Microbubble-mediated drug delivery revealed at microsecond and micrometer resolution
Treating cardiovascular disease and cancer using ultrasound-activated vibrating microbubbles (1-10 µm in size) has shown preclinical potential to boost drug therapy and reduce side-effects because drugs are delivered locally. Recently, several clinical trials have demonstrated safety of the treatment and increased survival. Despite advances in the field, the underlying mechanism of microbubble-mediated drug delivery are poorly understood. One of the reasons for this is the huge range in time scales involved. The time scale of the microbubble vibration is 2 million times per second in a 2 MHz ultrasound field (microseconds), which is many orders of magnitude smaller than the time scale of physiological effects (milliseconds), let alone that of biological effects (seconds to minutes) and clinical relevance (days to months). To allow the investigation of the microbubble-cell-drug interaction at a microsecond and micrometer resolution, unique technology was created by coupling the Brandaris 128 ultra-high-speed camera (~25 million frames per second recordings) to a custom-built confocal microscope. In this talk, I will describe new insights gained into the microbubble-cell-drug interaction by using this technology for two different cell types: endothelial cells and bacteria. For endothelial cells the focus will be on the microbubble behavior in relation to the drug delivery pathways sonoporation and cell-cell contact opening, as well as how intracellular calcium fluctuations play a role. Novel microbubble-mediated treatments for the life-threatening disease bacterial infective endocarditis, either on native heart valves or cardiac devices such as pacemakers, are the focus for the bacteria biofilm work.
Exotic Sound Interactions in Acoustic Metamaterials
Metamaterials are artificial materials with properties well beyond what offered by nature, providing unprecedented opportunities to tailor and enhance the control of waves. In this talk, I discuss our recent activity in acoustics and mechanics, showing how suitably tailored meta-atoms and their arrangements open exciting venues for new technology. I will focus in particular on the opportunities offered by time modulation and switching, as well as gain, in acoustic metamaterials, which offer an interesting platform for enhanced sensing, one-way signal transport and nonlinear phenomena. These concepts are ideally suited for the new technological opportunities in the context of ultrasound technologies. Physical insights into the underlying phenomena, and new devices based on these concepts will be presented.
Soft Transducer Materials – Polymer-Based Electrets for Sensors and Actuators
Since the first report of natural electrets – pieces of amber that could attract or repel light objects or draw tiny electric sparks – more than 2500 years ago, electret science and technology underwent more and more rapid developments via the electrophorus (1760s) and wax-resin mixtures (1920s) to modern polymer-based electrets. Today, we can distinguish between space-charge electrets, electro-electrets (a.k.a. dielectric elastomers), ferro- or piezo-electrets, ferro-, pyro- and piezoelectric polymers and ceramic-polymer composites. Stress-induced movements of their internal electric charges or dipoles, and electric-field-induced displacements of the charged or poled polymer, give rise to direct and inverse electro-mechanical/piezo-electrical effects, respectively. Longitudinal and transverse transduction effects may be used in sensors (micro-energy harvesters, microphones, etc.) and in actuators (sound and ultrasound emitters, haptic-feedback devices, soft micro-actuators, etc.). A significant range of densities, as well as isotropic or anisotropic elastic properties, of the various soft materials lead to a broad range of specific acoustic impedances. Recent advances, e.g. in polymer science and technology, in rather stable high-field dielectrics, and in additive manufacturing of patterned and heterogeneous materials, promise a bright future for soft transducer materials – in particular, but not only, for sound and ultrasound applications.
The Second Affiliated Hospital of Zhejiang University
Contrast Enhanced Ultrasound from diagnostics to the therapy
The emergence of CEUS has brought about a new revolution in ultrasound imaging. CEUS has been increasingly mature in diagnosing different kinds of diseases over the recent years. Meanwhile, the interaction between ultrasound and MBs can induce various acoustic effects, including thermo effect, sonoporation, and cavitation. In the recent decade, more and more researches indicated that ultrasound mediated microbubble stable cavitation (UMMC), as an anti-tumor drug delivery system, played a supplementary role in tumor therapy. In this presentation, I will provide an overview of approved and off-labeled clinical applications of CEUS, and some pre-clinical results of UMMC in tumor therapy and T2DM therapy in animal models from our group. Our studies indicated that UMMD could inhibit the growth of VX2 hepatic tumors in rabbits by irreversible destroying tumor microvessel and tumor cells. Meanwhile, UTMD GLP-1 gene therapy may be an effective approach to regenerate islet beta cells and normalize glycemic control in type 2 diabetes humans.
Magnetic resonance imaging-guided ultrasound brain stimulation in non-human primates
Neuromodulation is a fundamental tool in neuroscience to explore neural mechanisms from molecular to behavioral levels. Recently, ultrasound has been found to be an effective noninvasive neuromodulation tool. This cutting-edge discovery may have great potential for the therapy of many functional brain diseases. One major limitation of ultrasound neuromodulation is the accurate steering of ultrasound beams throughout the skull to the target position inside the brain. Magnetic resonance imaging (MRI) plays an important role in the precise and dynamic guidance of ultrasound neuromodulation by providing target localization, neural activity monitoring, and safety assurance. In the presentation, MRI-guided ultrasound neuromodulation techniques are reviewed, including transcranial focused ultrasound technology, localization and visualization by magnetic resonance (MR) acoustic radiation force imaging, brain activity monitoring and assessment by functional MRI, and applications of ultrasound neuromodulation. The principles of all the above-mentioned techniques are briefly introduced, and some preliminary results of our group are described. The results of our study showed that ultrasound stimulation of the primary visual cortex of rhesus monkeys activated the target area and its downstream and associated brain regions, which suggested that ultrasound stimulation is capable of exciting neuronal activities that may be transmitted to related functional regions. MRI is believed to be a powerful imaging modality for accurate ultrasound neuromodulation.
Leveraging scattering to unlock lung quantitative ultrasound
Conventional ultrasound imaging of the lung has remained elusive due to the complexity of the parenchyma. The millions of air-filled alveoli are responsible for large amounts of scattering, precluding the common assumptions underlying B-mode imaging. We propose to leverage this purported weakness. Each scattering event can be seen as an opportunity for the ultrasound wave to embed information on the architecture of lung parenchyma. By leveraging scattering, we developed new methods for the quantitative assessment of the lung. The diffusivity of ultrasound is exploited as a new source of contrast for lung tissue characterization. Lung diseases such as pulmonary edema and pulmonary fibrosis affect the micro-architecture of the parenchyma. We show how ultrasound scattering parameters can be used to quantify these changes, and ultimately be used as a biomarkers for these diseases. There is tremendous potential of such non-invasive biomarkers for monitoring and follow up of response to treatment. Finally, we will also show how these concepts can be used for ultrasound-based lung imaging to detect and localize pulmonary nodules in real time during surgery, to ensure lung nodules resection with safe margins so no cancerous tissue is left behind.
Promoting the Cancer Immunity Cycle with Focused Ultrasound
In this presentation, I will provide an overview of recent studies from our group aimed at driving anti-cancer immunity using both thermal and mechanical forms of focused ultrasound energy deposition. Our research in thermal focused ultrasound centers primarily on applications for breast cancer and melanoma. Here, we employ a variety of pre-clinical approaches (e.g. flow cytometry and RNA sequencing) to understand how the immune system is modulated by focused ultrasound, as well as to design and implement new immunotherapeutic regimens that will most effectively cooperate with focused ultrasound. Ongoing clinical trials at our institution are now exploring how partial thermal ablation interacts with checkpoint inhibitors in patients with metastatic disease. Meanwhile, our research on mechanical forms of focused ultrasound primarily entails lifting immunosuppression in brain tumors via the delivery of immunotherapies across the blood-brain tumor barrier under MR image-guidance.
Using acoustics to demonstrate topological and non-Hermitian physics
Acoustic systems are relatively simple to design, implement and characterize. As such, they are good platforms to demonstrate new physics concepts and the associated phenomena. We will use some examples to illustrate the realization of topological and non-Hermitian physics in acoustic systems.
We show that an acoustic metamaterial consisting of an array of spinning cylindrical inclusions can possess many novel properties that cannot be achieved in static systems. These interesting effects include folded bulk bands and folded interface-state bands. The folding of bands inside the first Brillouin zone is generally not possible because such dispersions violate causality principles but in acoustic systems with rotation, this is made possible by a rotation-induced anti-resonance of compressibility and the rotational Doppler effect. Robust one-way transport properties can be enabled by non-degenerate interface states, but within the same band, interface states at different frequencies can have different propagation directions. If we form an interface between two acoustic crystals composing of spinning cylinders with equal but opposite spinning velocities embedded in a liquid, long-range and robust acoustic pulling can be enabled by a pair of one-way chiral surface waves supported on the interface between two counter-rotating phononic crystals. When the chiral surface mode with a relative small Bloch wave vector is excited, the particle located in the interface waveguide will scatter the excited surface mode to another chiral surface mode with a greater Bloch wave vector, and resulting in an acoustic pulling force, irrespective of the size and material of the particle. The absence of backscattering channels make the pulling force robust against local disorders, and the particle can be pulled in any trajectory as determined by the shape of the interface. This new acoustic pulling scheme overcomes some of the limitations of the traditional acoustic pulling using structured beams, such as short pulling distances, straight-line type pulling and strong dependence on the scattering properties of the particle.
Acoustic systems are also good platforms to illustrate exceptional point physics. The signature of non-Hermitian systems is the existence of exceptional points. In some cases, the exceptional points can form interesting connected structures. We will see that an astroid shaped loop of exceptional points can emerge from a non-Hermitician Lieb lattice when specific hoppings are introduced. Such interesting exceptional point structure is realized in an acoustic implementation, which demonstrates that exceptional nexus with a hybrid topological invariant can be formed.
Soft ultrasonic patches for continuous monitoring of deep tissues
Soft electronic devices that can acquire vital signs from the human body represent an important trend for healthcare. Combined strategies of materials design and advanced microfabrication allow the integration of a variety of components and devices on a stretchable platform, resulting in functional systems with minimal constraints on the human body. In this presentation, I will demonstrate a soft ultrasonic patch that can emit ultrasound waves to penetrate the skin and noninvasively capture dynamic events in deep tissues, such as blood pressure and blood flow waveforms in central arteries and veins. This stretchable platform holds profound implications for a wide range of applications in consumer electronics, sports medicine, defense, and clinical practices.
Controlling Elastic Wave With Solid Pentamode Metamaterials
Solid pentamode materials are degenerated elastic solids with quasi-zero shear rigidity, it can be approximately realized by genius microstructure design. Due to the flexibility in designing wave impedance, the pentamode material is potential for the control of elastic waves with broad frequency performance. In this talk, the concept and design method of pentamode materials are firstly explained, then two examples are provided to illustrate the capacity of wave manipulation by this kind of material. The first example focuses on elastic wave filtering, pentamode materials are shown to be able to support only single polarization mode (either transverse wave or longitudinal wave) depending on their microstructure design, which can hardly be possible with traditional solids. The functions of elastic wave mode splitting and sound isolation in water with this kind of metamaterials are illustrated. The second example explores broadband underwater acoustic cloak. It is shown that by carefully designing unit cells of pentamode materials and arranging them in space, a broadband underwater acoustic cloak can be designed. Both examples are validated by experiments. These findings demonstrate a great capacity of broadband mechanical wave control by solid pentamode materials.
University of Electronic Science and Technology of China
Quantum Leap in Simulation Technologies for Radio Frequency Acoustic Wave Devices Gifted by Hierarchical Cascading Technique
This talk is aimed at introducing the hierarchical cascading technique (HCT) not only as a speed-up tool for FEM simulation but also as a versatile technique for attacking unexplored problems.
In 2016, Koskela, et al., proposed HCT for fast 2D FEM simulation of SAW devices. The technique is quite powerful when the device structure under concern is mainly composed of identical cells and the number of cells N is large. This is because the time consumption is almost proportional to logN, while the required memory is almost independent of N. Now HCT-based 2D FEM is widely used in SAW device development.
The author’s group applied HCT to attack various wave excitation and scattering problems including those believed to be impossible. Examples are SAW scattering at irregularity inserted in an infinitely long grating and that at IDT finger tips. The traveling wave excitation source proposed by the author’s group fits well with HCT and can be adapted efficiently in the analysis. In addition, combination of HCT with high-end GPU makes 3D FEM simulation possible for practical SAW device structures.
Now we can apply periodic 2D, full 2D, periodic 3D and full 3D FEM simulations to SAW resonators. Comparison of results from these simulations enables evaluation of different loss contributions separately, and field analyses may reveal remaining loss mechanisms hidden in the structures. Once the degradation mechanism is understood, we can search possible countermeasures using the fast parameter-scan function of HCT-based FEM.
Heterogeneous material integration: from advanced substrates to acoustic resonators
The innovation of advanced substrates reflects today’s new paradigm for semiconductor technologies: key figures of merit for most advanced device technologies depend on the starting substrate material. Thin film technologies are currently being used for advanced MEMS such as acoustic filters and ultrasonic devices. Combined with single-crystalline quality of the materials, such engineered substrates enable higher device performance and better manufacturing yield.
This paper reports on recent advances in material innovation and substrate technologies enabling high performance acoustic and ultrasound resonators. One example is the SAW resonators using guided acoustic modes of Piezoelectric-On-Insulator (POI) substrate combining single-crystal LiTaO3 thin film, an intermediate SiO2 layer and Silicon handle substrate. The SAW resonators fabricated using POI substrate lead to significant performance improvements compared to the conventional bulk substrates, such as very low TCF, higher coupling factor, lowest RF losses and maximum quality factor (Bode-Q).
The Smart CutTM technology provides a versatile manufacturing platform for POI advanced substrates and can be adapted to different piezoelectric materials (LiTaO3, LiNbO3, etc), various crystal orientations and film thicknesses. Therefore, it enables new solutions for acoustic filter designers to overcome some of the 5G technological challenges and further explore new device concepts.
This work is based on contributions of many colleagues from Soitec, frec|n|sys and collaboration projects with CEA-LETI under the Substrate Innovation Center.
Breaking Limits in Photoacoustic Imaging: Deeper, Faster, Smaller and More colorful
By acoustically detecting the optical absorption contrast in biological tissues, photoacoustic imaging (PAI) has proven increasingly powerful for multi-scale anatomical, functional, and molecular imaging. In PAI, a short-pulsed laser beam illuminates the biological tissue to generate a small but rapid temperature rise, which leads to emission of ultrasonic waves due to thermoelastic expansion. The wideband ultrasonic waves are detected to form a high-resolution tomographic image that maps the original optical absorption in the tissue. My talk will focus on several major new fronts of PAI that have collectively enabled fast, miniaturized, deep, and high-sensitivity biomedical applications in functional neuronal imaging, drug testing, early cancer detection, and interventional therapy. First, PAI has broken the penetration limit and achieved super-deep (~10 cm) imaging by using advanced internal light delivery, extending its applications ready into internal organ imaging on large animal models. Second, by innovating novel scanning technologies, PAI has been accelerated by more than 1000 times in imaging speed with a large field of view and high spatial resolution, allowing for the monitoring of highly dynamic biological processes. Third, by adapting novel fabrication technologies in optics and acoustics, miniaturized PAI has achieved handheld, wearable and head-mounted imaging with high spatial–temporal resolutions and high throughput. Lastly, taking advantage of switchable or tunable near-infrared photoacoustic-specific probes, PAI has improved its sensitivity and specificity by more than 100 times, enabling highly sensitive detection of malignant cancer, tissue hypoxia, and neuronal activities.