Dynamic and structural behavior of magnetic PVA-shelled microbubbles: Acoustic characterization

Combination of superparamagnetic iron oxide nanoparticles (SPOINs) and the polymer-shelled microbubble (MB) are proposed to be a contrast agent for both magnetic resonance and ultrasound imaging. The introduction of nanoparticles into MBs changes the material properties of encapsulating shell, which further influences on MBs performance as an ultrasound contrast agent. Magnetic MBs were prepared in two following strategies: 1. SPIONs were attached on the surface of MBs surface (Type A) and 2. SPIONs were physically entrapped in the MBs shell during the initial formation of PVA shell (Type B). A modified Church model was used to fit the attenuation coefficient spectra acquired experimentally. This allowed to recalculate the viscoelastic properties, i.e. storage and loss modulus, and dynamical properties, i.e. resonance frequency and damping coefficient of two types of magnetic MBs. The cross-correlation analysis of the time-domain response from the MBs suspension was used to identify pressure threshold at which MBs shell fractures. Higher values of both viscoelastic and dynamic characteristic were identified for MBs Type B. The estimated total damping ratio above 1 suggested that the MBs Type B behave as an overdamped harmonic oscillator whereas MBs Type A with total damping ratio below 1 possess underdamped harmonic oscillator nature. The predicted resonance frequencies are approximately 13 and 27 MHz for MBs Type A and B respectively. Moreover, the fracture pressure threshold measurements revealed that, higher peak negative pressure is required to fracture MBs Type B than Type A. When the driving pulse consists of 12 cycles, pressure threshold was 1.1 MPa and 1.3 MPa for MBs Type A and B respectively. In conclusion, MBs with nanoparticles loaded on the surface (Type A) appear to be more acoustically active, demonstrate lower resonance frequency, damping and fracture pressure threshold, than MBs with nanoparticles incorporated in the shell (Type B)

Investigation of polymer-shelled microbubble motions in acoustophoresis

The objective of this paper is to explore the trajectory motion of microsize (typically smaller than a red blood cell) encapsulated polymer-shelled gas bubbles propelled by radiation force in an acoustic standing-wave field and to compare the corresponding movements of solid polymer microbeads. The experimental setup consists of a microfluidic chip coupled to a piezoelectric crystal (PZT) with a reso- nance frequency of about 2.8 MHz. The microfluidic channel consists of a rectangular chamber with a width, w, corresponding to one wavelength of the ultrasound standing wave. It creates one full wave ultrasound of a standing-wave pattern with two pressure nodes at w/4 and 3w/4 and three antinodes at 0, w/2, and w. The peak-to-peak amplitude of the electrical potential over the PZT was varied between 1 and 10 V. The study is limited to no-flow condition. From Gor’kov’s potential equation, the acoustic con- trast factor, U, for the polymer-shelled microbubbles was calculated to about 60.7. Experimental results demonstrate that the polymer-shelled microbubbles are translated and accumulated at the pressure antinode planes. This trajectory motion of polymer-shelled microbubbles toward the pressure antinode plane is similar to what has been described for other acoustic contrast particles with a negative U. First, primary radiation forces dragged the polymer-shelled microbubbles into proximity with each other at the pressure antinode planes. Then, primary and secondary radiation forces caused them to quickly aggregate at different spots along the channel. The relocation time for polymer-shelled microbubbles was 40 times shorter than that for polymer microbeads, and in contrast to polymer microbeads, the polymer-shelled microbubbles were actuated even at driving voltages (proportional to radiation forces) as low as 1 V. In short, the polymer-shelled microbubbles demonstrate the behavior attributed to the negative acoustic contrast factor particles and thus can be trapped at the antinode plane and thereby sep- arated from particles having a positive acoustic contrast factor, such as for example solid particles and cells. This phenomenon could be utilized in exploring future applications, such as bioassay, bioaffinity, and cell interaction studies in vitro in a well-controlled environment

Magnetic microbubbles for multimodality imaging: the importance of the shell structure for low and high frequency mechanics

There is a growing interest in magnetic microbubbles (MBs) for simultaneous enhanced ultrasound (US) and enhanced magnetic resonance imaging (MRI) to support well-established imaging procedures as well as new emerging diagnostic and therapeutic applications. However, the development of hybrid contrast agents is challenging, because their design needs to satisfy a variety of requirements such as a sufficient stability of the probe for the circulation within the cardiovascular system, the production of an adequate US echo signal and a reasonable reduced relaxation time of nearby located protons. The studied magnetic MBs consist of an air-filled core, which is encapsulated by a soft hydrogel-like shell composed of poly(vinyl alcohol) and superparamagnetic iron oxide nanoparticles (SPIONs)[1]. Two strategies were used to combine magnetic nanoparticles with the polymeric shell: SPIONs were either covalently attached to the shell surface via a post-chemical treatment or embedded physically inside the shell during the MBs’ synthesis. In particular, we were interested on the impact of the used SPIONs integration strategy on low and high frequency mechanics of the magnetic MBs. Therefore, we used a straightforward characterization of the MBs on the single particle level to correlate the synthesis with the MBs’ morphological properties and low frequency mechanics that were studied in quasi-static force measurements with atomic force microscopy. High frequency mechanics were investigated by exposure of an ensemble of MBs to an acoustic field. By further correlation of low and high frequency mechanics, we were able to bridge the gap between synthesis and the MBs macroscopic properties relevant for their application. The shown approach offers the possibility to sustainable design and optimize complex probes based on an improved understanding of structure/property relations

Magnetite Nanoparticles Can Be Coupled to Microbubbles to Support Multimodal Imaging

Microbubbles (MBs) are commonly used as injectable ultrasound contrast agent (UCA) in modern ultrasonography. Polymer-shelled UCAs present additional potentialities with respect to marketed lipid-shelled UCAs. They are more robust; that is, they have longer shelf and circulation life, and surface modifications are quite easily accomplished to obtain enhanced targeting and local drug delivery. The next generation of UCAs will be required to support not only ultrasound-based imaging methods but also other complementary diagnostic approaches such as magnetic resonance imaging or computer tomography. This work addresses the features of MBs that could function as contrast agents for both ultrasound and magnetic resonance imaging. The results indicate that the introduction of iron oxide nanoparticles (SPIONs) in the poly(vinyl alcohol) shell or on the external surface of the MBs does not greatly decrease the echogenicity of the host MBs compared with the unmodified one. The presence of SPIONs provides enough magnetic susceptibility to the MBs to accomplish good detectability both in vitro and in vivo. The distribution of SPIONs on the shell and their aggregation state seem to be key factors for the optimization of the transverse relaxation rate

On the interplay of shell structure with low- and high-frequency mechanics of multifunctional magnetic microbubbles

Polymer-shelled magnetic microbubbles have great potential as hybrid contrast agents for ultrasound and magnetic resonance imaging. In this work, we studied US/MRI contrast agents based on air-filled poly(vinyl alcohol)-shelled microbubbles combined with superparamagnetic iron oxide nanoparticles (SPIONs). The SPIONs are integrated either physically or chemically into the polymeric shell of the microbubbles (MBs). As a result, two different designs of a hybrid contrast agent are obtained. With the physical approach, SPIONs are embedded inside the polymeric shell and with the chemical approach SPIONs are covalently linked to the shell surface. The structural design of hybrid probes is important, because it strongly determines the contrast agent's response in the considered imaging methods. In particular, we were interested how structural differences affect the shell's mechanical properties, which play a key role for the MBs' US imaging performance. Therefore, we thoroughly characterized the MBs' geometric features and investigated low-frequency mechanics by using atomic force microscopy (AFM) and high-frequency mechanics by using acoustic tests. Thus, we were able to quantify the impact of the used SPIONs integration method on the shell's elastic modulus, shear modulus and shear viscosity. In summary, the suggested approach contributes to an improved understanding of structure-property relations in US-active hybrid contrast agents and thus provides the basis for their sustainable development and optimization