Optical observations of acoustical radiation force effects on individual air bubbles

Previous studies dealing with contrast agent microbubbles have demonstrated that ultrasound (US) can significantly influence the movement of microbubbles. In this paper, we investigated the influence of the acoustic radiation force on individual air bubbles using high-speed photography. We emphasize the effects of the US parameters (pulse length, acoustic pressure) on different bubble\ud patterns and their consequences on the translational motion of the bubbles. A stream of uniform air bubbles with diameter ranging from 35 um to 79 um was generated and insonified with a single US pulse emitted at a frequency of 130 kHz. The bubble sizes have been chosen to be above, below, and at resonance. The peak acoustic pressures used in these experiments ranged from 40 kPa to 120 kPa. The axial displacements of the bubbles produced by the action of the US pulse were optically recorded using a high-speed camera at 1 kHz frame rate. The experimental results were compared to a simplified force balance theoretical model, including the action of the primary radiation force and the fluid drag force. Although the model is quite simple and does not take into account phenomena like bubble shape oscillations and added mass, the experimental findings agree with the predictions. The measured axial displacement increases quasilinearly with the burst length and the transmitted acoustic pressure. The axial displacement varies with the size and the density of the air bubbles, reaching a maximum at the resonance size of 48 um. The predicted displacement values differ by 15% from the measured data, except for resonant bubbles for which the displacement was overestimated by about 40%. This study demonstrates that even a single US pulse produces radiation forces that are strong enough to affect the bubble position

Monitoring Progression of Ductal Carcinoma In Situ Using Photoacoustics and Contrast-Enhanced Ultrasound.

Breast cancer is the leading form of cancer in women, accounting for approximately 41,400 deaths in 2018. While a variety of risk factors have been identified, physical exercise has been linked to reducing both the risk and aggressiveness of breast cancer. Within breast cancer, ductal carcinoma in situ (DCIS) is a common finding. However, less than 25% of DCIS tumors actually progress into invasive breast cancer, resulting in overtreatment. This overtreatment is due to a lack of predictive precursors to assess aggressiveness and development of DCIS. We hypothesize that tissue oxygenation and perfusion measured by photoacoustic and contrast-enhanced ultrasound imaging, respectively, can predict DCIS aggressiveness. To test this, 20 FVB/NJ and 20 SV40Tag mice that genetically develop DCIS-like breast cancers were divided evenly into exercise and control groups and imaged over the course of 6 weeks. Tissue oxygenation was a predictive precursor to invasive breast cancer for FVB/NJ mice (P = 0.015) in the early stages of tumor development. Meanwhile, perfusion results were inconclusive (P \u3e 0.2) as a marker for disease progression. Moreover, voluntary physical exercise resulted in lower weekly tumor growth and significantly improved median survival (P = 0.014)

The impact of vaporized nanoemulsions on ultrasound-mediated ablation

BACKGROUND: The clinical feasibility of using high-intensity focused ultrasound (HIFU) for ablation of solid tumors is limited by the high acoustic pressures and long treatment times required. The presence of microbubbles during sonication can increase the absorption of acoustic energy and accelerate heating. However, formation of microbubbles within the tumor tissue remains a challenge. Phase-shift nanoemulsions (PSNE) have been developed as a means for producing microbubbles within tumors. PSNE are emulsions of submicron-sized, lipid-coated, and liquid perfluorocarbon droplets that can be vaporized into microbubbles using short (5 MPa) acoustic pulses. In this study, the impact of vaporized phase-shift nanoemulsions on the time and acoustic power required for HIFU-mediated thermal lesion formation was investigated in vitro. METHODS: PSNE containing dodecafluoropentane were produced with narrow size distributions and mean diameters below 200 nm using a combination of sonication and extrusion. PSNE was dispersed in albumin-containing polyacrylamide gel phantoms for experimental tests. Albumin denatures and becomes opaque at temperatures above 58°C, enabling visual detection of lesions formed from denatured albumin. PSNE were vaporized using a 30-cycle, 3.2-MHz, at an acoustic power of 6.4 W (free-field intensity of 4,586 W/cm(2)) pulse from a single-element, focused high-power transducer. The vaporization pulse was immediately followed by a 15-s continuous wave, 3.2-MHz signal to induce ultrasound-mediated heating. Control experiments were conducted using an identical procedure without the vaporization pulse. Lesion formation was detected by acquiring video frames during sonication and post-processing the images for analysis. Broadband emissions from inertial cavitation (IC) were passively detected with a focused, 2-MHz transducer. Temperature measurements were acquired using a needle thermocouple. RESULTS: Bubbles formed at the HIFU focus via PSNE vaporization enhanced HIFU-mediated heating. Broadband emissions detected during HIFU exposure coincided in time with measured accelerated heating, which suggested that IC played an important role in bubble-enhanced heating. In the presence of bubbles, the acoustic power required for the formation of a 9-mm(3) lesion was reduced by 72% and the exposure time required for the onset of albumin denaturation was significantly reduced (by 4 s), provided that the PSNE volume fraction in the polyacrylamide gel was at least 0.008%. CONCLUSIONS: The time or acoustic power required for lesion formation in gel phantoms was dramatically reduced by vaporizing PSNE into bubbles. These results suggest that PSNE may improve the efficiency of HIFU-mediated thermal ablation of solid tumors; thus, further investigation is warranted to determine whether bubble-enhanced HIFU may potentially become a viable option for cancer therapy.R21 EB009493 - NIBIB NIH HH

Quantitative Assessment of Cancer Vascular Architecture by Skeletonization of High-resolution 3-D Contrast-enhanced Ultrasound Images: Role of Liposomes and Microbubbles.

The accurate characterization and description of the vascular network of a cancer lesion is of paramount importance in clinical practice and cancer research in order to improve diagnostic accuracy or to assess the effectiveness of a treatment. The aim of this study was to show the effectiveness of liposomes as an ultrasound contrast agent to describe the 3-D vascular architecture of a tumor. Eight C57BL/6 mice grafted with syngeneic B16-F10 murine melanoma cells were injected with a bolus of 1,2-Distearoyl-sn-glycero-3-phosphocoline (DSPC)-based non-targeted liposomes and with a bolus of microbubbles. 3-D contrast-enhanced images of the tumor lesions were acquired in three conditions: pre-contrast, after the injection of micro bubbles, and after the injection of liposomes. By using a previously developed reconstruction and characterization image processing technique, we obtained the 3-D representation of the vascular architecture in these three conditions. Six descriptive parameters of these networks were also computed: the number of vascular trees (NT), the vascular density (VD), the number of branches, the 2-D curvature measure, the number of vascular flexes of the vessels, and the 3-D curvature. Results showed that all the vascular descriptors obtained by liposome-based images were statistically equal to those obtained by using microbubbles, except the VD which was found to be lower for liposome images. All the six descriptors computed in pre-contrast conditions had values that were statistically lower than those computed in presence of contrast, both for liposomes and microbubbles. Liposomes have already been used in cancer therapy for the selective ultrasound-mediated delivery of drugs. This work demonstrated their effectiveness also as vascular diagnostic contrast agents, therefore proving that liposomes can be used as efficient “theranostic” (i.e. therapeutic 1 diagnostic) ultrasound probes

Microbubbles in vascular imaging

Ultrasound is integral in diagnostic imaging of vascular disease. It is a common first line imaging modality in the detection of deep vein thrombosis (DVT) and carotid atherosclerosis. The therapeutic use of ultrasound in vascular disease is also clinically established through ultrasound thrombolysis for acute DVT. Contrast agents are widely used in other imaging modalities, however, contrast enhanced ultrasound (CEUS) using microbubbles remains a largely specialist clinical investigation with truly established roles in hepatic imaging only. Aim The aim of this thesis was to investigate diagnostic and therapeutic roles of CEUS in vascular disease. Diagnostically, carotid plaque characteristics were evaluated for stroke risk stratification in patients with carotid atherosclerosis. Therapeutically, microbubble augmented ultrasound thrombolysis was investigated in-vitro as a novel technique for acute thrombus removal in the prevention of post thrombotic syndrome. Methods A validated in-vitro flow model of DVT was adapted and developed for a formal feasibility study of microbubble augmented ultrasound thrombolysis. Two cross sectional studies of patients with 50-99% carotid stenosis were performed assessing firstly, plaque ulceration and secondly plaque perfusion using CEUS. Results Using commercially available microbubbles and ultrasound platform, significantly improved thrombus dissolution was demonstrated using CEUS over ultrasound alone in the in-vitro flow model of acute DVT. In particular, increased destruction of the thrombus fibrin mesh network was observed. CEUS demonstrated greater sensitivity than carotid duplex in the detection of carotid plaque ulceration with a trend toward symptomatic carotid plaques. A reduced plaque perfusion detected by both semi-qualitative and quantitative analysis was associated with a symptomatic status in patients with a 50-99% stenosis. Conclusion CEUS is a viable adjunct to vascular imaging with ultrasound. Microbubble augmented ultrasound thrombolysis is a feasible, non-invasive, non-irradiating intervention which warrants further investigation in-vivo. Carotid plaque CEUS may contribute to future scoring systems in stroke risk stratification but requires prospective validation.Open Acces

Capsule-based ultrasound-mediated targeted gastrointestinal drug delivery

Diseases which are prevalent in the gastrointestinal (GI) tract, such as Crohn's disease, are a topic of increasing concern because diagnosis and specific treatment are difficult and may be ineffective. New techniques are therefore sought after and this paper describes a proof-of-concept tethered capsule for targeted drug delivery (TDD) in the GI tract. The capsule consists of a camera, illumination, a drug delivery channel and an ultrasound (US) transducer. The transducer is described in detail, including a comparison of different piezoceramic materials that has been carried out. It was found that PZ54 (Ferroperm Piezoceramics, Kvistgaard, Denmark) was the most suitable material for our application. When driven at 4 Vpp, the outer diameter 5 mm PZ54 transducer operates at a frequency f = 4.05 MHz providing an acoustic pressure, Pac = 125 kPa, with a beam diameter, BD = 0.75 mm at the focus. Pressures in the range 50 - 300 kPa have been previously reported as suitable for sonoporation, a process vital in many TDD applications, so this is a promising result. Basic functional testing of the capsule was performed by supplying glass microbubbles (MBs) through the drug delivery channel into the US focus, monitored via the onboard camera. It was found that the acoustic radiation forces have a clear influence on the MBs, significantly changing their direction at the US focus. This suggests that drugs may be targeted to specific tissue in the GI tract by the new capsule. The results translate into a capsule configuration with the potential to be clinically and biologically useful