Cell Rover-a miniaturized magnetostrictive antenna for wireless operation inside living cells.

An intracellular antenna can open up new horizons for fundamental and applied biology. Here, we introduce the Cell Rover, a magnetostrictive antenna which can operate wirelessly inside a living cell and is compatible with 3D biological systems. It is sub-mm in size, acoustically actuated by an AC magnetic field and resonantly operated at low MHz frequencies, which is ideal for living systems. We developed an injection scheme involving non-uniform magnetic fields for intracellular injection of the Cell Rovers and demonstrated their operation in fully opaque, stage VI Xenopus oocytes, for which real-time imaging with conventional technologies is challenging. We also show that they provide a pathway for multiplexing applications to individually address multiple cells or to tune to more than one antenna within the same cell for versatile functionalities. This technology forms the foundation stone that can enable the integration of future capabilities such as smart sensing, modulation as well as energy harvesting to power in-cell nanoelectronic computing and can potentially bring the prowess of information technology inside a living cell. This could lead to unprecedented opportunities for fundamental understanding of biology as well as diagnostics and therapeutics.

A miniature robotic steerable endoscope for maxillary sinus surgery called PliENT.

In endoscopic maxillary sinus surgery, the maxillary sinus is accessed through the nasal cavity which constitutes a narrow and tortuous pathway. However, surgeons still use rigid endoscopes and rigid, straight or pre-bent instruments for this procedure. Resection of the uncinate process and creation of a medial antrostomy is warranted to access the pathology inside the maxillary sinus and depending on the location of the pathology (lateral, inferior or anterior wall), additional resection of healthy tissue and/or functional structures like the lacrimal duct and/or inferior turbinate is necessary to gain optimal access. In order to avoid this additional resection, a functional single-handed, steerable endoscope for endoscopic maxillary sinus surgery has been designed and built. This endoscope is, to our knowledge, the most slender active steerable endoscope ever reported for maxillary sinus surgery. The performance of the endoscope was validated by two surgeons on a cadaver. An increased field of view was found in comparison to currently used endoscopes. As a direct consequence, a reduced need for resection of healthy tissue was confirmed.

Molecular electronics sensors on a scalable semiconductor chip: A platform for single-molecule measurement of binding kinetics and enzyme activity.

For nearly 50 years, the vision of using single molecules in circuits has been seen as providing the ultimate miniaturization of electronic chips. An advanced example of such a molecular electronics chip is presented here, with the important distinction that the molecular circuit elements play the role of general-purpose single-molecule sensors. The device consists of a semiconductor chip with a scalable array architecture. Each array element contains a synthetic molecular wire assembled to span nanoelectrodes in a current monitoring circuit. A central conjugation site is used to attach a single probe molecule that defines the target of the sensor. The chip digitizes the resulting picoamp-scale current-versus-time readout from each sensor element of the array at a rate of 1,000 frames per second. This provides detailed electrical signatures of the single-molecule interactions between the probe and targets present in a solution-phase test sample. This platform is used to measure the interaction kinetics of single molecules, without the use of labels, in a massively parallel fashion. To demonstrate broad applicability, examples are shown for probe molecule binding, including DNA oligos, aptamers, antibodies, and antigens, and the activity of enzymes relevant to diagnostics and sequencing, including a CRISPR/Cas enzyme binding a target DNA, and a DNA polymerase enzyme incorporating nucleotides as it copies a DNA template. All of these applications are accomplished with high sensitivity and resolution, on a manufacturable, scalable, all-electronic semiconductor chip device, thereby bringing the power of modern chips to these diverse areas of biosensing.

Three-dimensional electronic microfliers inspired by wind-dispersed seeds.

Large, distributed collections of miniaturized, wireless electronic devices1,2 may form the basis of future systems for environmental monitoring3, population surveillance4, disease management5 and other applications that demand coverage over expansive spatial scales. Aerial schemes to distribute the components for such networks are required, and-inspired by wind-dispersed seeds6-we examined passive structures designed for controlled, unpowered flight across natural environments or city settings. Techniques in mechanically guided assembly of three-dimensional (3D) mesostructures7-9 provide access to miniature, 3D fliers optimized for such purposes, in processes that align with the most sophisticated production techniques for electronic, optoelectronic, microfluidic and microelectromechanical technologies. Here we demonstrate a range of 3D macro-, meso- and microscale fliers produced in this manner, including those that incorporate active electronic and colorimetric payloads. Analytical, computational and experimental studies of the aerodynamics of high-performance structures of this type establish a set of fundamental considerations in bio-inspired design, with a focus on 3D fliers that exhibit controlled rotational kinematics and low terminal velocities. An approach that represents these complex 3D structures as discrete numbers of blades captures the essential physics in simple, analytical scaling forms, validated by computational and experimental results. Battery-free, wireless devices and colorimetric sensors for environmental measurements provide simple examples of a wide spectrum of applications of these unusual concepts.

Living with an Insertable Cardiac Monitor: Influences on Self-Care Management.

The insertable cardiac monitor (ICM) is technology for diagnosing cardiac arrhythmias. The perception of those living with the device and how this relates to self-care management is unknown. The aim of this study was to explore the experiences of those with undiagnosed cardiac symptoms living with an ICM. This study used a qualitative descriptive design. Analysis of data was by intraparticipant analysis, interparticipant analysis, and interrelationships. Three global categories emerged: (a) influences on self-care, (b) dealing and (c) monitoring. Self-care management after insertion of the ICM was determined by the participant's perception of health, what symptoms they were experiencing and whether there was a positive or negative experience with the clinician. Many indicated little to no regular communication regarding symptoms and ICM results. Increasing communication relevant to management of health and long-term findings may assist in enhancing physical and psychological health.

Miniaturised Wireless Power Transfer Systems for Neurostimulation: A Review.

In neurostimulation, wireless power transfer is an efficient technology to overcome several limitations affecting medical devices currently used in clinical practice. Several methods were developed over the years for wireless power transfer. In this review article, we report and discuss the three most relevant methodologies for extremely miniaturised implantable neurostimulators: ultrasound coupling, inductive coupling and capacitive coupling. For each powering method, the discussion starts describing the physical working principle. In particular, we focus on the challenges given by the miniaturisation of the implanted integrated circuits and the related ad-hoc solutions for wireless power transfer. Then, we present recent developments and progresses in wireless power transfer for biomedical applications. Last, we compare each technique based on key performance indicators to highlight the most relevant and innovative solutions suitable for neurostimulation, with the gaze turned towards miniaturisation.

Miniature all-optical flexible forward-viewing photoacoustic endoscopy probe for surgical guidance.

A miniature flexible photoacoustic endoscopy probe that provides high-resolution 3D images of vascular structures in the forward-viewing configuration is described. A planar Fabry-Perot ultrasound sensor with a -3dB bandwidth of 53 MHz located at the tip of the probe is interrogated via a flexible fiber bundle and a miniature optical relay system to realize an all-optical probe measuring 7.4 mm in outer diameter at the tip. This approach to photoacoustic endoscopy offers advantages over previous piezoelectric based distal-end scanning probes. These include a forward-viewing configuration in widefield photoacoustic tomography mode, finer spatial sampling (87 µm spatial sampling interval), and wider detection bandwidth (53 MHz) than has been achievable with conventional ultrasound detection technology and an all-optical passive imaging head for safe endoscopic use.

Laser Driven Miniature Diamond Implant for Wireless Retinal Prostheses.

The design and benchtop operation of a wireless miniature epiretinal stimulator implant is reported. The implant is optically powered and controlled using safe illumination at near-infrared wavelengths. An application-specific integrated circuit (ASIC) hosting a digital control unit is used to control the implant's electrodes. The ASIC is powered using an advanced photovoltaic (PV) cell and programmed using a single photodiode. Diamond packaging technology is utilized to achieve high-density integration of the implant optoelectronic circuitry, as well as individual connections between a stimulator chip and 256 electrodes, within a 4.6 mm × 3.7 mm × 0.9 mm implant package. An ultrahigh efficiency PV cell with a monochromatic power conversion efficiency of 55% is used to power the implant. On-board photodetection circuity with a bandwidth of 3.7 MHz is used for forward data telemetry of stimulation parameters. In comparison to implants which utilize inductively coupled coils, laser power delivery enables a high degree of miniaturization and lower surgical complexity. The device presented combines the benefits of implant miniaturization and a flexible stimulation strategy provided by a dedicated stimulator chip. This development provides a route to fully wireless miniaturized minimally invasive implants with sophisticated functionalities.

Optimizing Volumetric Efficiency and Backscatter Communication in Biosensing Ultrasonic Implants.

Ultrasonic backscatter communication has gained popularity in recent years with the advent of deep-tissue sub-mm scale biosensing implants in which piezoceramic (piezo) resonators are used as acoustic antennas. Miniaturization is a key design goal for such implants to reduce tissue displacement and enable minimally invasive implantation techniques. Here, we provide a systematic design approach for the implant piezo geometry and operation frequency to minimize the overall volume of the implant. Optimal geometry of the implant piezo for backscatter communication is discussed and contrasted with that of power harvesting. A critical design aspect of an ultrasonic backscatter communication link is the response of the piezo acoustic reflection coefficient Γ with respect to the variable shunt impedance, ZE, of the implant uplink modulator. Due to the complexity of the piezo governing equations and multi-domain, electro-acoustical nature of the piezo, Γ(ZE) has often been characterized numerically and the implant uplink modulator has been designed empirically resulting in sub-optimal performance in terms of data rate and linearity. Here, we present a SPICE friendly end-to-end equivalent circuit model of the channel as a piezo-IC co-simulation tool that incorporates inherent path losses present in a typical ultrasonic backscatter channel. To provide further insight into the channel response, we present experimentally validated closed form expressions for Γ(ZE) under various boundary conditions. These expressions couple Γ to the commonly used Thevenin equivalent circuit model of the piezo, facilitating systematic design and synthesis of ultrasonic backscatter uplink modulators.

Successful In vivo Calcium Imaging with a Head-Mount Miniaturized Microscope in the Amygdala of Freely Behaving Mouse.

In vivo real-time monitoring of neuronal activities in freely moving animals is one of key approaches to link neuronal activity to behavior. For this purpose, an in vivo imaging technique that detects calcium transients in neurons using genetically encoded calcium indicators (GECIs), a miniaturized fluorescence microscope, and a gradient refractive index (GRIN) lens has been developed and successfully applied to many brain structures1 , 2 , 3 , 4 , 5 , 6. This imaging technique is particularly powerful because it enables chronic simultaneous imaging of genetically defined cell populations for a long-term period up to several weeks. Although useful, this imaging technique has not been easily applied to brain structures that locate deep within the brain such as amygdala, an essential brain structure for emotional processing and associative fear memory7. There are several factors that make it difficult to apply the imaging technique to the amygdala. For instance, motion artifacts usually occur more frequently during the imaging conducted in the deeper brain regions because a head-mount microscope implanted deep in the brain is relatively unstable. Another problem is that the lateral ventricle is positioned close to the implanted GRIN lens and its movement during respiration may cause highly irregular motion artifacts that cannot be easily corrected, which makes it difficult to form a stable imaging view. Furthermore, because cells in the amygdala are usually quiet at a resting or anesthetized state, it is hard to find and focus the target cells expressing GECI in the amygdala during baseplating procedure for later imaging. This protocol provides a helpful guideline for how to efficiently target cells expressing GECI in the amygdala with head-mount miniaturized microscope for successful in vivo calcium imaging in such a deeper brain region. It is noted that this protocol is based on a particular system (e.g., Inscopix) but not restricted to it.

Development of a miniaturized 96-Transwell air-liquid interface human small airway epithelial model.

In order to overcome the challenges associated with a limited number of airway epithelial cells that can be obtained from clinical sampling and their restrained capacity to divide ex vivo, miniaturization of respiratory drug discovery assays is of pivotal importance. Thus, a 96-well microplate system was developed where primary human small airway epithelial (hSAE) cells were cultured at an air-liquid interface (ALI). After four weeks of ALI culture, a pseudostratified epithelium containing basal, club, goblet and ciliated cells was produced. The 96-well ALI cultures displayed a cellular composition, ciliary beating frequency, and intercellular tight junctions similar to 24-well conditions. A novel custom-made device for 96-parallelized transepithelial electric resistance (TEER) measurements, together with dextran permeability measurements, confirmed that the 96-well culture developed a tight barrier function during ALI differentiation. 96-well hSAE cultures were responsive to transforming growth factor ß1 (TGF-ß1) and tumor necrosis factor α (TNF-α) in a concentration dependent manner. Thus, the miniaturized cellular model system enables the recapitulation of a physiologically responsive, differentiated small airway epithelium, and a robotic integration provides a medium throughput approach towards pharmaceutical drug discovery, for instance, in respect of fibrotic distal airway/lung diseases.

Injectable Sensors Based on Passive Rectification of Volume-Conducted Currents.

Sensing implants that can be deployed by catheterization or by injection are preferable over implants requiring invasive surgery. However, present powering methods for active implants and present interrogation methods for passive implants require bulky parts within the implants that hinder the development of such minimally invasive devices. In this article, we propose a novel approach that potentially enables the development of passive sensing systems overcoming the limitations of previous implantable sensing systems in terms of miniaturization. In this approach implants are shaped as thread-like devices suitable for implantation by injection. Their basic structure consists of a thin elongated body with two electrodes at opposite ends and a simple and small circuit made up of a diode, a capacitor and a resistor. The interrogation method to obtain measurements from the implants consists in applying innocuous bursts of high frequency (≥1 MHz) alternating current that reach the implants by volume conduction and in capturing and processing the voltage signals that the implants produce after the bursts. As proof-of-concept, and for illustrating how to put in practice this novel approach, here we describe the development and characterization of a system for measuring the conductivity of tissues surrounding the implant. We also describe the implementation and the in vitro validation of a 0.95 mm-thick, flexible injectable implant made of off-the-shelf components. For conductivities ranging from about 0.2 to 0.8 S/m, when compared to a commercial conductivity meter, the accuracy of the implemented system was about ±10%.

A Novel Design Approach for Compact Wearable Antennas Based on Metasurfaces.

This paper presents a novel approach to design compact wearable antennas based on metasurfaces. The behavior of compact metasurfaces is modeled with a composite right-left handed transmission line (CRLH TL). By controlling the dispersion curve, the resonant modes of the compact metasurface can be tuned efficiently. A printed coplanar waveguide (CPW) monopole antenna is used as the feed structure to excite the compact metasurface, which will result in a low profile antenna with low backward radiation. Following this approach, two compact antennas are designed for wearable applications. The first antenna is designed to operate at its first negative mode (-1 mode), which can realize miniaturization, but maintain the broadside radiation as for a normal microstrip antenna. The proposed prototype resonates around 2.65 GHz, with a matching bandwidth of 300 MHz. The total dimensions of the antenna are 39.4 × 33.4 mm2 (0.1 λ02), and its maximum gain is 2.99 dBi. The second antenna targets dual-band operation at 2.45 and 3.65 GHz. A pair of symmetric modes (±1 modes) are used to generate similar radiation patterns in these two bands. The size of the antenna is 55.79 × 52.25 mm2 (0.2 λ02), and the maximum gains are 4.25 and 7.35 dBi in the two bands, respectively. Furthermore, the performance of the antennas is analyzed on the human body. The results show that the proposed antennas are promising candidates for Wireless Body Area Networks (WBAN).

A 1 MHz Miniaturized Electrical Impedance Tomography System for Prostate Imaging.

An ASIC for a high frequency electrical impedance tomography (EIT) imaging system for prostate cancer screening is presented. The ASIC enables a small form-factor architecture, which ensures high signal-to-noise ratio (SNR) at MHz frequencies. The 4-channel ASIC was designed and fabricated in a standard CMOS 0.18- µm technology and integrates a novel current driver for current stimulus, instrumentation amplifier to interface with the tissue, VGA to provide variable gain and ADC with SPI interface for digitization. A prototype miniaturized EIT system was built and it was evaluated using a model transrectal imaging probe immersed into a tank filled with saline and a metal inclusion that demonstrated the open-domain problem of imaging prostate cancer lesion. The system maintained an SNR between 66 and 76 dB over the frequency range of 500 Hz to 1 MHz. Also, it produced reconstructed EIT images that depicted the presence of the small metal inclusion that modeled a prostate cancer imaging application.

Miniaturized precalibration-based Lissajous scanning fiber probe for high speed endoscopic optical coherence tomography.

We present a miniaturized precalibration-based forward-viewing Lissajous scanning fiber probe for high speed endoscopic optical coherence tomography (OCT). The probe is based on an asymmetric fiber cantilever driven by the piezoelectric bender to realize two-dimensional (2D) Lissajous scanning. The stability and repeatability of the Lissajous scanning trajectory of the probe is tested by a position sensitive detector (PSD)-based position calibration setup. The two orthogonal resonant frequencies of the cantilever are measured to be 167.2 and 121 Hz. A 25 µm focal spot is formed at the working distance of 5 mm by the graded-index (GRIN) lens, and the field of view of the imaging probe is around ${1.5}\;{\rm mm} \times {1.5}\;{\rm mm}$1.5mm×1.5mm. The probe is fully packaged in a hypodermic tube for endoscopic imaging. The total rigid length and outer diameter are 35 mm and 3.5 mm, respectively. The probe is incorporated in a 50 KHz swept source OCT system with the axial resolution of 14 µm, and its imaging performance is validated by the 2D en face and 3D volumetric OCT imaging of the phantom and the biological tissue.

Development of a rapid phenotypic test on a microfluidic device for carbapenemase detection using the chromogenic compound nitrocefin.

Routine identification of carbapenemase-producing bacterial isolates is a lengthy process often taking up to 72 h to generate results with standard culture-based tests. Here we describe a rapid test based on the hydrolysis of nitrocefin to identify isolates producing ß-lactamase enzymes. A cocktail of inhibitors has been optimized in the reaction mix to provide specificity for carbapenemase enzymes. The developed assay has also been translated to a microfluidic platform with an optical readout (optofluidic chip). The chip has a long absorbance path (25 mm) to provide high sensitivity. A sample-to-answer has been achieved in under 30 min on these chips using colonies from culture plates. The test on this platform has the potential to provide a rapid indicative (presumptive positive) test for carbapenemase producers direct from bacteria isolated from patient samples, to rapidly trigger infection control measures and identify samples that should be prioritized for more specialized carbapenemase diagnostic assays.

Assessment of miniaturized ultrasound-powered implants: an in vivo study.

OBJECTIVE: Therapeutic applications of implantable active medical devices have improved the quality of patient life. Numerous on-going research in the field of neuromodulation and bioelectronic medicine are exploring the use of these implants for treating diseases and conditions. Miniaturized implantable medical devices that are wirelessly powered by ultrasound (US) can be placed close to the target sites deep inside the body for effective therapy with less invasiveness. In this study, we assessed the long-term in vivo performance of miniaturized US powered implants (UPI) using a rodent model. APPROACH: Prototype UPI devices were implanted in rodents and powered wirelessly using an unfocused US transmitter over 12 weeks, and the corresponding device output was recorded. Structural integrity of UPI before and after implantation was studied using scanning electron microscopy (SEM). We also conducted qualitative histological assessment of skin and muscle surrounding the UPI and compared it to naïve control and US exposed tissues. MAIN RESULTS: We found that it is feasible to power UPI devices wirelessly with US over long-term. The encapsulation of UPIs did not degrade over time and the tissues surrounding the UPI were comparable to both naïve control and US exposed tissues. SIGNIFICANCE: This study is the first to assess the long-term performance of miniaturized UPI devices using a rodent model over 12-weeks. The set of tests used in this study can be extended to assess other US-powered miniaturized implants.

The detection of cannabinoids in veterinary feeds by microNIR/chemometrics: a new analytical platform.

In this work, the capabilities of a novel miniaturized and portable microNIR spectrometer were investigated in order to propose a practical and intelligible test allowing the rapid and easy screening of cannabinoids in veterinary feeds. In order to develop a predictive model that could identify and simultaneously quantify the residual amounts of cannabinoids, specimens from popular veterinary feeds were considered and spiked with increasing amounts of cannabidiol (CBD), Δ9-tetrahydrocannabinol (THC), and cannabigerol (CBG). Partial least squares discriminant analysis (PLS-DA) and partial least squares regression (PLSr) were applied for the simultaneous detection and quantification of cannabinoids. The results demonstrated that the microNIR/chemometric platform could statistically identify the presence of CBD, THC and CBG in the simulated samples containing cannabinoids from 0.001 to 0.01%w/w, with the accuracy and sensitivity of the official reference methods actually proposed. The method was checked against false positive and true positive responses, and the results proved to be those required for confirmatory analyses, permitting to provide a fast and accurate method for monitoring cannabinoids in veterinary feeds.

µ-NMR at the point of care testing.

NMR shows strong analytical capability for obtaining molecular information on materials and is used in a variety of fields. Micro-NMR (µNMR) is mainly based on low-field NMR (LF-NMR), which makes NMR detection portable and inexpensive. Point-of-care testing (POCT) has gradually become an area of major concern, and scientists have made much progress in applying µNMR systems for POCT. To the best of our knowledge, this is the first review of the latest development in miniaturization of µNMR systems. Then, we discuss cutting-edge µNMR-based applications in POCT and the outlook for future developments.

A 25 micron-thin microscope for imaging upconverting nanoparticles with NIR-I and NIR-II illumination.

Rationale: Intraoperative visualization in small surgical cavities and hard-to-access areas are essential requirements for modern, minimally invasive surgeries and demand significant miniaturization. However, current optical imagers require multiple hard-to-miniaturize components including lenses, filters and optical fibers. These components restrict both the form-factor and maneuverability of these imagers, and imagers largely remain stand-alone devices with centimeter-scale dimensions. Methods: We have engineered INSITE (Immunotargeted Nanoparticle Single-Chip Imaging Technology), which integrates the unique optical properties of lanthanide-based alloyed upconverting nanoparticles (aUCNPs) with the time-resolved imaging of a 25-micron thin CMOS-based (complementary metal oxide semiconductor) imager. We have synthesized core/shell aUCNPs of different compositions and imaged their visible emission with INSITE under either NIR-I and NIR-II photoexcitation. We characterized aUCNP imaging with INSITE across both varying aUCNP composition and 980 nm and 1550 nm excitation wavelengths. To demonstrate clinical experimental validity, we also conducted an intratumoral injection into LNCaP prostate tumors in a male nude mouse that was subsequently excised and imaged with INSITE. Results: Under the low illumination fluences compatible with live animal imaging, we measure aUCNP radiative lifetimes of 600 µs - 1.3 ms, which provides strong signal for time-resolved INSITE imaging. Core/shell NaEr0.6Yb0.4F4 aUCNPs show the highest INSITE signal when illuminated at either 980 nm or 1550 nm, with signal from NIR-I excitation about an order of magnitude brighter than from NIR-II excitation. The 55 µm spatial resolution achievable with this approach is demonstrated through imaging of aUCNPs in PDMS (polydimethylsiloxane) micro-wells, showing resolution of micrometer-scale targets with single-pixel precision. INSITE imaging of intratumoral NaEr0.8Yb0.2F4 aUCNPs shows a signal-to-background ratio of 9, limited only by photodiode dark current and electronic noise. Conclusion: This work demonstrates INSITE imaging of aUCNPs in tumors, achieving an imaging platform that is thinned to just a 25 µm-thin, planar form-factor, with both NIR-I and NIR-II excitation. Based on a highly paralleled array structure INSITE is scalable, enabling direct coupling with a wide array of surgical and robotic tools for seamless integration with tissue actuation, resection or ablation.