Lars Hoff

Absorption and scatter of encapsulated gas filled microspheres: theoretical considerations and some measurements.

Albunex is an ultrasound contrast agent for use in echocardiology and other areas. It is capable of passing the lung circulation after intravenous injection. A theoretical model is developed for some acoustic properties, particularly the scatter and absorption, of this contrast agent, considering the individual microspheres as air bubbles surrounded by a thin shell. The attenuation, the sum of absorption and scatter, of this contrast medium is measured with five transducers to cover the frequency range from 700 kHz to 8.5 MHz. It is concluded that the model correlates well with these acoustic measurements. When Albunex is used intravenously the backscatter enhancement in the left ventricle is caused mainly by the microspheres with diameters between 5 and 8 microns.

Ultrasound scattering properties of Albunex microspheres

Albunex is an ultrasound contrast agent used in echocardiography and in other areas, it consists of microspheres of which more than 95% have a diameter in the range 1-10 microns. The scattering properties of this agent as functions of ultrasound frequency and microsphere diameter and concentration are investigated. A model of the Albunex microspheres has been previously described, considering the individual microspheres as air bubbles surrounded by a thin elastic shell. In the present study this model is extended by including into it the internal friction in the shell when the microsphere vibrates. Acoustic scattering and transmission are measured in the frequency range from 700 kHz to 12.5 MHz. The measured transmitted power is used to estimate the two parameters in the theoretical model: the shell elasticity parameter, Sp and the shell friction, Sf. Introduction of the shell friction into the model improves the agreement between theory and measurements. For the scattered power, differences between measured and calculated values lie within 3 dB. It is concluded that for the frequencies 2.5 and 5 MHz, microspheres with a diameter between 5 and 12 microns are preferred as these deliver the most significant contribution to the total scattered power and cause relatively little attenuation.

Acoustic properties of NC100100 and their relation with the microbubble size distribution.

RATIONALE AND OBJECTIVES NC100100 is a contrast agent for medical imaging with ultrasonography consisting of stabilized gas microbubbles in an aqueous suspension. The objective of this article is to explore the acoustic properties of NC100100 and their relation with the microbubble size distribution. The results are used to motivate the choice of a suitable assay/dosage parameter for precise control of product efficacy. METHODS The concentration and size distribution of microbubbles in > 50 preparations of NC100100 were determined by Coulter counting, and the acoustic attenuation and backscatter efficacy were determined for all samples. The in vivo efficacy of the product was investigated by harmonic imaging of the heart in a dog model. RESULTS The results demonstrated that the attenuation and backscatter efficacy per microbubble volume vary strongly with size, showing distinct maxima with respect to microbubble diameter. Sizes for optimal attenuation per volume ranged from 2.6 to 5.8 microns, depending on ultrasound frequency. The contribution of the smaller end tail of the microbubble distribution was shown to be negligible. From the observed size dependency for the acoustic properties, the volume concentration of microbubbles was chosen as the assay/dosage parameter for NC100100. The accuracy of this parameter as a descriptor of product efficacy was demonstrated by precise, linear relations between volume, concentration, and attenuation/backscatter. In comparison, the correlation between the microbubble number and acoustic properties was not significant. Results from the in vivo study showed a precise, linear relation between injected microbubble volume and the observed in vivo efficacy. CONCLUSIONS The acoustic properties of NC100100 are dependent on microbubble size. The observed batch-to-batch variance in the acoustic properties of the product may be fully explained by variation in concentration and size. Microbubble volume is a more precise predictor of in vitro/in vivo efficacy than microbubble number and consequently was chosen as the assay/dosage parameter for NC100100.

Acoustic properties of ultrasonic contrast agents

Abstract Diameters of particles used as ultrasound contrast agents are limited by capillary diameters to about 8 μm, much smaller than the acoustic wavelength used in diagnostic ultrasound. Strong acoustic backscatter from such small particles is achieved by using gas-containing particles encapsulated in a shell. The shell makes the acoustic properties of these particles differ from that of gas-bubbles. It is shown how acoustic behaviour of such particles can be explained from their size and compressibility. The particle bulk modulus K was described with the Kelvin-Voigt model for visco-elastic solids, K = K0 + iωμ, where the parameters K0 and μ were found from acoustic attenuation spectra. Application of this model to an experimental contrast agent from Nycomed Imaging gave as a result K0 = 2.2 MPa, μ = 0.080 Pa · s.

Modelling of the ultrasound return from Albunex microspheres

Abstract A mathematical model that predicts the changes to the ultrasound frequency spectrum after passing through human tissue and Albunex (a registered trademark of Molecular Biosystems Inc, San Diego, CA) microspheres is proposed. Changes in backscattered intensity and mean frequency of the reflected signal can be estimated as a function of imaging geometry, ultrasound frequency, and microsphere concentration and size distribution. An important result is that the frequency shifts and the intensity variations are caused both by the microspheres in the path between the transducer and the region of interest, and by the reflection properties of the contrast agent in the region of interest. The model enables one to explain and predict clinically observed intensity effects such as the shadow effect in the right ventricle, and the fact that received intensity increases with concentration up to a certain point where it falls off. The effect of the removal of the larger microspheres in the lungs is so significant that concentrations that give positive frequency shifts with increasing concentration in the right ventricle will give negative shifts in the left ventricle. The frequency shift is only a good indicator of concentration for ultrasound frequencies below 4 MHz, while the intensity is very sensitive to the Albunex microsphere concentration and the imaged depth at the higher frequencies. It is also found that the periodic variation in heart muscle thickness during the heart cycle will significantly affect the intensity and mean frequency of the backscattered ultrasound observed in the left ventricle, and in such a way as to give a periodic variation over the heart cycle.

Nonlinear response of Sonazoid. Numerical simulations of pulse-inversion and subharmonics

The oscillation of Sonazoid contrast agent bubbles has been simulated numerically, using a modified Rayleigh-Plesset model including the effect of a shell. Pulse-inversion simulations showed how the echoes changed from inverted to time-shifted versions of each other as the driving amplitude increased. Simulations of subharmonic oscillations showed that the subharmonic mode was only present for some diameter-frequency combinations, and only above an amplitude threshold. This threshold was about 500 kPa, which is higher than values published for bubbles without a shell. For large bubbles, a chaotic oscillation pattern was found. A subharmonic mode was not always achieved for a finite-length pulse, even if it was predicted by CW results.

Effect of microsphere size distribution on the ultrasonographic contrast efficacy of air-filled albumin microspheres in the left ventricle of dog hearts.

RATIONALE AND OBJECTIVES The in vitro ultrasonographic contrast efficacy of air-filled albumin microspheres has been found to depend on the size distribution of microspheres. The objective of the current study was to empirically describe the relationship between the size distribution of injected air-filled albumin microspheres and the in vivo contrast efficacy after lung capillary filtration in a dog model. METHODS Twenty different air-filled microspheres with large and well-defined differences in size distribution were prepared from nine different batches of Albunex (Molecular Biosystems Inc.) and subsequently characterized by Coulter counting. The in vivo ultrasonographic contrast enhancement of these preparations was investigated with a VingMed CFM750 in closed chest model in six mongrel dogs. The observed contrast efficacy, measured as gray-level enhancement in the left ventricle (LV), was correlated to the microsphere size distribution, using both univariate and multivariate approaches. RESULTS The results demonstrated a significant contribution to LV contrast efficacy from microspheres larger than approximately 7 microm, and a lack of contribution from microspheres smaller than approximately 7 microm. Linear relationships were found between LV contrast efficacy, and both the number concentration of microspheres between 8 to 12 microm and the total microsphere volume concentration. No significant covariance between in vivo contrast efficacy and the number concentration between 1 to 38 microm or 4 to 10 microm was observed. The multivariate model showed a significant contribution to the in vivo gray-level enhancement from microspheres in the size range 7 to 15 microm, with optimal efficacy per microsphere at approximately 13 microm. CONCLUSIONS Large microspheres (> 7 microm), which had been expected to be trapped in the lung capillary bed, contribute most of the observed ultrasound contrast in the LV of the heart.

Diagnosis of osteoporosis using nonlinear ultrasound

Our aim is to diagnose osteoporosis by using nonlinear acoustics to detect microscopic cracks in human bone. We constructed a system to measure 2nd harmonic generation in human heel bone, where special care was taken to suppress 2nd harmonics generated in the electronics. Experiments showed that this system did detect harmonics generated bone, and amplitude independent estimates for the 2nd harmonic strength were found. The methods were tested in two small studies comparing healthy volunteers and patients with osteoporosis. These studies have not yet been able to verify a difference between normal and osteoporotic bone. The initial studies are regarded preliminary, and suffer from weaknesses in patient selection and measurement setup. Studies with improved equipment and better patient selection are planned.

Microbubble volume concentration: a better efficacy parameter for US contrast agents than the number concentration.

Both microbubble number concentration and volume concentration have been proposed as assay parameters for ultrasonographic (US) contrast agents. If the microbubble size distribution varies, the microbubble number dose and volume dose may not be equally good descriptors of the efficacy of the agents. Therefore, in this study, we compared the efficacy of several microbubble formulations with different size distributions to find out which of the two parameters to use.

Nonlinear scatter from Sonazoid

Presents a nonlinear model for the response of shell-encapsulated gas bubbles to an ultrasound pulse. Values for the viscoelastic properties of the shell were estimated from ultrasound measurements at low amplitude. Results from simulations were compared with experiments. Ultrasound pulses were transmitted with a 1 MHz transducer into samples of Sonazoid. Pressure amplitudes were varied between 20 and 500 kPa. In the received echoes, frequency components up to the 9th harmonic of the transmit frequency were detected. Good agreement was found between the experimental results and predictions from the theory. Theories based on gas-bubbles without shell give poor agreement between theoretical and experimental results.