Kevin Haworth

Histotripsy, a form of therapeutic ultrasound that uses the mechanical action of microbubble clouds for tissue ablation, is under development to treat chronic deep vein thrombosis (DVT). We hypothesize that combining thrombolytic agents with histotripsy will enhance clot lysis. Recombinant tissue plasminogen activator (rt-PA) and rt-PA-loaded echogenic liposomes that entrain octafluoropropane microbubbles (OFP t-ELIP) were used in combination with highly shocked histotripsy pulses. Fully retracted porcine venous clots, with similar features of DVT occlusions, were exposed either to histotripsy pulses alone (peak negative pressures of 7-20 MPa), histotripsy and OFP t-ELIP, or histotripsy and rt-PA. Microbubble cloud activity was monitored with passive cavitation imaging during histotripsy exposure. The power levels of cavitation emissions from within the clot were not statistically different between treatment types, likely due to the near instantaneous rupture and destruction of OFP t-ELIP. The thrombolytic efficacy was significantly improved in the presence of rt-PA. These results suggest the combination of histotripsy and rt-PA could serve as a potent therapeutic strategy for the treatment of DVT. © 2016 Institute of Physics and Engineering in Medicine.

Previously, passive cavitation imaging has been described in the context of continuous-wave high-intensity focused ultrasound thermal ablation. However, the technique has potential use as a feedback mechanism for pulsed-wave therapies, such as ultrasound-mediated drug delivery. In this paper, results of experiments and simulations are reported to demonstrate the feasibility of passive cavitation imaging using pulsed ultrasound insonations and how the images depend on pulsed ultrasound parameters. The passive cavitation images were formed from channel data that was beamformed in the frequency domain. Experiments were performed in an invitro flow phantom with an experimental echo contrast agent, echogenic liposomes, as cavitation nuclei. It was found that the pulse duration and envelope have minimal impact on the image resolution achieved. The passive cavitation image amplitude scales linearly with the cavitation emission energy. Cavitation images for both stable and inertial cavitation can be obtained from the same received data set.

Echogenic liposomes (ELIP) are being developed for the early detection and treatment of atherosclerotic lesions. An 80% loss of echogenicity of ELIP has been found to be concomitant with the onset of stable and inertial cavitation. The ultrasound pressure amplitude at which this occurs is weakly dependent on pulse duration. It has been reported that the rapid fragmentation threshold of ELIP (based on changes in echogenicity) is dependent on the insonation pulse repetition frequency (PRF). The study described here evaluates the relationship between loss of echogenicity and cavitation emissions from ELIP insonified by duplex Doppler pulses at four PRFs (1.25, 2.5, 5 and 8.33 kHz). Loss of echogenicity was evaluated on B-mode images of ELIP. Cavitation emissions from ELIP were recorded passively on a focused single-element transducer and a linear array. Emissions recorded by the linear array were beamformed, and the spatial widths of stable and inertial cavitation emissions were compared with the calibrated azimuthal beamwidth of the Doppler pulse exceeding the stable and inertial cavitation thresholds. The inertial cavitation thresholds had a very weak dependence on PRF, and stable cavitation thresholds were independent of PRF. The spatial widths of the cavitation emissions recorded by the passive cavitation imaging system agreed with the calibrated Doppler beamwidths. The results also indicate that 64%-79% loss of echogenicity can be used to classify the presence or absence of cavitation emissions with greater than 80% accuracy.

Angioplasty and stenting of a stenosed artery enable acute restoration of blood flow. However, restenosis or a lack of re-endothelization can subsequently occur depending on the stent type. Cavitation-mediated drug delivery is a potential therapy for these conditions, but requires that particular types of cavitation be induced by ultrasound insonation. Because of the heterogeneity of tissue and stochastic nature of cavitation, feedback mechanisms are needed to determine whether the sustained bubble activity is induced. The objective of this study was to determine the feasibility of passive cavitation imaging through a metal stent in a flow phantom and an animal model. In this study, an endovascular stent was deployed in a flow phantom and in porcine femoral arteries. Fluorophore-labeled echogenic liposomes, a theragnostic ultrasound contrast agent, were injected proximal to the stent. Cavitation images were obtained by passively recording and beamforming the acoustic emissions from echogenic liposomes insonified with a low-frequency (500 kHz) transducer. In vitro experiments revealed that the signal-to-noise ratio for detecting stable cavitation activity through the stent was greater than 8 dB. The stent did not significantly reduce the signal-to-noise ratio. Trans-stent cavitation activity was also detected in vivo via passive cavitation imaging when echogenic liposomes were insonified by the 500-kHz transducer. When stable cavitation was detected, delivery of the fluorophore into the arterial wall was observed. Increased echogenicity within the stent was also observed when echogenic liposomes were administered. Thus, both B-mode ultrasound imaging and cavitation imaging are feasible in the presence of an endovascular stent in vivo. Demonstration of this capability supports future studies to monitor restenosis with contrast-enhanced ultrasound and pursue image-guided ultrasound-mediated drug delivery to inhibit restenosis.

Echogenic liposomes (ELIP) encapsulate gas bubbles and drugs within lipid vesicles, but the mechanisms of ultrasound-mediated drug release from ELIP are not well understood. The effect of cavitation activity on drug release from ELIP was investigated in flowing solutions using two fluorescent molecules: a lipophilic drug (rosiglitazone) and a hydrophilic drug substitute (calcein). ELIP samples were exposed to pulsed Doppler ultrasound from a clinical diagnostic ultrasound scanner at pressures above and below the inertial and stable cavitation thresholds. Control samples were exposed to a surfactant, Triton X-100 (positive control), or to flow alone (negative control). Fluorescence techniques were used to detect release. Encapsulated microbubbles reduced the measured fluorescence intensity and this effect should be considered when assessing drug release from ELIP. The origin of this effect is not specific to ELIP. Release of rosiglitazone or calcein compared to the negative control was only observed with detergent treatment, but not with ultrasound exposure, despite the presence of stable and inertial cavitation activity. Release of rosiglitazone or calcein from ELIP exposed to diagnostic ultrasound was not observed, even in the presence of cavitation activity. Ultrasound-mediated drug delivery strategies with ELIP will thus rely on passage of the drug-loaded liposomes to target tissues.

ABSTRACT Passive cavitation imaging (PCI) is a method for spatially mapping acoustic emissions caused by microbubble activity, including subharmonic and ultraharmonic emissions that denote stable cavitation. The point spread function (PSF) of passive cavitation images is diffraction limited. When typical clinical diagnostic linear arrays are used for PCI, the diffraction limit results in high azimuthal resolution but low axial resolution. Abadi et al. (2013)recently demonstrated a method called frequency-sum beamforming, which employs second-order or higher products of the acoustic emissions to manufacture higher frequencies, thereby reducing the size of the PSF. We applied this approach to cavitation emissions recorded from albumin-shelled bubbles insonified by 2 MHz ultrasound. Cavitation emissions were recorded on a 5 MHz, 128 element linear array using a Vantage scanner (Verasonics Inc.). Quadratic and fourth-order frequency-sum beamforming was applied to both harmonic and ultraharmonic cavitation emissions. Corresponding simulations were also performed to illustrate frequency-sum passive cavitation imaging of multiple bubbles. In comparison to delay-and-sum PCI, apparent areas of cavitation activity decreased when products of the emissions were used to perform frequency-sum beamforming. However, frequency-sum beamforming also produced artifacts, including the appearance of spurious emission sources.

Abstract Echogenic liposomes (ELIP) encapsulate gas bubbles and drugs within lipid vesicles, but the mechanisms of ultrasound-mediated drug release from ELIP are not well understood. The effect of cavitation activity on drug release from ELIP was investigated in flowing solutions using two fluorescent molecules: a lipophilic drug (rosiglitazone) and a hydrophilic drug substitute (calcein).

Ultrasound enhances recombinant tissue plasminogen activator (rt‐PA) thrombolysis via a cavitational mechanism. An ex vivo porcine carotid arterial model incorporating physiologic flow and pressure was developed and stable cavitation promoted for thrombolysis. Aged, retracted whole blood clots were exposed to plasma alone, plasma containing rt‐PA (3.15 μg∕ ml), or plasma with rt‐PA and the Definity ultrasound contrast agent (0.31 μl∕ ml), with and without 120‐kHz continuous wave ultrasound at a peak‐to‐peak pressure amplitude ...

Stable cavitation is correlated with thrombolytic efficacy for recombinant tissue plasminogen activator (rt‐PA) mediated thrombolysis. An infusion of Definity nucleated, promoted, and sustained stable cavitation in an ex vivo porcine carotid model exposed to 120‐kHz continuous wave ultrasound. The optimal ultrasound pressure amplitude and the durations of active and quiescent periods were determined to maximize stable cavitation. Oxygenated porcine plasma with Definity (0.31 μL∕ mL) and rt‐PA (3.15 μL∕ mL) flowed through ...

Echogenic liposomes (ELIPs), encapsulating air and drug, are being developed for use as vesicles for ultrasound‐mediated drug release. Both calcein and a thrombolytic drug have been encapsulated in ELIP and released with 6‐MHz color Doppler ultrasound in an in vitro flow system. To elucidate the role of stable or inertial cavitation in loss of echogenicity and drug release, ELIPs were insonified with 6‐MHz pulsed Doppler ultrasound within the same flow system. A 10‐MHz focused passive cavitation detector (PCD) was placed confocally ...

[underline Purpose:] Acoustic droplet vaporization (ADV) shows promise for the spatial control and acceleration of thermal lesion production. In this study, we investigated the hypothesis that ADV bubbles can substantially enhance HIFU ablation by increasing and ...

Palpitation detects tissue abnormalities by exploiting the vast range of elastic properties found in vivo. The method is limited by tactile sensitivity and the inability to probe tissues at depth. Recent efforts seek to remove these limitation by developing a medical imaging modality based ...

Applications of acoustic droplet vaporization in diagnostic and therapeutic ultrasound. [The Journal of the Acoustical Society of America 127, 1975 (2010)]. Mario L. Fabiilli, Oliver D. Kripfgans, Man Zhang, Kevin J. Haworth, Andrea H. Lo, Paul L. Carson, J. Brian Fowlkes. Abstract ...

Abstract The ability to localize, both spatially and temporally, a chemotherapeutic agent could be used to reduce the systemic toxicity associated with conventional chemotherapy regimens. Ultrasound (US)-triggered drug delivery systems, such as microbubbles or emulsions, present the ability to localize the effect of chemotherapy agents. In the case of phase-shift emulsions, the activation by US results in the production of gas bubbles-a process known as acoustic droplet vaporization (ADV). Here, the ability of ADV to ...

We are sorry, but NCBI web applications do not support your browser, and may not function properly. More information here... ... See "Generalized shot noise model for time-reversal in multiple-scattering media allowing for arbitrary inputs and windowing" in volume 125 on page 3129. ... This corrects the article "Generalized shot noise model for time-reversal in multiple-scattering media allowing for arbitrary inputs and windowing" in volume 125 on page 3129. ... On page 3138, Fig. ​Fig.6d6d was inadvertently an identical copy of Fig. 6(c). ...

Passive cavitation imaging provides spatially resolved monitoring of cavitation emissions. However, the diffraction limit of a linear imaging array results in relatively poor range resolution. Poor range resolution has limited prior analyses of the spatial specificity and sensitivity of passive cavitation imaging in predicting thermal lesion formation. In this study, this limitation is overcome by orienting a linear array orthogonal to the high-intensity focused ultrasound propagation direction and performing passive imaging. Fourteen lesions were formed in ex vivo bovine liver samples as a result of 1.1-MHz continuous-wave ultrasound exposure. The lesions were classified as focal, "tadpole" or pre-focal based on their shape and location. Passive cavitation images were beamformed from emissions at the fundamental, harmonic, ultraharmonic and inharmonic frequencies with an established algorithm. Using the area under a receiver operating characteristic curve (AUROC), fundamental, harmonic and ultraharmonic emissions were found to be significant predictors of lesion formation for all lesion types. For both harmonic and ultraharmonic emissions, pre-focal lesions were classified most successfully (AUROC values of 0.87 and 0.88, respectively), followed by tadpole lesions (AUROC values of 0.77 and 0.64, respectively) and focal lesions (AUROC values of 0.65 and 0.60, respectively).

Although coil embolization is known to prevent rebleeding from acutely ruptured cerebral aneurysms, the underlying biological and mechanical mechanisms have not been characterized. We sought to determine if microcoil-dependent interactions with thrombus induce structural and mechanical changes in the adjacent fibrin network. Such changes could play an important role in the prevention of aneurysm rebleeding. The stiffness of in vitro human blood clots and coil-clot complexes implanted into aneurysm phantoms were measured immediately after formation and after retraction for 3 days using unconfined uniaxial compression assays. Scanning electron microscopy of the coil-clot complexes showed the effect of coiling on clot structure. The coil packing densities achieved were in the range of clinical practice. Bare platinum coils increased clot stiffness relative to clot alone (Young's modulus 6.9 kPa and 0.83 kPa, respectively) but did not affect fibrin structure. Hydrogel-coated coils p...

ABSTRACT Acoustic droplet vaporization (ADV) has been investigated for capillary hemostasis, thermal ablation, and ultrasound imaging. The maximum diameter of a microbubble produced by ADV depends on the gas saturation of the surrounding fluid. This dependence is due to diffusion of dissolved gases from the fluid into the perfluoropentane (PFP) microbubble. This study investigated the change in oxygen concentration in the surrounding fluid after ADV. Albumin-shelled PFP droplets in air-saturated saline (1:30, v/v) were continuously pumped through a flow system and insonified by a focused 2-MHz single-element transducer to induce ADV. B-mode image echogenicity was used to determine the ADV threshold pressure amplitude. The dissolved oxygen concentration in the fluid upstream and downstream of the insonation region was measured using inline sensors. Droplet size distributions were measured before and after ultrasound exposure to determine the ADV transition efficiency. The ADV pressure threshold at 2 MHz was 1.7 MPa (peak negative). Exposure of PFP droplets to ultrasound at 5 MPa peak negative pressure caused the dissolved oxygen content in the surrounding fluid to decrease from 88 ± 3% to 20 ± 4%. The implications of oxygen scavenging during ADV will be discussed.

ABSTRACT The Image-guided Ultrasound Therapeutic Laboratories (IgUTL) are located at the University of Cincinnati in the Heart, Lung, and Vascular Institute, a key component of efforts to align the UC College of Medicine and UC Health research, education, and clinical programs. These extramurally funded laboratories, directed by Prof. Christy K. Holland, are comprised of graduate and undergraduate students, postdoctoral fellows, principal investigators, and physician-scientists with backgrounds in physics and biomedical engineering, and clinical and scientific collaborators in fields including cardiology, neurosurgery, neurology, and emergency medicine. Prof. Holland’s research focuses on biomedical ultrasound including sonothrombolysis, ultrasound-mediated drug and bioactive gas delivery, development of echogenic liposomes, early detection of cardiovascular diseases, and ultrasound-image guided tissue ablation. The Biomedical Ultrasonics and Cavitation Laboratory within IgUTL, directed by Prof. Kevin J. Haworth, employs ultrasound-triggered phase-shift emulsions (UPEs) for image-guided treatment of cardiovascular disease, especially thrombotic disease. Imaging algorithms incorporate both passive and active cavitation detection. The Biomedical Acoustics Laboratory within IgUTL, directed by Prof. T. Douglas Mast, employs ultrasound for monitoring thermal therapy, ablation of cancer and vascular targets, transdermal drug delivery, and noninvasive measurement of tissue deformation.

Echogenic liposomes (ELIP) are being developed for the early detection and treatment of atherosclerotic lesions. An 80% loss of echogenicity of ELIP has been found to be concomitant with the onset of stable and inertial cavitation. The ultrasound pressure amplitude at which this occurs is weakly dependent on pulse duration. It has been reported that the rapid fragmentation threshold of ELIP (based on changes in echogenicity) is dependent on the insonation pulse repetition frequency (PRF). The study described here evaluates the relationship between loss of echogenicity and cavitation emissions from ELIP insonified by duplex Doppler pulses at four PRFs (1.25, 2.5, 5 and 8.33 kHz). Loss of echogenicity was evaluated on B-mode images of ELIP. Cavitation emissions from ELIP were recorded passively on a focused single-element transducer and a linear array. Emissions recorded by the linear array were beamformed, and the spatial widths of stable and inertial cavitation emissions were compared with the calibrated azimuthal beamwidth of the Doppler pulse exceeding the stable and inertial cavitation thresholds. The inertial cavitation thresholds had a very weak dependence on PRF, and stable cavitation thresholds were independent of PRF. The spatial widths of the cavitation emissions recorded by the passive cavitation imaging system agreed with the calibrated Doppler beamwidths. The results also indicate that 64%-79% loss of echogenicity can be used to classify the presence or absence of cavitation emissions with greater than 80% accuracy.

Purpose: Acoustic droplet vaporization (ADV) of perfluorocarbon droplets with boiling points below ambient temperature shows promise for spatially and temporally targeted vascular occlusion. Vascular occlusion of a tumor or other target tissue can decrease the local heat dissipation relative to adjacent normal tissues during less directed or slow thermal therapies, such as RF or ultrasonic ablation. Also, encapsulated drugs can be released with the occluding bubbles into the target tissues. Method and Materials: In six canines, in vivo ...

ABSTRACT Acoustically induced loss of echogenicity (LOE) from ultrasound contrast agents (UCAs) has been exploited in imaging techniques to improve delineation of pathology. Determination of the type of cavitation that accompanies LOE can be experimentally difficult to determine due to the complex microbubble activity elicited. A theoretical model has been derived to predict the LOE originating from rupture of the UCA shell, from stable cavitation, or from inertial cavitation. The predictions of the model for each cavitation phenomena will be compared to recent experimental LOE measurements of the lipid-based UCA Definity® and echogenic liposomes insonified by Doppler pulses from a clinical scanner. The backscatter coefficient was calculated for a population of UCAs exposed to 6-MHz pulsed ultrasound of duration 1.67μs-8.33 μs. The change in the total backscatter coefficient was used to predict the LOE. The size distribution of UCAs was adjusted according to the specific type of cavitation triggered by the ultrasound exposure. Comparison of the theoretical predictions and experimental measurements suggest that shell rupture is the dominant mechanism for LOE for both Definity® and echogenic liposomes. These results will be discussed in conjunction with a recently developed cavitation index to predict the LOE of UCAs.