Assessment of ultrasound-induced fracture of polymer-shelled ultrasound contrast agents using superharmonic technique

Ultrasound imaging techniques can be greatly improved by the use of ultrasound contrast agents. Knowledge of the peak negative pressure at which contrast agents fracture is paramount for the imaging application as well as for local drug delivery. Gasholdning microbubbles encapsulated into biocompatible poly vinyl alcohol shells are of particular interest for their enhanced shelf life and demonstratedchemical versatility. A gas core allows microbubbles to efficiently scatter ultrasound waves. In vitro ultrasound tests showed a sufficient enhancement of the backscattered power (25±1 dB), comparable to the soft tissue attenuation coefficients (0.8±0.04 dB/cm MHz) and phase velocities (1519±2 m/s). At temperature values between 24 and 37 °C the monotonic increase of the attenuation and phase velocity with frequency indicates that thick-shelled microbubbles do not resonate in a typical medical ultrasound frequency range of 1-15 MHz. In fact, they work as an amplifier of the incident acoustic wave. The novel approach based on detection of superharmonics (3f and 4f) is proposed for assessment of the fracture pressure threshold, Pthr. In vitro tests suggests that fatigue, i.e. accumulation of damage within the shell, is the major physical mechanism responsible for the fracturing process. It has been observed that there is a decrease of Pthr from 1.15±0.09 MPa to 0.9±0.05 MPa when the number of cycles in the pulse, N, increases from 6 to 12. It is worth noting that the reported pressure values are within clinically approved safety limits. The main conclusion to be drawn from our study is that superharmonic approach appears to be more sensitive in Pthr assessment than traditional second harmonic imaging. This claim is supported also by images acquired with a commercially available system, where contrast pulse sequencing technique, specific to third harmonic, is required for visualization of thick-shelled microbubbles

Assessment of ultrasound-induced fracture of polymer-shelled ultrasound contrast agents using superharmonic technique

Ultrasound imaging techniques can be greatly improved by the use of ultrasound contrast agents. Knowledge of the peak negative pressure at which contrast agents fracture is paramount for the imaging application as well as for local drug delivery. Gasholdning microbubbles encapsulated into biocompatible poly vinyl alcohol shells are of particular interest for their enhanced shelf life and demonstratedchemical versatility. A gas core allows microbubbles to efficiently scatter ultrasound waves. In vitro ultrasound tests showed a sufficient enhancement of the backscattered power (25±1 dB), comparable to the soft tissue attenuation coefficients (0.8±0.04 dB/cm MHz) and phase velocities (1519±2 m/s). At temperature values between 24 and 37 °C the monotonic increase of the attenuation and phase velocity with frequency indicates that thick-shelled microbubbles do not resonate in a typical medical ultrasound frequency range of 1-15 MHz. In fact, they work as an amplifier of the incident acoustic wave. The novel approach based on detection of superharmonics (3f and 4f) is proposed for assessment of the fracture pressure threshold, Pthr. In vitro tests suggests that fatigue, i.e. accumulation of damage within the shell, is the major physical mechanism responsible for the fracturing process. It has been observed that there is a decrease of Pthr from 1.15±0.09 MPa to 0.9±0.05 MPa when the number of cycles in the pulse, N, increases from 6 to 12. It is worth noting that the reported pressure values are within clinically approved safety limits. The main conclusion to be drawn from our study is that superharmonic approach appears to be more sensitive in Pthr assessment than traditional second harmonic imaging. This claim is supported also by images acquired with a commercially available system, where contrast pulse sequencing technique, specific to third harmonic, is required for visualization of thick-shelled microbubbles

Characterization of acoustic properties of PVA-shelled ultrasound contrast agents: ultrasound-induced fracture (Part II)

Knowledge of the magnitude of the peak negative pressure, Pthr, at which ultrasound contrast agents fracture is relevant for using these microbubbles both as devices for contrast enhancement purposes, as well as carriers of drugs to be delivered locally. In the second part of this communication, the acoustic properties of three types of microbubbles stabilized by poly (vinyl alcohol) (PVA) shells are further investigated. In particular, the dependence of Pthr on system parameters such as the number of cycles, frequency and exposure is examined. The effects of temperature, blood and, wherever data are available, of the dimension of the microbubbles on Pthr are also considered. The large shell thickness notwithstanding, the results of this investigation show that at room temperature, PVA contrast agents fracture at negative peak pressure values within the recommended safety limit. Furthermore, Pthr decreases with increasing temperature, radius of the microbubbles and number of cycles of the incident wave. Fatigue seems to be a physical mechanism playing a dominant role in the fracture process. The effect of blood on Pthr varies according to condition under which the microbubbles have been synthesized, although stiffening of the shell is observed in most cases. In conclusion, these results suggest that PVA-shelled microbubbles may offer a potentially viable system to be employed for both imaging and therapeutic purposes

Characterization of acoustic properties of PVA-shelled ultrasound contrast agents: Linear properties (Part I)

This work examines the linear acoustic behavior of ultrasound contrast agents made of three types of poly (vinyl alcohol) (PVA) shelled microbubbles manufactured at different pH and temperature conditions. Backscattered power, attenuation coefficient and phase velocity of ultrasonic waves propagating through suspensions of PVA contrast agents were measured at temperature values ranging between 24 degrees C and 37 degrees C in a frequency range from 3 MHz to 13 MHz. Enhancement of the backscattered power higher than 20 dB and displaying a weak dependence on temperature was observed. Attenuation and phase velocity, on the other hand, showed higher sensitivity to temperature variations. A modified version of the Church model, which accounts for the dispersion of the dynamic modulus of the PVA shells, was developed to simultaneously fit the attenuation and phase velocity data at 24 degrees C. The frequency dependence of the storage modulus was found to be that of semiflexible polymeric networks. On the other hand, the frequency dependence of the dynamic loss modulus suggests that additional mechanisms, which may be related to the finite dimensions of the shell and/or to its inhomogeneity, may play a significant role in the dissipation of the acoustic energy. For the microbubbles of interest, this model predicts frequency dependent resonance frequency higher than 100 MHz

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)