Lead-free dual-frequency ultrasound implants for wireless, biphasic deep brain stimulation.

Ultrasound-driven bioelectronics could offer a wireless scheme with sustainable power supply; however, current ultrasound implantable systems present critical challenges in biocompatibility and harvesting performance related to lead/lead-free piezoelectric materials and devices. Here, we report a lead-free dual-frequency ultrasound implants for wireless, biphasic deep brain stimulation, which integrates two developed lead-free sandwich porous 1-3-type piezoelectric composite elements with enhanced harvesting performance in a flexible printed circuit board. The implant is ultrasonically powered through a portable external dual-frequency transducer and generates programmable biphasic stimulus pulses in clinically relevant frequencies. Furthermore, we demonstrate ultrasound-driven implants for long-term biosafety therapy in deep brain stimulation through an epileptic rodent model. With biocompatibility and improved electrical performance, the lead-free materials and devices presented here could provide a promising platform for developing implantable ultrasonic electronics in the future.

Noninvasive imaging-guided ultrasonic neurostimulation with arbitrary 2D patterns and its application for high-quality vision restoration.

Retinal degeneration, a leading cause of irreversible low vision and blindness globally, can be partially addressed by retina prostheses which stimulate remaining neurons in the retina. However, existing electrode-based treatments are invasive, posing substantial risks to patients and healthcare providers. Here, we introduce a completely noninvasive ultrasonic retina prosthesis, featuring a customized ultrasound two-dimensional array which allows for simultaneous imaging and stimulation. With synchronous three-dimensional imaging guidance and auto-alignment technology, ultrasonic retina prosthesis can generate programmed ultrasound waves to dynamically and precisely form arbitrary wave patterns on the retina. Neuron responses in the brain's visual center mirrored these patterns, evidencing successful artificial vision creation, which was further corroborated in behavior experiments. Quantitative analysis of the spatial-temporal resolution and field of view demonstrated advanced performance of ultrasonic retina prosthesis and elucidated the biophysical mechanism of retinal stimulation. As a noninvasive blindness prosthesis, ultrasonic retina prosthesis could lead to a more effective, widely acceptable treatment for blind patients. Its real-time imaging-guided stimulation strategy with a single ultrasound array, could also benefit ultrasound neurostimulation in other diseases.

Integrating a Fundus Camera with High-Frequency Ultrasound for Precise Ocular Lesion Assessment.

Ultrasound A-scan is an important tool for quantitative assessment of ocular lesions. However, its usability is limited by the difficulty of accurately localizing the ultrasound probe to a lesion of interest. In this study, a transparent LiNbO3 single crystal ultrasound transducer was fabricated, and integrated with a widefield fundus camera to guide the ultrasound local position. The electrical impedance, phase spectrum, pulse-echo performance, and optical transmission spectrum of the ultrasound transducer were validated. The novel fundus camera-guided ultrasound probe was tested for in vivo measurement of rat eyes. Anterior and posterior segments of the rat eye could be unambiguously differentiated with the fundus photography-guided ultrasound measurement. A model eye was also used to verify the imaging performance of the prototype device in the human eye. The prototype shows the potential of being used in the clinic to accurately measure the thickness and echogenicity of ocular lesions in vivo.

Ultrasound Flow Imaging Study on Rat Brain with Ultrasound and Light Stimulations.

Functional ultrasound (fUS) flow imaging provides a non-invasive method for the in vivo study of cerebral blood flow and neural activity. This study used functional flow imaging to investigate rat brain's response to ultrasound and colored-light stimuli. Male Long-Evan rats were exposed to direct full-field strobe flashes light and ultrasound stimulation to their retinas, while brain activity was measured using high-frequency ultrasound imaging. Our study found that light stimuli, particularly blue light, elicited strong responses in the visual cortex and lateral geniculate nucleus (LGN), as evidenced by changes in cerebral blood volume (CBV). In contrast, ultrasound stimulation elicited responses undetectable with fUS flow imaging, although these were observable when directly measuring the brain's electrical signals. These findings suggest that fUS flow imaging can effectively differentiate neural responses to visual stimuli, with potential applications in understanding visual processing and developing new diagnostic tools.

Wearable bioadhesive ultrasound shear wave elastography.

Acute liver failure (ALF) is a critical medical condition defined as the rapid development of hepatic dysfunction. Conventional ultrasound elastography cannot continuously monitor liver stiffness over the course of rapidly changing diseases for early detection due to the requirement of a handheld probe. In this study, we introduce wearable bioadhesive ultrasound elastography (BAUS-E), which can generate acoustic radiation force impulse (ARFI) to induce shear waves for the continuous monitoring of modulus changes. BAUS-E contains 128 channels with a compact design with only 24 mm in the azimuth direction for comfortable wearability. We further used BAUS-E to continuously monitor the stiffness of in vivo rat livers with ALF induced by d-galactosamine over 48 hours, and the stiffness change was observed within the first 6 hours. BAUS-E holds promise for clinical applications, particularly in patients after organ transplantation or postoperative care in the intensive care unit (ICU).

Ultrafast longitudinal imaging of haemodynamics via single-shot volumetric photoacoustic tomography with a single-element detector.

Techniques for imaging haemodynamics use ionizing radiation or contrast agents or are limited by imaging depth (within approximately 1 mm), complex and expensive data-acquisition systems, or low imaging speeds, system complexity or cost. Here we show that ultrafast volumetric photoacoustic imaging of haemodynamics in the human body at up to 1 kHz can be achieved using a single laser pulse and a single element functioning as 6,400 virtual detectors. The technique, which does not require recalibration for different objects or during long-term operation, enables the longitudinal volumetric imaging of haemodynamics in vasculature a few millimetres below the skin's surface. We demonstrate this technique in vessels in the feet of healthy human volunteers by capturing haemodynamic changes in response to vascular occlusion. Single-shot volumetric photoacoustic imaging using a single-element detector may facilitate the early detection and monitoring of peripheral vascular diseases and may be advantageous for use in biometrics and point-of-care testing.

Growing recyclable and healable piezoelectric composites in 3D printed bioinspired structure for protective wearable sensor.

Bionic multifunctional structural materials that are lightweight, strong, and perceptible have shown great promise in sports, medicine, and aerospace applications. However, smart monitoring devices with integrated mechanical protection and piezoelectric induction are limited. Herein, we report a strategy to grow the recyclable and healable piezoelectric Rochelle salt crystals in 3D-printed cuttlebone-inspired structures to form a new composite for reinforcement smart monitoring devices. In addition to its remarkable mechanical and piezoelectric performance, the growth mechanisms, the recyclability, the sensitivity, and repairability of the 3D-printed Rochelle salt cuttlebone composite were studied. Furthermore, the versatility of composite has been explored and applied as smart sensor armor for football players and fall alarm knee pads, focusing on incorporated mechanical reinforcement and electrical self-sensing capabilities with data collection of the magnitude and distribution of impact forces, which offers new ideas for the design of next-generation smart monitoring electronics in sports, military, aerospace, and biomedical engineering.

Non-Invasive Hybrid Ultrasound Stimulation of Visual Cortex In Vivo.

The optic nerve is the second cranial nerve (CN II) that connects and transmits visual information between the retina and the brain. Severe damage to the optic nerve often leads to distorted vision, vision loss, and even blindness. Such damage can be caused by various types of degenerative diseases, such as glaucoma and traumatic optic neuropathy, and result in an impaired visual pathway. To date, researchers have not found a viable therapeutic method to restore the impaired visual pathway; however, in this paper, a newly synthesized model is proposed to bypass the damaged portion of the visual pathway and set up a direct connection between a stimulated visual input and the visual cortex (VC) using Low-frequency Ring-transducer Ultrasound Stimulation (LRUS). In this study, by utilizing and integrating various advanced ultrasonic and neurological technologies, the following advantages are achieved by the proposed LRUS model: 1. This is a non-invasive procedure that uses enhanced sound field intensity to overcome the loss of ultrasound signal due to the blockage of the skull. 2. The simulated visual signal generated by LRUS in the visual-cortex-elicited neuronal response in the visual cortex is comparable to light stimulation of the retina. The result was confirmed by a combination of real-time electrophysiology and fiber photometry. 3. VC showed a faster response rate under LRUS than light stimulation through the retina. These results suggest a potential non-invasive therapeutic method for restoring vision in optic-nerve-impaired patients using ultrasound stimulation (US).

3D Printing and processing of miniaturized transducers with near-pristine piezoelectric ceramics for localized cavitation.

The performance of ultrasonic transducers is largely determined by the piezoelectric properties and geometries of their active elements. Due to the brittle nature of piezoceramics, existing processing tools for piezoelectric elements only achieve simple geometries, including flat disks, cylinders, cubes and rings. While advances in additive manufacturing give rise to free-form fabrication of piezoceramics, the resultant transducers suffer from high porosity, weak piezoelectric responses, and limited geometrical flexibility. We introduce optimized piezoceramic printing and processing strategies to produce highly responsive piezoelectric microtransducers that operate at ultrasonic frequencies. The 3D printed dense piezoelectric elements achieve high piezoelectric coefficients and complex architectures. The resulting piezoelectric charge constant, d33, and coupling factor, kt, of the 3D printed piezoceramic reach 583 pC/N and 0.57, approaching the properties of pristine ceramics. The integrated printing of transducer packaging materials and 3D printed piezoceramics with microarchitectures create opportunities for miniaturized piezoelectric ultrasound transducers capable of acoustic focusing and localized cavitation within millimeter-sized channels, leading to miniaturized ultrasonic devices that enable a wide range of biomedical applications.

Single-shot 3D photoacoustic tomography using a single-element detector for ultrafast imaging of hemodynamics.

Imaging hemodynamics is crucial for the diagnosis, treatment, and prevention of vascular diseases. However, current imaging techniques are limited due to the use of ionizing radiation or contrast agents, short penetration depth, or complex and expensive data acquisition systems. Photoacoustic tomography shows promise as a solution to these issues. However, existing photoacoustic tomography methods collect signals either sequentially or through numerous detector elements, leading to either low imaging speed or high system complexity and cost. To address these issues, here we introduce a method to capture a 3D photoacoustic image of vasculature using a single laser pulse and a single-element detector that functions as 6,400 virtual ones. Our method enables ultrafast volumetric imaging of hemodynamics in the human body at up to 1 kHz and requires only a single calibration for different objects and for long-term operations. We demonstrate 3D imaging of hemodynamics at depth in humans and small animals, capturing the variability in blood flow speeds. This concept can inspire other imaging technologies and find applications such as home-care monitoring, biometrics, point-of-care testing, and wearable monitoring.

High-speed wide-field photoacoustic microscopy using a cylindrically focused transparent high-frequency ultrasound transducer.

Combining focused optical excitation and high-frequency ultrasound detection, optical-resolution photoacoustic microscopy (OR-PAM) can provide micrometer-level spatial resolution with millimeter-level penetration depth and has been employed in a variety of biomedical applications. However, it remains a challenge for OR-PAM to achieve a high imaging speed and a large field of view at the same time. In this work, we report a new approach to implement high-speed wide-field OR-PAM, using a cylindrically-focused transparent ultrasound transducer (CFT-UT). The CFT-UT is made of transparent lithium niobate coated with indium-tin-oxide as electrodes. A transparent cylindrical lens is attached to the transducer surface to provide an acoustic focal line with a length of 9 mm. The excitation light can pass directly through the CFT-UT from the above and thus enables a reflection imaging mode. High-speed imaging is achieved by fast optical scanning of the focused excitation light along the CFT-UT focal line. With the confocal alignment of the optical excitation and acoustic detection, a relatively high detection sensitivity is maintained over the entire scanning range. The CFT-UT-based OR-PAM system has achieved a cross-sectional frame rate of 500 Hz over the scanning range of 9 mm. We have characterized the system's performance on phantoms and demonstrated its application on small animal models in vivo. We expect the new CFT-UT-based OR-PAM will find matched biomedical applications that need high imaging speed over a large field of view.

2-D Array Design and Fabrication With Pitch-Shifting Interposer at Frequencies From 4 MHz up to 10 MHz.

High element density and strict constraints of the element's size have significantly limited the design and fabrication of 2-D ultrasonic arrays, especially fully sampled 2-D arrays. Recently, 3-D printing technology has been one of the most rapidly developing fields. Along with the great progress of 3-D printing technology, complex and detailed 3-D structures have become readily available with a short iteration cycle, which allows us to reduce the complexity of routing and helps to ameliorate assembly problems in 2-D ultrasound array fabrication. In this work, we designed and fabricated 2-D ultrasound arrays for an array of applications with a pitch-shifting interposer, which allowed us to fit different array designs with the same circuit design and significantly reduce the requirements in routing and connection for 2-D array fabrication at frequencies from 4 to 10 MHz. Results demonstrated that this design would make 2-D arrays more available and affordable.

Flexible ultrasound-induced retinal stimulating piezo-arrays for biomimetic visual prostheses.

Electronic visual prostheses, or biomimetic eyes, have shown the feasibility of restoring functional vision in the blind through electrical pulses to initiate neural responses artificially. However, existing visual prostheses predominantly use wired connections or electromagnetic waves for powering and data telemetry, which raises safety concerns or couples inefficiently to miniaturized implant units. Here, we present a flexible ultrasound-induced retinal stimulating piezo-array that can offer an alternative wireless artificial retinal prosthesis approach for evoking visual percepts in blind individuals. The device integrates a two-dimensional piezo-array with 32-pixel stimulating electrodes in a flexible printed circuit board. Each piezo-element can be ultrasonically and individually activated, thus, spatially reconfigurable electronic patterns can be dynamically applied via programmable ultrasound beamlines. As a proof of concept, we demonstrate the ultrasound-induced pattern reconstruction in ex vivo murine retinal tissue, showing the potential of this approach to restore functional, life-enhancing vision in people living with blindness.

Flexible lead-free piezoelectric arrays for high-efficiency wireless ultrasonic energy transfer and communication.

Implantable medical electronics (IMEs) are now becoming increasingly prevalent for diagnostic and therapeutic purposes. Despite extensive efforts, a primary challenge for IMEs is reliable wireless power and communication to provide well-controlled, therapeutically relevant effects. Ultrasonic energy transfer and communication (UETC) employing traveling ultrasound waves to transmit energy has emerged as a promising wireless strategy for IMEs. Nevertheless, conventional UETC systems are rigid, bulky, and based on toxic lead-based piezoelectric materials, raising efficiency and safety concerns. Here, we present a novel transcutaneous UETC system based on a two-dimensional flexible lead-free piezoelectric array (f-LFPA) that hybridizes high-performance (piezoelectric coefficient d33 ≈ 503 pC N-1) (K,Na)NbO3-based eco-friendly piezo-units with soft structural components. The newly developed lead-free piezo-unit exhibits submicron ferroelectric domains and superior energy harvesting figures of merit (d33g33 ≈ 20 000 × 10-15 m2 N-1), resulting in the prepared f-LFPA demonstrating a high output voltage of 22.4 V, a power density of 0.145 W cm-2, and a signal-to-noise ratio of more than 30 dB within the FDA safety limits, while maintaining the flexibility for wide-angle receiving. Further ex vivo experiment demonstrates the adequate power supply capabilities of the f-LFPA and its possible application in future implantable eco-friendly bioelectronics for diagnostics, therapy, and real-time monitoring.

Potassium Sodium Niobate-Based Lead-Free High-Frequency Ultrasonic Transducers for Multifunctional Acoustic Tweezers.

Ultrasonic transducers may need to operate in direct contact with the human body, especially with the skin or closer to blood vessels. Eco-friendly lead-free materials and devices are therefore being vigorously developed for biosafety considerations. This work presents high-performance potassium sodium niobate [(K,Na)NbO3, KNN]-based lead-free ceramics with composition-driven multiphase coexistence and their application on high-frequency ultrasonic transducers for multifunctional acoustic tweezers. A high piezoelectric constant d33 value of 332 pC/N, a good Curie temperature TC value of 348 °C, and improved in situ temperature stability were obtained in the piezoceramics via the construction multiple phases near room temperature and domain engineering. One to three piezocomposites were further fabricated based on the synthesized ceramics for higher electromechanical coupling properties. Lead-free high-frequency transducers as multifunctional acoustic tweezers for precise and selective manipulation of microparticles were designed and manufactured with a high center frequency of 23.4 MHz and a broad -6 dB bandwidth of 75.4%. Additionally, a stable transducer performance was obtained over a test temperature range of 23-60 °C, indicating good thermal stability in environments with fluctuating temperatures. Research on lead-free high-frequency transducers for ultrasound imaging and precise and selective manipulation of microparticles demonstrates their broad potential in fields such as medical therapy and diagnosis.

Manipulation and Mechanical Deformation of Leukemia Cells by High-Frequency Ultrasound Single Beam.

Ultrasound single-beam acoustic tweezer system has attracted increasing attention in the field of biomechanics. Cell biomechanics play a pivotal role in leukemia cell functions. To better understand and compare the cell mechanics of the leukemia cells, herein, we fabricated an acoustic tweezer system in-house connected with a 50-MHz high-frequency cylinder ultrasound transducer. Selected leukemia cells (Jurkat, K562, and MV-411 cells) were cultured, trapped, and manipulated by high-frequency ultrasound single beam, which was transmitted from the ultrasound transducer without contacting any cells. The relative deformability of each leukemia cell was measured, characterized, and compared, and the leukemia cell (Jurkat cell) gaining the highest deformability was highlighted. Our results demonstrate that the high-frequency ultrasound single beam can be utilized to manipulate and characterize leukemia cells, which can be applied to study potential mechanisms in the immune system and cell biomechanics in other cell types.

3D Printing of Nacre-Inspired Structures with Exceptional Mechanical and Flame-Retardant Properties.

Flame-retardant and thermal management structures have attracted great attention due to the requirement of high-temperature exposure in industrial, aerospace, and thermal power fields, but the development of protective fire-retardant structures with complex shapes to fit arbitrary surfaces is still challenging. Herein, we reported a rotation-blade casting-assisted 3D printing process to fabricate nacre-inspired structures with exceptional mechanical and flame-retardant properties, and the related fundamental mechanisms are studied. 3-(Trimethoxysilyl)propyl methacrylate (TMSPMA) modified boron nitride nanoplatelets (BNs) were aligned by rotation-blade casting during the 3D printing process to build the "brick and mortar" architecture. The 3D printed structures are more lightweight, while having higher fracture toughness than the natural nacre, which is attributed to the crack deflection, aligned BN (a-BNs) bridging, and pull-outs reinforced structures by the covalent bonding between TMSPMA grafted a-BNs and polymer matrix. Thermal conductivity is enhanced by 25.5 times compared with pure polymer and 5.8 times of anisotropy due to the interconnection of a-BNs. 3D printed heat-exchange structures with vertically aligned BNs in complex shapes were demonstrated for efficient thermal control of high-power light-emitting diodes. 3D printed helmet and armor with a-BNs show exceptional mechanical and fire-retardant properties, demonstrating integrated mechanical and thermal protection.

Design and Fabrication of 15-MHz Ultrasonic Transducers Based on a Textured Pb(Mg1/3Nb2/3)O3-Pb(Zr, Ti)O3 Ceramic.

Ultrasound medical imaging is an entrenched and powerful tool for medical diagnosis. Image quality in ultrasound is mainly dependent on performance of piezoelectric transducer elements, which is further related to the electromechanical performance of the constituent piezoelectric materials. With rising need for piezoelectric materials with better performance and low cost, a highly 〈001〉 textured piezo ceramic, Pb(Mg1/3Nb2/3)O3-Pb(Zr, Ti)O3, has been developed. Recently, textured ceramic materials can be produced at low cost and exhibit high piezoelectric strain constants and large electromechanical coupling coefficients. In this work, 15-MHz ultrasonic transducers with an effective aperture of 2.5 mm in diameter based on these highly 〈001〉 textured ceramics have been successfully fabricated. The fabricated transducers achieved a central frequency of 15 MHz, a fractional bandwidth of 67% (at -6 dB), a high effective electromechanical coupling coefficient [Formula: see text] of 0.55, and a low insertion loss (IL) of 21 dB. Ex vivo ultrasonic imaging of a porcine eyeball was used to assess the tomography quality of the transducer. The results show that utilized textured ceramic has a great potential in developing ultrasonic devices for biomedical imaging purposes.

3D-Printing Piezoelectric Composite with Honeycomb Structure for Ultrasonic Devices.

Piezoelectric composites are considered excellent core materials for fabricating various ultrasonic devices. For the traditional fabrication process, piezoelectric composite structures are mainly prepared by mold forming, mixing, and dicing-filing techniques. However, these techniques are limited on fabricating shapes with complex structures. With the rapid development of additive manufacturing (AM), many research fields have applied AM technology to produce functional materials with various geometric shapes. In this study, the Mask-Image-Projection-based Stereolithography (MIP-SL) process, one of the AM (3D-printing) methods, was used to build BaTiO3-based piezoelectric composite ceramics with honeycomb structure design. A sintered sample with denser body and higher density was achieved (i.e., density obtained 5.96 g/cm3), and the 3D-printed ceramic displayed the expected piezoelectric and ferroelectric properties using the complex structure (i.e., piezoelectric constant achieved 60 pC/N). After being integrated into an ultrasonic device, the 3D-printed component also presents promising material performance and output power properties for ultrasound sensing (i.e., output voltage reached 180 mVpp). Our study demonstrated the effectiveness of AM technology in fabricating piezoelectric composites with complex structures that cannot be fabricated by dicing-filling. The approach may bring more possibilities to the fabrication of micro-electromechanical system (MEMS)-based ultrasonic devices via 3D-printing methods in the future.