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Opioid overdose accounts for nearly 75,000 deaths per year in the United States, representing a leading cause of mortality amongst the prime working age population (25-54 years). At overdose levels, opioid-induced respiratory depression becomes fatal without timely administration of the rescue drug naloxone. Currently, overdose survival relies entirely on bystander intervention, requiring a nearby person to discover and identify the overdosed individual, and have immediate access to naloxone to administer. Government efforts have focused on providing naloxone in abundance but do not address the equally critical component for overdose rescue: a willing and informed bystander. To address this unmet need, we developed the Naloximeter: a class of life-saving implantable devices that autonomously detect and treat overdose, with the ability to simultaneously contact first-responders. We present three Naloximeter platforms, for both fundamental research and clinical translation, all equipped with optical sensors, drug delivery mechanisms, and a supporting ecosystem of technology to counteract opioid-induced respiratory depression. In small and large animal studies, the Naloximeter rescues from otherwise fatal opioid overdose within minutes. This work introduces life-changing, clinically translatable technologies that broadly benefit a susceptible population recovering from opioid use disorder.
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Neurotechnologies and genetic tools for dissecting neural circuit functions have advanced rapidly over the past decade, although the development of complementary pharmacological method-ologies has comparatively lagged. Understanding the precise pharmacological mechanisms of neuroactive compounds is critical for advancing basic neurobiology and neuropharmacology, as well as for developing more effective treatments for neurological and neuropsychiatric disorders. However, integrating modern tools for assessing neural activity in large-scale neural networks with spatially localized drug delivery remains a major challenge. Here, we present a dual microfluidic-photometry platform that enables simultaneous intracranial drug delivery with neural dynamics monitoring in the rodent brain. The integrated platform combines a wireless, battery-free, miniaturized fluidic microsystem with optical probes, allowing for spatially and temporally specific drug delivery while recording activity-dependent fluorescence using genetically encoded calcium indicators (GECIs), neurotransmitter sensors GRAB NE and GRAB DA , and neuropeptide sensors. We demonstrate the performance this platform for investigating neuropharmacological mechanisms in vivo and characterize its efficacy in probing precise mechanistic actions of neuroactive compounds across several rapidly evolving neuroscience domains.
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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.
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Tato , Realidade Virtual , Tecnologia sem Fio , Humanos , Tecnologia sem Fio/instrumentação , Tato/fisiologia , Pele , Robótica/instrumentação , Robótica/métodosRESUMO
Wireless modules that provide telecommunications and power-harvesting capabilities enabled by radio-frequency (RF) electronics are vital components of skin-interfaced stretchable electronics1-7. However, recent studies on stretchable RF components have demonstrated that substantial changes in electrical properties, such as a shift in the antenna resonance frequency, occur even under relatively low elastic strains8-15. Such changes lead directly to greatly reduced wireless signal strength or power-transfer efficiency in stretchable systems, particularly in physically dynamic environments such as the surface of the skin. Here we present strain-invariant stretchable RF electronics capable of completely maintaining the original RF properties under various elastic strains using a 'dielectro-elastic' material as the substrate. Dielectro-elastic materials have physically tunable dielectric properties that effectively avert frequency shifts arising in interfacing RF electronics. Compared with conventional stretchable substrate materials, our material has superior electrical, mechanical and thermal properties that are suitable for high-performance stretchable RF electronics. In this paper, we describe the materials, fabrication and design strategies that serve as the foundation for enabling the strain-invariant behaviour of key RF components based on experimental and computational studies. Finally, we present a set of skin-interfaced wireless healthcare monitors based on strain-invariant stretchable RF electronics with a wireless operational distance of up to 30 m under strain.
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Elasticidade , Eletrônica , Desenho de Equipamento , Ondas de Rádio , Pele , Estresse Mecânico , Dispositivos Eletrônicos Vestíveis , Tecnologia sem Fio , Humanos , Eletrônica/instrumentação , Tecnologia sem Fio/instrumentação , Monitorização Fisiológica/instrumentaçãoRESUMO
Continuous monitoring of biomarkers at locations adjacent to targeted internal organs can provide actionable information about postoperative status beyond conventional diagnostic methods. As an example, changes in pH in the intra-abdominal space after gastric surgeries can serve as direct indicators of potentially life-threatening leakage events, in contrast to symptomatic reactions that may delay treatment. Here, we report a bioresorbable, wireless, passive sensor that addresses this clinical need, designed to locally monitor pH for early detection of gastric leakage. A pH-responsive hydrogel serves as a transducer that couples to a mechanically optimized inductor-capacitor circuit for wireless readout. This platform enables real-time monitoring of pH with fast response time (within 1 hour) over a clinically relevant period (up to 7 days) and timely detection of simulated gastric leaks in animal models. These concepts have broad potential applications for temporary sensing of relevant biomarkers during critical risk periods following diverse types of surgeries.
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Implantes Absorvíveis , Transdutores , Animais , Tecnologia sem Fio , Concentração de Íons de Hidrogênio , BiomarcadoresRESUMO
Diagnosing and monitoring inflammatory bowel diseases, such as Crohn's disease, involves the use of endoscopic imaging, biopsies and serology. These infrequent tests cannot, however, identify sudden onsets and severe flare-ups to facilitate early intervention. Hence, about 70% of patients with Crohn's disease require surgical intestinal resections in their lifetime. Here we report wireless, miniaturized and implantable temperature sensors for the real-time chronic monitoring of disease progression, which we tested for nearly 4 months in a mouse model of Crohn's-disease-like ileitis. Local measurements of intestinal temperature via intraperitoneally implanted sensors held in place against abdominal muscular tissue via two sutures showed the development of ultradian rhythms at approximately 5 weeks before the visual emergence of inflammatory skip lesions. The ultradian rhythms showed correlations with variations in the concentrations of stress hormones and inflammatory cytokines in blood. Decreasing average temperatures over the span of approximately 23 weeks were accompanied by an increasing percentage of inflammatory species in ileal lesions. These miniaturized temperature sensors may aid the early treatment of inflammatory bowel diseases upon the detection of episodic flare-ups.
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Systems for capture, storage and analysis of eccrine sweat can provide insights into physiological health status, quantify losses of water, electrolytes, amino acids and/or other essential species, and identify exposures to adverse environmental species or illicit drugs. Recent advances in materials and device designs serve as the basis for skin-compatible classes of microfluidic platforms and in situ colorimetric assays for precise assessments of sweat rate, sweat loss and concentrations of wide-ranging types of biomarkers in sweat. This paper presents a set of findings that enhances the performance of these systems through the use of microfluidic networks, integrated valves and microscale optical cuvettes formed by three dimensional printing in hard/soft hybrid materials systems, for accurate spectroscopic and fluorometric assays. Field studies demonstrate the capability of these microcuvette systems to evaluate the concentrations of copper, chloride, and glucose in sweat, along with the pH of sweat, with laboratory-grade accuracy and sensitivity.
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Microfluídica , Suor , Suor/química , Suor/metabolismo , Microfluídica/métodos , Dispositivos Lab-On-A-Chip , Epiderme , Pele/química , Pele/metabolismoRESUMO
Magnetic resonance imaging (MRI) is widely used in clinical care and medical research. The signal-to-noise ratio (SNR) in the measurement affects parameters that determine the diagnostic value of the image, such as the spatial resolution, contrast, and scan time. Surgically implanted radiofrequency coils can increase SNR of subsequent MRI studies of adjacent tissues. The resulting benefits in SNR are, however, balanced by significant risks associated with surgically removing these coils or with leaving them in place permanently. As an alternative, here the authors report classes of implantable inductor-capacitor circuits made entirely of bioresorbable organic and inorganic materials. Engineering choices for the designs of an inductor and a capacitor provide the ability to select the resonant frequency of the devices to meet MRI specifications (e.g., 200 MHz at 4.7 T MRI). Such devices enhance the SNR and improve the associated imaging capabilities. These simple, small bioelectronic systems function over clinically relevant time frames (up to 1 month) at physiological conditions and then disappear completely by natural mechanisms of bioresorption, thereby eliminating the need for surgical extraction. Imaging demonstrations in a nerve phantom and a human cadaver suggest that this technology has broad potential for post-surgical monitoring/evaluation of recovery processes.
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Peripheral nerve injuries cause various disabilities related to loss of motor and sensory functions. The treatment of these injuries typically requires surgical operations for improving functional recovery of the nerve. However, capabilities for continuous nerve monitoring remain a challenge. Herein, a battery-free, wireless, cuff-type, implantable, multimodal physical sensing platform for continuous in vivo monitoring of temperature and strain from the injured nerve is introduced. The thin, soft temperature, and strain sensors wrapped around the nerve exhibit good sensitivity, excellent stability, high linearity, and minimum hysteresis in relevant ranges. In particular, the strain sensor integrated with circuits for temperature compensation provides reliable, accurate strain monitoring with negligible temperature dependence. The system enables power harvesting and data communication to wireless, multiple implanted devices wrapped around the nerve. Experimental evaluations, verified by numerical simulations, with animal tests, demonstrate the feasibility and stability of the sensor system, which has great potential for continuous in vivo nerve monitoring from an early stage to complete regeneration.
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Fontes de Energia Elétrica , Próteses e Implantes , Animais , Temperatura , Tecnologia sem FioRESUMO
Devices for monitoring blood haemodynamics can guide the perioperative management of patients with cardiovascular disease. Current technologies for this purpose are constrained by wired connections to external electronics, and wireless alternatives are restricted to monitoring of either blood pressure or blood flow. Here we report the design aspects and performance parameters of an integrated wireless sensor capable of implantation in the heart or in a blood vessel for simultaneous measurements of pressure, flow rate and temperature in real time. The sensor is controlled via long-range communication through a subcutaneously implanted and wirelessly powered Bluetooth Low Energy system-on-a-chip. The device can be delivered via a minimally invasive transcatheter procedure or it can be mounted on a passive medical device such as a stent, as we show for the case of the pulmonary artery in a pig model and the aorta and left ventricle in a sheep model, where the device performs comparably to clinical tools for monitoring of blood flow and pressure. Battery-less and wireless devices such as these that integrate capabilities for flow, pressure and temperature sensing offer the potential for continuous monitoring of blood haemodynamics in patients.
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Chronic wounds, particularly those associated with diabetes mellitus, represent a growing threat to public health, with additional notable economic impacts. Inflammation associated with these wounds leads to abnormalities in endogenous electrical signals that impede the migration of keratinocytes needed to support the healing process. This observation motivates the treatment of chronic wounds with electrical stimulation therapy, but practical engineering challenges, difficulties in removing stimulation hardware from the wound site, and absence of means to monitor the healing process create barriers to widespread clinical use. Here, we demonstrate a miniaturized wireless, battery-free bioresorbable electrotherapy system that overcomes these challenges. Studies based on a splinted diabetic mouse wound model confirm the efficacy for accelerated wound closure by guiding epithelial migration, modulating inflammation, and promoting vasculogenesis. Changes in the impedance provide means for tracking the healing process. The results demonstrate a simple and effective platform for wound site electrotherapy.
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Diabetes Mellitus , Terapia por Estimulação Elétrica , Camundongos , Animais , Implantes Absorvíveis , Impedância Elétrica , Cicatrização , Modelos Animais de Doenças , InflamaçãoRESUMO
Elastomeric encapsulation layers are widely used in soft, wearable devices to physically isolate rigid electronic components from external environmental stimuli (e.g., stress) and facilitate device sterilization for reusability. In devices experiencing large deformations, the stress-isolation effect of the top encapsulation layer can eliminate the damage to the electronic components caused by external forces. However, for health monitoring and sensing applications, the strain-isolation effect of the bottom encapsulation layer can partially block the physiological signals of interest and degrade the measurement accuracy. Here, an analytic model is developed for the strain- and stress-isolation effects present in wearable devices with elastomeric encapsulation layers. The soft, elastomeric encapsulation layers and main electronic components layer are modeled as transversely isotropic-elastic mediums and the strain- and stress-isolation effects are described using isolation indexes. The analysis and results show that the isolation effects strongly depend on the thickness, density, and elastic modulus of both the elastomeric encapsulation layers and the main electronic component layer. These findings, combined with the flexible mechanics design strategies of wearable devices, provide new design guidelines for future wearable devices to protect them from external forces while capturing the relevant physiological signals underneath the skin. Electronic Supplementary Material: Supplementary material is available in the online version of this article at 10.1007/s11431-022-2034-y.
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In vivo optogenetics and photopharmacology are two techniques for controlling neuronal activity that have immense potential in neuroscience research. Their applications in tether-free groups of animals have been limited in part due to tools availability. Here, we present a wireless, battery-free, programable multilateral optofluidic platform with user-selected modalities for optogenetics, pharmacology and photopharmacology. This system features mechanically compliant microfluidic and electronic interconnects, capabilities for dynamic control over the rates of drug delivery and real-time programmability, simultaneously for up to 256 separate devices in a single cage environment. Our behavioral experiments demonstrate control of motor behaviors in grouped mice through in vivo optogenetics with co-located gene delivery and controlled photolysis of caged glutamate. These optofluidic systems may expand the scope of wireless techniques to study neural processing in animal models.
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Neurociências , Optogenética , Animais , Encéfalo/fisiologia , Glutamatos , Camundongos , Optogenética/métodos , Tecnologia sem FioRESUMO
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.
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Implantes Absorvíveis , Bloqueio Nervoso , Neuralgia , Manejo da Dor , Nervos Periféricos , Animais , Materiais Biocompatíveis , Bloqueio Nervoso/instrumentação , Neuralgia/terapia , Manejo da Dor/instrumentação , Nervos Periféricos/fisiopatologia , RatosRESUMO
Temporary postoperative cardiac pacing requires devices with percutaneous leads and external wired power and control systems. This hardware introduces risks for infection, limitations on patient mobility, and requirements for surgical extraction procedures. Bioresorbable pacemakers mitigate some of these disadvantages, but they demand pairing with external, wired systems and secondary mechanisms for control. We present a transient closed-loop system that combines a time-synchronized, wireless network of skin-integrated devices with an advanced bioresorbable pacemaker to control cardiac rhythms, track cardiopulmonary status, provide multihaptic feedback, and enable transient operation with minimal patient burden. The result provides a range of autonomous, rate-adaptive cardiac pacing capabilities, as demonstrated in rat, canine, and human heart studies. This work establishes an engineering framework for closed-loop temporary electrotherapy using wirelessly linked, body-integrated bioelectronic devices.
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Implantes Absorvíveis , Estimulação Cardíaca Artificial , Marca-Passo Artificial , Cuidados Pós-Operatórios , Tecnologia sem Fio , Animais , Cães , Frequência Cardíaca , Humanos , Cuidados Pós-Operatórios/instrumentação , RatosRESUMO
Flowrate control in flexible bioelectronics with targeted drug delivery capabilities is essential to ensure timely and safe delivery. For neuroscience and pharmacogenetics studies in small animals, these flexible bioelectronic systems can be tailored to deliver small drug volumes on a controlled fashion without damaging surrounding tissues from stresses induced by excessively high flowrates. The drug delivery process is realized by an electrochemical reaction that pressurizes the internal bioelectronic chambers to deform a flexible polymer membrane that pumps the drug through a network of microchannels implanted in the small animal. The flowrate temporal profile and global maximum are governed and can be modeled by the ideal gas law. Here, we obtain an analytical solution that groups the relevant mechanical, fluidic, environmental, and electrochemical terms involved in the drug delivery process into a set of three nondimensional parameters. The unique combinations of these three nondimensional parameters (related to the initial pressure, initial gas volume, and microfluidic resistance) can be used to model the flowrate and scale up the flexible bioelectronic design for experiments in medium and large animal models. The analytical solution is divided into (1) a fast variable that controls the maximum flowrate and (2) a slow variable that models the temporal profile. Together, the two variables detail the complete drug delivery process and control using the three nondimensional parameters. Comparison of the analytical model with alternative numerical models shows excellent agreement and validates the analytic modeling approach. These findings serve as a theoretical framework to design and optimize future flexible bioelectronic systems used in biomedical research, or related medical fields, and analytically control the flowrate and its global maximum for successful drug delivery.
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Early identification of atypical infant movement behaviors consistent with underlying neuromotor pathologies can expedite timely enrollment in therapeutic interventions that exploit inherent neuroplasticity to promote recovery. Traditional neuromotor assessments rely on qualitative evaluations performed by specially trained personnel, mostly available in tertiary medical centers or specialized facilities. Such approaches are high in cost, require geographic proximity to advanced healthcare resources, and yield mostly qualitative insight. This paper introduces a simple, low-cost alternative in the form of a technology customized for quantitatively capturing continuous, full-body kinematics of infants during free living conditions at home or in clinical settings while simultaneously recording essential vital signs data. The system consists of a wireless network of small, flexible inertial sensors placed at strategic locations across the body and operated in a wide-bandwidth and time-synchronized fashion. The data serve as the basis for reconstructing three-dimensional motions in avatar form without the need for video recordings and associated privacy concerns, for remote visual assessments by experts. These quantitative measurements can also be presented in graphical format and analyzed with machine-learning techniques, with potential to automate and systematize traditional motor assessments. Clinical implementations with infants at low and at elevated risks for atypical neuromotor development illustrates application of this system in quantitative and semiquantitative assessments of patterns of gross motor skills, along with body temperature, heart rate, and respiratory rate, from long-term and follow-up measurements over a 3-mo period following birth. The engineering aspects are compatible for scaled deployment, with the potential to improve health outcomes for children worldwide via early, pragmatic detection methods.
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Comportamento do Lactente/fisiologia , Monitorização Fisiológica/instrumentação , Movimento/fisiologia , Sinais Vitais/fisiologia , Tecnologia sem Fio/instrumentação , Viés , Criança , Desenho de Equipamento , Frequência Cardíaca , Humanos , Imageamento Tridimensional , Lactente , Miniaturização , Monitorização Fisiológica/estatística & dados numéricos , Taxa Respiratória , Pele , Gravação em Vídeo , Tecnologia sem Fio/estatística & dados numéricosRESUMO
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.