RESUMEN
Innovations in soft materials bridge electronic conduction in conventional electronics and ionic conduction in biology. In a recent issue of Science, Dobashi et al. describe a hydrogel that generates large ionic currents in response to applied force. The technology could enable sensors and energy generators for wearable and implantable devices.
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Hidrogeles , Dispositivos Electrónicos Vestibles , Fenómenos Mecánicos , Prótesis e ImplantesRESUMEN
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.
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Materiales Biocompatibles/uso terapéutico , Sistema Nervioso , Prótesis e Implantes , Animales , Humanos , Estimulación Eléctrica Transcutánea del Nervio/métodosRESUMEN
Voluntary movement is a result of signals transmitted through a communication channel that links the internal world in our minds to the physical world around us. Intention can be considered the desire to effect change on our environment, and this is contained in the signals from the brain, passed through the nervous system to converge on muscles that generate displacements and forces on our surroundings. The resulting changes in the world act to generate sensations that feed back to the nervous system, closing the control loop. This Perspective discusses the experimental and theoretical underpinnings of current models of movement generation and the way they are modulated by external information. Movement systems embody intentionality and prediction, two factors that are propelling a revolution in engineering. Development of movement models that include the complexities of the external world may allow a better understanding of the neuronal populations regulating these processes, as well as the development of solutions for autonomous vehicles and robots, and neural prostheses for those who are motor impaired.
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Encéfalo/fisiología , Movimiento , Animales , Retroalimentación Psicológica , Humanos , Modelos Neurológicos , Fenómenos Fisiológicos del Sistema Nervioso , Prótesis e Implantes , RobóticaRESUMEN
Implanted biomaterials and devices face compromised functionality and efficacy in the long term owing to foreign body reactions and subsequent formation of fibrous capsules at the implant-tissue interfaces1-4. Here we demonstrate that an adhesive implant-tissue interface can mitigate fibrous capsule formation in diverse animal models, including rats, mice, humanized mice and pigs, by reducing the level of infiltration of inflammatory cells into the adhesive implant-tissue interface compared to the non-adhesive implant-tissue interface. Histological analysis shows that the adhesive implant-tissue interface does not form observable fibrous capsules on diverse organs, including the abdominal wall, colon, stomach, lung and heart, over 12 weeks in vivo. In vitro protein adsorption, multiplex Luminex assays, quantitative PCR, immunofluorescence analysis and RNA sequencing are additionally carried out to validate the hypothesis. We further demonstrate long-term bidirectional electrical communication enabled by implantable electrodes with an adhesive interface over 12 weeks in a rat model in vivo. These findings may offer a promising strategy for long-term anti-fibrotic implant-tissue interfaces.
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Materiales Biocompatibles , Fibrosis , Reacción a Cuerpo Extraño , Prótesis e Implantes , Adhesivos Tisulares , Animales , Femenino , Humanos , Masculino , Ratones , Ratas , Pared Abdominal , Adsorción , Materiales Biocompatibles/química , Colon , Electrodos Implantados , Fibrosis/patología , Fibrosis/prevención & control , Reacción a Cuerpo Extraño/prevención & control , Reacción a Cuerpo Extraño/patología , Corazón , Pulmón , Ratones Endogámicos C57BL , Especificidad de Órganos , Reacción en Cadena de la Polimerasa , Ratas Sprague-Dawley , Estómago , Porcinos , Factores de Tiempo , Adhesivos Tisulares/química , Técnica del Anticuerpo Fluorescente , Reproducibilidad de los Resultados , Análisis de Secuencia de ARNRESUMEN
Stretchable hybrid devices have enabled high-fidelity implantable1-3 and on-skin4-6 monitoring of physiological signals. These devices typically contain soft modules that match the mechanical requirements in humans7,8 and soft robots9,10, rigid modules containing Si-based microelectronics11,12 and protective encapsulation modules13,14. To make such a system mechanically compliant, the interconnects between the modules need to tolerate stress concentration that may limit their stretching and ultimately cause debonding failure15-17. Here, we report a universal interface that can reliably connect soft, rigid and encapsulation modules together to form robust and highly stretchable devices in a plug-and-play manner. The interface, consisting of interpenetrating polymer and metal nanostructures, connects modules by simply pressing without using pastes. Its formation is depicted by a biphasic network growth model. Soft-soft modules joined by this interface achieved 600% and 180% mechanical and electrical stretchability, respectively. Soft and rigid modules can also be electrically connected using the above interface. Encapsulation on soft modules with this interface is strongly adhesive with an interfacial toughness of 0.24 N mm-1. As a proof of concept, we use this interface to assemble stretchable devices for in vivo neuromodulation and on-skin electromyography, with high signal quality and mechanical resistance. We expect such a plug-and-play interface to simplify and accelerate the development of on-skin and implantable stretchable devices.
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Electromiografía , Electrónica Médica , Nanoestructuras , Docilidad , Polímeros , Prótesis e Implantes , Dispositivos Electrónicos Vestibles , Humanos , Nanoestructuras/química , Polímeros/química , Piel , Monitoreo Fisiológico , Electrónica Médica/instrumentación , Electrónica Médica/métodos , Electromiografía/instrumentaciónRESUMEN
To construct tissue-like prosthetic materials, soft electroactive hydrogels are the best candidate owing to their physiological mechanical modulus, low electrical resistance and bidirectional stimulating and recording capability of electrophysiological signals from biological tissues1,2. Nevertheless, until now, bioelectronic devices for such prostheses have been patch type, which cannot be applied onto rough, narrow or deep tissue surfaces3-5. Here we present an injectable tissue prosthesis with instantaneous bidirectional electrical conduction in the neuromuscular system. The soft and injectable prosthesis is composed of a biocompatible hydrogel with unique phenylborate-mediated multiple crosslinking, such as irreversible yet freely rearrangeable biphenyl bonds and reversible coordinate bonds with conductive gold nanoparticles formed in situ by cross-coupling. Closed-loop robot-assisted rehabilitation by injecting this prosthetic material is successfully demonstrated in the early stage of severe muscle injury in rats, and accelerated tissue repair is achieved in the later stage.
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Materiales Biocompatibles , Hidrogeles , Prótesis e Implantes , Heridas y Lesiones , Animales , Ratas , Materiales Biocompatibles/administración & dosificación , Materiales Biocompatibles/química , Materiales Biocompatibles/uso terapéutico , Conductividad Eléctrica , Oro/química , Hidrogeles/administración & dosificación , Hidrogeles/química , Hidrogeles/uso terapéutico , Nanopartículas del Metal/química , Músculos/lesiones , Músculos/inervación , Robótica , Heridas y Lesiones/rehabilitación , Heridas y Lesiones/cirugíaRESUMEN
Spinal cord injury (SCI) induces haemodynamic instability that threatens survival1-3, impairs neurological recovery4,5, increases the risk of cardiovascular disease6,7, and reduces quality of life8,9. Haemodynamic instability in this context is due to the interruption of supraspinal efferent commands to sympathetic circuits located in the spinal cord10, which prevents the natural baroreflex from controlling these circuits to adjust peripheral vascular resistance. Epidural electrical stimulation (EES) of the spinal cord has been shown to compensate for interrupted supraspinal commands to motor circuits below the injury11, and restored walking after paralysis12. Here, we leveraged these concepts to develop EES protocols that restored haemodynamic stability after SCI. We established a preclinical model that enabled us to dissect the topology and dynamics of the sympathetic circuits, and to understand how EES can engage these circuits. We incorporated these spatial and temporal features into stimulation protocols to conceive a clinical-grade biomimetic haemodynamic regulator that operates in a closed loop. This 'neuroprosthetic baroreflex' controlled haemodynamics for extended periods of time in rodents, non-human primates and humans, after both acute and chronic SCI. We will now conduct clinical trials to turn the neuroprosthetic baroreflex into a commonly available therapy for people with SCI.
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Barorreflejo , Biomimética , Hemodinámica , Prótesis e Implantes , Traumatismos de la Médula Espinal/fisiopatología , Traumatismos de la Médula Espinal/terapia , Animales , Modelos Animales de Enfermedad , Femenino , Humanos , Masculino , Vías Nerviosas , Primates , Ratas , Ratas Endogámicas Lew , Sistema Nervioso Simpático/citología , Sistema Nervioso Simpático/fisiologíaRESUMEN
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.
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Vejiga Urinaria , Infecciones Urinarias , Animales , Humanos , Vejiga Urinaria/cirugía , Urodinámica/fisiología , Prótesis e Implantes , CistectomíaRESUMEN
Advances in soft materials, miniaturized electronics, sensors, stimulators, radios, and battery-free power supplies are resulting in a new generation of fully implantable organ interfaces that leverage volumetric reduction and soft mechanics by eliminating electrochemical power storage. This device class offers the ability to provide high-fidelity readouts of physiological processes, enables stimulation, and allows control over organs to realize new therapeutic and diagnostic paradigms. Driven by seamless integration with connected infrastructure, these devices enable personalized digital medicine. Key to advances are carefully designed material, electrophysical, electrochemical, and electromagnetic systems that form implantables with mechanical properties closely matched to the target organ to deliver functionality that supports high-fidelity sensors and stimulators. The elimination of electrochemical power supplies enables control over device operation, anywhere from acute, to lifetimes matching the target subject with physical dimensions that supports imperceptible operation. This review provides a comprehensive overview of the basic building blocks of battery-free organ interfaces and related topics such as implantation, delivery, sterilization, and user acceptance. State of the art examples categorized by organ system and an outlook of interconnection and advanced strategies for computation leveraging the consistent power influx to elevate functionality of this device class over current battery-powered strategies is highlighted.
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Suministros de Energía Eléctrica , Tecnología Inalámbrica , Prótesis e Implantes , ElectrónicaRESUMEN
Soft robotics presents innovative solutions across different scales. The flexibility and mechanical characteristics of soft robots make them particularly appealing for wearable and implantable applications. The scale and level of invasiveness required for soft robots depend on the extent of human interaction. This review provides a comprehensive overview of wearable and implantable soft robots, including applications in rehabilitation, assistance, organ simulation, surgical tools, and therapy. We discuss challenges such as the complexity of fabrication processes, the integration of responsive materials, and the need for robust control strategies, while focusing on advances in materials, actuation and sensing mechanisms, and fabrication techniques. Finally, we discuss the future outlook, highlighting key challenges and proposing potential solutions.
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Prótesis e Implantes , Robótica , Dispositivos Electrónicos Vestibles , Humanos , Robótica/instrumentaciónRESUMEN
Implanted medical devices, from artificial heart valves and arthroscopic joints to implantable sensors, often induce a foreign body response (FBR), a form of chronic inflammation resulting from the inflammatory reaction to a persistent foreign stimulus. The FBR is characterized by a subset of multinucleated giant cells (MGCs) formed by macrophage fusion, the foreign body giant cells (FBGCs), accompanied by inflammatory cytokines, matrix deposition, and eventually deleterious fibrotic implant encapsulation. Despite efforts to improve biocompatibility, implant-induced FBR persists, compromising the utility of devices and making efforts to control the FBR imperative for long-term function. Controlling macrophage fusion in FBGC formation presents a logical target to prevent implant failure, but the actual contribution of FBGCs to FBR-induced damage is controversial. CD13 is a molecular scaffold, and in vitro induction of CD13KO bone marrow progenitors generates many more MGCs than the wild type, suggesting that CD13 regulates macrophage fusion. In the mesh implant model of FBR, CD13KO mice produced significantly more peri-implant FBGCs with enhanced TGF-ß expression and increased collagen deposition versus the wild type. Prior to fusion, increased protrusion and microprotrusion formation accompanies hyperfusion in the absence of CD13. Expression of fusogenic proteins driving cell-cell fusion was aberrantly sustained at high levels in CD13KO MGCs, which we show is due to a novel CD13 function, to our knowledge, regulating ubiquitin/proteasomal protein degradation. We propose CD13 as a physiologic brake limiting aberrant macrophage fusion and the FBR, and it may be a novel therapeutic target to improve the success of implanted medical devices. Furthermore, our data directly implicate FBGCs in the detrimental fibrosis that characterizes the FBR.
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Cuerpos Extraños , Reacción a Cuerpo Extraño , Ratones , Animales , Reacción a Cuerpo Extraño/inducido químicamente , Reacción a Cuerpo Extraño/metabolismo , Células Gigantes de Cuerpo Extraño/metabolismo , Inflamación/metabolismo , Cuerpos Extraños/metabolismo , Prótesis e Implantes/efectos adversos , UbiquitinaciónRESUMEN
Equilibrium bifurcation in natural systems can sometimes be explained as a route to stress shielding for preventing failure. Although compressive buckling has been known for a long time, its less-intuitive tensile counterpart was only recently discovered and yet never identified in living structures or organisms. Through the analysis of an unprecedented all-in-one paradigm of elastic instability, it is theoretically and experimentally shown that coexistence of two curvatures in human finger joints is the result of an optimal design by nature that exploits both compressive and tensile buckling for inducing luxation in case of traumas, so realizing a unique mechanism for protecting tissues and preventing more severe damage under extreme loads. Our findings might pave the way to conceive complex architectured and bio-inspired materials, as well as next generation artificial joint prostheses and robotic arms for bio-engineering and healthcare applications.
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Materiales Biomiméticos , Dedos , Humanos , Prótesis e ImplantesRESUMEN
Somatosensory neuroprostheses restore, replace, or enhance tactile and proprioceptive feedback for people with sensory impairments due to neurological disorders or injury. Somatosensory neuroprostheses typically couple sensor inputs from a wearable device, prosthesis, robotic device, or virtual reality system with electrical stimulation applied to the somatosensory nervous system via noninvasive or implanted interfaces. While prior research has mainly focused on technology development and proof-of-concept studies, recent acceleration of clinical studies in this area demonstrates the translational potential of somatosensory neuroprosthetic systems. In this review, we provide an overview of neurostimulation approaches currently undergoing human testing and summarize recent clinical findings on the perceptual, functional, and psychological impact of somatosensory neuroprostheses. We also cover current work toward the development of advanced stimulation paradigms to produce more natural and informative sensory feedback. Finally, we provide our perspective on the remaining challenges that need to be addressed prior to translation of somatosensory neuroprostheses.
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Corteza Somatosensorial , Humanos , Corteza Somatosensorial/fisiología , Retroalimentación Sensorial/fisiología , Investigación Biomédica Traslacional/tendencias , Investigación Biomédica Traslacional/métodos , Prótesis Neurales , Interfaces Cerebro-Computador/tendencias , Estimulación Eléctrica/métodos , Prótesis e Implantes/tendenciasRESUMEN
Insertable biosensor systems are medical diagnostic devices with two primary components: an implantable biosensor within the body and a wearable monitor that can remotely interrogate the biosensor from outside the body. Because the biosensor does not require a physical connection to the electronic monitor, insertable biosensor systems promise improved patient comfort, reduced inflammation and infection risk, and extended operational lifetimes relative to established percutaneous biosensor systems. However, the lack of physical connection also presents technical challenges that have necessitated new innovations in developing sensing chemistries, transduction methods, and communication modalities. In this review, we discuss the key developments that have made insertables a promising option for longitudinal biometric monitoring and highlight the essential needs and existing development challenges to realizing the next generation of insertables for extended-use diagnostic and prognostic devices.
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Técnicas Biosensibles , Diseño de Equipo , Dispositivos Electrónicos Vestibles , Técnicas Biosensibles/instrumentación , Técnicas Biosensibles/métodos , Humanos , Prótesis e Implantes , Monitoreo Fisiológico/instrumentación , Monitoreo Fisiológico/métodosRESUMEN
ConspectusThe coupling of magnetic and electric properties manifested in magnetoelectric (ME) materials has unlocked numerous possibilities for advancing technologies like energy harvesting, memory devices, and medical technologies. Due to this unique coupling, the magnetic properties of these materials can be tuned by an electric field; conversely, their electric polarization can be manipulated through a magnetic field.Over the past seven years, our lab work has focused on leveraging these materials to engineer implantable bioelectronics for various neuromodulation applications. One of the main challenges for bioelectronics is to design miniaturized solutions that can be delivered with minimally invasive procedures and yet can receive sufficient power to directly stimulate tissue or power electronics to perform functions like communication and sensing.Magnetoelectric coupling in ME materials is strongest when the driving field matches a mechanical resonant mode. However, miniaturized ME transducers typically have resonance frequencies >100 kHz, which is too high for direct neuromodulation as neurons only respond to low frequencies (typically <1 kHz). We discuss two approaches that have been proposed to overcome this frequency mismatch: operating off-resonance and rectification. The off-resonance approach is most common for magnetoelectric nanoparticles (MENPs) that typically have resonance frequencies in the gigahertz range. In vivo experiments on rat models have shown that MENPs could induce changes in neural activity upon excitation with <200 Hz magnetic fields. However, the neural response has latencies of several seconds due to the weak coupling in the off-resonance regime.To stimulate neural responses with millisecond precision, we developed methods to rectify the ME response so that we could drive the materials at their resonant frequency but still produce the slowly varying voltages needed for direct neural stimulation. The first version of the stimulator combined a ME transducer and analog electronics for rectification. To create even smaller solutions, we introduced the first magnetoelectric metamaterial (MNM) that exhibits self-rectification. Both designs have effectively induced neural modulation in rat models with less than 5 ms latency.Based on our experience with in vivo testing of the rectified ME stimulators, we found it challenging to deliver the precisely controlled therapy required for clinical applications, given the ME transducer's sensitivity to the external transmitter alignment. To overcome this challenge, we developed the ME-BIT (MagnetoElectric BioImplanT), a digitally programmable stimulator that receives wireless power and data through the ME link.We further expanded the utility of this technology to neuromodulation applications that require high stimulation thresholds by introducing the DOT (Digitally programmable Overbrain Therapeutic). The DOT has voltage compliance up to 14.5 V. We have demonstrated the efficacy of these designs through various in vivo studies for applications like peripheral nerve stimulation and epidural cortical stimulation.To further improve these systems to be adaptive and enable a network of coordinated devices, we developed a bidirectional communication system to transmit data to and from the implant. To enable even greater miniaturization, we developed a way to use the same ME transducer for wireless power and data communication by developing the first ME backscatter communication protocol.
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Prótesis e Implantes , Animales , Humanos , Ratas , Electrónica/instrumentaciónRESUMEN
Flying insects capable of navigating in highly cluttered natural environments can withstand in-flight collisions because of the combination of their low inertia1 and the resilience of their wings2, exoskeletons1 and muscles. Current insect-scale (less than ten centimetres long and weighing less than five grams) aerial robots3-6 use rigid microscale actuators, which are typically fragile under external impact. Biomimetic artificial muscles7-10 that are capable of large deformation offer a promising alternative for actuation because they can endure the stresses caused by such impacts. However, existing soft actuators11-13 have not yet demonstrated sufficient power density to achieve lift-off, and their actuation nonlinearity and limited bandwidth create further challenges for achieving closed-loop (driven by an input control signal that is adjusted based on sensory feedback) flight control. Here we develop heavier-than-air aerial robots powered by soft artificial muscles that demonstrate open-loop (driven by a predetermined signal without feedback), passively stable (upright during flight) ascending flight as well as closed-loop, hovering flight. The robots are driven by multi-layered dielectric elastomer actuators that weigh 100 milligrams each and have a resonance frequency of 500 hertz and power density of 600 watts per kilogram. To increase the mechanical power output of the actuator and to demonstrate flight control, we present ways to overcome challenges unique to soft actuators, such as nonlinear transduction and dynamic buckling. These robots can sense and withstand collisions with surrounding obstacles and can recover from in-flight collisions by exploiting material robustness and vehicle passive stability. We also fly two micro-aerial vehicles simultaneously in a cluttered environment. They collide with the wall and each other without suffering damage. These robots rely on offboard amplifiers and an external motion-capture system to provide power to the dielectric elastomer actuators and to control their flight. Our work demonstrates how soft actuators can achieve sufficient power density and bandwidth to enable controlled flight, illustrating the potential of developing next-generation agile soft robots.