Generation of ultraharmonics in surfactant based ultrasound contrast agents: use and advantages.

A unique distinction between surfactant stabilized ultrasound contrast agent ST68 and water (or tissue), is the enhanced ability of the agent to generate non-linear frequencies such as sub-harmonics (f0/2), higher harmonics (2fo, 3fo, 4fo,...), and ultraharmonics (3f0/2, Sf0/2, 7f0/2,...), when insonated with fundamental frequency f0. Currently, second harmonics (2f0) have been predominantly researched, to exploit the diagnostic benefits of the contrast-specific non-linear imaging. However, we found that at normal imaging pressures (100 kPa-1 MPa), ST68 agent-generated second harmonic enhancements dropped to approximately 8 dB at 100 kPa and approximately 2 dB at 1 MPa. Moreover, at these pressures water (or tissue) produced strong second harmonics due to non-linear propagation. Ultraharmonics and sub-harmonics on the other hand, were generated only by the agent, and were not produced due to the non-linear propagation of ultrasound in either water or tissue. Additionally, ultraharmonic (3f0/2) enhancements of approximately 23 dB at 100 kPa, approximately 35 dB at 0.5 MPa and approximately 41dB at 1.1 MPa for ST68-PFC, offer much greater signal to noise ratio than higher harmonics.

Influence of environmental conditions on a new surfactant-based contrast agent: ST68.

Environmental influences on the new surfactant-stabilized bubbles, ST68, were investigated. We have developed a new surfactant-based contrast agent ST68, which is prepared by insonating buffered mixtures of Span 60 and Tween 80 in the presence of either air, PFC, or SF(6) gas. The effect of dilution, shear, and sonication on size distribution of ST68 showed that PFC-containing bubbles (ST68-PFC) were most stable. ST68-PFC bubbles lasted more than 15 min with approximately 30 dB backscatter enhancement in degassed phosphate-buffered saline, (pH 7.4), and air bubbles lasted approximately 3 s, suggesting the effects of diffusion. Additionally, it was found that the ionic strength of the suspending medium (for example, PBS), did not have any effect on ST68 bubbles containing SF(6) or PFC, but had a dramatic impact on bubbles containing air.

Effect of filling gases on the backscatter from contrast microbubbles: theory and in vivo measurements.

Two surfactant-based contrast agents, ST44 and ST68, were produced according to US Patent # 5,352,436 and filled with either air, C4F10 (perfluorobutane) or SF6 (sulfur hexaflouride). Ten rabbits received i.v. injections of each agent/gas combination with 5 repetitions of each dose (range: 0.005-0.13 mL/kg). A custom-made 10-MHz cuff transducer was placed around the surgically exposed distal aorta and audio Doppler signals were acquired in vivo. Quantitative in vivo dose responses were calculated off-line using spectral power analysis and compared to a theoretical model of microbubble dissolution and enhancement. For qualitative comparisons, 10 rabbits were imaged pre- and postcontrast administration (dose: 0.1 mL/kg) in gray-scale and colour. All agent/gas combinations produced marked Doppler enhancement with air bubbles enhancing least of all (p < 0.0001) and ST68-SF6 best of all (maximum: 27.6 +/- 2.04 dB; p < 0.012). There were no significant differences between other agent/gas combinations (0.30 < p < 0.70). Theoretical enhancement was within 1 order of magnitude of the experimental observations (i.e., deviations of up to 10 dB). The duration of contrast enhancement was 1-2 min for air-filled bubbles, 3-5 min for SF6-filled bubbles and more than 7 min for C4F10-filled bubbles. In conclusion, ST68-SF6 microbubbles produced most in vivo enhancement of the agent/gas combinations studied. Theory matched the measurements within an order of magnitude.

Incorporating O2-Hb reaction kinetics and the Fåhraeus effect into a microcirculatory O2-CO2 transport model.

The influence of O2-Hb reaction kinetics and the Fåhraeus effect on steady state O2 and CO2 transport in cat brain microcirculation was investigated using our refined multicompartmental model. The most important model predictions include: 1) capillaries are the sites in the microcirculation where the effect of O2-Hb kinetics is most pronounced; 2) while there is only a small difference between equilibrium and actual oxygen saturation, this effect is not negligible; 3) O2-Hb kinetics tends to make the PO2 level at the venous entrance higher than in venules; 4) the influence of the Fåhraeus effect leads to a lower tissue PO2 level than in venules and the outlet vein. The resultant decline in tissue PO2 may lead to a decrease in O2 consumption rate and extraction ratio; 5) although the Fåhraeus effect changes the ratio between arteriolar flux and capillary flux, incorporating the Fåhraeus effect and O2-Hb kinetics into the simulation does not change our previous conclusion, that most of the O2 and CO2 exchange takes place at the capillary level; 6) in general, influences of O2-Hb kinetics and Fåhraeus effect are synergistic; 7) a model that excludes these two mechanisms might overestimate the tissue oxygenation level especially during severe hypoxia.