Jonathan J. Macoskey

Bubble-Induced Color Doppler Feedback Correlates with Histotripsy-Induced Destruction of Structural Components in Liver Tissue

Bubble-induced color Doppler (BCD) is a histotripsy-therapy monitoring technique that uses Doppler ultrasound to track the motion of residual cavitation nuclei that persist after the collapse of the histotripsy bubble cloud. In this study, BCD is used to monitor tissue fractionation during histotripsy tissue therapy, and the BCD signal is correlated with the destruction of structural and non-structural components identified histologically to further understand how BCD monitors the extent of treatment. A 500-kHz, 112-element phased histotripsy array is used to generate approximately 6- × 6- × 7-mm lesions within ex vivo bovine liver tissue by scanning more than 219 locations with 30-1000 pulses per location. A 128-element L7-4 imaging probe is used to acquire BCD signals during all treatments. The BCD signal is then quantitatively analyzed using the time-to-peak rebound velocity (tprv) metric. Using the Pearson correlation coefficient, the tprv is compared with histologic analytics of lesions generated by various numbers of pulses using a significance level of 0.001. Histologic analytics in this study include viable cell count, reticulin-stained type III collagen area and trichrome-stained type I collagen area. It is found that the tprv metric has a statistically significant correlation with the change in reticulin-stained type III collagen area with a Pearson correlation coefficient of -0.94 (p <0.001), indicating that changes in BCD are more likely because of destruction of the structural components of tissue.

Real-time acoustic-based feedback for histotripsy therapy

Histotripsy uses high-pressure microsecond ultrasound pulses to generate cavitation to fractionate cells in target tissues. Two acoustic-based feedback mechanisms are being investigated to monitor histotripsy therapy in real-time. First, bubble-induced color Doppler (BICD) is received by an ultrasound probe co-aligned with the histotripsy transducer to monitor the cavitation-induced motion of residual cavitation nuclei in tissue throughout treatment. Second, acoustic backscatter of the histotripsy pulse from the cavitation bubbles is received by directly probing elements of histotripsy transducer to monitor acoustic emissions from the cavitation bubbles during treatment. In these experiments, histotripsy was applied to agarose phantoms and ex vivo tissue by a 112-element, 500 kHz semi-hemispherical ultrasound array with a 15 cm focal distance. The BICD signals were collected on a Verasonics system by an L7-4 probe. The BICD and backscatter signals were compared to high-speed optical images of cavitation i...

Integrated Histotripsy and Bubble Coalescence Transducer for Thrombolysis

After the collapse of a cavitation bubble cloud, residual microbubbles can persist for up to seconds and function as weak cavitation nuclei for subsequent pulses in a phenomenon known as cavitation memory effect. In histotripsy, the cavitation memory effect can cause bubble clouds to repeatedly form at the same discrete set of sites. This effect limits the efficacy of histotripsy-based tissue fractionation. Our previous studies have indicated that low-amplitude bubble-coalescing (BC) ultrasound sequences interleaved with high-amplitude histotripsy pulses can coalesce the residual bubbles into one large bubble quickly. This reduces the cavitation memory effect and may increase treatment efficacy. Histotripsy has been investigated for thrombolysis by breaking up clots into debris smaller than red blood cells. However, this treatment has low efficacy for aged or retracted clots. In this study, we investigate the use of histotripsy with BC to improve the efficacy of treatment of retracted clots. An integrated histotripsy and bubble-coalescing (HBC) transducer system with specialized electronic driving system was built in-house. One high-amplitude (32 MPa), one-cycle histotripsy pulse followed by 36 low-amplitude (2.4 MPa), one-cycle BC pulses formed one HBC sequence. Results indicate that HBC sequences successfully generated a flow channel through the retracted clots at scan speeds of 0.2-0.5 mm/s. The channel size created using the HBC sequence was 128% to 480% larger than that created using histotripsy alone. The clot debris particles generated during HBC treatments were within the tolerable range. These results illustrate the concept that BC improves the treatment efficacy of histotripsy thrombolysis for retracted clots.

Using the cavitation collapse time to indicate the extent of histotripsy-induced tissue fractionation

Histotripsy is an ultrasonic tissue ablation method based on acoustic cavitation. It has been shown that cavitation dynamics change depending on the mechanical properties of the host medium. During histotripsy treatment, the target-tissue is gradually fractionated and eventually liquefied to acellular homogenate. In this study, the change in the collapse time (t col) of the cavitation bubble cloud over the course of histotripsy treatment is investigated as an indicator for progression of the tissue fractionation process throughout treatment. A 500 kHz histotripsy transducer is used to generate single-location lesions within tissue-mimicking agar phantoms of varying stiffness levels as well as ex vivo bovine liver samples. Cavitation collapse signals are acquired with broadband hydrophones, and cavitation is imaged optically using a high-speed camera in transparent tissue-mimicking phantoms. The high-speed-camera-acquired measurements of t col validate the acoustic hydrophone measurements. Increases in t col are observed both with decreasing phantom stiffness and throughout histotripsy treatment with increasing number of pulses applied. The increasing trend of t col throughout the histotripsy treatment correlates well with the progression of lesion formation generated in tissue-mimicking phantoms (R 2  =  0.87). Finally, the increasing trend of t col over the histotripsy treatment is validated in ex vivo bovine liver.

Acoustic cavitation emission feedback to monitor tissue fractionation during histotripsy therapy

Histotripsy uses high-pressure, microsecond-long ultrasound pulses to generate a cloud of cavitation to fractionate cells in target tissues such as tumors, blood clots and brain applications. B-mode ultrasound has been used to detect the cavitation and tissue fractionation generated by histotripsy, but it requires a separate imaging probe and can only detect substantial amounts of tissue fractionation. In this study, a specialized circuit and digitizer was designed to allow all the elements of a 112-element array to transmit extremely high-pressure (>40MPa) histotripsy pulses and receive the low-pressure Acoustic Cavitation Emission (ACE) signals. ACE feedback can be achieved via the histotripsy array itself and may have a high sensitivity to detect tissue fractionation.

Investigation of the source of histotripsy acoustic backscatter signals

Recent work has demonstrated that acoustic backscatter signals from histotripsy-generated bubble clouds may be used to localize generated bubble clouds and perform non-invasive aberration correction transcranially. However, the primary source of the measured signals, whether from emissions generated during bubble expansion, or scattering of the incoming pulses off of the incipient bubble clouds, remains to be determined and may have important implications for how the acquired signals may be used. Here, we present results from experiments comparing the acoustic emissions and growth-collapse curves of single bubbles generated optically to those generated via histotripsy. Histotripsy bubbles were generated using a 32-element, 1.5 MHz spherical transducer with pulse durations <2-cycles; optical bubbles were nucleated using a pulsed Nd:YAG laser focused at the center of the histotripsy transducer. Optical imaging was used to capture the time evolution of the generated bubbles from inception to collapse. Acoust...

Transcranial histotripsy acoustic-backscatter localization and aberration correction for volume treatments

Here, we present results from experiments using histotripsy pulses backscattered off of therapy-generated bubble clouds to perform point-by-point aberration correction and bubble cloud localization transcranially over large steering ranges to demonstrate the efficacy of these methods at improving treatment efficiency and mapping volumetric treatments. Histotripsy pulses were delivered through an ex vivo human skullcap mounted centrally within a 500 kHz, 256-element histotripsy transducer with transmit-receive capable elements. Electronic focal steering was used to steer the therapy focus through individual points spanning a 30 mm diameter volume centered about the transducers geometric focus. Backscatter signals from the generated bubble clouds were collected using array elements as receivers. Separate algorithms, based on time-domain information extracted from the collected signals, were used to perform aberration correction and localize the generated bubble clouds, respectively. The effectiveness of th...

Histotripsy pulse-reflection for 3D image forming and bubble cloud localization in transcranial applications

Here, we present results from experiments using histotripsy pulses scattered off the surface of the skull, as well as bubble clouds generated within, to reconstruct 3D images of the exterior skull surface and localize bubbles within. These capabilities have the potential to provide image coregistration and real-time ultrasound monitoring for transcranial histotripsy treatment, without the need for MRI guidance. Histotripsy pulses were delivered to an ex vivo human skullcap mounted centrally within a 500 kHz, 256-element histotripsy transducer with transmit-receive capable elements. Straight-line ray tracing approximations based on the times-of-flight of the emitted pulses and the known geometry of the array were used to calculate points on the skull surface and to localize bubble clouds generated within. Using these methods, we were able to accurately locate and orient the skull within the array and generate a 3D map of its surface for coregistration with an a priori 3D scan. The points calculated based o...