Improving the heating efficiency of high intensity focused ultrasound ablation through the use of phase change nanodroplets and multifocus sonication.

Thermal ablation by ultrasound is being explored as a local therapy for cancers of soft tissue, such as the liver or breast. One challenge for these treatments are off-target effects, including heating outside of the intended region or skin burns. Improvements in heating efficiency can mitigate these undesired outcomes, and here, we describe methods for using phase-shift nanodroplets (PSNDs) with multi-focus sonications to enhance volumetric ablation and ablation efficiency at constant powers while increasing the pre-focal temperature by less than 6 [Formula: see text]C. Multi-focus ablation with 4 foci performed the best and achieved a mean ablation volume of 120.2 ± 22.4 mm3 and ablation efficiency of 0.04 mm3 J-1 versus an ablation volume of 61.2 ± 21.16 mm3 and ablation efficiency of 0.02 mm3 J-1 in single focus case. The combined use of PSNDs with multi-focal ultrasound presented here is a new approach to increasing ablation efficiency while reducing off-target effects and could be generally applied in various focused ultrasound thermal ablation treatments.

The biological response of rodent kidneys to low frequency, full volume diagnostic contrast-enhanced ultrasound imaging: Pilot data.

With the growth of contrast-enhanced ultrasound (CEUS) clinically, there are concerns about histologic bioeffects in regards to the implementation of high mechanical index (MI) imaging, such as the imaging sequence used for a specific CEUS technique known as flash-replenishment. The data presented are results from a pilot study, which explored flash-replenishment with high and moderate MI imaging sequences at time points of 24 hours and 2 weeks post imaging. This pilot study was followed by a larger study, which can be found in a journal article entitled "Histological and Blood Chemistry Examination of the Rodent Kidney After Exposure to Flash-Replenishment Ultrasound Contrast Imaging" Nyankima et al., 2019.

Histological and blood chemistry examination of the rodent kidney after exposure to flash-replenishment ultrasound contrast imaging.

The purpose of this work is to investigate whether imaging sequences of flash-replenishment contrast enhanced ultrasound (CEUS) of the kidney result in chronic or acute bioeffects. Kidneys of female Fischer 344 rats were imaged using the flash-replenishment technique. Animals were separated into four groups (N = 31). Imaging was conducted with a 4C1 probe, driven by an Acuson Sequoia system with Definity microbubbles as the ultrasound contrast agent. During the flash phase of the imaging sequence, one kidney in each animal was exposed to either a mechanical index (MI) of 1.0 or 1.9. For each MI, half of the animals were sacrificed shortly after imaging (4 h) or after 2 weeks. A blinded veterinary nephropathologist reviewed the histopathology of both the imaged and control (non-imaged) kidney. Blood urea nitrogen (BUN) was measured for each animal prior to imaging and at the time of necropsy. Histopathology assessments in both the 1.0 and 1.9 MI groups revealed no signs of hemorrhage at either the 4-h or 2-week time point. BUN showed minor but statistically significant elevations in both the 1.0 and 1.9 MI groups, but no significant difference was present at the 2-week time point in the 1.0 MI group. All BUN levels (at both time points) remained in the normal range. In conclusion, CEUS with flash-replenishment imaging sequences did not result in kidney bioeffects observable with histology at early or late time points. Increases in BUN levels were observed after imaging, but were minimized when using a moderate MI (1.0).

Accelerated Clearance of Ultrasound Contrast Agents Containing Polyethylene Glycol is Associated with the Generation of Anti-Polyethylene Glycol Antibodies.

Emerging evidence suggests that the immune system can recognize polyethylene glycol (PEG), leading to the accelerated blood clearance (ABC) of PEGylated particles. Our aim here was to study the generation of anti-PEG immunity and changes in PEGylated microbubble pharmacokinetics during repeated contrast-enhanced ultrasound imaging in rats. We administered homemade PEGylated microbubbles multiple times over a 28-d period and observed dramatically accelerated clearance (4.2 × reduction in half-life), which was associated with robust anti-PEG IgM and anti-PEG IgG antibody production. Dosing animals with free PEG as a competition agent before homemade PEGylated microbubble administration significantly prolonged microbubble circulation, suggesting that ABC was largely driven by circulating anti-PEG antibodies. Experiments with U.S. Food and Drug Administration-approved Definity microbubbles similarly resulted in ABC and the generation of anti-PEG antibodies. Experiments repeated with non-PEGylated Optison microbubbles revealed a slight shift in clearance, indicating that immunologic factors beyond anti-PEG immunity may play a role in ABC, especially of non-PEGylated agents.

In Vivo Assessment of the Potential for Renal Bio-Effects from the Vaporization of Perfluorocarbon Phase-Change Contrast Agents.

Low-boiling-point perfluorocarbon phase-change contrast agents (PCCAs) provide an alternative to microbubble contrast agents. Although parameter ranges related to in vivo bio-effects of microbubbles are fairly well characterized, few studies have been done to evaluate the potential of bio-effects related to PCCAs. To bridge this gap, we present an assessment of biological effects (e.g., hemorrhage) related to acoustically excited PCCAs in the rodent kidney. The presence or absence of bio-effects was observed after sonication with various perfluorocarbon core PCCAs (decafluorobutane, octafluoropropane or a 1:1 mixture) and as a function of activation pulse mechanical index (MI; minimum activation threshold, which was a moderate MI of 0.81-1.35 vs. a clinical maximum of 1.9). Bio-effects on renal tissue were assessed through hematology and histology including measurement of blood creatinine levels and the quantity of red blood cell (RBC) casts present in hematoxylin and eosin-stained kidney tissue sections after sonication. Short-term (24 h) and long-term (2 and 4 wk) analyses were performed after treatment. Results indicated that bio-effects from PCCA vaporization were not observed at lower mechanical indices. At higher mechanical indices, bio-effects were observed at 24 h, although these were not observable 2 wk after treatment.

Free-Standing Films from Aqueous Dispersions of Lysozyme, Single-Walled Carbon Nanotubes, and Polyvinyl Alcohol.

Transparent antibacterial films were produced by casting concentrated dispersions of lysozyme (LSZ), single-walled carbon nanotubes (SWNTs), and polyvinyl alcohol (PVA). The initial SWNT dispersion state had a significant influence on the films' mechanical properties. Films containing 9 wt % bundled SWNTs had six times higher Young's modulus than control films produced without SWNTs. Removal of SWNT bundles by centrifugation prior to concentrating the dispersions resulted in films that contained only 4.5 wt % SWNT but had over eight times higher Young's modulus than the control films.