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Work performed in BUCL is an integrated part of the ultrasound research program at the University of Cincinnati. The team of ultrasound researchers has formed Image-guided Ultrasound Therapeutics Laboratories (IgUTL). IgUTL is directed by Christy K. Holland, Ph.D. and includes her lab, BUCL, and the Biomedical Acoustics Laboratory. The main research foci in BUCL include Acoustic Droplet Vaporization and Passive Cavitation Imaging.
Acoustic Droplet Vaporization
Acoustic droplet vaporization (ADV) is the process whereby liquid perfluorocarbon droplets undergo a phase transition into gas microbubbles when insonified with ultrasound above a pressure threshold (Figure 1).
Figure 1: The top portion of the figure is a magnified schematic of the ADV process, shown on a B-mode image in the lower part of the figure. Droplets are convected through a flow tube from left to right. The droplets appear hypoechoic (dark) in the lumen. After ADV, the resulting microbubbles are hyperechoic (bright). The droplets (small blue circles) do not phase transition into microbubbles (yellow circles) until they are exposed to ultrasound.
The volumetric expansion of the perfluorocarbon during the phase transition results in microbubbles that are highly undersaturated with non-perfluorocarbon gas molecules relative to the surrounding fluid. In particular, the relative oxygen saturation in the microbuuble could be three orders of magnitude lower than that of the surrounding fluid. Thus, the microbubbles formed via ADV act as potent sinks that scavenge dissolved gases from surrounding fluids (Figure 2).
Figure 2: Schematic of the mechanism of gas scavenging during ADV. The left panel shows a perfluorocarbon droplet (blue circle) that has the same oxygen content inside the droplet as the fluid outside the droplet. The middle panel shows that after the droplet is converted to a gas bubble, the number of oxygen molecules inside the bubble is the same as that of the originating droplet. However, the concentration inside the bubble is less because of the volumetric expansion of the perfluorocarbon. The right panel shows that as a result of the differences in the gas concentrations and oxygen solubilities of the surrounding fluid and the perfluorocarbon, oxygen diffuses into the bubble from the surrounding fluid, reducing the concentration of oxygen in the surrounding fluid.
We have demonstrated the ability to scavenge dissolved oxygen from both saline and from porcine whole blood using an in vitro flow model (Figure 3). A numerical model based on the mechanisms concentration gradients has been developed and can be used to predict the expected decrease in dissolved oxygen (Radhakrishnan et al. 2016). This numerical model indicates that the key factor in scavenging oxygen is the total volume of perfluorocarbon that is converted from a liquid to a gas.
Figure 3: Dissolved oxygen scavenging. The dissolved oxygen of fluids containing perfluoropentane droplets was measured before and after ultrasound exposure in a flow phantom. Approximately, a 75% and 50% reduction in dissolved oxygen was measured after ultrasound exposure in saline and whole blood, respectively.
To translate the effect in vivo, we have developed a differential centrifugation protocol to size-isolate droplets that transition most efficiently, while also removing droplets that are too large to pass through the vasculature (Mercado et al. 2016). An alternative approach being investigated is the use of microfluidic droplet manufacturing (Figure 4). On going studies are investigating the ability to precisely control oxygen scavenging levels and measuring changes in myocardial reperfusion injury using ex vivo and in vivo models.
Figure 4: Microfluidic Droplet Size Distributions. By varying the flow parameters of droplet components, it is possible to manufacture different size droplet distributions for performing acoustic droplet vaporization. All distributions were made using a commercial microfluidic flow-focusing device.
References
Mercado KP, Radhakrishnan K, Stewart K, Snider L, Ryan D, Haworth KJ. Size-isolation of ultrasound-mediated phase change perfluorocarbon droplets using differential centrifugation. J Acoust Soc Am, 2016;139:EL142–EL148.
Mercado-Shekhar KP, Su H, Kalaikadal DS, Lorenz JN, Manglik RM, Holland CK, Redington AN, Haworth KJ. Acoustic droplet vaporization-mediated dissolved oxygen scavenging in blood-mimicking fluids, plasma, and blood. Ultrason Sonochem, 2019;56:114–124.
Radhakrishnan K, Holland CK, Haworth KJ. Scavenging dissolved oxygen via acoustic droplet vaporization. Ultrason Sonochem 2016;31:394–403.
As we have demonstrated at UC and other laboratories around the world, cavitation is associated with a several bioeffects, including sonothrombolysis, HIFU thermal ablation, sonoporation, and drug and gene delivery. The microbubble activities that induce these bioeffects also produce characteristic cavitation emissions, which can be detected using single-element transducers. Single-element transducers provide good spatial sensitivity or specificity for the detection of cavitation emissions, but not both. Passive cavitation imaging is an array-based approach to processing cavitation emissions that have excellent spatial sensitivity and specificity. Array-based passive cavitation imaging can provide superior signal-to-noise as compared to single-element transducers by destructive interference of incoherent noise across the individual elements in an array. Through our experiments and analysis, we have demonstrated that the resolution of passive cavitation imaging is diffraction dependent (i.e., primarily depends on the frequency content of the signals being beamformed and the passive array element spacing and geometry). Therefore the image resolution does not depend on pulse shape or length, in contrast to standard B-mode imaging.
Furthermore, we have demonstrated that frequency-domain delay-and-sum passive cavitation imaging can accurately map different types of cavitation activity based on the frequency content of cavitation emissions (Haworth et al. 2012; Haworth et al. 2016). The frequency-domain approach can be substantially faster than time-domain delay-and-sum algorithms due to the inherent frequency-selectivity of the approach. Studies at IgULT have developed and implemented passive cavitation imaging in vitro, ex vivo, and in vivo on clinical and research ultrasound scanners. We have also applied passive cavitation imaging to the study of bubble dynamics (Radhakrishnan et al. 2015), ultrasound-mediated drug delivery (Haworth et al. 2016), and high-intensity focused ultrasound thermal (Haworth et al. 2015) and mechanical ablation (Bader et al. 2015). These results show that passive cavitation imaging has the potential to be a powerful tool for monitoring and controlling cavitation-based therapies.
Figure 1: Passive cavitation images of subharmonic emissions overlaid on ultrasound B-mode images of echogenic liposomes flowing (left to right) through a vessel phantom. Cavitation of the echogenic liposomes is induced with a clinical scanner in spectral Doppler mode (MI = 0.8). Loss of echogenicity in the B-mode images occurs at the same spatial location as subharmonic emissions in the passive cavitation images.
Figure 2: Duplex passive cavitation images without (A) and with (B) octafluoropropane filled echogenic liposomes injected into a porcine femoral artery and insonified with 500-kHz pulsed therapeutic ultrasound at a mechanical index of 0.51. The therapeutic ultrasound insonation created artifacts that appear as rays in the B-mode image. Stable cavitation activity, indicated by the ultraharmonic (UC) energy was detected only in the presence of the therapeutic ultrasound and echogenic liposomes.
Bader KB, Haworth KJ, Maxwell AD, Peng T, McPherson DD, Holland CK. Fibrin-targeted echogenic liposomes for localized ablation of thrombi with histotripsy pulses. J Acoust Soc Am Acoustical Society of America, 2015;138:1820–1820.
Bader KB, Haworth KJ, Maxwell AD, and Holland CK. (2018). Post Hoc Analysis of Passive Cavitation Imaging for Classification of Histotripsy-induced Liq- uefaction In Vitro. IEEE Medical Imaging. 37(1):106-115 doi: 10.1109/TMI.2017.2735238
Haworth KJ, Mast TD, Radhakrishnan K, Burgess MT, Kopechek JA, Huang S-L, McPherson DD, Holland CK. Passive imaging with pulsed ultrasound insonations. J Acoust Soc Am Acoustical Society of America, 2012;132:544–553.
Haworth KJ, Bader KB, Rich KT, Holland CK, Mast TD. (2017). Quantitative Frequency-Domain Passive Cavitation Imaging. IEEE Transactions on Ultrasonics, Ferroelectrics, and Frequency Control. 64(1):177-191 doi: 10.1109/TUFFC.2016.2620492
Haworth KJ, Raymond JL, Radhakrishnan K, Moody MR, Huang S-L, Peng T, Shekhar H, Klegerman ME, Kim H, McPherson DD, Holland CK. Trans-Stent B-Mode Ultrasound And Passive Cavitation Imaging. Ultrasound Med Biol 2016;42:518–527.
Haworth KJ, Salgaonkar VA, Corregan NM, Holland CK, Mast TD. Using Passive Cavitation Images to Classify High-Intensity Focused Ultrasound Lesions. Ultrasound Med Biol 2015;41:2420–2434.
Mercado KP, Radhakrishnan K, Stewart K, Snider L, Ryan D, Haworth KJ. (2016). Empirical model for size isolating ultrasound-triggered phase-shift emulsions using differential centrifugation. Journal of the Acoustical Society of America - Express Letters. 135(5):EL142-148 doi: 10.1121/1.4946831
Radhakrishnan K, Haworth KJ, Peng T, McPherson DD, Holland CK. Loss of echogenicity and onset of cavitation from echogenic liposomes: pulse repetition frequency independence. Ultrasound Med Biol 2015;41:208–221.
Radhakrishnan K, Holland CK, Haworth KJ. (2016). Scavenging dissolved oxygen via acoustic droplet vaporization. Ultrasonics Sonochemistry. 31:394-403 doi: 10.1016/j.ultsonch.2016.01.019
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