An implantable piezoelectric ultrasound stimulator (ImPULS) for deep brain activation.

Precise neurostimulation can revolutionize therapies for neurological disorders. Electrode-based stimulation devices face challenges in achieving precise and consistent targeting due to the immune response and the limited penetration of electrical fields. Ultrasound can aid in energy propagation, but transcranial ultrasound stimulation in the deep brain has limited spatial resolution caused by bone and tissue scattering. Here, we report an implantable piezoelectric ultrasound stimulator (ImPULS) that generates an ultrasonic focal pressure of 100 kPa to modulate the activity of neurons. ImPULS is a fully-encapsulated, flexible piezoelectric micromachined ultrasound transducer that incorporates a biocompatible piezoceramic, potassium sodium niobate [(K,Na)NbO3]. The absence of electrochemically active elements poses a new strategy for achieving long-term stability. We demonstrated that ImPULS can i) excite neurons in a mouse hippocampal slice ex vivo, ii) activate cells in the hippocampus of an anesthetized mouse to induce expression of activity-dependent gene c-Fos, and iii) stimulate dopaminergic neurons in the substantia nigra pars compacta to elicit time-locked modulation of nigrostriatal dopamine release. This work introduces a non-genetic ultrasound platform for spatially-localized neural stimulation and exploration of basic functions in the deep brain.

A Dynamic Ultrasound Phantom with Tissue-Mimicking Mechanical and Acoustic Properties.

Tissue-mimicking phantoms are valuable tools that aid in improving the equipment and training available to medical professionals. However, current phantoms possess limited utility due to their inability to precisely simulate multiple physical properties simultaneously, which is crucial for achieving a system understanding of dynamic human tissues. In this work, novel materials design and fabrication processes to produce various tissue-mimicking materials (TMMs) for skin, adipose, muscle, and soft tissue at a human scale are developed. Target properties (Young's modulus, density, speed of sound, and acoustic attenuation) are first defined for each TMM based on literature. Each TMM recipe is developed, associated mechanical and acoustic properties are characterized, and the TMMs are confirmed to have comparable mechanical and acoustic properties with the corresponding human tissues. Furthermore, a novel sacrificial core to fabricate a hollow, ellipsoid-shaped bladder phantom complete with inlet and outlet tubes, which allow liquids to flow through and expand this phantom, is adopted. This dynamic bladder phantom with realistic mechanical and acoustic properties to human tissues in combination with the developed skin, soft tissue, and subcutaneous adipose tissue TMMs, culminates in a human scale torso tank and electro-mechanical system that can be systematically utilized for characterizing various medical imaging devices.

An Emerging Era: Conformable Ultrasound Electronics.

Conformable electronics are regarded as the next generation of personal healthcare monitoring and remote diagnosis devices. In recent years, piezoelectric-based conformable ultrasound electronics (cUSE) have been intensively studied due to their unique capabilities, including nonradiative monitoring, soft tissue imaging, deep signal decoding, wireless power transfer, portability, and compatibility. This review provides a comprehensive understanding of cUSE for use in biomedical and healthcare monitoring systems and a summary of their recent advancements. Following an introduction to the fundamentals of piezoelectrics and ultrasound transducers, the critical parameters for transducer design are discussed. Next, five types of cUSE with their advantages and limitations are highlighted, and the fabrication of cUSE using advanced technologies is discussed. In addition, the working function, acoustic performance, and accomplishments in various applications are thoroughly summarized. It is noted that application considerations must be given to the tradeoffs between material selection, manufacturing processes, acoustic performance, mechanical integrity, and the entire integrated system. Finally, current challenges and directions for the development of cUSE are highlighted, and research flow is provided as the roadmap for future research. In conclusion, these advances in the fields of piezoelectric materials, ultrasound transducers, and conformable electronics spark an emerging era of biomedicine and personal healthcare.

Conformable ultrasound breast patch for deep tissue scanning and imaging.

Ultrasound is widely used for tissue imaging such as breast cancer diagnosis; however, fundamental challenges limit its integration with wearable technologies, namely, imaging over large-area curvilinear organs. We introduced a wearable, conformable ultrasound breast patch (cUSBr-Patch) that enables standardized and reproducible image acquisition over the entire breast with less reliance on operator training and applied transducer compression. A nature-inspired honeycomb-shaped patch combined with a phased array is guided by an easy-to-operate tracker that provides for large-area, deep scanning, and multiangle breast imaging capability. The in vitro studies and clinical trials reveal that the array using a piezoelectric crystal [Yb/Bi-Pb(In1/2Nb1/2)O3-Pb(Mg1/3Nb2/3)O3-PbTiO3] (Yb/Bi-PIN-PMN-PT) exhibits a sufficient contrast resolution (~3 dB) and axial/lateral resolutions of 0.25/1.0 mm at 30 mm depth, allowing the observation of small cysts (~0.3 cm) in the breast. This research develops a first-of-its-kind ultrasound technology for breast tissue scanning and imaging that offers a noninvasive method for tracking real-time dynamic changes of soft tissue.

Technology Roadmap for Flexible Sensors.

Humans rely increasingly on sensors to address grand challenges and to improve quality of life in the era of digitalization and big data. For ubiquitous sensing, flexible sensors are developed to overcome the limitations of conventional rigid counterparts. Despite rapid advancement in bench-side research over the last decade, the market adoption of flexible sensors remains limited. To ease and to expedite their deployment, here, we identify bottlenecks hindering the maturation of flexible sensors and propose promising solutions. We first analyze challenges in achieving satisfactory sensing performance for real-world applications and then summarize issues in compatible sensor-biology interfaces, followed by brief discussions on powering and connecting sensor networks. Issues en route to commercialization and for sustainable growth of the sector are also analyzed, highlighting environmental concerns and emphasizing nontechnical issues such as business, regulatory, and ethical considerations. Additionally, we look at future intelligent flexible sensors. In proposing a comprehensive roadmap, we hope to steer research efforts towards common goals and to guide coordinated development strategies from disparate communities. Through such collaborative efforts, scientific breakthroughs can be made sooner and capitalized for the betterment of humanity.

A Conformable Ultrasound Patch for Cavitation-Enhanced Transdermal Cosmeceutical Delivery.

Increased consumer interest in healthy-looking skin demands a safe and effective method to increase transdermal absorption of innovative therapeutic cosmeceuticals. However, permeation of small-molecule drugs is limited by the innate barrier function of the stratum corneum. Here, a conformable ultrasound patch (cUSP) that enhances transdermal transport of niacinamide by inducing intermediate-frequency sonophoresis in the fluid coupling medium between the patch and the skin is reported. The cUSP consists of piezoelectric transducers embedded in a soft elastomer to create localized cavitation pockets (0.8 cm2 , 1 mm deep) over larger areas of conformal contact (20 cm2 ). Multiphysics simulation models, acoustic spectrum analysis, and high-speed videography are used to characterize transducer deflection, acoustic pressure fields, and resulting cavitation bubble dynamics in the coupling medium. The final system demonstrates a 26.2-fold enhancement in niacinamide transport in a porcine model in vitro with a 10 min ultrasound application, demonstrating the suitability of the device for short-exposure, large-area application of sonophoresis for patients and consumers suffering from skin conditions and premature skin aging.

On-Body Piezoelectric Energy Harvesters through Innovative Designs and Conformable Structures.

Recent advancements in wearable technology have improved lifestyle and medical practices, enabling personalized care ranging from fitness tracking, to real-time health monitoring, to predictive sensing. Wearable devices serve as an interface between humans and technology; however, this integration is far from seamless. These devices face various limitations such as size, biocompatibility, and battery constraints wherein batteries are bulky, are expensive, and require regular replacement. On-body energy harvesting presents a promising alternative to battery power by utilizing the human body's continuous generation of energy. This review paper begins with an investigation of contemporary energy harvesting methods, with a deep focus on piezoelectricity. We then highlight the materials, configurations, and structures of such methods for self-powered devices. Here, we propose a novel combination of thin-film composites, kirigami patterns, and auxetic structures to lay the groundwork for an integrated piezoelectric system to monitor and sense. This approach has the potential to maximize energy output by amplifying the piezoelectric effect and manipulating the strain distribution. As a departure from bulky, rigid device design, we explore compositions and microfabrication processes for conformable energy harvesters. We conclude by discussing the limitations of these harvesters and future directions that expand upon current applications for wearable technology. Further exploration of materials, configurations, and structures introduce interdisciplinary applications for such integrated systems. Considering these factors can revolutionize the production and consumption of energy as wearable technology becomes increasingly prevalent in everyday life.

Decoding of facial strains via conformable piezoelectric interfaces.

Devices that facilitate nonverbal communication typically require high computational loads or have rigid and bulky form factors that are unsuitable for use on the face or on other curvilinear body surfaces. Here, we report the design and pilot testing of an integrated system for decoding facial strains and for predicting facial kinematics. The system consists of mass-manufacturable, conformable piezoelectric thin films for strain mapping; multiphysics modelling for analysing the nonlinear mechanical interactions between the conformable device and the epidermis; and three-dimensional digital image correlation for reconstructing soft-tissue surfaces under dynamic deformations as well as for informing device design and placement. In healthy individuals and in patients with amyotrophic lateral sclerosis, we show that the piezoelectric thin films, coupled with algorithms for the real-time detection and classification of distinct skin-deformation signatures, enable the reliable decoding of facial movements. The integrated system could be adapted for use in clinical settings as a nonverbal communication technology or for use in the monitoring of neuromuscular conditions.

Simultaneous recording and marking of brain microstructures.

The vast majority of techniques to study the physiology of the nervous system involve inserting probes into the brain for stimulation, recording, or sampling. Research is increasingly uncovering the fine microstructure of the brain, each of its regions with dedicated functions. Accurate knowledge of the placement of probes interrogating these regions is critical. We have developed a customizable concentric marking electrode (CME) consisting of an iron core within a 125 µm-stainless steel (SS) sheath for co-localization of targeted regions in the brain. We used a dielectric layer stack of SiO2, Al2O3, SiO2 to electrically encapsulate the iron core and minimize exposure area to avoid significant increases in inflammatory response triggered by the probes. The CME can record multi-neuronal extracellular firing patterns. Appropriate electrical polarity of the iron and SS components controls the deposition of iron microdeposits on brain tissue. We show that in vivo labels by this method can be as small as 100 µm, visible via noninvasive magnetic resonance imaging (MRI) as well as post-mortem histology, and illustrate how deposit size can be tuned by varying stimulus parameters. We targeted the CA3 area of the hippocampus in adult rats and demonstrate that iron microdeposits are remarkably stable and persist up to 10 months post-deposition. Using a single probe for recording and marking avoids inaccuracies with re-insertion of separate probes and utilizes iron microdeposits as valuable fiducial markers in vivo and ex vivo.

The Future of Neuroimplantable Devices: A Materials Science and Regulatory Perspective.

The past two decades have seen unprecedented progress in the development of novel materials, form factors, and functionalities in neuroimplantable technologies, including electrocorticography (ECoG) systems, multielectrode arrays (MEAs), Stentrode, and deep brain probes. The key considerations for the development of such devices intended for acute implantation and chronic use, from the perspective of biocompatible hybrid materials incorporation, conformable device design, implantation procedures, and mechanical and biological risk factors, are highlighted. These topics are connected with the role that the U.S. Food and Drug Administration (FDA) plays in its regulation of neuroimplantable technologies based on the above parameters. Existing neuroimplantable devices and efforts to improve their materials and implantation protocols are first discussed in detail. The effects of device implantation with regards to biocompatibility and brain heterogeneity are then explored. Topics examined include brain-specific risk factors, such as bacterial infection, tissue scarring, inflammation, and vasculature damage, as well as efforts to manage these dangers through emerging hybrid, bioelectronic device architectures. The current challenges of gaining clinical approval by the FDA-in particular, with regards to biological, mechanical, and materials risk factors-are summarized. The available regulatory pathways to accelerate next-generation neuroimplantable devices to market are then discussed.

A tailored, electronic textile conformable suit for large-scale spatiotemporal physiological sensing in vivo.

The rapid advancement of electronic devices and fabrication technologies has further promoted the field of wearables and smart textiles. However, most of the current efforts in textile electronics focus on a single modality and cover a small area. Here, we have developed a tailored, electronic textile conformable suit (E-TeCS) to perform large-scale, multimodal physiological (temperature, heart rate, and respiration) sensing in vivo. This platform can be customized for various forms, sizes and functions using standard, accessible and high-throughput textile manufacturing and garment patterning techniques. Similar to a compression shirt, the soft and stretchable nature of the tailored E-TeCS allows intimate contact between electronics and the skin with a pressure value of around ~25 mmHg, allowing for physical comfort and improved precision of sensor readings on skin. The E-TeCS can detect skin temperature with an accuracy of 0.1 °C and a precision of 0.01 °C, as well as heart rate and respiration with a precision of 0.0012 m/s2 through mechano-acoustic inertial sensing. The knit textile electronics can be stretched up to 30% under 1000 cycles of stretching without significant degradation in mechanical and electrical performance. Experimental and theoretical investigations are conducted for each sensor modality along with performing the robustness of sensor-interconnects, washability, and breathability of the suit. Collective results suggest that our E-TeCS can simultaneously and wirelessly monitor 30 skin temperature nodes across the human body over an area of 1500 cm2, during seismocardiac events and respiration, as well as physical activity through inertial dynamics.

Focal, remote-controlled, chronic chemical modulation of brain microstructures.

Direct delivery of fluid to brain parenchyma is critical in both research and clinical settings. This is usually accomplished through acutely inserted cannulas. This technique, however, results in backflow and significant dispersion away from the infusion site, offering little spatial or temporal control in delivering fluid. We present an implantable, MRI-compatible, remotely controlled drug delivery system for minimally invasive interfacing with brain microstructures in freely moving animals. We show that infusions through acutely inserted needles target a region more than twofold larger than that of identical infusions through chronically implanted probes due to reflux and backflow. We characterize the dynamics of in vivo infusions using positron emission tomography techniques. Volumes as small as 167 nL of copper-64 and fludeoxyglucose labeled agents are quantified. We further demonstrate the importance of precise drug volume dosing to neural structures to elicit behavioral effects reliably. Selective modulation of the substantia nigra, a critical node in basal ganglia circuitry, via muscimol infusion induces behavioral changes in a volume-dependent manner, even when the total dose remains constant. Chronic device viability is confirmed up to 1-y implantation in rats. This technology could potentially enable precise investigation of neurological disease pathology in preclinical models, and more efficacious treatment in human patients.

Miniaturized neural system for chronic, local intracerebral drug delivery.

Recent advances in medications for neurodegenerative disorders are expanding opportunities for improving the debilitating symptoms suffered by patients. Existing pharmacologic treatments, however, often rely on systemic drug administration, which result in broad drug distribution and consequent increased risk for toxicity. Given that many key neural circuitries have sub-cubic millimeter volumes and cell-specific characteristics, small-volume drug administration into affected brain areas with minimal diffusion and leakage is essential. We report the development of an implantable, remotely controllable, miniaturized neural drug delivery system permitting dynamic adjustment of therapy with pinpoint spatial accuracy. We demonstrate that this device can chemically modulate local neuronal activity in small (rodent) and large (nonhuman primate) animal models, while simultaneously allowing the recording of neural activity to enable feedback control.

Energy Harvesting from the Animal/Human Body for Self-Powered Electronics.

Living subjects (i.e., humans and animals) have abundant sources of energy in chemical, thermal, and mechanical forms. The use of these energies presents a viable way to overcome the battery capacity limitation that constrains the long-term operation of wearable/implantable devices. The intersection of novel materials and fabrication techniques offers boundless possibilities for the benefit of human health and well-being via various types of energy harvesters. This review summarizes the existing approaches that have been demonstrated to harvest energy from the bodies of living subjects for self-powered electronics. We present material choices, device layouts, and operation principles of these energy harvesters with a focus on in vivo applications. We discuss a broad range of energy harvesters placed in or on various body parts of human and animal models. We conclude with an outlook of future research in which the integration of various energy harvesters with advanced electronics can provide a new platform for the development of novel technologies for disease diagnostics, treatment, and prevention.

Flexible piezoelectric devices for gastrointestinal motility sensing.

Improvements in ingestible electronics with the capacity to sense physiological and pathophysiological states have transformed the standard of care for patients. Yet, despite advances in device development, significant risks associated with solid, non-flexible gastrointestinal transiting systems remain. Here, we report the design and use of an ingestible, flexible piezoelectric device that senses mechanical deformation within the gastric cavity. We demonstrate the capabilities of the sensor in both in vitro and ex vivo simulated gastric models, quantify its key behaviours in the gastrointestinal tract using computational modelling and validate its functionality in awake and ambulating swine. Our proof-of-concept device may lead to the development of ingestible piezoelectric devices that might safely sense mechanical variations and harvest mechanical energy inside the gastrointestinal tract for the diagnosis and treatment of motility disorders, as well as for monitoring ingestion in bariatric applications.

Computational models for the determination of depth-dependent mechanical properties of skin with a soft, flexible measurement device.

Conformal modulus sensors (CMS) incorporate PZT nanoribbons as mechanical actuators and sensors to achieve reversible conformal contact with the human skin for non-invasive, in vivo measurements of skin modulus. An analytic model presented in this paper yields expressions that connect the sensor output voltage to the Young moduli of the epidermis and dermis, the thickness of the epidermis, as well as the material and geometrical parameters of the CMS device itself and its encapsulation layer. Results from the model agree well with in vitro experiments on bilayer structures of poly(dimethylsiloxane). These results provide a means to determine the skin moduli (epidermis and dermis) and the thickness of the epidermis from in vivo measurements of human skin.

Shear Piezoelectricity in Poly(vinylidenefluoride-co-trifluoroethylene): Full Piezotensor Coefficients by Molecular Modeling, Biaxial Transverse Response, and Use in Suspended Energy-Harvesting Nanostructures.

The intrinsic flexible character of polymeric materials causes remarkable strain deformations along directions perpendicular to the applied stress. The biaxial response in the shear piezoelectricity of polyvinylidenefluoride copolymers is analyzed and their full piezoelectric tensors are provided. The microscopic shear is exploited in single suspended nanowires bent by localized loading to couple flexural deformation and transverse piezoelectric response.

Conformal piezoelectric systems for clinical and experimental characterization of soft tissue biomechanics.

Mechanical assessment of soft biological tissues and organs has broad relevance in clinical diagnosis and treatment of disease. Existing characterization methods are invasive, lack microscale spatial resolution, and are tailored only for specific regions of the body under quasi-static conditions. Here, we develop conformal and piezoelectric devices that enable in vivo measurements of soft tissue viscoelasticity in the near-surface regions of the epidermis. These systems achieve conformal contact with the underlying complex topography and texture of the targeted skin, as well as other organ surfaces, under both quasi-static and dynamic conditions. Experimental and theoretical characterization of the responses of piezoelectric actuator-sensor pairs laminated on a variety of soft biological tissues and organ systems in animal models provide information on the operation of the devices. Studies on human subjects establish the clinical significance of these devices for rapid and non-invasive characterization of skin mechanical properties.