Exploiting the mechanical effects of ultrasound for noninvasive therapy.

Focused ultrasound is a platform technology capable of eliciting a wide range of biological responses with high spatial precision deep within the body. Although focused ultrasound is already in clinical use for focal thermal ablation of tissue, there has been a recent growth in development and translation of ultrasound-mediated nonthermal therapies. These approaches exploit the physical forces of ultrasound to produce a range of biological responses dependent on exposure conditions.

Three-dimensional super resolution ultrasound imaging with a multi-frequency hemispherical phased array.

Background: High resolution imaging of the microvasculature plays an important role in both diagnostic and therapeutic applications in the brain. However, ultrasound pulse-echo sonography imaging the brain vasculatures has been limited to narrow acoustic windows and low frequencies due to the distortion of the skull bone, which sacrifices axial resolution since it is pulse length dependent.

Purpose: To overcome the detect limit, a large aperture 256-module sparse hemispherical transmit/receive array was used to visualize the acoustic emissions of ultrasound-vaporized lipid-coated decafluorobutane nanodroplets flowing through tube phantoms and within rabbit cerebral vasculature in vivo via passive acoustic mapping and super resolution techniques.

A numerical investigation of passive acoustic mapping for monitoring bubble-mediated focused ultrasound treatment of the spinal cord.

Focused ultrasound (FUS) combined with intravenous microbubbles (MBs) has been shown to increase drug delivery to the spinal cord in animal models. Eventual clinical translation of such a technique in the sensitive spinal cord requires robust treatment monitoring to ensure efficacy, localization, safety, and provide key intraprocedural feedback. Here, the use of passive acoustic mapping (PAM) of MB emissions with a spine-specific detector array in the context of transvertebral FUS sonications is investigated in silico.

A PVDF Receiver for Acoustic Monitoring of Microbubble-Mediated Ultrasound Brain Therapy.

The real-time monitoring of spectral characteristics of microbubble (MB) acoustic emissions permits the prediction of increases in blood-brain barrier (BBB) permeability and of tissue damage in MB-mediated focused ultrasound (FUS) brain therapy. Single-element passive cavitation detectors provide limited spatial information regarding MB activity, greatly affecting the performance of acoustic control. However, an array of receivers can be used to spatially map cavitation events and thus improve treatment control.

Establishing density-dependent longitudinal sound speed in the vertebral lamina.

Focused ultrasound treatments of the spinal cord may be facilitated using a phased array transducer and beamforming to correct spine-induced focal aberrations. Simulations can non-invasively calculate aberration corrections using x-ray computed tomography (CT) data that are correlated to density (ρ) and longitudinal sound speed (c). We aimed to optimize vertebral lamina-specific c(ρ) functions at a physiological temperature (37 °C) to maximize time domain simulation accuracy.

An Ultrasound-Guided Hemispherical Phased Array for Microbubble-Mediated Ultrasound Therapy.

Goal: To develop a low-cost magnetic resonance imaging (MRI)-free transcranial focused ultrasound (FUS) system for microbubble-mediated therapy.

Methods: A 128-element 11 MHz array for skull localization was integrated within a 256-module multi-frequency (306/612/1224 kHz) dual-mode phased array. The system's transcranial transmit and receive performance was evaluated with ex-vivo human skullcaps using phase aberration corrections calculated from computed tomography (CT)-based simulations via ultrasound-based (USCT) and landmark-based (LMCT) registrations, and a gold-standard fixed source emitter (FSE)-based method.

The mechanical potential of ultrasound on nervous tissue.

The Reflections series takes a look back on historical articles from The Journal of the Acoustical Society of America that have had a significant impact on the science and practice of acoustics.

Focused Ultrasound-Induced Blood-Spinal Cord Barrier Opening Using Short-Burst Phase-Keying Exposures in Rats: A Parameter Study.

Transient opening of the blood-spinal cord barrier has the potential to improve drug delivery options to the spinal cord. We previously developed short-burst phase-keying exposures to reduce focal depth of field and mitigate standing waves in the spinal canal. However, optimal short-burst phase-keying parameters for drug delivery have not been identified.

Therapeutic Agent Delivery Across the Blood-Brain Barrier Using Focused Ultrasound.

Specialized features of vasculature in the central nervous system greatly limit therapeutic treatment options for many neuropathologies. Focused ultrasound, in combination with circulating microbubbles, can be used to transiently and noninvasively increase cerebrovascular permeability with a high level of spatial precision. For minutes to hours following sonication, drugs can be administered systemically to extravasate in the targeted brain regions and exert a therapeutic effect, after which permeability returns to baseline levels.

Characterization of ultrasound-mediated delivery of trastuzumab to normal and pathologic spinal cord tissue.

Extensive studies on focused ultrasound (FUS)-mediated drug delivery through the blood-brain barrier have been published, yet little work has been published on FUS-mediated drug delivery through the blood-spinal cord barrier (BSCB). This work aims to quantify the delivery of the monoclonal antibody trastuzumab to rat spinal cord tissue and characterize its distribution within a model of leptomeningeal metastases. 10 healthy Sprague-Dawley rats were treated with FUS + trastuzumab and sacrificed at 2-h or 24-h post-FUS.

Increased P450 aromatase levels in post-menopausal women after acute ischemic stroke.

Background: Sex differences in stroke have been attributed to the neuroprotective effects of estrogen, yet most clinical trials of estrogen supplementation for stroke prevention have failed. The contribution of sex hormones to stroke outcome remains a subject of debate. Aromatization of testosterone to estradiol in neural tissue leads to sexual differentiation.

Vasculotide restores the blood-brain barrier after focused ultrasound-induced permeability in a mouse model of Alzheimer's disease.

Focused ultrasound (FUS) is used to locally and transiently induce blood-brain barrier (BBB) permeability, allowing targeted drug delivery to the brain. The purpose of the current study is to evaluate the potential of Vasculotide to accelerate the recovery of the BBB following FUS disruption in the TgCRND8 mouse model of amyloidosis, characteristic of Alzheimer's disease (AD). Accelerating the restoration of the BBB post-FUS would represent an additional safety procedure, which could be beneficial for clinical applications.

A Porcine Model of Transvertebral Ultrasound and Microbubble-Mediated Blood-Spinal Cord Barrier Opening.

Blood-spinal cord barrier opening, using focused ultrasound and microbubbles, has the potential to improve drug delivery for the treatment of spinal cord pathologies. Delivering and detecting ultrasound through the spine is a challenge for clinical translation. We have previously developed short burst, phase keying exposures, which can be used in a dual-aperture configuration to address clinical scale targeting challenges.

Simultaneous Intravital Optical and Acoustic Monitoring of Ultrasound-Triggered Nanobubble Generation and Extravasation.

Ultrasound-activated nanobubbles are being widely investigated as contrast agents and therapeutic vehicles. Nanobubbles hold potential for accessing the tumor extravascular compartment, though this relies on clinically debated passive accumulation for which evidence to date is indirect. We recently reported ultrasound-triggered conversion of high payload porphyrin-encapsulated microbubbles to nanobubbles, with actively enhanced permeability for local delivery.

Localized anesthesia of a specific brain region using ultrasound-responsive barbiturate nanodroplets.

: Targeted neuromodulation is a valuable technique for the study and treatment of the brain. Using focused ultrasound to target the local delivery of anesthetics in the brain offers a safe and reproducible option for suppressing neuronal activity. : To develop a potential new tool for localized neuromodulation through the triggered release of pentobarbital from ultrasound-responsive nanodroplets.

Ultrasound-Responsive Cavitation Nuclei for Therapy and Drug Delivery.

Therapeutic ultrasound strategies that harness the mechanical activity of cavitation nuclei for beneficial tissue bio-effects are actively under development. The mechanical oscillations of circulating microbubbles, the most widely investigated cavitation nuclei, which may also encapsulate or shield a therapeutic agent in the bloodstream, trigger and promote localized uptake. Oscillating microbubbles can create stresses either on nearby tissue or in surrounding fluid to enhance drug penetration and efficacy in the brain, spinal cord, vasculature, immune system, biofilm or tumors.

Super-resolution Ultrasound Imaging.

The majority of exchanges of oxygen and nutrients are performed around vessels smaller than 100 μm, allowing cells to thrive everywhere in the body. Pathologies such as cancer, diabetes and arteriosclerosis can profoundly alter the microvasculature. Unfortunately, medical imaging modalities only provide indirect observation at this scale.

Enhanced Detection of Bubble Emissions Through the Intact Spine for Monitoring Ultrasound-Mediated Blood-Spinal Cord Barrier Opening.

Objective: We previously developed short burst, phase keying (SBPK) focused ultrasound (FUS) to mitigate standing waves in the human vertebral canal. Here, we show microbubble emissions from these pulses can be detected through the human vertebral arch and that these pulses are effective for blood-spinal cord barrier (BSCB) opening.

Methods: At f = 514 kHz, circulating microbubbles were sonicated through ex vivo human vertebrae (60 kPa-1 MPa) using a dual-aperture approach and SBPK exposures engineered to incorporate pulse inversion (PI).

A Spine-Specific Phased Array for Transvertebral Ultrasound Therapy: Design and Simulation.

Objective: To design and simulate the performance of two spine-specific phased arrays in sonicating targets spanning the thoracic spine, with the objective of efficiently producing controlled foci in the spinal canal.

Methods: Two arrays (256 elements each, 500 kHz) were designed using multi-layered ray acoustics simulation: a four-component array with dedicated components for sonicating via the paravertebral and transvertebral paths, and a two-component array with spine-specific adaptive focusing. Mean array efficiency (canal focus pressure/water focus pressure) was evaluated using forward simulation in neutral and flexed spines to investigate methods that reduce spine-induced insertion loss.

Analysis of Multifrequency and Phase Keying Strategies for Focusing Ultrasound to the Human Vertebral Canal.

Focused ultrasound has been shown to increase the permeability of the blood-brain barrier and its feasibility for opening the blood-spinal cord barrier has also been demonstrated in small animal models, with great potential to impact the treatment of spinal cord (SC) disorders. For clinical translation, challenges to transvertebral focusing of ultrasound energy on the human spinal canal, such as a focal depth of field and standing-wave formation, must be addressed. A dual-aperture approach using multifrequency and phase-shift keying (PSK) strategies for achieving a controlled focus in human thoracic vertebrae was investigated through numerical simulations and benchtop experiments in ex vivo human vertebrae.

Ultrasound and Microbubble-Mediated Blood-Brain Barrier Disruption for Targeted Delivery of Therapeutics to the Brain.

Ultrasound and microbubble-mediated disruption of the Blood-Brain barrier is a noninvasive and targetable technique that permits the investigation of pharmacological interventions in the brain and CNS. This technique provides an alternative to direct injection of agents into the brain parenchyma or chemical disruption of the Blood-Brain barrier. Here, we detail one protocol for inducing transient Blood-Brain barrier disruption in a rodent model using a commercially available microbubble contrast agent (Definity).

Microbubble Localization for Three-Dimensional Superresolution Ultrasound Imaging Using Curve Fitting and Deconvolution Methods.

Superresolution algorithms in ultrasound imaging are attracting the interest of researchers recently due to the ability of these methods to enable enhanced vascular imaging. In this study, two superresolution imaging methods are compared for postprocessing images of microbubbles generated using passive acoustic mapping (PAM) methods with a potential application of three-dimensional (3-D) brain vascular imaging. The first method is based on fitting single bubble images one at a time with a 3-D Gaussian profile to localize the microbubbles and a superresolution image is then formed using the uncertainty of the localization as the standard deviation of the Gaussian profile.