Ultra-low frequency magnetic energy focusing for highly effective wireless powering of deep-tissue implantable electronic devices.

The limited lifespan of batteries is a challenge in the application of implantable electronic devices. Existing wireless power technologies such as ultrasound, near-infrared light and magnetic fields cannot charge devices implanted in deep tissues, resulting in energy attenuation through tissues and thermal generation. Herein, an ultra-low frequency magnetic energy focusing (ULFMEF) methodology was developed for the highly effective wireless powering of deep-tissue implantable devices. A portable transmitter was used to output the low-frequency magnetic field (<50 Hz), which remotely drives the synchronous rotation of a magnetic core integrated within the pellet-like implantable device, generating an internal rotating magnetic field to induce wireless electricity on the coupled coils of the device. The ULFMEF can achieve energy transfer across thick tissues (up to 20 cm) with excellent transferred power (4-15 mW) and non-heat effects in tissues, which is remarkably superior to existing wireless powering technologies. The ULFMEF is demonstrated to wirelessly power implantable micro-LED devices for optogenetic neuromodulation, and wirelessly charged an implantable battery for programmable electrical stimulation on the sciatic nerve. It also bypassed thick and tough protective shells to power the implanted devices. The ULFMEF thus offers a highly advanced methodology for the generation of wireless powered biodevices.

Development of enzyme-inorganic hybrid nanoflower-modified electrodes and a smartphone-controlled electrochemical analyzer for point-of-care testing of salivary amylase in saliva.

Quantitation of salivary alpha-amylase (sAA) plays a significant role in not only theoretical studies but also clinical practice. This study reports a quantitative point-of-care testing (POCT) system for sAA quantitation anywhere, anytime and by anyone, which consists of customized electrodes and a smartphone-controlled electrochemical analyzer. Organic-inorganic hybrid nanoflowers (NFs) encapsulating α-glucosidase (AG) and glucose dehydrogenase (GDH) have been synthesized and modified onto screen-printed electrodes (SPCEs) to fabricate the customized electrodes. The SPCEs integrated with the smartphone-controlled electrochemical analyzer exhibit good analytical performance for sAA with a low detection limit of 5.02 U mL-1 and a wide dynamic range of 100-2000 U mL-1 using chronoamperometry. The reported POCT system has been successfully demonstrated for quantitation of sAA in clinical saliva samples, and the quantitation results correlated well with those of the Bernfeld method which is extensively used in clinics. More importantly, this study reveals the great potential of sAA as an early warning indicator of abnormal glucose metabolism in obese individuals. Considering the non-invasive saliva sampling process as well as the easy-to-use and cost-effectiveness features of this quantitative POCT system, quantitation of salivary sAA at home by laypersons might become an appealing choice for obese individuals to monitor their glucose metabolism status anytime.

Implantable magnetically-actuated capsule for on-demand delivery.

Many implantable drug delivery systems (IDDS) have been developed for long-term, pulsatile drug release. However, they are often limited by bulky size, complex electronic components, unpredictable drug delivery, as well as the need for battery replacement and consequent replacement surgery. Here, we develop an implantable magnetically-actuated capsule (IMAC) and its portable magnetic actuator (MA) for on-demand and robust drug delivery in a tether-free and battery-free manner. IMAC utilizes the bistable mechanism of two magnetic balls inside IMAC to trigger drug delivery under a strong magnetic field (|Ba| > 90 mT), ensuring precise and reproducible drug delivery (9.9 ± 0.17 µg per actuation, maximum actuation number: 180) and excellent anti-magnetic capability (critical trigger field intensity: ∼90 mT). IMAC as a tetherless robot can navigate to and anchor at the lesion sites driven by a gradient magnetic field (∇ Bg = 3 T/m, |Bg| < 60 mT), and on-demand release drug actuated by a uniform magnetic field (|Ba| = âˆ¼100 mT) within the gastrointestinal tract. During a 15-day insulin administration in vivo, the diabetic rats treated with IMAC exhibited highly similar pharmacokinetic and pharmacodynamic profiles to those administrated via subcutaneous injection, demonstrating its robust and on-demand drug release performance. Moreover, IMAC is biocompatible, batter-free, refillable, miniature (only Φ 6.3 × 12.3 mm3), and lightweight (just 0.8 g), making it an ideal alternative for precise implantable drug delivery and friendly patient-centered drug administration.

Using microneedle array electrodes for non-invasive electrophysiological signal acquisition and sensory feedback evoking.

Introduction: Bidirectional transmission of information is needed to realize a closed-loop human-machine interaction (HMI), where electrophysiological signals are recorded for man-machine control and electrical stimulations are used for machine-man feedback. As a neural interface (NI) connecting man and machine, electrodes play an important role in HMI and their characteristics are critical for information transmission. Methods: In this work, we fabricated a kind of microneedle array electrodes (MAEs) by using a magnetization-induced self-assembly method, where microneedles with a length of 500-600 µm and a tip diameter of ∼20 µm were constructed on flexible substrates. Part of the needle length could penetrate through the subjects' stratum corneum and reach the epidermis, but not touch the dermis, establishing a safe and direct communication pathway between external electrical circuit and internal peripheral nervous system. Results: The MAEs showed significantly lower and more stable electrode-skin interface impedance than the metal-based flat array electrodes (FAEs) in various testing scenarios, demonstrating their promising impedance characteristics. With the stable microneedle structure, MAEs exhibited an average SNR of EMG that is more than 30% higher than FAEs, and a motion-intention classification accuracy that is 10% higher than FAEs. The successful sensation evoking demonstrated the feasibility of the MAE-based electrical stimulation for sensory feedback, where a variety of natural and intuitive feelings were generated in the subjects and thereafter objectively verified through EEG analysis. Discussion: This work confirms the application potential of MAEs working as an effective NI, in both electrophysiological recording and electrical stimulation, which may provide a technique support for the development of HMI.

Coaxially printed magnetic mechanical electrical hybrid structures with actuation and sensing functionalities.

Soft electromagnetic devices have great potential in soft robotics and biomedical applications. However, existing soft-magneto-electrical devices would have limited hybrid functions and suffer from damaging stress concentrations, delamination or material leakage. Here, we report a hybrid magnetic-mechanical-electrical (MME) core-sheath fiber to overcome these challenges. Assisted by the coaxial printing method, the MME fiber can be printed into complex 2D/3D MME structures with integrated magnetoactive and conductive properties, further enabling hybrid functions including programmable magnetization, somatosensory, and magnetic actuation along with simultaneous wireless energy transfer. To demonstrate the great potential of MME devices, precise and minimally invasive electro-ablation was performed with a flexible MME catheter with magnetic control, hybrid actuation-sensing was performed by a durable somatosensory MME gripper, and hybrid wireless energy transmission and magnetic actuation were demonstrated by an untethered soft MME robot. Our work thus provides a material design strategy for soft electromagnetic devices with unexplored hybrid functions.

A smartphone-based fluorospectrophotometer and ratiometric fluorescence nanoprobe for on-site quantitation of pesticide residue.

Cost-effective and user-friendly quantitation at points-of-need plays an important role in food safety inspection, environmental monitoring, and biomedical analysis. This study reports a stand-alone smartphone-based fluorospectrophotometer (the SBS) installed with a custom-designed application (the SBS-App) for on-site quantitation of pesticide using a ratiometric sensing scheme. The SBS can collect fluorescence emission spectra in the wavelength range of 380-760 nm within 5 s. A ratiometric fluorescence probe is facilely prepared by directly mixing the blue-emissive carbon nanodots (the Fe3+-specific fluorometric indicator) and red-emissive quantum dots (the internal standard) at a ratio of 11.6 (w/w). Based on the acetylcholinesterase/choline oxidase dual enzyme-mediated cascade catalytic reactions of Fe2+/Fe3+ transformation, a ratiometric fluorescence sensing scheme is developed. The practicability of the SBS is validated by on-site quantitation of chlorpyrifos in apple and cabbage with a comparable accuracy to the GC-MS method, offering a scalable solution to establish a cost-effective surveillance system for pesticide pollution.

Iontophoresis-driven microneedle patch for the active transdermal delivery of vaccine macromolecules.

COVID-19 has seriously threatened public health, and transdermal vaccination is an effective way to prevent pathogen infection. Microneedles (MNs) can damage the stratum corneum to allow passive diffusion of vaccine macromolecules, but the delivery efficiency is low, while iontophoresis can actively promote transdermal delivery but fails to transport vaccine macromolecules due to the barrier of the stratum corneum. Herein, we developed a wearable iontophoresis-driven MN patch and its iontophoresis-driven device for active and efficient transdermal vaccine macromolecule delivery. Polyacrylamide/chitosan hydrogels with good biocompatibility, excellent conductivity, high elasticity, and a large loading capacity were prepared as the key component for vaccine storage and active iontophoresis. The transdermal vaccine delivery strategy of the iontophoresis-driven MN patch is "press and poke, iontophoresis-driven delivery, and immune response". We demonstrated that the synergistic effect of MN puncture and iontophoresis significantly promoted transdermal vaccine delivery efficiency. In vitro experiments showed that the amount of ovalbumin delivered transdermally using the iontophoresis-driven MN patch could be controlled by the iontophoresis current. In vivo immunization studies in BALB/c mice demonstrated that transdermal inoculation of ovalbumin using an iontophoresis-driven MN patch induced an effective immune response that was even stronger than that of traditional intramuscular injection. Moreover, there was little concern about the biosafety of the iontophoresis-driven MN patch. This delivery system has a low cost, is user-friendly, and displays active delivery, showing great potential for vaccine self-administration at home.

Development of Smartphone-Controlled and Microneedle-Based Wearable Continuous Glucose Monitoring System for Home-Care Diabetes Management.

Continuous glucose monitoring (CGM) can mini-invasively track blood glucose fluctuation and reduce the risk of hyperglycemia and hypoglycemia, and this is is in great demand for diabetes management. However, cost-effective manufacture of CGM systems with continuously improved convenience and performance is still the persistent goal. Herein, we developed a smartphone-controlled and microneedle (MN)-based wearable CGM system for long-term glucose monitoring. The CGM system modified with a sandwich-type enzyme immobilization strategy can satisfy the clinical requirement of interstitial fluid (ISF) glucose monitoring for 14 days with a mean absolute relative difference of 10.2% and a cost of less than $15, which correlated well with the commercial glucometer and FDA-approved CGM system FreeStyle Libre (Abbott Inc., Illinois, USA). The self-developed CGM system is demonstrated to accurately monitor glucose fluctuations and provide abundant clinical information. It is better to find the cause of individual blood glucose changes and beneficial for the guide of precise glucose control. On the whole, the intelligently wearable CGM system may provide an alternative solution for home-care diabetes management.

Ferromagnetic Flexible Electronics for Brain-Wide Selective Neural Recording.

Flexible microelectronics capable of straightforward implantation, remotely controlled navigation, and stable long-term recording hold great promise in diverse medical applications, particularly in deciphering complex functions of neural circuits in the brain. Existing flexible electronics, however, are often limited in bending and buckling during implantation, and unable to access a large brain region. Here, an injectable class of electronics with stable recording, omnidirectional steering, and precise navigating capabilities based on magnetic actuation is presented. After simple transcriptional injection, the rigid coatings are biodegraded quickly and the bundles of magnetic-nanoparticles-coated microelectrodes become separated, ultra-flexible, and magnetic actuated for further minimally invasive three-dimensional interpenetration in the brain. As proof of concept, this paradigm-shifting approach is demonstrated for selective and multiplexed neural activities recording across distant regions in the deep rodent brains. Coupling with optogenetic neural stimulation, the unique capabilities of this platform in electrophysiological readouts of projection dynamics in vivo are also demonstrated. The ability of these miniaturized, remotely controllable, and biocompatible ferromagnetic flexible electronics to afford minimally invasive manipulations in the soft tissues of the mammalian brain foreshadows applications in other organ systems, with great potential for broad utility in biomedical science and engineering.

Masticatory system-inspired microneedle theranostic platform for intelligent and precise diabetic management.

Integrated systems for diabetic theranostics present advanced technology to regulate diabetes yet still have critical challenges in terms of accuracy, long-term monitoring, and minimal invasiveness. Inspired by the feature and functions of animal masticatory system, we presented a biomimetic microneedle theranostic platform (MNTP) for intelligent and precise management of diabetes. The MNTP was supported by a miniatured circuit, which used microneedle arrays for on-demand skin penetration, enabling interstitial fluid exudation for simultaneous detection of glucose and physiological ions, and subcutaneous insulin delivery. Interstitial fluid exudation enabled sensing in oxygen-rich environment via the incorporated epidermal sensor functionalized with hybrid carbon nanomaterials. This feature addressed the biosafety issues due to implanted electrodes and the "oxygen-deficit" issues in vivo. The MNTP was demonstrated to accurately detect glucose and ions and deliver insulin to regulate hyperglycemia. The biomimetic and intelligent features of the MNTP endowed it as a highly advanced system for diabetes therapy.

High-throughput fabrication of soft magneto-origami machines.

Soft magneto-active machines capable of magnetically controllable shape-morphing and locomotion have diverse promising applications such as untethered biomedical robots. However, existing soft magneto-active machines often have simple structures with limited functionalities and do not grant high-throughput production due to the convoluted fabrication technology. Here, we propose a facile fabrication strategy that transforms 2D magnetic sheets into 3D soft magneto-active machines with customized geometries by incorporating origami folding. Based on automated roll-to-roll processing, this approach allows for the high-throughput fabrication of soft magneto-origami machines with a variety of characteristics, including large-magnitude deploying, sequential folding into predesigned shapes, and multivariant actuation modes (e.g., contraction, bending, rotation, and rolling locomotion). We leverage these abilities to demonstrate a few potential applications: an electronic robot capable of on-demand deploying and wireless charging, a mechanical 8-3 encoder, a quadruped robot for cargo-release tasks, and a magneto-origami arts/craft. Our work contributes for the high-throughput fabrication of soft magneto-active machines with multi-functionalities.

An implantable ultrasound-powered device for the treatment of brain cancer using electromagnetic fields.

Brain tumors have been proved challenging to treat. Here, we present a promising alternative by developing an implantable ultrasound-powered tumor treating device (UP-TTD) that electromagnetically disrupts the rapid division of cancer cells without any adverse effects on normal neurons, thereby safely inhibiting brain cancer recurrence. In vitro and in vivo experiments confirmed the significant therapeutic effect of the UP-TTD, with ~58% inhibition on growth rate of clinical tumor cells and ~78% reduction of cancer area in tumor-bearing rats. This UP-TTD is wireless ultrasound-powered, chip-sized, lightweight, and easy to operate on complex surfaces, with a largely boosting therapeutic efficiency and reducing energy consumption. Meanwhile, various treatment parameters could be tuned from the UP-TTD without increasing its size or adding circuits on the integrated chip. The tuning process was simulated and discussed, showing an excellent agreement with the experimental data. The encouraging results of the UP-TTD raise the possibility of a new modality for brain cancer treatment.

Solid-Liquid State Transformable Magnetorheological Millirobot.

Magnetically actuated soft millirobots (magneto-robot) capable of accomplishing on-demand tasks in a remote-control manner using noninvasive magnetic fields are of great interest in biomedical settings. However, the solid magneto-robots are usually restricted by the limited deformability due to the predesigned shape, while the liquid magneto-robots are capable of in situ shape reconfiguration but limited by the low stiffness and geometric instability due to the fluidity. Herein, we propose a magneto-active solid-liquid state transformable millirobot (named MRF-Robot) made from a magnetorheological fluid (MRF). The MRF-Robot can transform freely and rapidly between the Newtonian fluid in the liquid state upon a weak magnetic field (∼0 mT) and the Bingham plasticity in the solid state upon a strong magnetic field (∼100 mT). The MRF-Robot in the liquid state can realize diverse behaviors of large deformation, smooth navigation, in situ splitting, merging, and gradient pulling actuated by a weak magnetic field with a high gradient. The MRF-Robot in the solid state is distinguished for the controllable locomotion with reconfigured shapes and versatile object manipulations (including pull, push, and rotate the objects) driven by a strong magnetic field with a high gradient. Moreover, the MRF-Robot could continuously maneuver to accomplish diverse tasks in the comprehensive scenes and achieve liquid-drug delivery, thrombus clearance, and fluid-flow blockage in the phantom vascular model under magnetic actuation.

Intelligent wireless theranostic contact lens for electrical sensing and regulation of intraocular pressure.

Engineering wearable devices that can wirelessly track intraocular pressure and offer feedback-medicine administrations are highly desirable for glaucoma treatments, yet remain challenging due to issues of limited sizes, wireless operations, and wireless cross-coupling. Here, we present an integrated wireless theranostic contact lens for in situ electrical sensing of intraocular pressure and on-demand anti-glaucoma drug delivery. The wireless theranostic contact lens utilizes a highly compact structural design, which enables high-degreed integration and frequency separation on the curved and limited surface of contact lens. The wireless intraocular pressure sensing modulus could ultra-sensitively detect intraocular pressure fluctuations, due to the unique cantilever configuration design of capacitive sensing circuit. The drug delivery modulus employs an efficient wireless power transfer circuit, to trigger delivery of anti-glaucoma drug into aqueous chamber via iontophoresis. The minimally invasive, smart, wireless and theranostic features endow the wireless theranostic contact lens as a highly promising system for glaucoma treatments.

3D Bioprinting of Living Materials for Structure-Dependent Production of Hyaluronic Acid.

3D bioprinting of living materials represents an interesting paradigm toward the efficacy enhancement for the biosynthesis of various functional compounds in microorganisms. Previous studies have shown the success of 3D-printed bioactive systems in the production of small molecular compounds. However, the feasibility of such a strategy in producing macromolecules and how the geometry of the 3D scaffold influences the productivity are still unknown. In this study, we printed a series of 3D gelatin-based hydrogels immobilized with fermentation bacteria that can secrete hyaluronic acid (HA), a very useful natural polysaccharide in the fields of biomedicine and tissue engineering. The 3D-printed bioreactor was capable of producing HA, and an elevated yield was obtained with the system bearing a grid structure compared to that either with a solid structure or in a scaffold-free fermentation condition. As for the grid structure, bioreactors with a 90° strut angel and a median interfilament distance displayed the highest HA yield. Our findings highlighted the significant role of 3D printing in the spatial control of microorganism-laden hydrogel structures for the enhancement of biosynthesis efficiency.

A touch-actuated glucose sensor fully integrated with microneedle array and reverse iontophoresis for diabetes monitoring.

The development of non-invasive biosensor for monitoring glucose in interstitial fluid (ISF) is still challenging, because ISF extraction through classical reverse iontophoresis (RI) is limited by low extraction flux and consistency. Here, we developed a touch-actuated biosensor for monitoring glucose in ISF. The biosensor is composed of three main components: 1) the solid microneedle array (MA) for painless skin penetration; 2) the RI unit for ISF extraction through the MA-created microchannels; and 3) the sensing unit for glucose monitoring. The sensing strategy of this biosensor is "skin penetration-RI extraction-electrochemical detection". Compared with RI extraction only, the reported skin penetration-RI extraction sampling strategy obviously increased the glucose extraction flux by ∼1.6 times not only in vitro but also in vivo. Moreover, we developed a wearable glucose monitoring system by incorporating this touch-actuated biosensor, a wireless electrochemical detector, and a smartphone application. In vivo experiments using healthy and diabetic rats revealed a high correlation between the results measured by the reported wearable system and commercially blood glucometer. This sampling strategy which combined skin penetration and RI extraction paves the way to develop wearable platforms for not only glucose monitoring but also various ISF biomarkers without the need of painful finger-stick blood sampling.

Recent Progress in Microneedles-Mediated Diagnosis, Therapy, and Theranostic Systems.

Theranostic system combined diagnostic and therapeutic modalities is critical for the real-time monitoring of disease-related biomarkers and personalized therapy. Microneedles, as a multifunctional platform, are promising for transdermal diagnostics and drug delivery. They have shown attractive properties including painless skin penetration, easy self-administration, prominent therapeutic effects, and good biosafety. Herein, an overview of the microneedles-based diagnosis, therapies, and theranostic systems is given. Four microneedles-based detection methods are concluded based on the sensing mechanism: i) electrochemistry, ii) fluorometric, iii) colorimetric, and iv) Raman methods. Additionally, robust microneedles are suitable for implantable drug delivery. Microneedles-assisted transdermal drug delivery can be primarily classified as passive, active, and responsive drug release, based on the release mechanisms. Microneedles-assisted oral and implantable drug delivery mechanisms are also presented in this review. Furthermore, the key frontier developments in microneedles-mediated theranostic systems as the major selling points are emphasized in this review. These systems are classified into open-loop and closed-loop theranostic systems based on the indirectness and directness of feedback between the transdermal diagnosis and therapy, respectively. Finally, conclusions and future perspectives for next-generation microneedles-mediated theranostic systems are also discussed. Taken together, microneedle-based systems are promising as the new avenue for diagnosis, therapy, and disease-specific closed-loop theranostic applications.

Magneto-Responsive Shutter for On-Demand Droplet Manipulation.

Magnetically responsive structured surfaces enabling multifunctional droplet manipulation are of significant interest in both scientific and engineering research. To realize magnetic actuation, current strategies generally employ well-designed microarrays of high-aspect-ratio structure components (e.g., microcilia, micropillars, and microplates) with incorporated magnetism to allow reversible bending deformation driven by magnets. However, such magneto-responsive microarray surfaces suffer from highly restricted deformation range and poor control precision under magnetic field, restraining their droplet manipulation capability. Herein, a novel magneto-responsive shutter (MRS) design composed of arrayed microblades connected to a frame is developed for on-demand droplet manipulation. The microblades can perform two dynamical transformation operations, including reversible swing and rotation, and significantly, the transformation can be precisely controlled over a large rotation range with the highest rotation angle up to 3960°. Functionalized MRSs based on the above design, including Janus-MRS, superhydrophobic MRS (SHP-MRS) and lubricant infused slippery MRS (LIS-MRS), can realize a wide range of droplet manipulations, ranging from switchable wettability, directional droplet bounce, droplet distribution, and droplet merging, to continuous droplet transport along either straight or curved paths. MRS provides a new paradigm of using swing/rotation topographic transformation to replace conventional bending deformation for highly efficient and on-demand multimode droplet manipulation under magnetic actuation.

A Fully Integrated Closed-Loop System Based on Mesoporous Microneedles-Iontophoresis for Diabetes Treatment.

A closed-loop system that can mini-invasively track blood glucose and intelligently treat diabetes is in great demand for modern medicine, yet it remains challenging to realize. Microneedles technologies have recently emerged as powerful tools for transdermal applications with inherent painlessness and biosafety. In this work, for the first time to the authors' knowledge, a fully integrated wearable closed-loop system (IWCS) based on mini-invasive microneedle platform is developed for in situ diabetic sensing and treatment. The IWCS consists of three connected modules: 1) a mesoporous microneedle-reverse iontophoretic glucose sensor; 2) a flexible printed circuit board as integrated and control; and 3) a microneedle-iontophoretic insulin delivery component. As the key component, mesoporous microneedles enable the painless penetration of stratum corneum, implementing subcutaneous substance exchange. The coupling with iontophoresis significantly enhances glucose extraction and insulin delivery and enables electrical control. This IWCS is demonstrated to accurately monitor glucose fluctuations, and responsively deliver insulin to regulate hyperglycemia in diabetic rat model. The painless microneedles and wearable design endows this IWCS as a highly promising platform to improve the therapies of diabetic patients.

Atomic-engineering Au-Ag nanoalloys for screening antimicrobial agents with low toxicity towards mammalian cells.

Silver nanoparticles (AgNPs) have shown potent antibacterial activity against numerous bacteria strains. However, their toxicity against mammalian cells is still a big challenge, limiting their in vivo applications. Here, we found that alloying Ag and Au in an atomic level to form Au-Ag nanoalloys (NAs) could effectively reduce the cytotoxicity of AgNPs, and the antimicrobial activity of NAs could be well maintained by tuning the composition of Ag. By means of a facile and robust laser-based technique, which involves the laser ablation of metal films toward water (LATW), we fabricated a series of Au-Ag NAs with different elemental compositions. Precise control over the compositions of Au and Ag was achieved via adjusting the thickness ratio of ablated Au/Ag films. Following the systematic examinations of these NAs on their antibacterial performance and the toxicity against the normal mammalian cells, we found that significant bactericidal effect with negligible cytotoxicity could be achieved with the NAs bearing 40 % of Au and 60 % Ag. Furthermore, Au-Ag NAs displayed a lower cytotoxicity than their corresponding monometallic NP mixtures due to the decreased Ag+ release from alloying structures of Au-Ag. This work showed the great potential of Au-Ag NAs in in vivo applications to fight against bacterial infections.