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Peripheral vascular interventions (PVIs) offer several benefits to patients with lower extremity arterial diseases, including reduced pain, simpler anesthesia, and shorter recovery time, compared to open surgery. However, to monitor the endovascular tools inside the body, PVIs are conducted under X-ray fluoroscopy, which poses serious long-term health risks to physicians and patients. Shortwave infrared (SWIR) imaging of quantum dots (QDs) has shown great potential in bioimaging due to the non-ionizing penetration of SWIR light through tissues. In this paper, a QD-based magnetic guidewire and its system is introduced that allows X-ray-free detection under SWIR imaging and precise steering via magnetic manipulation. The QD magnetic guidewire contains a flexible silicone tube encapsulating a QD polydimethylsiloxane (PDMS) composite, where HgCdSe/HgS/CdS/CdZnS/ZnS/SiO 2 core/multi-shell QDs are dispersed in the PDMS matrix for SWIR imaging upon near-infrared excitation, as well as a permanent magnet for magnetic steering. The SWIR penetration of the QD magnetic guidewire is investigated within an artificial tissue model (1% Intralipid) and explore the potential for non-fluoroscopic PVIs within a vascular phantom model. The QD magnetic guidewire is biocompatible in its entirety, with excellent resistance to photobleaching and chemical alteration, which is a promising sign for its future clinical implementation., (© 2024 Wiley‐VCH GmbH.)

A spiral-artificial basilar membrane (S-ABM) sensor is reported that mimics the basilar membrane (BM) of the human cochlea and can detect sound by separating it into 24 sensing channels based on the frequency band. For this, an analytical function is proposed to design the width of the BM so that the frequency bands are linearly located along the length of the BM. To fabricate the S-ABM sensor, a spiral-shaped polyimide film is used as a vibrating membrane, with maximum displacement at locations corresponding to specific frequency bands of sound, and attach piezoelectric sensor modules made of poly(vinylidene fluoride-trifluoroethylene) film on top of the polyimide film to measure the vibration amplitude at each channel location. As the result, the S-ABM sensor implements a characteristic frequency band of 96-12,821 Hz and 24-independent critical bands. Using real-time signals from discriminate channels, it is demonstrated that the sensor can rapidly identify the operational noises from equipment processes as well as vehicle sounds from environmental noises on the road. The sensor can be used in a variety of applications, including speech recognition, dangerous situation recognition, hearing aids, and cochlear implants, and more., (© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)

Although the number of patients with eye diseases is increasing, efficient drug delivery to the posterior segment of the eyeball remains challenging. The reasons include the unique anatomy of the eyeball, the blood-aqueous barrier, the blood-retina barrier, and drug elimination via the anterior chamber and uveoscleral routes. Solutions to these obstacles for therapeutic delivery to the posterior segment will increase the efficacy, efficiency, and safety of ophthalmic treatment. Micro/nanorobots are promising tools to deliver therapeutics to the retina under the direction of an external magnetic field. Although many groups have evaluated potential uses of micro/nanorobots in retinal treatment, most experiments have been performed under idealized in vitro laboratory conditions and thus do not fully demonstrate the clinical feasibility of this approach. This study examined the use of magnetic nanoparticles (MNPs) to deliver dexamethasone, a drug widely used in retinal disease treatment. The MNPs allowed sustainable drug release and successful magnetic manipulation inside bovine vitreous humor and the vitreous humor of living rabbits. Therefore, controlled drug distribution via magnetic manipulation of MNPs is a promising strategy for targeted drug delivery to the retina., Competing Interests: The authors declare no competing financial interest., (© 2024 The Authors. Published by American Chemical Society.)

In individuals with hearing loss, protection of residual hearing is essential following cochlear implantation to facilitate acoustic and electric hearing. Hearing preservation requires slow insertion, atraumatic electrode and delivery of the optimal quantity of a pharmacological agent. Several studies have reported variable hearing outcomes with osmotic pump-mediated steroid delivery. New drugs, such as sialyllactose (SL) which have anti-inflammatory effect in many body parts, can prevent tissue overgrowth. In the present study, the positive effects of the pharmacological agent SL against insults were evaluated in vitro using HEI-OC1 cells. An animal model to simulate the damage due to electrode insertion during cochlear implantation was used. SL was delivered using osmotic pumps to prevent loss of the residual hearing in this animal model. Hearing deterioration, tissue fibrosis and ossification were confirmed in this animal model. Increased gene expressions of inflammatory cytokines were identified in the cochleae following dummy electrode insertion. Following the administration of SL, insertion led to a decrease in hearing threshold shifts, tissue reactions, and inflammatory markers. These results emphasize the possible role of SL in hearing preservation and improve our understanding of the mechanism underlying hearing loss after cochlear implantation., (© 2024. The Author(s).)

Synthetic micromotor has gained substantial attention in biomedicine and environmental remediation. Metal-based degradable micromotor composed of magnesium (Mg), zinc (Zn), and iron (Fe) have promise due to their nontoxic fuel-free propulsion, favorable biocompatibility, and safe excretion of degradation products Recent advances in degradable metallic micromotor have shown their fast movement in complex biological media, efficient cargo delivery and favorable biocompatibility. A noteworthy number of degradable metal-based micromotors employ bubble propulsion, utilizing water as fuel to generate hydrogen bubbles. This novel feature has projected degradable metallic micromotors for active in vivo drug delivery applications. In addition, understanding the degradation mechanism of these micromotors is also a key parameter for their design and performance. Its propulsion efficiency and life span govern the overall performance of a degradable metallic micromotor. Here we review the design and recent advancements of metallic degradable micromotors. Furthermore, we describe the controlled degradation, efficient in vivo drug delivery, and built-in acid neutralization capabilities of degradable micromotors with versatile biomedical applications. Moreover, we discuss micromotors' efficacy in detecting and destroying environmental pollutants. Finally, we address the limitations and future research directions of degradable metallic micromotors., (© 2023. The Author(s).)

Cd x Hg 1- x Se/HgS/Cd y Zn 1- y S core/multi-shell quantum dots (QDs) exhibiting bright tissue-penetrating shortwave infrared (SWIR; 1000-1700 nm) photoluminescence (PL) are engineered. The new structure consists of a quasi-type-II Cd x Hg 1- x Se/HgS core/inner shell domain creating luminescent bandgap tunable across SWIR window and a wide-bandgap Cd y Zn 1- y S outer shell boosting the PL quantum yield (QY). This compositional sequence also facilitates uniform and coherent shell growth by minimizing interfacial lattice mismatches, resulting in high QYs in both organic (40-80%) and aqueous (20-70%) solvents with maximum QYs of 87 and 73%, respectively, which are comparable to those of brightest visible-to-near infrared QDs. Moreover, they maintain bright PL in a photocurable resin (QY 40%, peak wavelength ≈ 1300 nm), enabling the fabrication of SWIR-luminescent composites of diverse morphology and concentration. These composites are used to localize controlled amounts of SWIR QDs inside artificial (Intralipid) and porcine tissues and quantitatively evaluate the applicability as luminescent probes for deep-tissue imaging., (© 2023 Wiley-VCH GmbH.)

Superparamagnetic iron oxide nanoparticles (SPIONs) have been widely employed in biomedical fields, including targeted delivery of antitumor therapy. Conventional magnetic tumor targeting has used simple static magnetic fields (SMFs), which cause SPIONs to linearly aggregate into a long chain-like shape. Such agglomeration greatly hinders the intracellular targeting of SPIONs into tumors, thus reducing the therapeutic efficacy. In this study, we investigated the enhancement of the intracellular uptake of SPIONs through the application of rotating magnetic fields (RMFs). Based on the physical principles of SPION chain disassembly, we investigated physical parameters to predict the chain length favorable for intracellular uptake. Our prediction was validated by clear visualization of the intracellular distributions of SPIONs in tumor cells at both cellular and three-dimensional microtissue levels. To identify the potential therapeutic effects of enhanced intracellular uptake, magnetic hyperthermia as antitumor therapy was investigated under varying conditions of magnetic hyperthermia and RMFs. The results showed that enhanced intracellular uptake reduced magnetic hyperthermia time and strength as well as particle concentration. The proposed method will be useful in the development of techniques to determine the optimized physical conditions for the enhanced intracellular uptake of SPIONs in antitumor therapy.

Functional restoration by the re-establishment of cellular or neural connections remains a major challenge in targeted cell therapy and regenerative medicine. Recent advances in magnetically powered microrobots have shown potential for use in controlled and targeted cell therapy. In this study, a magnetic neurospheroid (Mag-Neurobot) that can form both structural and functional connections with an organotypic hippocampal slice (OHS) is assessed using an ex vivo model as a bridge toward in vivo application. The Mag-Neurobot consists of hippocampal neurons and superparamagnetic nanoparticles (SPIONs); it is precisely and skillfully manipulated by an external magnetic field. Furthermore, the results of patch-clamp recordings of hippocampal neurons indicate that neither the neuronal excitabilities nor the synaptic functions of SPION-loaded cells are significantly affected. Analysis of neural activity propagation using high-density multi-electrode arrays shows that the delivered Mag-Neurobot is functionally connected with the OHS. The applications of this study include functional verification for targeted cell delivery through the characterization of novel synaptic connections and the functionalities of transported and transplanted cells. The success of the Mag-Neurobot opens up new avenues of research and application; it offers a test platform for functional neural connections and neural regenerative processes through cell transplantation., (© 2023 Wiley-VCH GmbH.)

Dopamine (DA) homeostasis influences emotions, neural circuit development, cognition, and the reward system. Dysfunctions in DA regulation can lead to neurological disorders, including depression, developmental disorders, and addiction. DA homeostasis disruption is a primary cause of Parkinson's Disease (PD). Therefore, understanding the relationship between DA homeostasis and PD progression may clarify the mechanisms for pharmacologically treating PD. This study developed a novel in vitro DA homeostasis platform which consists of three main parts: (1) a microfluidic device for culturing DAergic neurons, (2) an optical detection system for reading DA levels, and (3) an automatic closed-loop control system that establishes when and how much medication to infuse; this uses a microfluidic device that can cultivate DAergic neurons, perfuse solutions, perform in vitro PD modeling, and continuously monitor DA concentrations. The automatically controlled closed-loop control system simultaneously monitors pharmacological PD treatment to support long-term monitoring of DA homeostasis. SH-SY5Y neuroblastoma cells were chosen as DAergic neurons. They were cultivated in the microfluidic device, and real-time cellular DA level measurements successfully achieved long-term monitoring and modulation of DA homeostasis. When applied in combination with multiday cell culture, this advanced system can be used for drug screening and fundamental biological studies.

The shape recovery ability of shape-memory alloys vanishes below a critical size (~50 nm), which prevents their practical applications at the nanoscale. In contrast, ferroic materials, even when scaled down to dimensions of a few nanometers, exhibit actuation strain through domain switching, though the generated strain is modest (~1%). Here, we develop freestanding twisted architectures of nanoscale ferroic oxides showing shape-memory effect with a giant recoverable strain (>8%). The twisted geometrical design amplifies the strain generated during ferroelectric domain switching, which cannot be achieved in bulk ceramics or substrate-bonded thin films. The twisted ferroic nanocomposites allow us to overcome the size limitations in traditional shape-memory alloys and open new avenues in engineering large-stroke shape-memory materials for small-scale actuating devices such as nanorobots and artificial muscle fibrils., (© 2023. The Author(s).)

A vector hydrophone is an underwater acoustic sensor that can detect the direction of a sound source. Wide-band characteristics and high sensitivity enhance the performance of underwater surveillance systems in complex environments. A vector hydrophone comprising a triaxial piezoelectric accelerometer and spherical hydrophone was fabricated and tested in the air and underwater. The vector hydrophone was designed to exceed the quantitative figures of merit (i.e., receiving voltage sensitivity and bandwidth) of commercially available hydrophones. Accelerometer performance was enhanced by placing a pair of piezoelectric single crystals on each axis and modifying the seismic mass material. The receiving voltage sensitivity of the omnidirectional hydrophone was approximately −160 dB relative to 1 V/μPa with the amplifier in water; the sensitivity of the accelerometer exceeded 300 mV/g in air and −215 dB relative to 1 V/μPa underwater over the frequency range of interest. The receiving directivity of the vector hydrophone was validated underwater, which confirmed that it could detect the direction of a sound source., Competing Interests: The authors declare no conflict of interest.

Cell therapy refers to a treatment that involves the delivery of cells or cellular material by means of injection, grafting, or implantation in order to replace damaged tissue and restore its function, or to aid the body in fighting disease. However, limitations include poor targeting delivery and low therapeutic efficacy due to low cell survival. Hence, novel approaches are required to increase cell delivery efficiency and enhance therapeutic efficacy via selective cell differentiation at target areas. Here, we present a stamping magnetoelectric microscale biorobot (SMMB) consisting of neuron-like cell spheroids loaded with magnetoelectric nanoparticles. The SMMB enables not only effective targeted delivery of cells to multiple target areas ( via minimally invasive stamping employing magnetic actuation) but also facilitates selective neuronal differentiation via magnetoelectric (ME) stimulation. This ensures rapid colonization and enhances efficacy. SMMBs were fabricated using SH-SY5Y cells. Magnetoelectric nanoparticles for ME stimulation responded to an alternating magnetic field that ensured targeted cell differentiation. Multi-target cell therapy facilitated the targeted delivery and selective differentiation of SH-SY5Y cells to multiple regions using a single SMMB with rotating and alternating magnetic fields for delivery and ME stimulation. This promising tool may overcome the limitations of existing cell therapy for neurodegenerative diseases.

Robotic magnetic manipulation systems offer a wide range of potential benefits in medical fields, such as precise and selective manipulation of magnetically responsive instruments in difficult-to-reach vessels and tissues. However, more preclinical/clinical studies are necessary before robotic magnetic interventional systems can be widely adopted. In this study, a clinically translatable, electromagnetically controllable microrobotic interventional system (ECMIS) that assists a physician in remotely manipulating and controlling microdiameter guidewires in real time, is reported. The ECMIS comprises a microrobotic guidewire capable of active magnetic steering under low-strength magnetic fields, a human-scale electromagnetic actuation (EMA) system, a biplane X-ray imaging system, and a remote guidewire/catheter advancer unit. The proposed ECMIS demonstrates targeted real-time cardiovascular interventions in vascular phantoms through precise and rapid control of the microrobotic guidewire under EMA. Further, the potential clinical effectiveness of the ECMIS for real-time cardiovascular interventions is investigated through preclinical studies in coronary, iliac, and renal arteries of swine models in vivo, where the magnetic steering of the microrobotic guidewire and control of other ECMIS modules are teleoperated by operators in a separate control booth with X-ray shielding. The proposed ECMIS can help medical physicians optimally manipulate interventional devices such as guidewires under minimal radiation exposure., (© 2022 Wiley-VCH GmbH.)

A great deal of research has focused on small-scale robots for biomedical applications and minimally invasive delivery of therapeutics (e.g., cells, drugs, and genes) to a target area. Conventional fabrication methods, such as two-photon polymerization, can be used to build sophisticated micro- and nanorobots, but the long fabrication cycle for a single microrobot has limited its practical use. This study proposes a biodegradable spherical gelatin methacrylate (GelMA) microrobot for mass production in a microfluidic channel. The proposed microrobot is fabricated in a flow-focusing droplet generator by shearing a mixture of GelMA, photoinitiator, and superparamagnetic iron oxide nanoparticles (SPIONs) with a mixture of oil and surfactant. Human nasal turbinate stem cells (hNTSCs) are loaded on the GelMA microrobot, and the hNTSC-loaded microrobot shows precise rolling motion in response to an external rotating magnetic field. The microrobot is enzymatically degraded by collagenase, and released hNTSCs are proliferated and differentiated into neuronal cells. In addition, the feasibility of the GelMA microrobot as a cell therapeutic delivery system is investigated by measuring electrophysiological activity on a multielectrode array. Such a versatile and fully biodegradable microrobot has the potential for targeted stem cell delivery, proliferation, and differentiation for stem cell-based therapy., (© 2022 Wiley-VCH GmbH.)

Animals detect and discriminate countless environmental chemicals for their well-being and survival. Although a single chemical can trigger opposing behavioral responses depending on its concentration, the mechanisms underlying such a concentration-dependent switching remain poorly understood. Here, we show that C. elegans exhibits either attraction or avoidance of the bacteria-derived volatile chemical dimethyl trisulfide (DMTS) depending on its concentration. This behavioral switching is mediated by two different types of chemosensory neurons, both of which express the DMTS-sensitive seven-transmembrane G protein-coupled receptor (GPCR) SRI-14. These two sensory neurons share downstream interneurons that process and translate DMTS signals via distinct glutamate receptors to generate the appropriate behavioral outcome. Thus, our results present one mechanism by which an animal connects two distinct types of chemosensory neurons detecting a common ligand to alternate downstream circuitry, thus efficiently switching between specific behavioral programs based on ligand concentration., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Targeted stem cell delivery with microrobots has emerged as a potential alternative therapeutic strategy in regenerative medicine, and intranasal administration is an effective approach for minimally invasive delivery of therapeutic agents into the brain. In this study, a magnetically powered stem cell-based microrobot ("Cellbot") is used for minimally invasive targeted stem cell delivery to the brain through the intranasal passage. The Cellbot is developed by internalizing superparamagnetic iron oxide nanoparticles (SPIONs) into human nasal turbinate stem cells. The SPIONs have no influence on hNTSC characteristics, including morphology, cell viability, and neuronal differentiation. The Cellbots are capable of proliferation and differentiation into neurons, neural precursor cells, and neurogliocytes. The Cellbots in the microfluidic channel can be reliably manipulated by an external magnetic field for orientation and position control. Using an ex vivo model based on brain organoids, it is determined that the Cellbots can be transplanted into brain tissue. Using a murine model, it is demonstrated that the Cellbots can be intranasally administered and magnetically guided to the target tissue in vivo. This approach has the potential to effectively treat central nervous system disorders in a minimally invasive manner., (© 2021 Wiley-VCH GmbH.)

Neutrophil-based microrobots accomplish the mission of crossing the blood-brain barrier for targeted drug delivery., (Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Therapeutic agents, such as drugs and cells, play an essential role in virtually every treatment of injury, illness, or disease. However, the conventional practices of drug delivery often result in undesirable side effects caused by drug overdose and off-target delivery. In the case of cell delivery, the survival rate of the transplanted cells is extremely low and difficulties with the administration route of cells remain a problem. Recently, magnetically actuated microrobots have started offering unique opportunities in targeted therapeutic delivery due to their tiny size and ability to access hard-to-reach lesions in a minimally invasive manner; considerable advances in this regard have been made over the past decade. Here, recent progress in magnetically actuated microrobots, developed for targeted drug/cell delivery, is presented, with a focus on their design features and mechanisms for controlled therapeutic release. Additionally, the practical challenges faced by the microrobots, and future research directions toward the swift bench-to-bedside translation of the microrobots are addressed., (© 2020 Wiley-VCH GmbH.)

Microrobots for targeted drug delivery are of great interest due to their minimal invasiveness and wireless controllability. Here, a magnetically driven porous degradable microrobot (PDM) is reported that consists of a 3D printed helical soft polymeric chassis made of a poly(ethylene glycol) diacrylate and pentaerythritol triacrylate matrix containing magnetite nanoparticles and the anticancer drug 5-fluorouracil (5-FU). The encapsulated Fe 3 O 4 nanoparticles render the PDM a precise wireless magnetic actuation by means of rotating magnetic fields (RMFs). The increased surface area of the porous PDM facilitates the acoustically induced drug release due to a higher response to the acoustic energy. The drug release profile from the PDM can be selected on command from three different modes, referred to herein as natural, burst, and constant, by differentiating the ultrasound exposure condition. Finally, in vitro test results reveal different therapeutic results for each release mode. The observed great reduction of cancer cell viability in the burst- and constant-release modes confirms that ultrasound with the proposed PDM can enhance the therapeutic effect by increasing drug concentration and sonoporation., (© 2020 Wiley-VCH GmbH.)

There has been a great deal of interest in the development of technologies for actively manipulating neural networks in vitro, providing natural but simplified environments in a highly reproducible manner in which to study brain function and related diseases. Platforms for these in vitro neural networks require precise and selective neural connections at the target location, with minimal external influences, and measurement of neural activity to determine how neurons communicate. Here, we report a neuron-loaded microrobot for selective connection of neural networks via precise delivery to a gap between two neural clusters by an external magnetic field. In addition, the extracellular action potential was propagated from one cluster to the other through the neurons on the microrobot. The proposed technique shows the potential for use in experiments to understand how neurons communicate in the neural network by actively connecting neural clusters., (Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).)

Background: Clinically, steroids have been used for hearing preservation both topically and systemically during cochlear implantation. Objective: This study compared steroid efficacy for hearing preservation among different types of delivery modes using an animal experiment. Materials and methods: For 76 guinea pigs, topical and systemic delivery methods, four pump types with different infusion rates, delivery durations, and total steroid amounts were used. Threshold changes of 8, 16, and 32 kHz after dummy electrode insertion were evaluated at 1 and 4 weeks and compared among delivery method and pump types. Inflammatory response in the cochlea was histologically compared. Results: For topical delivery groups, long-term release showed advantages in preserving hearing. Systemic delivery groups showed smaller threshold shifts than control group in all frequencies ( p  > .05). In short-term low dose application, compared to topical delivery, systemic delivery showed advantage in hearing preservation at both time point. However, others fail to show significant difference between two methods. Histologically, inflammatory response in the scala tympani at the basal turn was less in systemic delivery, especially in high dose and long-term. Conclusion and significance: The difference of hearing preservation was not obvious between two delivery methods. Higher dose and longer duration might have advantages in hearing preservation.

This study presents the fabrication and characterization of a piezoelectric micromachined ultrasonic transducer (pMUT; radius: 40 µm) using a patterned aluminum nitride (AlN) thin film as the active piezoelectric material. A 20 × 20 array of pMUTs using a 1 µm thick AlN thin film was designed and fabricated on a 2 × 2 mm 2 footprint for a high fill factor. Based on the electrical impedance and phase of the pMUT array, the electromechanical coefficient was ~1.7% at the average resonant frequency of 2.82 MHz in air. Dynamic displacement of the pMUT surface was characterized by scanning laser Doppler vibrometry. The pressure output while immersed in water was 19.79 kPa when calculated based on the peak displacement at the resonant frequency. The proposed AlN pMUT array has potential applications in biomedical sensing for healthcare, medical imaging, and biometrics.

Objective: Interventional ultrasound imaging is a prerequisite for guiding implants and treatment within the hearts and blood vessels. Due to limitations on the catheter's diameter, interventional ultrasonic transducers have side-looking structures although forward-looking imaging may provide more intuitive and real time guidance in treating diseased sites ahead of catheters. To address the issue, a magnetically actuated forward-looking interventional ultrasound imaging device is implemented for the first time., Methods: A forward-looking catheter containing a 1 mm ring type focused 35 MHz ultrasound transducer and a micro magnet, was fabricated. For imaging, the transducer was placed at the center of four electromagnetic coils positioned on four sides of a squared acrylic housing. By modifying the magnetic field, the catheter tip could be remotely translated for sector scanning., Results: The scanning angle could reach up to 3° in 1 Hz with 15 mT, while wider angles of 5° could be achieved with a higher magnetic field of 25 mT for ex-vivo imaging. The position of the transducer could be detected by monitoring the motion with a CCD camera, mimicking clinical X-ray imaging. In the wire target and tissue mimicking phantom studies, the measured hole size, spatial resolution and distance between wires by the proposed system were comparable with the values from a linear scanner. Multi-frame real time data acquisition was demonstrated via ex-vivo imaging on a pig's coronary artery., Conclusion/significance: The feasibility of magnetically actuated forward-looking interventional ultrasound imaging was demonstrated. The remote-controlled scanning method may allow to simplify the structures of forward-looking interventional ultrasound imaging catheters.

A needle-type microrobot (MR) for targeted drug delivery is developed to stably deliver drugs to a target microtissue (MT) for a given period time without the need for an external force after affixing. The MRs are fabricatedby 3D laser lithography and nickel (Ni)/titanium oxide (TiO 2 ) layers are coated by physical vapor deposition. The translational velocity of the MR is 714 µm s -1 at 20 mT and affixed to the target MT under the control of a rotating magnetic field. The manipulability of the MR is shown by using both manual and automatic controls. Finally, drug release from the paclitaxel-loaded MR is characterized to determine the efficiency of targeted drug delivery. This study demonstrates the utility of the proposed needle-type MR for targeted drug delivery to MT with various flow rates in vitro physiological fluidic environments., (© 2020 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

This research focuses on the development of a flexible tactile sensor array consisting of aluminum nitride (AlN) based on micro-electro-mechanical system (MEMS) technology. A total of 2304 tactile sensors were integrated into a small area of 2.5 × 2.5 cm 2 . Five hundred nm thick AlN film with strong c-axis texture was sputtered on Cr/Au/Cr (50/50/5 nm) layers as the sacrificial layer coated on a Si wafer. To achieve device flexibility, polydimethylsiloxane (PDMS) polymer and SU-8 photoresist layer were used as the supporting layers after etching away a release layer. Twenty-five mM (3-mercaptopropyl) trimethoxysilane (MPTMS) improves the adhesion between metal and polymers due to formation of a self-assembled monolayer (SAM) on the surface of the top electrode. The flexible tactile sensor has 8 × 8 channels and each channel has 36 sensor elements with nine SU-8 bump blocks. The tactile sensor array was demonstrated to be flexible by bending 90 degrees. The tactile sensor array was demonstrated to show clear spatial resolution through detecting the distinct electrical response of each channel under local mechanical stimulus.

An artificial tactile system has attracted tremendous interest and intensive study, since it can be applied as a new functional interface between humans and electronic devices. Unfortunately, most previous works focused on improving the sensitivity of sensors. However, humans also respond to psychological feelings for sensations such as pain, softness, or roughness, which are important factors for interacting with others and objects. Here, we present an electronic skin concept that generates a "pain" warning signal, specifically, to sharp "prick" and "hot" sensations. To simplify the sensor structure for these two feelings, a single-body tactile sensor design is proposed. By exploiting "hot" feeling based on the Seebeck effect instead of the pyroelectric property, it is possible to distinguish points registering a "hot" feeling from those generating a "prick" feeling, which is based on the piezoelectric effect. The control of free carrier concentration in nanowire induced the appropriate level of Seebeck current, which enabled the sensor system to be more reliable. The first derivatives of the piezo and Seebeck output signals are the key factors for the signal processing of the "pain" feeling. The main idea can be applied to mimic other psychological tactile feelings.

Underwater sensors that detect the distance and direction of acoustic sources are critical for surveillance monitoring and target detection in the water. Here, we propose an axial vector sensor that utilizes a small (~1 cm 3 ) compressive-type piezoelectric accelerometer using piezoelectric single crystals. Initially, finite element analysis (FEA) was used to optimize the structure that comprised piezoelectric Pb(Mb 1/3 Nb 2/3 )O 3 -28%PbTiO 3 single crystals on a tungsten seismic mass. The receiving voltage sensitivity (RVS) was enhanced through geometric optimization of the thickness and sensing area of the piezoelectric material and the seismic mass. The estimated maximum RVS of the optimized vector sensor was -212 dB. FEA simulations and practical measurements were used to verify the directivity of the vector sensor design, which exhibited a dipole pattern. The dipole beam pattern was used to obtain cardioid patterns using the simulated and measured results for comparison. The results clearly showed the feasibility of using the proposed piezoelectric single-crystal accelerometer for a compressive-type vector sensor.

A silicon carbonitride (SICN) ceramic microrobot, biocompatible and magnetically activable, is developed for the delivery of viable cells to defective tissue by sequential steps of microstructuring, magnetization, and cell loading. The ceramic carrier of porous cylindrical framework is fabricated by 3D laser lithography using a photocurable preceramic polymer, chemically modified polyvinylsilazane, and subsequent pyrolysis at 600 °C under an inert atmosphere. Magnetic nanoparticles (MNP) are integrated into the surface-modified ceramic carrier by thiol-ene click reaction. Finally, the microrobot is loaded with fibroblast cells, which can be guided by a rotating external magnetic field. The proposed ceramic microrobot is mechanically durable, adequately controllable with external magnetic field, and quite compatible with mammalian cells., (© 2019 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

In cochlear implants, the electrode insertion trauma during surgery can cause damage residual hearing. Preserving the residual hearing is an important challenge and the localized administration of drugs, such as steroids, is one of the most promising ways, but remains a challenge. Here, a microscaffold cochlear electrode array (MiSCEA) consisting of a microfabricated flexible electrode array and a 3D microscaffold for steroid reservoir is reported. The MiSCEA without loaded drug is tested by measuring the electrically evoked auditory brainstem response of the cochlea in guinea pigs (n = 4). The scaffold is then coated with steroid (dexamethasone) encapsulated in polylactic-co-glycolic acid and the continuous release of the steroid into artificial perilymph during six weeks is monitored. The steroid-containing scaffolds are then implanted into guinea pigs (n = 4) and threshold shifts are analyzed for four weeks by measuring the acoustically evoked auditory brainstem response. The threshold shifts tend to be lower in the group implanted with the steroid-containing MiSCEAs. The feasibility of 3D MiSCEA opens up the development of potential next-generation cochlear electrode with improved steroid release dynamics into cochlea., (© 2019 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Microrobots facilitate targeted therapy due to their small size, minimal invasiveness, and precise wireless control. A degradable hyperthermia microrobot (DHM) with a 3D helical structure is developed, enabling actively controlled drug delivery, release, and hyperthermia therapy. The microrobot is made of poly(ethylene glycol) diacrylate (PEGDA) and pentaerythritol triacrylate (PETA) and contains magnetic Fe 3 O 4 nanoparticles (MNPs) and 5-fluorouracil (5-FU). Its locomotion is remotely and precisely controlled by a rotating magnetic field (RMF) generated by an electromagnetic actuation system. Drug-free DHMs reduce the viability of cancer cells by elevating the temperature under an alternating magnetic field (AMF), a hyperthermic effect. 5-FU is released from the proposed DHMs in normal-, high-burst-, and constant-release modes, controlled by the AMF. Finally, actively controlled drug release from the DHMs in normal- and high-burst-release mode results in a reduction in cell viability. The reduction in cell viability is of greater magnitude in high-burst- than in normal-release mode. In summary, biodegradable DHMs have potential for actively controlled drug release and hyperthermia therapy., (© 2019 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Magnetic microrobots were developed for three-dimensional culture and the precise delivery of stem cells in vitro, ex vivo, and in vivo. Hippocampal neural stem cells attached to the microrobots proliferated and differentiated into astrocytes, oligodendrocytes, and neurons. Moreover, microrobots were used to transport colorectal carcinoma cancer cells to tumor microtissue in a body-on-a-chip, which comprised an in vitro liver-tumor microorgan network. The microrobots were also controlled in a mouse brain slice and rat brain blood vessel. Last, microrobots carrying mesenchymal stem cells derived from human nose were manipulated inside the intraperitoneal cavity of a nude mouse. The results indicate the potential of microrobots for the culture and delivery of stem cells., (Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Biocompatibility and high responsiveness to magnetic fields are fundamental requisites to translate magnetic small-scale robots into clinical applications. The magnetic element iron exhibits the highest saturation magnetization and magnetic susceptibility while exhibiting excellent biocompatibility characteristics. Here, a process to reliably fabricate iron microrobots by means of template-assisted electrodeposition in 3D-printed micromolds is presented. The 3D molds are fabricated using a modified two-photon absorption configuration, which overcomes previous limitations such as the use of transparent substrates, low writing speeds, and limited depth of field. By optimizing the geometrical parameters of the 3D molds, metallic structures with complex features can be fabricated. Fe microrollers and microswimmers are realized that demonstrate motion at ≈20 body lengths per second, perform 3D motion in viscous environments, and overcome higher flow velocities than those of "conventional 3D printed helical microswimmers." The cytotoxicity of these microrobots is assessed by culturing them with human colorectal cancer (HCT116) cells for four days, demonstrating their good biocompatibility characteristics. Finally, preliminary results regarding the degradation of iron structures in simulated gastric acid liquid are provided., (© 2019 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Magnetically actuated soft robots may improve the treatment of disseminated intravascular coagulation. Significant progress has been made in the development of soft robotic systems that steer catheters. A more challenging task, however, is the development of systems that steer sub-millimeter-diameter guidewires during intravascular treatments; a novel microrobotic approach is required for steering. In this article, we develop a novel, magnetically actuated, soft microrobotic system, increasing the steerability of a conventional guidewire. The soft microrobot is attached to the tip of the guidewire, and it is magnetically steered by changing the direction and intensity of an external magnetic field. The microrobot is fabricated via replica molding and features a soft body made of polydimethylsiloxane, two permanent magnets, and a microspring. We developed a mathematical model mapping deformation of the soft microrobot using a feed-forward approach toward steering. Then, we used the model to steer a guidewire. The angulation of the microrobot can be controlled from 21.1° to 132.7° by using a magnetic field of an intensity of 15 mT. Steerability was confirmed by two-dimensional in vitro tracking. Finally, a guidewire with the soft microrobot was tested by using a three-dimensional (3D) phantom of the coronary artery to verify steerability in 3D space.

Magnetically driven microrobots have been widely studied for various biomedical applications in the past decade. An important application of these biomedical microrobots is heart disease treatment. In intravascular treatments, a particular challenge is the submillimeter-sized guidewire steering; this requires a new microrobotic approach. In this study, a flexible microrobot was fabricated by the replica molding method, which consists of three parts: (1) a flexible polydimethylsiloxane (PDMS) body, (2) two permanent magnets, and (3) a micro-spring connector. A mathematical model was developed to describe the relationship between the magnetic field and the deformation. A system identification approach and an algorithm were proposed for steering. The microrobot was fabricated, and the models for steering were experimentally validated under a magnetic field intensity of 15 mT. Limitations to control were identified, and the microrobot was steered in an arbitrary path using the proposed model. Furthermore, the flexible microrobot was steered using the guidewire within a three-dimensional (3D) transparent phantom of the right coronary artery filled with water, to show the potential application in a realistic environment. The flexible microrobot presented here showed promising results for enhancing guidewire steering in percutaneous coronary intervention (PCI).

Animals change sensory responses and their eventual behaviors, depending on their internal metabolic status and external food availability. However, the mechanisms underlying feeding state-dependent behavioral changes remain undefined. Previous studies have shown that Caenorhabditis elegans hermaphrodite exhibits avoidance behaviors to acute exposure of a pheromone, ascr#3 (asc-ΔC9, C9). Here, we show that the ascr#3 avoidance behavior is modulated by feeding state via the insulin signaling pathway. Starvation increases ascr#3 avoidance behavior, and loss-of-function mutations in daf-2 insulin-like receptor gene dampen this starvation-induced ascr#3 avoidance behavior. DAF-2 and its downstream signaling molecules, including the DAF-16 FOXO transcription factor, act in the ascr#3-sensing ADL neurons to regulate synaptic transmission to downstream target neurons, including the AVA command interneurons. Moreover, we found that starvation decreases the secretion of INS-18 insulin-like peptides from the intestine, which antagonizes DAF-2 function in the ADL neurons. Altogether, this study provides insights about the molecular communication between intestine and sensory neurons delivering hunger message to sensory neurons, which regulates avoidance behavior from pheromones to facilitate survival chance., (© 2018 The Authors.)

A capsule-type microrobot exhibits "pick-and-drop" (P&D) motion to hold a particle within a confined volume and transports it via a corkscrewing motion. The P&D motion is possible because the capsule-type microrobot has two parts: a plunger and a cap. The fabricated microrobots are wirelessly controlled by a magnetic manipulator. Drugs or cells can be encapsulated in the container of the capsule-type microrobot by the P&D motion or attached to the surface of the cap, which can be used as a supporting structure. Therefore, the capsule-type microrobot can deliver suspended or adherent cells. The drug or cells are minimally exposed or not completely exposed to the surrounding fluid and do not experience shear force when encapsulated in the container. As a proof-of-concept, secure transportation of microparticles in the confined volume of the capsule via P&D motion is demonstrated. In addition, the cap is used as a scaffold for neuronal cell culture on a rat brain slice to demonstrate its biocompatibility and feasibility for targeted cell delivery. The proposed capsule-type microrobot is suitable for diverse applications, as it protects the encapsulated materials., (© 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Intravascular microrobots have emerged as a promising tool for vascular diseases. They can be wirelessly and precisely manipulated with a high degree of freedom. Previous studies have evaluated their drilling performance and locomotion, and showed the feasibility of using microrobots for biomedical applications in two-dimensional space. However, it is critical to validate micro-drillers in a three-dimensional (3D) environment because gravity plays an important role in a 3D environment and significantly affects the performance of the micro-drillers in vascular networks. In this work, we fabricated magnetic drilling actuators (MDAs) and characterized their locomotion and drilling performance in vascular network-mimicking fluidic channels. The MDAs were precisely manipulated in the fluidic channel network in both horizontal and vertical planes, selecting and moving through the desired path via the junctions of multiple channels. The MDAs also accurately navigated an artificial thrombosis in an artificial 3D vascular network and successfully drilled through it. The results obtained here confirmed the precise manipulation and drilling performance of the developed MDAs in 3D. We think that the MDAs presented in this paper have great potential as intravascular drillers for precise thrombus treatment.

[This corrects the article on p. 210 in vol. 11, PMID: 28572760.].

Patients with sensorineural hearing loss can recover their hearing using a cochlear implant (CI). However, there is a need to develop next-generation CIs to overcome the limitations of conventional CIs caused by extracorporeal devices. Recently, artificial basilar membranes (ABMs) are actively studied for next-generation CIs. The ABM is an acoustic transducer that mimics the mechanical frequency selectivity of the BM and acoustic-to-electrical energy conversion of hair cells. This paper presents recent progress in biomimetic ABMs. First, the characteristics of frequency selectivity of the ABMs by the trapezoidal membrane and beam array are addressed. Second, to reflect the latest research of energy conversion technologies, ABMs using various piezoelectric materials and triboelectric-based ABMs are discussed. Third, in vivo evaluations of the ABMs in animal models are discussed according to the target position for implantation. Finally, future perspectives of ABM studies for the development of practical hearing devices are discussed., (© 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Experiences during early development can influence neuronal functions and modulate adult behaviors [1, 2]. However, the molecular mechanisms underlying the long-term behavioral effects of these early experiences are not fully understood. The C. elegans ascr#3 (asc-ΔC9; C9) pheromone triggers avoidance behavior in adult hermaphrodites [3-7]. Here, we show that hermaphrodites that are briefly exposed to ascr#3 immediately after birth exhibit increased ascr#3-specific avoidance as adults, indicating that ascr#3-experienced animals form a long-lasting memory or imprint of this early ascr#3 exposure [8]. ascr#3 imprinting is mediated by increased synaptic activity between the ascr#3-sensing ADL neurons and their post-synaptic SMB motor neuron partners via increased expression of the odr-2 glycosylated phosphatidylinositol (GPI)-linked signaling gene in the SMB neurons. Our study suggests that the memory for early ascr#3 experience is imprinted via alteration of activity of a single synaptic connection, which in turn shapes experience-dependent plasticity in adult ascr#3 responses., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

A novel cell-stimulation system was fabricated using 10 × 29 piezoelectric micromachined ultrasonic transducer (pMUT) arrays for targeted ultrasonic cell stimulation. Both the diameter of a single pMUT element and the edge-to-edge gap were 120 μm, and the size of a pMUT array was 2.27 × 6.84 mm, to be placed at the bottom of a Transwell. The measured resonance frequency of a single pMUT element was 1.48 ± 0.13 MHz and the measured acoustic intensity of the pMUT array was 0.15 ± 0.03 MPa at 1 mm away from the transducer. A pMUT array was mounted on a print circuit board (PCB), which was designed in accordance with the size of a 12-well Transwell. The Transwell was placed on the PCB and wire bonding was performed to electrically connect the PCB and pMUT arrays. After wiring, the PCB and pMUT arrays were coated with 2.6-μm thick parylene-C to ensure biocompatibility and waterproofing. PC12 cells were used for ultrasonic cell stimulation tests to examine the proposed all-in-one low-intensity pulsed ultrasound stimulation system. Various stimulation times and duty cycles were used simultaneously for cell proliferation in a confined cell culture environment. All stimulation groups showed increased cell proliferation rates, in the range 138-166%, versus the proliferation rate of the control group.

The mechanism of tinnitus suppression after cochlear implantation (CI) in single-sided deafness (SSD) is not fully understood. In this regard, by comparing pre- and post-CI quantitative electroencephalography (qEEG), we explored cortical changes relevant to tinnitus improvement. In SSD patients who underwent CI, qEEG data were collected: (1) before CI, (2) 6 months post-operatively with CI-on, and (3) 30 min after CI-off and source-localized cortical activity/functional connectivity analyses were performed. Compared to the pre-operative baseline, the CI-on condition demonstrated significantly decreased activity in the right auditory- and orbitofrontal cortices (OFC) for the delta frequency band as well as decreased connectivity between the auditory cortex/posterior cingulate cortex for the delta/beta2 bands. Meanwhile, compared to the CI-off condition, the CI-on condition displayed decreased activity in the right auditory cortices/OFC for the delta band, and in bilateral auditory cortices, left inferior frontal cortex/OFC for the gamma band. However, qEEG analyses showed no significant differences between the CI-off and baseline conditions. CI induced overall decreased cortical activity and functional connectivity. However, judging from no differences between the CI-off and baseline conditions, CI-induced cortical activity and functional connectivity changes are not by cortical plastic changes, but by dynamic peripheral reafferentation.

We investigate the effect of electric field on VO 2 back-gated field effect transistor (FET) devices. Using hybrid dielectric layers, we demonstrate the highest resistance modulation on the order of 10 2 in VO 2 at a positive gate bias of 80 V (1.6 MV/cm). VO 2 FET devices are prepared on SiO 2 substrates of different thicknesses (100-300 nm) and hybrid dielectric layers of Al 2 O 3 /SiO 2 (500 nm). For thicknesses less than 300 nm, no electric-field effects are observed, whereas for a 300 nm thickness, a small decrease in resistance is observed under a 0.2 MV/cm electric field. Under the electrostatic effect, the carrier concentration increases in VO 2 devices, decreasing the resistance and the transition temperature from 66.75 to 64 °C. The leakage analysis shows that the interface quality of VO 2 films on hybrid dielectric layers can be further improved. These studies suggest a multilevel fast resistance switching with the electric field and give an insight into the gate-source leakage current, which limits the phase transition in VO 2 in an electric field.

A triboelectric-based artificial basilar membrane (TEABM) can mimic cochlear tonotopy by triboelectrification between Kapton film and aluminum foil. The two films are stacked and clamped to form a beam structure. The TEABM tonotopy is tested using an animal model to verify the feasibility of a self-powered acoustic sensor for a prototype cochlear implant., (© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Magnetically actuated ciliary microrobots were designed, fabricated, and manipulated to mimic cilia-based microorganisms such as paramecia. Full three-dimensional (3D) microrobot structures were fabricated using 3D laser lithography to form a polymer base structure. A nickel/titanium bilayer was sputtered onto the cilia part of the microrobot to ensure magnetic actuation and biocompatibility. The microrobots were manipulated by an electromagnetic coil system, which generated a stepping magnetic field to actuate the cilia with non-reciprocal motion. The cilia beating motion produced a net propulsive force, resulting in movement of the microrobot. The magnetic forces on individual cilia were calculated with various input parameters including magnetic field strength, cilium length, applied field angle, actual cilium angle, etc., and the translational velocity was measured experimentally. The position and orientation of the ciliary microrobots were precisely controlled, and targeted particle transportation was demonstrated experimentally.

Mimicking the nanoscale surface texture of the extracellular matrix can affect the regulation of cellular behavior, including adhesion, differentiation, and neurite outgrowth. In this study, SU-8-based polymer surfaces with well-ordered nanowell arrays were fabricated using nanosphere lithography with polystyrene nanoparticles. We show that the SU-8 surface with nanowells resulted in similar neuronal development of rat pheochromocytoma (PC12) cells compared with an unpatterned poly-L-lysine (PLL)-coated SU-8 surface. Additionally, even after soaking the substrate in cell culture medium for two weeks, cells on the nanowell SU-8 surface showed long-term neurite outgrowth compared to cells on the PLL-coated SU-8 surface. The topographical surface modification of the nanowell array demonstrates potential as a replacement for cell adhesive material coatings such as PLL, for applications requiring long-term use of polymer-based implantable devices.

The aim of this study was to investigate the efficacy of preoperative and intraoperative steroid administration for inner ear protection in cochlear implantation (CI). Nineteen subjects who underwent CI were included in the study, and 10 subjects were enrolled as controls (steroid-administered group, n = 19; control group, n = 10). Dexamethasone (dexamethasone sodium phosphate, 5 mg/ml) was systemically administered preoperatively (1 ml) and topically applied during CI (0.5 ml). The extent of hearing preservation (HP) after CI and the change in the bithermal caloric response were evaluated. Hearing level was calculated using mean thresholds [(250 Hz + 500 Hz + 1,000 Hz + 2,000 Hz)/4]. Preoperative hearing thresholds were similar in the steroid-administered and control groups (100.92 ± 12.60 vs. 103.29 ± 14.39 dB, p = 0.650). The mean thresholds significantly increased in both groups after surgery (108.46 ± 14.08 dB, p = 0.006, for the steroid-administered group; 117.50 ± 6.34 dB, p = 0.027, for the control group), and the difference between the groups was also significant (p = 0.027). The postoperative shift in the hearing thresholds at frequencies of 500 and 1,000 Hz was significant in the steroid-administered group and that at the frequencies of 500, 1,000 and 2,000 Hz was significant in the control group. However, the extent of the shift in hearing threshold levels at each frequency was not significantly different between the groups. Preservation of hearing thresholds was compared between the groups, and there were significantly more subjects with complete and partial HP in the steroid-administered group than in the control group (p = 0.008). The preoperative caloric response was maintained after CI in the steroid-administered group. This study suggests that the perioperative use of a steroid could minimize the inner ear damage after CI., (© 2016 S. Karger AG, Basel.)

Background: Quantitative electroencephalography (qEEG) is effective when used to analyze ongoing cortical oscillations in cochlear implant (CI) users. However, localization of cortical activity in such users via qEEG is confounded by the presence of artifacts produced by the device itself. Typically, independent component analysis (ICA) is used to remove CI artifacts in auditory evoked EEG signals collected upon brief stimulation and it is effective for auditory evoked potentials (AEPs). However, AEPs do not reflect the daily environments of patients, and thus, continuous EEG data that are closer to such environments are desirable. In this case, device-related artifacts in EEG data are difficult to remove selectively via ICA due to over-completion of EEG data removal in the absence of preprocessing., New Methods: EEGs were recorded for a long time under conditions of continuous auditory stimulation. To obviate the over-completion problem, we limited the frequency of CI artifacts to a significant characteristic peak and apply ICA artifact removal., Results: Topographic brain mapping results analyzed via band-limited (BL)-ICA exhibited a better energy distribution, matched to the CI location, than data obtained using conventional ICA. Also, source localization data verified that BL-ICA effectively removed CI artifacts., Comparison With Existing Method: The proposed method selectively removes CI artifacts from continuous EEG recordings, while ICA removal method shows residual peak and removes important brain activity signals., Conclusion: CI artifacts in EEG data obtained during continuous passive listening can be effectively removed with the aid of BL-ICA, opening up new EEG research possibilities in subjects with CIs., (Copyright © 2015 Elsevier B.V. All rights reserved.)