the volume/flowrate results from the proposed analytical model agree with the numerical results and experiments. These results have relevance to the many emerging applications of programmable delivery in clinical studies within the neuroscience and broader biomedical communities.

Wireless, battery-free, subdermally implantable platforms for transcranial and long-range optogenetics in freely moving animals.

Wireless, battery-free, and fully subdermally implantable optogenetic tools are poised to transform neurobiological research in freely moving animals. Current-generation wireless devices are sufficiently small, thin, and light for subdermal implantation, offering some advantages over tethered methods for naturalistic behavior. Yet current devices using wireless power delivery require invasive stimulus delivery, penetrating the skull and disrupting the blood-brain barrier. This can cause tissue displacement, neuronal damage, and scarring. Power delivery constraints also sharply curtail operational arena size. Here, we implement highly miniaturized, capacitive power storage on the platform of wireless subdermal implants. With approaches to digitally manage power delivery to optoelectronic components, we enable two classes of applications: transcranial optogenetic activation millimeters into the brain (validated using motor cortex stimulation to induce turning behaviors) and wireless optogenetics in arenas of more than 1 m2 in size. This methodology allows for previously impossible behavioral experiments leveraging the modern optogenetic toolkit.

Compliant 3D frameworks instrumented with strain sensors for characterization of millimeter-scale engineered muscle tissues.

Tissue-on-chip systems represent promising platforms for monitoring and controlling tissue functions in vitro for various purposes in biomedical research. The two-dimensional (2D) layouts of these constructs constrain the types of interactions that can be studied and limit their relevance to three-dimensional (3D) tissues. The development of 3D electronic scaffolds and microphysiological devices with geometries and functions tailored to realistic 3D tissues has the potential to create important possibilities in advanced sensing and control. This study presents classes of compliant 3D frameworks that incorporate microscale strain sensors for high-sensitivity measurements of contractile forces of engineered optogenetic muscle tissue rings, supported by quantitative simulations. Compared with traditional approaches based on optical microscopy, these 3D mechanical frameworks and sensing systems can measure not only motions but also contractile forces with high accuracy and high temporal resolution. Results of active tension force measurements of engineered muscle rings under different stimulation conditions in long-term monitoring settings for over 5 wk and in response to various chemical and drug doses demonstrate the utility of such platforms in sensing and modulation of muscle and other tissues. Possibilities for applications range from drug screening and disease modeling to biohybrid robotic engineering.