Search

The study of the effects of ultrasound-induced acoustic cavitation on biological structures is an active field in biomedical research. Of particular interest for therapeutic applications is the ability of oscillating microbubbles to promote both cellular and tissue membrane permeabilisation and to improve the distribution of therapeutic agents in tissue through extravasation and convective transport. The mechanisms that underpin the interaction between cavitating agents and tissues are, however, still poorly understood. One challenge is the practical difficulty involved in performing optical microscopy and acoustic emissions monitoring simultaneously in a biologically compatible environment. Here we present and characterise a microfluidic layered acoustic resonator (µLAR) developed for simultaneous ultrasound exposure, acoustic emissions monitoring and microscopy of biological samples. The µLAR facilitates in vitro ultrasound experiments in which measurements of microbubble dynamics, microstreaming velocity fields, acoustic emissions and cell-microbubble interactions can be performed simultaneously. The device and analyses presented provide a means of performing mechanistic in vitro studies that may benefit the design of predictable and effective cavitation-based ultrasound treatments.

Photoacoustic (PA) imaging offers several attractive features as a biomedical imaging modality, including excellent spatial resolution and functional information such as tissue oxygenation. A key limitation, however, is the contrast to noise ratio that can be obtained from tissue depths greater than 1-2 mm. Microbubbles coated with an optically absorbing shell have been proposed as a possible contrast agent for PA imaging, offering greater signal amplification and improved biocompatibility compared to metallic nanoparticles. A theoretical description of the dynamics of a coated microbubble subject to laser irradiation has been developed previously. The aim of this study was to test the predictions of the model. Two different types of oil-coated microbubbles were fabricated and then exposed to both pulsed and continuous wave (CW) laser irradiation. Their response was characterized using ultra high-speed imaging. Although there was considerable variability across the population, good agreement was found between the experimental results and theoretical predictions in terms of the frequency and amplitude of microbubble oscillation following pulsed excitation. Under CW irradiation, highly nonlinear behavior was observed which may be of considerable interest for developing different PA imaging techniques with greatly improved contrast enhancement.

Microbubbles are used to enhance the contrast in ultrasound imaging. When coated with an optically absorbing material, these bubbles can also provide contrast in photoacoustic imaging. This multimodal aspect is of pronounced interest to the field of medical imaging. The aim of this paper is to provide a theoretical framework to describe the physical phenomena underlying the photoacoustic response. This article presents a model for a spherical gas microbubble suspended in an aqueous environment and coated with an oil layer containing an optically absorbing dye. The model includes heat transfer between the gas core and the surrounding liquids. This framework is suitable for the investigation of both continuous wave and pulsed laser excitation. This work utilizes a combination of finite difference simulations and numerical integration to determine the dependancy on the physical properties, including composition and thickness of the oil layer on the microbubble response. A normalization scheme for a linearized version of the model was derived to facilitate comparison with experimental measurements. The results show that viscosity and thickness of the oil layer determine whether or not microbubble resonance can be excited. This work also examines the use of non-sinusoidal excitation to promote harmonic imaging techniques to further improve the imaging sensitivity.

The use of stem cells for the repair of damaged cardiac tissue after a myocardial infarction holds great promise. However, a common finding in experimental studies is the low number of cells delivered at the area at risk. To improve the delivery, we are currently investigating a novel delivery platform in which stem cells are conjugated with targeted microbubbles, creating echogenic complexes dubbed StemBells. These StemBells vibrate in response to incoming ultrasound waves making them susceptible to acoustic radiation force. The acoustic force can then be employed to propel circulating StemBells from the centerline of the vessel to the wall, facilitating localized stem cell delivery. In this study, we investigate the feasibility of manipulating StemBells acoustically in vivo after injection using a chicken embryo model. Bare stem cells or unsaturated stem cells (30bubbles/cell) can be propelled toward and arrested at the vessel wall. The mean translational velocities measured are 61 and 177μm/s for P-=200 and 450kPa, respectively. This technique therefore offers potential for enhanced and well-controlled stem cell delivery for improved cardiac repair after a myocardial infarction.

The use of stem cells for the repair of damaged cardiac tissue after a myocardial infarction holds great promise. However, a common finding in experimental studies is the low number of cells delivered at the area at risk. To improve the delivery, we are currently investigating a novel delivery platform in which stem cells are conjugated with targeted microbubbles, creating echogenic complexes dubbed StemBells. These StemBells vibrate in response to incoming ultrasound waves making them susceptible to acoustic radiation force. The acoustic force can then be employed to propel circulating StemBells from the centerline of the vessel to the wall, facilitating localized stem cell delivery. In this study, we investigate the feasibility of manipulating StemBells acoustically in vivo after injection using a chicken embryo model. Bare stem cells or unsaturated stem cells (30 bubbles/cell) can be propelled toward and arrested at the vessel wall. The mean translational velocities measured are 61 and 177 mu m/s for P_ = 200 and 450 kPa, respectively. This technique therefore offers potential for enhanced and well-controlled stem cell delivery for improved cardiac repair after a myocardial infarction. (C) 2014 Wiley Periodicals, Inc.

The occurrence of nonspherical oscillations (or surface modes) of coated-microbubbles, used as ultrasound contrast agents in medical imaging, is investigated using ultra-high-speed optical imaging. Optical tweezers designed to micromanipulate single bubbles in 3-D are used to trap the bubbles far from any boundary, enabling a controlled study of the nonspherical oscillations of free-floating bubbles. Nonspherical oscillations appear as a parametric instability and display subharmonic behavior: they oscillate at half the forcing frequency, which was fixed at 1.7 MHz in this study. Surface modes are shown to preferentially develop for a bubble radius near the resonance of radial oscillations. In the studied range of acoustic pressures, the growth of surface modes saturates at a level far below bubble breakage. With the definition of a single, dimensionless deformation parameter, the amplitude of nonspherical deformation is quantified as a function of the bubble radius (between 1.5 and 5 mu m) and of the acoustic pressure (up to 200 kPa).

Dopamine causes a dose-dependent contraction of the rat rectum in vitro followed by a relaxation. This contraction can be inhibited by apomorphine and phenylephrine. This inhibition can be attenuated by the beta-endorphin (beta E) fragments 2-17 (des-Tyr1-gamma-endorphin, DT gamma E) and 6-17 (des-enkephalin-gamma-endorphin, DE gamma E). beta E 6-17 seems to be the shortest sequence with full activity in this respect since a shorter fragment (beta E 10-17) was less effective. The atypical neuroleptics oxypertine, sulpiride, and clozapine, the classic neuroleptic haloperidol and metoclopramide have a similar action to DE gamma E. The peptides and atypical neuroleptics do not affect the dopamine response per se while the classic neuroleptics haloperidol and metoclopramide enhance the dopamine response. The effects of the alpha-type endorphins are opposite to those of the gamma-type endorphins, since des-Tyr1-alpha-endorphin (DT alpha E, beta E 2-16) and des-enkephalin-alpha-endorphin (DE alpha E, beta E 6-16) enhance the phenylephrine-induced decreased responsiveness to dopamine. Structure-activity studies revealed that the active moiety of the alpha-endorphin fragments probably resides in the 6-9 region. In addition the alpha-type endorphins directly inhibit the dopamine response. It is concluded that the rat rectum may be used to analyse neuroleptic-like action. In this model alpha- and gamma-endorphin fragments may directly or indirectly influence the interaction of dopamine with the rectum. Because of the strong similarities between the effects of gamma-type endorphins and that of neuroleptics the results support the purported neuroleptic-like action of gamma-type endorphins. The influence of alpha-type endorphins and gamma-type endorphins on the apomorphine or phenylephrine induced decreased responsiveness to dopamine, although opposite, seems to be mediated by an influence on different dopamine sensitive systems.

Given the poor optical contrast of bright field imaging, fluorescence imaging is required to image ultrasound microbubbles in stratified vascular flows and to visualize drug release from loaded capsules. Fluorescence recordings using a combination of a high power CW laser and the Brandaris 128 ultra high-speed imaging facility give unique insight into the physical mechanisms of local intravascular drug delivery. Recordings of fluorescently labeled phospholipid-coated contrast agents show an excellent delineation of the bubble wall at frame rates of up to 5 million frames per second. This allowed us to reveal the time-resolved dynamic distribution of the shell material, including lipid shedding. Oil-filled polymeric microcapsules with a high dye concentration mixed in the hexadecane liquid core demonstrate a profound photo-acoustic effect when excited with a laser intensity of 1 MW/cm 2 or higher. The dye molecules absorb the laser light leading to intense heating of the liquid core. A rapid phase change leads to an impulsive thermal expansion. The resulting vapor bubble dynamics imaged using fluorescence imaging at a timescale of 100 nanoseconds revealed a typical oscillation frequency of 220 kHz. The generated acoustic pressure is in the order of 100 Pa at a distance of 2.5 cm from the capsule.