Acoustic Sensing and Ultrasonic Drug Delivery in Multimodal Theranostic Capsule Endoscopy.

Video capsule endoscopy (VCE) is now a clinically accepted diagnostic modality in which miniaturized technology, an on-board power supply and wireless telemetry stand as technological foundations for other capsule endoscopy (CE) devices. However, VCE does not provide therapeutic functionality, and research towards therapeutic CE (TCE) has been limited. In this paper, a route towards viable TCE is proposed, based on multiple CE devices including important acoustic sensing and drug delivery components. In this approach, an initial multimodal diagnostic device with high-frequency quantitative microultrasound that complements video imaging allows surface and subsurface visualization and computer-assisted diagnosis. Using focused ultrasound (US) to mark sites of pathology with exogenous fluorescent agents permits follow-up with another device to provide therapy. This is based on an US-mediated targeted drug delivery system with fluorescence imaging guidance. An additional device may then be utilized for treatment verification and monitoring, exploiting the minimally invasive nature of CE. While such a theranostic patient pathway for gastrointestinal treatment is presently incomplete, the description in this paper of previous research and work under way to realize further components for the proposed pathway suggests it is feasible and provides a framework around which to structure further work.

Piezoelectric micromachined ultrasound transducer (PMUT) arrays for integrated sensing, actuation and imaging.

Many applications of ultrasound for sensing, actuation and imaging require miniaturized and low power transducers and transducer arrays integrated with electronic systems. Piezoelectric micromachined ultrasound transducers (PMUTs), diaphragm-like thin film flexural transducers typically formed on silicon substrates, are a potential solution for integrated transducer arrays. This paper presents an overview of the current development status of PMUTs and a discussion of their suitability for miniaturized and integrated devices. The thin film piezoelectric materials required to functionalize these devices are discussed, followed by the microfabrication techniques used to create PMUT elements and the constraints the fabrication imposes on device design. Approaches for electrical interconnection and integration with on-chip electronics are discussed. Electrical and acoustic measurements from fabricated PMUT arrays with up to 320 diaphragm elements are presented. The PMUTs are shown to be broadband devices with an operating frequency which is tunable by tailoring the lateral dimensions of the flexural membrane or the thicknesses of the constituent layers. Finally, the outlook for future development of PMUT technology and the potential applications made feasible by integrated PMUT devices are discussed.

Acoustic tractor beam.

Negative radiation forces act opposite to the direction of propagation, or net momentum, of a beam but have previously been challenging to definitively demonstrate. We report an experimental acoustic tractor beam generated by an ultrasonic array operating on macroscopic targets (>1 cm) to demonstrate the negative radiation forces and to map out regimes over which they dominate, which we compare to simulations. The result and the geometrically simple configuration show that the effect is due to nonconservative forces, produced by redirection of a momentum flux from the angled sides of a target and not by conservative forces from a potential energy gradient. Use of a simple acoustic setup provides an easily understood illustration of the negative radiation pressure concept for tractor beams and demonstrates continuous attraction towards the source, against a net momentum flux in the system.

Synthesis and inclusion study of a novel γ-cyclodextrin derivative as a potential thermo-sensitive carrier for doxorubicin.

A novel γ-cyclodextrin (γ-CD) based carrier for molecular encapsulation of cancer chemotherapeutic agent doxorubicin (DOX) was synthesized and fully characterized by various analytical approaches. The γ-CD derivative, with a ß-naphthyl alanine residue attached in its primary face, exhibits potent binding capacity with DOX. The encapsulation efficiency was assessed under various temperatures and pHs and it was demonstrated that the carrier-DOX inclusion complex is highly stable under a wide range of acidic conditions (pH 1.0-7.0); however, the encapsulated drug is slowly released under hyperthermic conditions (up to 50°C). Cell culture studies showed that the complexation of DOX with the carrier protected the drug from being uptaken by the cells and also greatly reduced its toxicity. Thermo-triggered DOX release was validated and the increase in cellular uptake was observed in in-vitro experiments. We concluded that this novel γ-CD derivative is able to effectively encapsulate DOX and the inclusion is responsive to temperature change, hence renders it a potential encapsulating agent for DOX delivery in combination with hyperthermia treatments.

Acoustic devices for particle and cell manipulation and sensing.

An emerging demand for the precise manipulation of cells and particles for applications in cell biology and analytical chemistry has driven rapid development of ultrasonic manipulation technology. Compared to the other manipulation technologies, such as magnetic tweezing, dielectrophoresis and optical tweezing, ultrasonic manipulation has shown potential in a variety of applications, with its advantages of versatile, inexpensive and easy integration into microfluidic systems, maintenance of cell viability, and generation of sufficient forces to handle particles, cells and their agglomerates. This article briefly reviews current practice and reports our development of various ultrasonic standing wave manipulation devices, including simple devices integrated with high frequency (>20 MHz) ultrasonic transducers for the investigation of biological cells and complex ultrasonic transducer array systems to explore the feasibility of electronically controlled 2-D and 3-D manipulation. Piezoelectric and passive materials, fabrication techniques, characterization methods and possible applications are discussed. The behavior and performance of the devices have been investigated and predicted with computer simulations, and verified experimentally. Issues met during development are highlighted and discussed. To assist long term practical adoption, approaches to low-cost, wafer level batch-production and commercialization potential are also addressed.

Can Mn:PIN-PMN-PT piezocrystal replace hard piezoceramic in power ultrasonic devices?

Mn:PIN-PMN-PT piezocrystal is investigated to determine whether its enhanced energy density makes it a candidate transducer material for power ultrasonics applications. To this end, the electromechanical and vibrational characteristics of a simple configuration of a bolted Langevin transducer (BLT) and then an ultrasonic surgical device, both incorporating Mn:PIN-PMN-PT piezocrystal, are compared with the same transducer configurations incorporating a conventional hard PZT piezoceramic commonly used in high-power ultrasonic transducers. The material properties of Mn:PIN-PMN-PT are determined using a single sample characterisation technique and these are used in finite element analysis (FEA) to design and then fabricate the BLT and ultrasonic surgical device, tuned to the first and second longitudinal modes at 20 kHz respectively. FEA is similarly used for the hard PZT versions. It is found that the superior elastic compliance of Mn:PIN-PMN-PT results in a higher radial piezo-stack deformation than the hard PZT under ultrasonic excitation of the BLT. However, the resulting longitudinal displacement amplitude of the two BLTs and two ultrasonic surgical devices is found to be equal, despite the higher figure of merit (Qkeff2) of those incorporating Mn:PIN-PMN-PT. The electrical impedance is measured at increasing excitation levels to evaluate the quality factor, Q. It is found that damping in the BLT with hard PZT is negligibly affected in the excitation range considered; however, the BLT incorporating Mn:PIN-PMN-PT exhibits a large reduction in Q. These findings indicate that, for measurements in air, the advantages of the high figure of merit of the piezocrystal material are not realised in a high-power transducer due to significantly increased damping at high excitation levels. To compare the vibrational response of the two ultrasonic surgical devices, L-C electrical impedance matching was implemented to maximise the efficiency of energy transfer from the source to the transducer under load. Results suggest that similar responses occurred for the two surgical devices in cutting tests using a low strength bone mimic material. However, the Mn:PIN-PMN-PT device exhibited better performance in cutting through higher strength ex-vivo chicken femur.

Unsupervised machine learning for flaw detection in automated ultrasonic testing of carbon fibre reinforced plastic composites.

The use of Carbon Fibre Reinforced Plastic (CFRP) composite materials for critical components has significantly surged within the energy and aerospace industry. With this rapid increase in deployment, reliable post-manufacturing Non-Destructive Evaluation (NDE) is critical for verifying the mechanical integrity of manufactured components. To this end, an automated Ultrasonic Testing (UT) NDE process delivered by an industrial manipulator was developed, greatly increasing the measurement speed, repeatability, and locational precision, while increasing the throughput of data generated by the selected NDE modality. Data interpretation of UT signals presents a current bottleneck, as it is still predominantly performed manually in industrial settings. To reduce the interpretation time and minimise human error, this paper presents a two-stage automated NDE evaluation pipeline consisting of a) an intelligent gating process and b) an autoencoder (AE) defect detector. Both stages are based on an unsupervised method, leveraging density-based spatial clustering of applications with noise clustering method for robust automated gating and undefective UT data for the training of the AE architecture. The AE network trained on ultrasonic B-scan data was tested for performance on a set of reference CFRP samples with embedded and manufactured defects. The developed model is rapid during inference, processing over 2000 ultrasonic B-scans in 1.26 s with the area under the receiver operating characteristic curve of 0.922 in simple and 0.879 in complex geometry samples. The benefits and shortcomings of the presented methods are discussed, and uncertainties associated with the reported results are evaluated.

The importance of physics to progress in medical treatment.

Physics in therapy is as diverse as it is substantial. In this review, we highlight the role of physics--occasionally transitioning into engineering--through discussion of several established and emerging treatments. We specifically address minimal access surgery, ultrasound, photonics, and interventional MRI, identifying areas in which complementarity is being exploited. We also discuss some of the fundamental physical principles involved in the application of each treatment to medical practice.

Effect of Phase-Change Nanodroplets and Ultrasound on Blood-Brain Barrier Permeability In Vitro.

Phase-change nanodroplets (PCND;NDs) are emulsions with a perfluorocarbon (PFC) core that undergo acoustic vaporisation as a response to ultrasound (US). Nanodroplets change to microbubbles and cavitate while under the effect of US. This cavitation can apply forces on cell connections in biological barrier membranes, such as the blood-brain barrier (BBB), and trigger a transient and reversible increased permeability to molecules and matter. This study aims to present the preparation of lipid-based NDs and investigate their effects on the brain endothelial cell barrier in vitro. The NDs were prepared using the thin-film hydration method, followed by the PFC addition. They were characterised for size, cavitation (using a high-speed camera), and PFC encapsulation (using FTIR). The bEnd.3 (mouse brain endothelial) cells were seeded onto transwell inserts. Fluorescein with NDs and/or microbubbles were applied on the bEND3 cells and the effect of US on fluorescein permeability was measured. The Live/Dead assay was used to assess the BBB integrity after the treatments. Size and PFC content analysis indicated that the NDs were stable while stored. High-speed camera imaging confirmed that the NDs cavitate after US exposure of 0.12 MPa. The BBB cell model experiments revealed a 4-fold increase in cell membrane permeation after the combined application of US and NDs. The Live/Dead assay results indicated damage to the BBB membrane integrity, but this damage was less when compared to the one caused by microbubbles. This in vitro study shows that nanodroplets have the potential to cause BBB opening in a similar manner to microbubbles. Both cavitation agents caused damage on the endothelial cells. It appears that NDs cause less cell damage compared to microbubbles.

Mechanical evidence of the orbital angular momentum to energy ratio of vortex beams.

We measure, in a single experiment, both the radiation pressure and the torque due to a wide variety of propagating acoustic vortex beams. The results validate, for the first time directly, the theoretically predicted ratio of the orbital angular momentum to linear momentum in a propagating beam. We experimentally determine this ratio using simultaneous measurements of both the levitation force and the torque on an acoustic absorber exerted by a broad range of helical ultrasonic beams produced by a 1000-element matrix transducer array. In general, beams with helical phase fronts have been shown to contain orbital angular momentum as the result of the azimuthal component of the Poynting vector around the propagation axis. Theory predicts that for both optical and acoustic helical beams the ratio of the angular momentum current of the beam to the power should be given by the ratio of the beam's topological charge to its angular frequency. This direct experimental observation that the ratio of the torque to power does convincingly match the expected value (given by the topological charge to angular frequency ratio of the beam) is a fundamental result.

Ultrasound activated nano-encapsulated targeted drug delivery and tumour cell poration.

INTRODUCTION: Recently, ultrasonic drug release has been a focus of many research groups for stimuli responsive drug release. It has been demonstrated that a focused ultrasound (FUS) beam rapidly increases the temperature at the focused tissue area. One potential mechanism of drug targeting is to utilize the induced heat to release or increase penetration of chemotherapy to cancer cells. The efficiency of targeted drug delivery may increase by using FUS beam in conjugation with nano--encapsulated drug carriers.The aim of this study is to investigate the effect of heat and ultrasound on the cellular uptake and therapeutic efficacy of an anticancer drug using Magnetic Resonance Imaging guided Focused Ultrasound (MRgFUS). MATERIALS AND METHODS: Human KB cells (CCL-17 cells) were seeded into 96-well plates and heat treated at 37-55°C for 2-10 min. Cell viability was determined using the colorimetric MTT assay. The cells were also subjected to MRgFUS and the degree of cell viability was determined. These experiments were conducted using an ExAblate 2000 system (InSightec, Haifa, Israel) and a GE 1.5 T MRI system, software release 15. RESULTS: We have observed a significant decrease in human KB cell viability due to heat (>41°C) in the presence of Doxorubicin (DOX), in comparison with DOX at normal culture temperature (37°C). The synergistic effect of heat with DOX may be explained by several mechanisms. One potential mechanism may be increased penetration of DOX to the cells during heating. In addition, we have shown that ultrasound induced cavitation causes cell necrosis. DISCUSSION AND FUTURE WORK: Further investigation is required to optimize the potential of MRgFUS to enhance cellular uptake of therapeutic agents. A novel delivery nano-vehicle developed by CapsuTech will be investigated with MRgFUS for its potential as a stimuli responsive delivery system.

Machine learning-enabled quantitative ultrasound techniques for tissue differentiation.

PURPOSE: Quantitative ultrasound (QUS) infers properties about tissue microstructure from backscattered radio-frequency ultrasound data. This paper describes how to implement the most practical QUS parameters using an ultrasound research system for tissue differentiation. METHODS: This study first validated chicken liver and gizzard muscle as suitable acoustic phantoms for human brain and brain tumour tissues via measurement of the speed of sound and acoustic attenuation. A total of thirteen QUS parameters were estimated from twelve samples, each using data obtained with a transducer with a frequency of 5-11 MHz. Spectral parameters, i.e., effective scatterer diameter and acoustic concentration, were calculated from the backscattered power spectrum of the tissue, and echo envelope statistics were estimated by modelling the scattering inside the tissue as a homodyned K-distribution, yielding the scatterer clustering parameter α and the structure parameter κ. Standard deviation and higher-order moments were calculated from the echogenicity value assigned in conventional B-mode images. RESULTS: The k-nearest neighbours algorithm was used to combine those parameters, which achieved 94.5% accuracy and 0.933 F1-score. CONCLUSION: We were able to generate classification parametric images in near-real-time speed as a potential diagnostic tool in the operating room for the possible use for human brain tissue characterisation.

Optimization and fabrication of programmable domains for soft magnetic robots: A review.

Driven by the aim of realizing functional robotic systems at the milli- and submillimetre scale for biomedical applications, the area of magnetically driven soft devices has received significant recent attention. This has resulted in a new generation of magnetically controlled soft robots with patterns of embedded, programmable domains throughout their structures. This type of programmable magnetic profiling equips magnetic soft robots with shape programmable memory and can be achieved through the distribution of discrete domains (voxels) with variable magnetic densities and magnetization directions. This approach has produced highly compliant, and often bio-inspired structures that are well suited to biomedical applications at small scales, including microfluidic transport and shape-forming surgical catheters. However, to unlock the full potential of magnetic soft robots with improved designs and control, significant challenges remain in their compositional optimization and fabrication. This review considers recent advances and challenges in the interlinked optimization and fabrication aspects of programmable domains within magnetic soft robots. Through a combination of improvements in the computational capacity of novel optimization methods with advances in the resolution, material selection and automation of existing and novel fabrication methods, significant further developments in programmable magnetic soft robots may be realized.

Full Set of Material Properties of Lead-Free PIC 700 for Transducer Designers.

The impact of Pb on the environment and human health and recent restrictions on its use in electronic devices are generating demand for Pb-free piezoelectric materials. Examples are now available commercially, but the full elastic-piezoelectric-dielectric (EPD) matrices needed for device design, including over a range of operating conditions, have not yet been published. The standard IEEE EPD matrix measurement method needs four sample geometries, making it inconvenient and increasing errors. Here, we present an alternative method combining resonant ultrasound spectroscopy with optimization algorithms to measure the EPD matrix from a single exact cube sample. The Levenberg-Marquardt (LM) and Nelder-Mead (NM) optimizations are compared in refining the independent parameters. Both give convergent solutions, but the LM algorithm is more accurate and efficient. The single-sample approach was used to obtain results from Pb-free Na1/2Bi1/2TiO3 (PIC 700, PI Ceramics, Lederhose, Germany) piezoceramic ( ∞ mm sample symmetry) characterized with the standard IEEE method at ambient temperature and with the single-sample method at ambient temperature and additionally up to 80 °C. The results are validated with the laser Doppler vibrometry via mode shape reconstruction and comparison with finite-element analysis (FEA). They demonstrate that convenient measurement of the EPD matrix of Pb-free materials with temperature dependence is possible, providing a crucial capability for the adoption of these materials in devices.

A Learning-Based Microultrasound System for the Detection of Inflammation of the Gastrointestinal Tract.

Inflammation of the gastrointestinal (GI) tract accompanies several diseases, including Crohn's disease. Currently, video capsule endoscopy and deep bowel enteroscopy are the main means for direct visualisation of the bowel surface. However, the use of optical imaging limits visualisation to the luminal surface only, which makes early-stage diagnosis difficult. In this study, we propose a learning enabled microultrasound ( µ US) system that aims to classify inflamed and non-inflamed bowel tissues. µ US images of the caecum, small bowel and colon were obtained from mice treated with agents to induce inflammation. Those images were then used to train three deep learning networks and to provide a ground truth of inflammation status. The classification accuracy was evaluated using 10-fold evaluation and additional B-scan images. Our deep learning approach allowed robust differentiation between healthy tissue and tissue with early signs of inflammation that is not detectable by current endoscopic methods or by human inspection of the µ US images. The methods may be a foundation for future early GI disease diagnosis and enhanced management with computer-aided imaging.

Flexible Piezoelectric Sensors for Miniaturized Sonomyography.

Sonomyography refers to the measurement of muscle activity with an ultrasonic transducer. It is a candidate modality for applications in diagnosis of muscle conditions, rehabilitation engineering and prosthesis control as an alternative to electromyography. We propose a mechanically-flexible piezoelectric sonomyography transducer. Simulating different components of the transducer, using COMSOL Multiphysics® software, we analyze various electromechanical parameters, such as von Mises stress and charge accumulation. Our findings on modelling of a single-element device, comprised of a PZT-5H layer of thickness 66µm, with a polymer substrate (E = 2.5 GPa), demonstrate optimal flexibility and charge accumulation for sonomyography. The addition of Polyimide and PMMA (Polymethyl methacrylate) as an acoustic matching layer and an acoustic lens, respectively, allowed for adequate energy transfer to the medium, whilst still maintaining good mechanical properties. In addition, preliminary ultrasound transmission simulations (200 kHz to 30 MHz) showed the importance of the aspect ratio of the device and how there is a need for further studies on it. The development of such a technology could be of great use within the healthcare sector, not only due to its ability to provide highly accurate and varied real-time muscle data, but also because of the range of applications that could benefit from its use.

Ultrasound mediated delivery of quantum dots from a proof of concept capsule endoscope to the gastrointestinal wall.

Biologic drugs, defined as therapeutic agents produced from or containing components of a living organism, are of growing importance to the pharmaceutical industry. Though oral delivery of medicine is convenient, biologics require invasive injections because of their poor bioavailability via oral routes. Delivery of biologics to the small intestine using electronic delivery with devices that are similar to capsule endoscopes is a promising means of overcoming this limitation and does not require reformulation of the therapeutic agent. The efficacy of such capsule devices for drug delivery could be further improved by increasing the permeability of the intestinal tract lining with an integrated ultrasound transducer to increase uptake. This paper describes a novel proof of concept capsule device capable of electronic application of focused ultrasound and delivery of therapeutic agents. Fluorescent markers, which were chosen as a model drug, were used to demonstrate in vivo delivery in the porcine small intestine with this capsule. We show that the fluorescent markers can penetrate the mucus layer of the small intestine at low acoustic powers when combining microbubbles with focused ultrasound during in vivo experiments using porcine models. This study illustrates how such a device could be potentially used for gastrointestinal drug delivery and the challenges to be overcome before focused ultrasound and microbubbles could be used with this device for the oral delivery of biologic therapeutics.

Introduction of a Measurement Setup to Monitor the Pressure Applied During Handheld Ultrasound Elastography.

Shear-wave elastography may produce misleadingly high values if too much pressure is applied during the imaging process. However, in clinical routine there is presently no way to monitor the pressure applied during the measurements. In this work we introduce a novel measurement setup which can directly be attached to an ultrasonic imaging transducer and allows observation of the applied pressure in real time. The setup supports free-hand imaging according to the clinical standard. We tested the setup by carrying out shear-wave elastography under varying pressures on ex vivo animal tissue. The values increased with pressure, as was expected. Thus, the setup is a possible solution for measuring applied pressure in real time.

Ultrasound Capsule Endoscopy With a Mechanically Scanning Micro-ultrasound: A Porcine Study.

Wireless capsule endoscopy has been used for the clinical examination of the gastrointestinal (GI) tract for two decades. However, most commercially available devices only utilise optical imaging to examine the GI wall surface. Using this sensing modality, pathology within the GI wall cannot be detected. Micro-ultrasound (µUS) using high-frequency (>20 MHz) ultrasound can provide a means of transmural or cross-sectional image of the GI tract. Depth of imaging is approximately 10 mm with a resolution of between 40-120 µm that is sufficient to differentiate between subsurface histologic layers of the various regions of the GI tract. Ultrasound capsule endoscopy (USCE) uses a capsule equipped with µUS transducers that are capable of imaging below the GI wall surface, offering thereby a complementary sensing technique to optical imaging capsule endoscopy. In this work, a USCE device integrated with a ∼30 MHz ultrasonic transducer was developed to capture a full 360° image of the lumen. The performance of the device was initially evaluated using a wire phantom, indicating an axial resolution of 69.0 µm and lateral resolution of 262.5 µm. Later, in vivo imaging performance was characterised in the oesophagus and small intestine of anaesthetized pigs. The reconstructed images demonstrate clear layer differentiation of the lumen wall. The tissue thicknesses measured from the B-scan images show good agreement with ex vivo images from the literature. The high-resolution ultrasound images in the in vivo porcine model achieved with this device is an encouraging preliminary step in the translation of these devices toward future clinical use.

Multi-Channel Signal-Generator ASIC for Acoustic Holograms.

A complementary metal-oxide-semiconductor (CMOS) application-specific integrated circuit (ASIC) has been developed to generate arbitrary, dynamic phase patterns for acoustic hologram applications. An experimental prototype has been fabricated to demonstrate phase shaping. It comprises a cascadable 1 ×9 array of identical, independently controlled signal generators implemented in a 0.35- [Formula: see text] minimum-feature-size process. It can individually control the phase of a square wave on each of the nine output pads. The footprint of the integrated circuit is [Formula: see text]. A 128-MHz clock frequency is used to produce outputs at 8 MHz with a phase resolution of 16 levels (4 bits) per channel. A 6 ×6 air-coupled matrix array ultrasonic transducer was built and driven by four ASICs, with the help of commercial buffer amplifiers, for the application demonstration. Acoustic pressure mapping and particle manipulation were performed. In addition, a 2 ×2 array piezoelectric micromachined ultrasonic transducer (PMUT) was connected and driven by four output channels of a single ASIC, demonstrating the flexibility of the ASIC to work with different transducers and the potential for direct integration of CMOS and PMUTs.