Publications by authors named "Eli Vlaisavljevich"

41 Publications

Transcostal Histotripsy Ablation in an In Vivo Acute Hepatic Porcine Model.

Cardiovasc Intervent Radiol 2021 Jul 9. Epub 2021 Jul 9.

Department of Radiology, University of Wiscosin-Madison, E3/311 CSC, 600 Highland Ave, Madison, WI, 53792, USA.

Purpose: To determine whether histotripsy can create human-scale transcostal ablations in porcine liver without causing severe thermal wall injuries along the beam path.

Materials And Methods: Histotripsy was applied to the liver using a preclinical prototype robotic system through a transcostal window in six female swine. A 3.0 cm spherical ablation zone was prescribed. Duration of treatment (75 min) was longer than a prior subcostal treatment study (24 min, 15 s) to minimize beam path heating. Animals then underwent contrast-enhanced MRI, necropsy, and histopathology. Images and tissue were analyzed for ablation zone size, shape, completeness of necrosis, and off-target effects.

Results: Ablation zones demonstrated complete necrosis with no viable tissue remaining in 6/6 animals by histopathology. Ablation zone volume was close to prescribed (13.8 ± 1.8 cm vs. prescribed 14.1 cm). Edema was noted in the body wall overlying the ablation on T2 MRI in 5/5 (one animal did not receive MRI), though there was no gross or histologic evidence of injury to the chest wall at necropsy. At gross inspection, lung discoloration in the right lower lobe was present in 5/6 animals (mean size: 1 × 2 × 4 cm) with alveolar hemorrhage, preservation of blood vessels and bronchioles, and minor injuries to pneumocytes noted at histology.

Conclusion: Transcostal hepatic histotripsy ablation appears feasible, effective, and no severe injuries were identified in an acute porcine model when prolonged cooling time is added to minimize body wall heating.
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http://dx.doi.org/10.1007/s00270-021-02914-1DOI Listing
July 2021

Immunological Effects of Histotripsy for Cancer Therapy.

Front Oncol 2021 31;11:681629. Epub 2021 May 31.

Graduate Program in Translational Biology, Medicine and Health, Virginia Tech, Roanoke, VA, United States.

Cancer is the second leading cause of death worldwide despite major advancements in diagnosis and therapy over the past century. One of the most debilitating aspects of cancer is the burden brought on by metastatic disease. Therefore, an ideal treatment protocol would address not only debulking larger primary tumors but also circulating tumor cells and distant metastases. To address this need, the use of immune modulating therapies has become a pillar in the oncology armamentarium. A therapeutic option that has recently emerged is the use of focal ablation therapies that can destroy a tumor through various physical or mechanical mechanisms and release a cellular lysate with the potential to stimulate an immune response. Histotripsy is a non-invasive, non-ionizing, non-thermal, ultrasound guided ablation technology that has shown promise over the past decade as a debulking therapy. As histotripsy therapies have developed, the full picture of the accompanying immune response has revealed a wide range of immunogenic mechanisms that include DAMP and anti-tumor mediator release, changes in local cellular immune populations, development of a systemic immune response, and therapeutic synergism with the inclusion of checkpoint inhibitor therapies. These studies also suggest that there is an immune effect from histotripsy therapies across multiple murine tumor types that may be reproducible. Overall, the effects of histotripsy on tumors show a positive effect on immunomodulation.
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http://dx.doi.org/10.3389/fonc.2021.681629DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8200675PMC
May 2021

Focused ultrasound tumour ablation in small animal oncology.

Vet Comp Oncol 2021 May 31. Epub 2021 May 31.

Animal Cancer Care and Research Center, Virginia-Maryland College of Veterinary Medicine, Roanoke, Virginia, USA.

The cancer incidence rates for humans and animals remain high, and efforts to improve cancer treatment are crucial. Cancer treatment for solid tumours includes both treatment of the primary tumour and of metastasis. Surgery is commonly employed to resect primary and metastatic tumours, but is invasive, and is not always the optimal treatment modality. Prevention and treatment of metastatic disease often utilizes a multimodal approach, but metastasis remains a major cause of death for both human and veterinary cancer patients. Focused ultrasound (FUS) tumour ablation techniques represent a novel non-invasive approach to treating cancer. FUS ablation is precise, thus sparing adjacent critical structures while ablating the tumour. FUS ablation can occur in a thermal or non-thermal fashion. Thermal FUS ablation, also known as high intensity focused ultrasound (HIFU) ablation, destroys tumour cells via heat, whereas non-thermal FUS, known as histotripsy, ablates tumour cells via mechanical disintegration of tissue. Not only can HIFU and histotripsy ablate tumours, they also demonstrate potential to upregulate the host immune system towards an anti-tumour response. The aim of this report is provide a description of HIFU and histotripsy tumour ablation, with a focus on the basic principles of their ablation mechanisms and their clinical applicability in the field of veterinary oncology.
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http://dx.doi.org/10.1111/vco.12742DOI Listing
May 2021

Histotripsy Ablation Alters the Tumor Microenvironment and Promotes Immune System Activation in a Subcutaneous Model of Pancreatic Cancer.

IEEE Trans Ultrason Ferroelectr Freq Control 2021 May 6;PP. Epub 2021 May 6.

Pancreatic cancer is a significant cause of cancer-related deaths in the United States with an abysmal 5-year overall survival rate that is under 9%. Reasons for this mortality include the lack of late-stage treatment options and the immunosuppressive tumor microenvironment. Histotripsy is an ultrasound-guided, non-invasive, non-thermal tumor ablation therapy that mechanically lyses targeted cells. To study the effects of histotripsy on pancreatic cancer, we utilized an in vitro model of pancreatic adenocarcinoma and compared the release of potential antigens following histotripsy treatment to other ablation modalities. Histotripsy was found to release immune-stimulating molecules at magnitudes similar to other non-thermal ablation modalities and superior to thermal ablation modalities, which corresponded to increased innate immune system activation in vivo. In subsequent in vivo studies, murine Pan02 tumors were grown in mice and treated with histotripsy. Flow cytometry and rtPCR were used to determine changes in the tumor microenvironment over time compared to untreated animals. In mice with pancreatic tumors, we observed significantly increased tumor-progression-free and general survival, with increased activation of the innate immune system 24 hours post-treatment and decreased tumor-associated immune cell populations within 14 days of treatment. This study demonstrates the feasibility of using histotripsy for pancreatic cancer ablation and provides mechanistic insight into the initial innate immune system activation following treatment. Further work is needed to establish the mechanisms behind the immunomodulation of the tumor microenvironment and immune effects.
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http://dx.doi.org/10.1109/TUFFC.2021.3078094DOI Listing
May 2021

Histotripsy for the Treatment of Cholangiocarcinoma Liver Tumors: In Vivo Feasibility and Ex Vivo Dosimetry Study.

IEEE Trans Ultrason Ferroelectr Freq Control 2021 Apr 15;PP. Epub 2021 Apr 15.

Histotripsy is a non-invasive, non-ionizing, and non-thermal focused ultrasound ablation method that is currently being developed for the treatment of liver cancer. Promisingly, histotripsy has been shown for ablating primary (hepatocellular carcinoma, HCC) and metastatic (colorectal liver metastasis, CLM) liver tumors in preclinical and early clinical studies. The feasibility of treating cholangiocarcinoma (CC), a less common primary liver tumor that arises from the bile ducts, has not been explored previously. Given that prior work has established that histotripsy susceptibility is based on tissue mechanical properties, there is a need to explore histotripsy as a treatment for CC due to their dense fibrotic stromal components. In this work, we first investigated the feasibility of histotripsy for ablating CC tumors in vivo in a patient-derived xenograft mouse model. The results showed that histotripsy could generate CC tumor ablation using a 1 MHz small animal histotripsy system with treatment doses of 250, 500, and 1000 pulses/point. A second set of experiments compared the histotripsy doses required to ablate CC tumors to HCC and CLM tumors ex vivo. For this, human tumor samples were harvested after surgery and treated ex vivo with a 700 kHz clinical histotripsy transducer. Results demonstrated significantly higher treatment doses were required to ablate CC and CLM tumors compared to HCC, with the highest treatment dose required for CC tumors. Overall, the results of this study suggest that histotripsy has the potential to be used for the ablation of CC tumors while also highlighting the need for tumor-specific treatment strategies.
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http://dx.doi.org/10.1109/TUFFC.2021.3073563DOI Listing
April 2021

Establishing an immunocompromised porcine model of human cancer for novel therapy development with pancreatic adenocarcinoma and irreversible electroporation.

Sci Rep 2021 Apr 7;11(1):7584. Epub 2021 Apr 7.

Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Blacksburg, VA, 24061, USA.

New therapies to treat pancreatic cancer are direly needed. However, efficacious interventions lack a strong preclinical model that can recapitulate patients' anatomy and physiology. Likewise, the availability of human primary malignant tissue for ex vivo studies is limited. These are significant limitations in the biomedical device field. We have developed RAG2/IL2RG deficient pigs using CRISPR/Cas9 as a large animal model with the novel application of cancer xenograft studies of human pancreatic adenocarcinoma. In this proof-of-concept study, these pigs were successfully generated using on-demand genetic modifications in embryos, circumventing the need for breeding and husbandry. Human Panc01 cells injected subcutaneously into the ears of RAG2/IL2RG deficient pigs demonstrated 100% engraftment with growth rates similar to those typically observed in mouse models. Histopathology revealed no immune cell infiltration and tumor morphology was highly consistent with the mouse models. The electrical properties and response to irreversible electroporation of the tumor tissue were found to be similar to excised human pancreatic cancer tumors. The ample tumor tissue produced enabled improved accuracy and modeling of the electrical properties of tumor tissue. Together, this suggests that this model will be useful and capable of bridging the gap of translating therapies from the bench to clinical application.
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http://dx.doi.org/10.1038/s41598-021-87228-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8027815PMC
April 2021

Histotripsy: the first noninvasive, non-ionizing, non-thermal ablation technique based on ultrasound.

Int J Hyperthermia 2021 ;38(1):561-575

Departments of Radiology, Biomedical Engineering, and Urology, University of Wisconsin, Madison, WI, USA.

Histotripsy is the first noninvasive, non-ionizing, and non-thermal ablation technology guided by real-time imaging. Using focused ultrasound delivered from outside the body, histotripsy mechanically destroys tissue through cavitation, rendering the target into acellular debris. The material in the histotripsy ablation zone is absorbed by the body within 1-2 months, leaving a minimal remnant scar. Histotripsy has also been shown to stimulate an immune response and induce abscopal effects in animal models, which may have positive implications for future cancer treatment. Histotripsy has been investigated for a wide range of applications in preclinical studies, including the treatment of cancer, neurological diseases, and cardiovascular diseases. Three human clinical trials have been undertaken using histotripsy for the treatment of benign prostatic hyperplasia, liver cancer, and calcified valve stenosis. This review provides a comprehensive overview of histotripsy covering the origin, mechanism, bioeffects, parameters, instruments, and the latest results on preclinical and human studies.
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http://dx.doi.org/10.1080/02656736.2021.1905189DOI Listing
July 2021

Bubble Cloud Behavior and Ablation Capacity for Histotripsy Generated from Intrinsic or Artificial Cavitation Nuclei.

Ultrasound Med Biol 2021 03 10;47(3):620-639. Epub 2020 Dec 10.

Department of Biomedical Engineering and Mechanics, Virginia Polytechnic Institute and State University, Blacksburg, Virginia, USA; ICTAS Center for Engineered Health, Virginia Polytechnic Institute and State University, Blacksburg, VA, USA.

The study described here examined the effects of cavitation nuclei characteristics on histotripsy. High-speed optical imaging was used to compare bubble cloud behavior and ablation capacity for histotripsy generated from intrinsic and artificial cavitation nuclei (gas-filled microbubbles, fluid-filled nanocones). Results showed a significant decrease in the cavitation threshold for microbubbles and nanocones compared with intrinsic-nuclei controls, with predictable and well-defined bubble clouds generated in all cases. Red blood cell experiments showed complete ablations for intrinsic and nanocone phantoms, but only partial ablation in microbubble phantoms. Results also revealed a lower rate of ablation in artificial-nuclei phantoms because of reduced bubble expansion (and corresponding decreases in stress and strain). Overall, this study demonstrates the potential of using artificial nuclei to reduce the histotripsy cavitation threshold while highlighting differences in the bubble cloud behavior and ablation capacity that need to be considered in the future development of these approaches.
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http://dx.doi.org/10.1016/j.ultrasmedbio.2020.10.020DOI Listing
March 2021

Effects of Histotripsy on Local Tumor Progression in an Orthotopic Rodent Liver Tumor Model.

BME Front 2020 25;2020. Epub 2020 Nov 25.

Department of Biomedical Engineering, University of Michigan, Ann Arbor, Michigan 48109, USA.

Objective And Impact Statement: This is the first longitudinal study investigating the effects of histotripsy on local tumor progression in an orthotopic, immunocompetent rat hepatocellular carcinoma (HCC) model.

Introduction: Histotripsy is the first noninvasive, nonionizing, nonthermal, mechanical ablation technique using ultrasound to generate acoustic cavitation to liquefy the target tissue into acellular debris with millimeter accuracy. Previously, histotripsy has demonstrated ablation of noncancerous liver tissue.

Methods: N1-S1 HCC tumors were generated in the livers of immunocompetent rats ( = 6, control; = 15, treatment). Real-time ultrasound-guided histotripsy was applied to ablate either 100% tumor volume + up to 2mm margin ( = 9, complete treatment) or 50-75% tumor volume ( = 6, partial treatment) by delivering 1-2 cycle histotripsy pulses at 100 Hz PRF (pulse repetition frequency) with - ≥30MPa using a custom 1MHz transducer. Rats were monitored weekly using MRI (magnetic resonance imaging) for 3 months or until tumors reached ~25mm.

Results: MRI revealed effective post-histotripsy reduction of tumor burden with near-complete resorption of the ablated tumor in 14/15 (93.3%) treated rats. Histopathology showed <5mm shrunken, non-tumoral, fibrous tissue at the treatment site at 3 months. Rats with increased tumor burden (3/6 control and 1 partial treatment) were euthanized early by 2-4 weeks. In 3 other controls, histology revealed fibrous tissue at original tumor site at 3 months. There was no evidence of histotripsy-induced off-target tissue injury.

Conclusion: Complete and partial histotripsy ablation resulted in effective tumor removal for 14/15 rats, with no evidence of local tumor progression or recurrence.
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http://dx.doi.org/10.34133/2020/9830304DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8318009PMC
November 2020

Modeling tissue-selective cavitation damage.

Phys Med Biol 2019 11 15;64(22):225001. Epub 2019 Nov 15.

Department of Mechanical Engineering, University of Michigan, Ann Arbor, MI, United States of America. University of Michigan Medical School, Ann Arbor, MI, United States of America.

The destructive growth and collapse of cavitation bubbles are used for therapeutic purposes in focused ultrasound procedures and can contribute to tissue damage in traumatic injuries. Histotripsy is a focused ultrasound procedure that relies on controlled cavitation to homogenize soft tissue. Experimental studies of histotripsy cavitation have shown that the extent of ablation in different tissues depends on tissue mechanical properties and waveform parameters. Variable tissue susceptibility to the large stresses, strains, and strain rates developed by cavitation bubbles has been suggested as a basis for localized liver tumor treatments that spare large vessels and bile ducts. However, field quantities developed within microns of cavitation bubbles are too localized and transient to measure in experiments. Previous numerical studies have attempted to circumvent this challenge but made limited use of realistic tissue property data. In this study, numerical simulations are used to calculate stress, strain, and strain rate fields produced by bubble oscillation under histotripsy forcing in a variety of tissues with literature-sourced viscoelastic and acoustic properties. Strain field calculations are then used to predict a theoretical damage radius using tissue ultimate strain data. Simulation results support the hypothesis that differential tissue responses could be used to design tissue-selective treatments. Results agree with studies correlating tissue ultimate fractional strain with resistance to histotripsy ablation and are also consistent with experiments demonstrating smaller lesion size under exposure to higher frequency waveforms. Methods presented in this study provide an approach for modeling tissue-selective cavitation damage in general.
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http://dx.doi.org/10.1088/1361-6560/ab5010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6925591PMC
November 2019

Development of Acoustically Active Nanocones Using the Host-Guest Interaction as a New Histotripsy Agent.

ACS Omega 2019 Feb 25;4(2):4176-4184. Epub 2019 Feb 25.

Department of Biomedical Engineering, School of Engineering and Natural Sciences, and Regenerative and Restorative Medicine Research Center (REMER), Istanbul Medipol University, Istanbul 34810, Turkey.

Histotripsy is a noninvasive and nonthermal ultrasound ablation technique, which mechanically ablates the tissues using very short, focused, high-pressured ultrasound pulses to generate dense cavitating bubble cloud. Histotripsy requires large negative pressures (≥28 MPa) to generate cavitation in the target tissue, guided by real-time ultrasound imaging guidance. The high cavitation threshold and reliance on real-time image guidance are potential limitations of histotripsy, particularly for the treatment of multifocal or metastatic cancers. To address these potential limitations, we have recently developed nanoparticle-mediated histotripsy (NMH) where perfluorocarbon (PFC)-filled nanodroplets (NDs) with the size of ∼200 nm were used as cavitation nuclei for histotripsy, as they are able to significantly lower the cavitation threshold. However, although NDs were shown to be an effective histotripsy agent, they pose several issues. Their generation requires multistep synthesis, they lack long-term stability, and determination of PFC concentration in the treatment dose is not possible. In this study, PFC-filled nanocones (NCs) were developed as a new generation of histotripsy agents to address the mentioned limitations of NDs. The developed NCs represent an inclusion complex of methylated β-cyclodextrin as a water-soluble analog of β-cyclodextrin and perfluorohexane (PFH) as more effective PFC derivatives for histotripsy. Results showed that NCs are easy to produce, biocompatible, have a size <50 nm, and have a quantitative complexation that allows us to directly calculate the PFH amount in the used NC dose. Results further demonstrated that NCs embedded into tissue-mimicking phantoms generated histotripsy cavitation "bubble clouds" at a significantly lower transducer amplitude compared to control phantoms, demonstrating the ability of NCs to function as effective histotripsy agents for NMH.
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http://dx.doi.org/10.1021/acsomega.8b02922DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6649115PMC
February 2019

Nanoparticle-mediated histotripsy (NMH) using perfluorohexane 'nanocones'.

Phys Med Biol 2019 06 20;64(12):125018. Epub 2019 Jun 20.

Department of Biomedical Engineering and Mechanics, Virginia Polytechnic Institute and State University, Blacksburg, VA, United States of America.

Nanoparticle-mediated histotripsy (NMH) is an ultrasound treatment strategy that combines acoustically sensitive nanoparticles with histotripsy. Previous NMH studies using perfluorocarbon (PFC) nanodroplets (ND's), ~200 nm in diameter, demonstrated that NMH can selectively generate cavitation by reducing the cavitation threshold from ~25-30 MPa to ~10-15 MPa. Recent studies have also shown that cavitation nucleation in NMH is directly caused by the incident negative pressure (p-) exposed to the PFC, as predicted by classical nucleation theory (CNT), suggesting that the NMH cavitation threshold is dependent on the total volume of PFC present in the focal region. In this study, we investigate the use of a newly developed NMH nanoparticle synthesized using an inclusion complex of methylated β-cyclodextrin and perfluorohexane (PFH). These 'nanocones' (NCs) have advantages compared to previously used ND's due to their smaller size (~50 nm), simple synthesis method, higher stability and information of definite PFH amount carried by the NC. To test the hypothesis that NCs can reduce the NMH cavitation threshold similar to ND's, and that the NMH cavitation threshold is dependent upon the total PFH concentration, tissue phantoms containing concentrations of NCs ranging from 10 to 10 (ml PFH/ml water) were exposed to single cycle ultrasound pulses using a 500 kHz focused transducer where high speed imaging captured cavitation data. Results showed that NCs significantly reduced the histotripsy cavitation threshold to 11.0 MPa for a concentration of 10 (ml PFH/ml water), with the threshold increasing at lower concentrations. Finally, the ability of NCs to be used for effective NMH ablation was demonstrated in tissue phantoms containing red blood cells (RBCs). Overall, the results of the study support our hypotheses that NCs can be used for effective NMH therapy and that NC concentration has a predictable threshold-reducing effect.
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http://dx.doi.org/10.1088/1361-6560/ab207eDOI Listing
June 2019

Robotically Assisted Sonic Therapy (RAST) for Noninvasive Hepatic Ablation in a Porcine Model: Mitigation of Body Wall Damage with a Modified Pulse Sequence.

Cardiovasc Intervent Radiol 2019 Jul 30;42(7):1016-1023. Epub 2019 Apr 30.

Department of Radiology, University of Wisconsin Hospital and Clinics, 600 Highland Ave, Madison, WI, 53705, USA.

Purpose: Robotically assisted sonic therapy (RAST) is a nonthermal, noninvasive ablation method based on histotripsy. Prior animal studies have demonstrated the ability to create hepatic ablation zones at the focal point of an ultrasound therapy transducer; however, these treatments resulted in thermal damage to the body wall within the path of ultrasound energy delivery. The purpose of this study was to evaluate the efficacy and safety of a pulse sequence intended to mitigate prefocal body wall injury.

Materials And Methods: Healthy swine (n = 6) underwent hepatic RAST (VortxRx software version 1.0.1.3, HistoSonics, Ann Arbor MI) in the right hepatic lobe. A 3.0 cm spherical ablation zone was prescribed for each. Following treatment, animals underwent MRI which was utilized for ablation zone measurement, evaluation of prefocal injury, and assessment of complications. Each animal was euthanized, underwent necropsy, and the tissue was processed for histopathologic analysis of the ablation zone and any other sites concerning for injury.

Results: No prefocal injury was identified by MRI or necropsy in the body wall or tissues overlying the liver. Ablation zones demonstrated uniform cell destruction, were nearly spherical (sphericity index = 0.988), and corresponded closely to the prescribed size (3.0 × 3.1 × 3.4 cm, p = 0.70, 0.36, and 0.01, respectively). Ablation zones were associated with portal vein (n = 3, one occlusive) and hepatic vein thrombosis (n = 4, one occlusive); however, bile ducts remained patent within ablation zones (n = 2).

Conclusions: Hepatic RAST performed with a modified ultrasound pulse sequence in a porcine model can mitigate prefocal body wall injuries while maintaining treatment efficacy. Further study of hepatic RAST appears warranted, particularly in tumor models.
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http://dx.doi.org/10.1007/s00270-019-02215-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7456499PMC
July 2019

For Whom the Bubble Grows: Physical Principles of Bubble Nucleation and Dynamics in Histotripsy Ultrasound Therapy.

Ultrasound Med Biol 2019 05 26;45(5):1056-1080. Epub 2019 Mar 26.

Department of Urology, University of Washington School of Medicine, Seattle, Washington, USA.

Histotripsy is a focused ultrasound therapy for non-invasive tissue ablation. Unlike thermally ablative forms of therapeutic ultrasound, histotripsy relies on the mechanical action of bubble clouds for tissue destruction. Although acoustic bubble activity is often characterized as chaotic, the short-duration histotripsy pulses produce a unique and consistent type of cavitation for tissue destruction. In this review, the action of histotripsy-induced bubbles is discussed. Sources of bubble nuclei are reviewed, and bubble activity over the course of single and multiple pulses is outlined. Recent innovations in terms of novel acoustic excitations, exogenous nuclei for targeted ablation and histotripsy-enhanced drug delivery and image guidance metrics are discussed. Finally, gaps in knowledge of the histotripsy process are highlighted, along with suggested means to expedite widespread clinical utilization of histotripsy.
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http://dx.doi.org/10.1016/j.ultrasmedbio.2018.10.035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6524960PMC
May 2019

Histotripsy for Non-Invasive Ablation of Hepatocellular Carcinoma (HCC) Tumor in a Subcutaneous Xenograft Murine Model.

Annu Int Conf IEEE Eng Med Biol Soc 2018 Jul;2018:6064-6067

Histotripsy fractionates tissue through a mechanical, non-invasive ultrasonic ablation process that precisely controls acoustic cavitation while utilizing real-time ultrasound (US) imaging guidance. This study investigates the potential, feasibility and tumor volume reduction effects of histotripsy for liver cancer ablation in a subcutaneous in vivo murine Hepatocellular Carcinoma (HCC) model. Hep3B tumors were generated in the right flanks of 14 NSG and 7 NOD-SCID mice. The mice were grouped as follows: A (acute, NSG with n=9 treatment and n=1 control), B (chronic, NSG with n=2 treatment and n=2 control) and C (chronic NODSCID, with n=6 treatment and n=1 control). Treatment was performed when the tumor diameters reached >5 mm. 1-2 cycle histotripsy pulses at 100 Hz PRF (p- >30 MPa) were delivered using a custom built 1 MHz therapy transducer attached to a motorized positioner, which scanned the transducer focus to traverse the targeted tumor volume, guided by real-time US imaging. Tumor ablation effectiveness was assessed by obtaining T1, T2 and T2* weighted MR images. Post euthanasia, treated tumor, brain, and lung tissue samples were harvested for histology. Histology of acute group A showed fractionation of targeted region with a sharp boundary separating it from untreated tissue. Groups B and C demonstrated effective tumor volume reduction post treatment on MRI as the homogenate and edema were resorbed within 23 weeks. However, as the tumor was subcutaneous, it was not possible to set adequate treatment margin and since the mice were immune-compromised, residual viable tumor cells eventually developed into tumor regrowth at 3-9 weeks after histotripsy. Groups B and C showed no signs of metastasis in the lung and brain. Our study successfully demonstrated the potential of histotripsy for non-invasive HCC ablation in a subcutaneous murine model. Additional work is ongoing to study the response of histotripsy in immune-competent orthotopic liver tumor models.
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http://dx.doi.org/10.1109/EMBC.2018.8513650DOI Listing
July 2018

Acoustic Methods for Increasing the Cavitation Initiation Pressure Threshold.

IEEE Trans Ultrason Ferroelectr Freq Control 2018 11 29;65(11):2012-2019. Epub 2018 Aug 29.

Histotripsy is a tissue ablation method that utilizes focused, high-amplitude ultrasound to generate a cavitation bubble cloud that mechanically fractionates tissue. Effective histotripsy depends on the initiation, control, and maintenance of cavitation bubble clouds in the targeted area. In this study, we hypothesized that a low-pressure acoustic pulse sequence applied before and/or during histotripsy therapy would increase the cavitation initiation pressure threshold and the growth of cavitation bubble clouds. This technique could shrink or "sharpen" the focal zone during histotripsy to produce more precise and well-defined lesions with minimal collateral damage. It may also be a way to actively protect the soft tissue from cavitation damage during lithotripsy by increasing the pressure threshold for bubble cloud initiation. We applied these low-amplitude acoustic pulse sequences before and during histotripsy treatments with the pulse repetition frequency of 1 and 100 Hz, in three different mediums: water, tissue phantom agarose gel, and bovine liver in vitro. Acoustic backscatter signals and optical imaging were used to detect and monitor the initiation, maintenance, and growth of the resulting cavitation bubble cloud. The results demonstrated that the use of low-amplitude acoustic pulse sequences could increase the cavitation pressure amplitude threshold by 20% in the targeted area.
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http://dx.doi.org/10.1109/TUFFC.2018.2867793DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6486826PMC
November 2018

Control of cellular adhesion and myofibroblastic character with sub-micrometer magnetoelastic vibrations.

J Biomech 2018 04 11;71:199-207. Epub 2018 Feb 11.

Michigan Technological University, Department of Biomedical Engineering, Houghton, MI 49931, USA. Electronic address:

The effect of sub-cellular mechanical loads on the behavior of fibroblasts was investigated using magnetoelastic (ME) materials, a type of material that produces mechanical vibrations when exposed to an external magnetic AC field. The integration of this functionality into implant surfaces could mitigate excessive fibrotic responses to many biomedical devices. By changing the profiles of the AC magnetic field, the amplitude, duration, and period of the applied vibrations was altered to understand the effect of each parameter on cell behavior. Results indicate fibroblast adhesion depends on the magnitude and total number of applied vibrations, and reductions in proliferative activity, cell spreading, and the expression of myofibroblastic markers occur in response to the vibrations induced by the ME materials. These findings suggest that the subcellular amplitude mechanical loads produced by ME materials could potentially remotely modulate myofibroblastic activity and limit undesirable fibrotic development.
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http://dx.doi.org/10.1016/j.jbiomech.2018.02.007DOI Listing
April 2018

Robotically Assisted Sonic Therapy as a Noninvasive Nonthermal Ablation Modality: Proof of Concept in a Porcine Liver Model.

Radiology 2018 05 30;287(2):485-493. Epub 2018 Jan 30.

From the Department of Radiology (A.R.S., M.M.C., T.J.Z., F.T.L.), Research Animal Resource Center (A.G.F.), Department of Statistics (C.G.), and Department of Biomedical Engineering (F.T.L.), University of Wisconsin, 600 Highland Ave, Madison, Wis 53792; Department of Biomedical Engineering and Mechanics, Virginia Polytechnic and State University, Blacksburg, Va (E.V.); and HistoSonics, Ann Arbor, Mich (E.V., J.C.).

Purpose To determine the feasibility of creating a clinically relevant hepatic ablation (ie, an ablation zone capable of treating a 2-cm liver tumor) by using robotically assisted sonic therapy (RAST), a noninvasive and nonthermal focused ultrasound therapy based on histotripsy. Materials and Methods This study was approved by the institutional animal use and care committee. Ten female pigs were treated with RAST in a single session with a prescribed 3-cm spherical treatment region and immediately underwent abdominal magnetic resonance (MR) imaging. Three pigs (acute group) were sacrificed immediately following MR imaging. Seven pigs (chronic group) were survived for approximately 4 weeks and were reimaged with MR imaging immediately before sacrifice. Animals underwent necropsy and harvesting of the liver for histologic evaluation of the ablation zone. RAST ablations were performed with a 700-kHz therapy transducer. Student t tests were performed to compare prescribed versus achieved ablation diameter, difference of sphericity from 1, and change in ablation zone volume from acute to chronic imaging. Results Ablation zones had a sphericity index of 0.99 ± 0.01 (standard deviation) (P < .001 vs sphericity index of 1). Anteroposterior and transverse dimensions were not significantly different from prescribed (3.4 ± 0.7; P = .08 and 3.2 ± 0.8; P = .29, respectively). The craniocaudal dimension was significantly larger than prescribed (3.8 ± 1.1; P = .04), likely because of respiratory motion. The central ablation zone demonstrated complete cell destruction and a zone of partial necrosis. A fibrous capsule surrounded the ablation zone by 4 weeks. On 4-week follow-up images, ablation zone volumes decreased by 64% (P < .001). Conclusion RAST is capable of producing clinically relevant ablation zones in a noninvasive manner in a porcine model. RSNA, 2018.
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http://dx.doi.org/10.1148/radiol.2018171544DOI Listing
May 2018

The response of MRI contrast parameters in in vitro tissues and tissue mimicking phantoms to fractionation by histotripsy.

Phys Med Biol 2017 Aug 18;62(17):7167-7180. Epub 2017 Aug 18.

Department of Biomedical Engineering, University of Michigan, 2200 Bonisteel Blvd. Ann Arbor, MI 48109, United States of America.

Histotripsy is a non-invasive, focused ultrasound lesioning technique that can ablate precise volumes of soft tissue using a novel mechanical fractionation mechanism. Previous research suggests that magnetic resonance imaging (MRI) may be a sensitive image-based feedback mechanism for histotripsy. However, there are insufficient data to form some unified understanding of the response of the MR contrast mechanisms in tissues to histotripsy. In this paper, we investigate the response of the MR contrast parameters R1, R2, and the apparent diffusion coefficient (ADC) to various treatment levels of histotripsy in in vitro porcine liver, kidney, muscle, and blood clot as well in formulations of bovine red blood cells suspended in agar gel. We also make a histological analysis of histotripsy lesions in porcine liver. We find that R2 and the ADC are both sensitive to ablation in all materials tested here, and the degree of response varies with tissue type. Correspondingly, under histologic analysis, the porcine liver exhibited various levels of mechanical disruption and necrotic debris that are characteristic of histotripsy. While the area of intact red blood cells and nuclei found within these lesions both decreased with increasing amounts of treatment, the area of red blood cells decreased much more rapidly than the area of intact nuclei. Additionally, the decrease in area of intact red blood cells saturated at the same treatment levels at which the response of the R2 saturated while the area of intact nuclei appeared to vary linearly with the response of the ADC.
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http://dx.doi.org/10.1088/1361-6560/aa81edDOI Listing
August 2017

Predicting Tissue Susceptibility to Mechanical Cavitation Damage in Therapeutic Ultrasound.

Ultrasound Med Biol 2017 07 10;43(7):1421-1440. Epub 2017 Apr 10.

Department of Mechanical Engineering, University of Michigan, Ann Arbor, Michigan, USA.

Histotripsy is a developing focused ultrasound procedure that uses cavitation bubbles to mechanically homogenize soft tissue. To better understand the mechanics of tissue damage, a numerical model of single-bubble dynamics was used to calculate stress, strain and strain rate fields produced by a cavitation bubble exposed to a tensile histotripsy pulse. The explosive bubble growth and its subsequent collapse were found to depend on the properties of the surrounding material and on the histotripsy pulse. Stresses far greater than gigapascals were observed close to the bubble wall, but attenuated by four to six orders of magnitude within 50 μm from the bubble wall, with at least two orders of magnitude attenuation occurring within the first 10 μm from the bubble. Elastic stresses were found to dominate close to the bubble wall, whereas viscous stresses tended to persist farther into the surroundings. A non-dimensional parameter combining tissue, waveform and bubble properties was identified that dictates the dominant stress (viscous vs. elastic) as a function of distance from the bubble nucleus. In a cycle of bubble growth and collapse, characteristic times at which mechanical damage is likely to occur and dominant mechanisms acting at each time were identified.
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http://dx.doi.org/10.1016/j.ultrasmedbio.2017.02.020DOI Listing
July 2017

Non-Invasive Liver Ablation Using Histotripsy: Preclinical Safety Study in an In Vivo Porcine Model.

Ultrasound Med Biol 2017 06 17;43(6):1237-1251. Epub 2017 Mar 17.

Department of Biomedical Engineering, University of Michigan, Ann Arbor, Michigan, USA; Department of Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, Michigan, USA.

This study investigates the safety profile for use of histotripsy, a non-invasive ultrasonic ablation method currently being developed for the treatment of liver cancer, for liver ablation in an in vivo porcine model. Histotripsy treatments were applied to the liver and hepatic veins of 22 porcine subjects, with half of the subjects receiving systemic heparinization. Vital signs (heart rate, blood pressure, temperature, electrocardiogram and SpO) were monitored throughout the procedure and for 1 h post-treatment. Blood was drawn at six points during the experiment to analyze blood gases, liver function and free hemoglobin levels. All treatments were guided and monitored by real-time ultrasound imaging. After treatment, the tissue was harvested for histological analysis. Results indicated that histotripsy generated well-defined lesions inside the liver and around the treated hepatic veins of all subjects in both treatment groups. Vital signs and blood analysis revealed that animals responded well to histotripsy, with all animals surviving the treatment. One animal in the non-heparinized group had a transient increase in pH and decreases in blood pressure, heart rate and PCO during the 15-min vessel treatment, with these changes returning to baseline levels soon after the treatment. Overall, the results indicate that histotripsy can safely be performed on the liver without the need for systemic heparinization, even in regions containing large hepatic vessels, supporting its future use for the treatment of liver cancer.
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http://dx.doi.org/10.1016/j.ultrasmedbio.2017.01.016DOI Listing
June 2017

Effects of Temperature on the Histotripsy Intrinsic Threshold for Cavitation.

IEEE Trans Ultrason Ferroelectr Freq Control 2016 08 10;63(8):1064-1077. Epub 2016 May 10.

Histotripsy is an ultrasound ablation method that depends on the initiation of a dense cavitation bubble cloud to fractionate soft tissue. Previous work has demonstrated that a cavitation cloud can be formed by a single acoustic pulse with one high amplitude negative cycle, when the negative pressure amplitude exceeds a threshold intrinsic to the medium. The intrinsic thresholds in soft tissues and tissue phantoms that are water-based are similar to the intrinsic threshold of water over an experimentally verified frequency range of 0.3-3 MHz. Previous work studying the histotripsy intrinsic threshold has been limited to experiments performed at room temperature (~20°C). In this study, we investigate the effects of temperature on the histotripsy intrinsic threshold in water, which is essential to accurately predict the intrinsic thresholds expected over the full range of in vivo therapeutic temperatures. Based on previous work studying the histotripsy intrinsic threshold and classical nucleation theory, we hypothesize that the intrinsic threshold will decrease with increasing temperature. To test this hypothesis, the intrinsic threshold in water was investigated both experimentally and theoretically. The probability of generating cavitation bubbles was measured by applying a single pulse with one high amplitude negative cycle at 1 MHz to distilled, degassed water at temperatures ranging from 10°C-90°C. Cavitation was detected and characterized by passive cavitation detection and high-speed photography, from which the probability of cavitation was measured vs. pressure amplitude. The results indicate that the intrinsic threshold (the negative pressure at which the cavitation probability=0.5) significantly decreases with increasing temperature, showing a nearly linear decreasing trend from 29.8±0.4 MPa at 10˚C to 14.9±1.4 MPa at 90˚C. Overall, the results of this study support our hypothesis that the intrinsic threshold is highly dependent upon the temperature of the medium, which may allow for better predictions of cavitation generation at body temperature in vivo and at the elevated temperatures commonly seen in high intensity focused ultrasound (HIFU) regimes.
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http://dx.doi.org/10.1109/TUFFC.2016.2565612DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5770247PMC
August 2016

Effects of f-number on the histotripsy intrinsic threshold and cavitation bubble cloud behavior.

Phys Med Biol 2017 02 20;62(4):1269-1290. Epub 2016 Dec 20.

Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, USA.

Histotripsy is an ultrasound ablation method that depends on the initiation of a cavitation bubble cloud to fractionate soft tissue. Although previous work has provided significant insight into the process of intrinsic threshold histotripsy, the majority of these studies have used highly focused (i.e. f-number  <  0.6) transducers. In this study, we investigate the effects of f-number on the histotripsy intrinsic threshold and cavitation bubble cloud behavior using a 500 kHz array transducer, with the effective f-number of the transducer varied from 0.51 to 0.89. The intrinsic threshold did not significantly change with f-number, with the threshold remaining ~27-30 MPa for all conditions. The predictability of intrinsic threshold histotripsy was further demonstrated by experiments comparing the predicted and experimentally measured bubble cloud dimensions, with results showing close agreement for all f-numbers. Finally, the effects of f-number on 'bubble density' and tissue fractionation efficiency were investigated, with results supporting the hypothesis that the density of the bubbles within the bubble cloud significantly decreases at higher f-numbers, resulting in decreased fractionation efficiency. Overall, this study provides significant insight into the effects of f-number on intrinsic threshold histotripsy that will help to guide the development of histotripsy for specific clinical applications.
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http://dx.doi.org/10.1088/1361-6560/aa54c7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5453715PMC
February 2017

Noninvasive Ablation of Prostate Cancer Spheroids Using Acoustically-Activated Nanodroplets.

Mol Pharm 2016 12 14;13(12):4054-4065. Epub 2016 Nov 14.

Department of Biomedical Engineering, University of Michigan , Ann Arbor, Michigan 48109, United States.

We have developed acoustically activated nanodroplets (NDs) using an amphiphilic triblock copolymer, which self-assembles and encapsulates different perfluorocarbons including perfluoropentane (PFP) and perfluorohexane (PFH). Applying histotripsy pulses (i.e., short, high pressure, ultrasound pulses) to solutions of PFP- and PFH-NDs generated bubble clouds at a significantly reduced acoustic pressure compared to the cavitation pressure observed for histotripsy treatment alone. In this report, we summarize the results of combining histotripsy at low frequency (345 and 500 kHz) with PFP-NDs and PFH-NDs on the ablation of PC-3 and C4-2B prostate cancer cells. Using custom built histotripsy transducers coupled to a microscope and a high speed recording camera, we imaged the generation of a cavitation bubble cloud in response to different ultrasound regimes in solution and in tissue-mimicking gel phantoms. We quantified the associated ablation of individual cancer cells and 3D spheroids suspended in solution and embedded in tissue phantoms to compare the ablative capacity of PFP-NDs and PFH-NDs. Results show that histotripsy pulses at high acoustic pressure (26.2 MPa) ablated 80% of prostate cancer spheroids embedded in tissue-mimicking gel phantoms. In comparison, combining histotripsy pulses at a dramatically lower acoustic pressure (12.8 MPa) with PFP-NDs and PFH-NDs caused an ablation of 40% and 80% of the tumor spheroid volumes, respectively. These results show the potential of acoustically activated NDs as an image-guided ablative therapy for solid tumors and highlight the higher ablative capacity of PFH-NDs, which correlates with the boiling point of the encapsulated PFH and the stability of the formed bubble cloud.
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http://dx.doi.org/10.1021/acs.molpharmaceut.6b00617DOI Listing
December 2016

Visualizing the Histotripsy Process: Bubble Cloud-Cancer Cell Interactions in a Tissue-Mimicking Environment.

Ultrasound Med Biol 2016 10 9;42(10):2466-77. Epub 2016 Jul 9.

Department of Biomedical Engineering, University of Michigan, Ann Arbor, Michigan, USA; Department of Pediatrics and Communicable Diseases, Division of Pediatric Cardiology, University of Michigan, Ann Arbor, Michigan, USA.

Histotripsy is a non-invasive ultrasonic ablation method that uses cavitation to mechanically fractionate tissue into acellular debris. With a sufficient number of pulses, histotripsy can completely fractionate tissue into a liquid-appearing homogenate with no cellular structures. The location, shape and size of lesion formation closely match those of the cavitation cloud. Previous work has led to the hypothesis that the rapid expansion and collapse of histotripsy bubbles fractionate tissue by inducing large stress and strain on the tissue structures immediately adjacent to the bubbles. In the work described here, the histotripsy bulk tissue fractionation process is visualized at the cellular level for the first time using a custom-built 2-MHz transducer incorporated into a microscope stage. A layer of breast cancer cells were cultured within an optically transparent fibrin-based gel phantom to mimic cells inside a 3-D extracellular matrix. To test the hypothesis, the cellular response to single and multiple histotripsy pulses was investigated using high-speed optical imaging. Bubbles were always generated in the extracellular space, and significant cell displacement/deformation was observed for cells directly adjacent to the bubble during both bubble expansion and collapse. The largest displacements were observed during collapse for cells immediately adjacent to the bubble, with cells moving more than 150-300 μm in less than 100 μs. Cells often underwent multiple large deformations (>150% strain) over multiple pulses, resulting in the bisection of cells multiple times before complete removal. To provide theoretical support to the experimental observations, a numerical simulation was conducted using a single-bubble model, which indicated that histotripsy exerts the largest strains and cell displacements in the regions immediately adjacent to the bubble. The experimental and simulation results support our hypothesis, which helps to explain the formation of the sharp lesions formed in histotripsy therapy localized to the regions directly exposed to the bubbles.
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http://dx.doi.org/10.1016/j.ultrasmedbio.2016.05.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5010997PMC
October 2016

Non-Invasive Ultrasound Liver Ablation Using Histotripsy: Chronic Study in an In Vivo Rodent Model.

Ultrasound Med Biol 2016 08 29;42(8):1890-902. Epub 2016 Apr 29.

Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, USA; Department of Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, MI, USA.

Hepatocellular carcinoma, or liver cancer, has the fastest growing incidence among cancers in the United States. Current liver ablation methods are thermal-based and share limitations due to the heat sink effect from the blood flow through the highly vascular liver. Recently, our group has investigated histotripsy as a non-invasive liver cancer ablation method. Histotripsy is a non-thermal ultrasonic ablation method that fractionates tissue through the control of acoustic cavitation. Previous experiments in an in vivo porcine model show that histotripsy can create well-confined lesions in the liver through ribcage obstruction without damaging the overlying ribs and other tissues. Histotripsy can also completely fractionate liver tissue surrounding major vessels while preserving the vessels. In this study, we investigate the long-term effects of histotripsy liver ablation in a rodent model. We hypothesize that the fractionated histotripsy lesion will be resorbed by the liver, resulting in effective tissue healing. To test this hypothesis, the livers of 20 healthy rats were treated with histotripsy using an 8-element 1-MHz histotripsy transducer. Rats were euthanized after 0, 3, 7, 14 and 28 days (n = 4). In vivo and post mortem results showed histotripsy lesions were successfully generated through the intact abdomen in all 20 rats. Magnetic resonance imaging found primarily negative contrast on day 0, positive contrast on day 3 and rapid normalization of signal intensity thereafter (i.e., signal amplitude returned to baseline levels seen in healthy liver tissue). Histologically, lesions were completely fractionated into an acellular homogenate. The lesions had a maximum cross-sectional area of 17.2 ± 1.9 mm(2) and sharp boundaries between the lesion and the healthy surrounding tissue after treatment. As the animals recovered after treatment, the histotripsy tissue homogenate was almost completely replaced by regenerated liver parenchyma, resulting in a small fibrous lesion (<1 mm(2) maximum cross-section) remaining after 28 d. The results of this study suggest that histotripsy has potential as a non-invasive liver ablation method for effective tissue removal.
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http://dx.doi.org/10.1016/j.ultrasmedbio.2016.03.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4912895PMC
August 2016

Effects of Droplet Composition on Nanodroplet-Mediated Histotripsy.

Ultrasound Med Biol 2016 Apr 14;42(4):931-46. Epub 2016 Jan 14.

Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, USA; Macromolecular Science and Engineering Program, University of Michigan, Ann Arbor, MI, USA. Electronic address:

Nanodroplet-mediated histotripsy (NMH) is a targeted ablation technique combining histotripsy with nanodroplets that can be selectively delivered to tumor cells. In two previous studies, polymer-encapsulated perfluoropentane nanodroplets were used to generate well-defined ablation similar to that obtained with histotripsy, but at significantly lower pressure, when NMH therapy was applied at a pulse repetition frequency (PRF) of 10 Hz. However, cavitation was not maintained over multiple pulses when ultrasound was applied at a lower PRF (i.e., 1-5 Hz). We hypothesized that nanodroplets with a higher-boiling-point perfluorocarbon core would provide sustainable cavitation nuclei, allowing cavitation to be maintained over multiple pulses, even at low PRF, which is needed for efficient and complete tissue fractionation via histotripsy. To test this hypothesis, we investigated the effects of droplet composition on NMH therapy by applying histotripsy at various frequencies (345 kHz, 500 kHz, 1.5 MHz, 3 MHz) to tissue phantoms containing perfluoropentane (PFP, boiling point ∼29°C, surface tension ∼9.5 mN/m) and perfluorohexane (PFH, boiling point ∼56°C, surface tension ∼11.9 mN/m) nanodroplets. First, the effects of droplet composition on the NMH cavitation threshold were investigated, with results revealing a significant decrease (>10 MPa) in the peak negative pressure (p-) cavitation threshold for both types of nanodroplets compared with controls. A slight decrease (∼1-3 MPa) in threshold was observed for PFP phantoms compared with PFH phantoms. Next, the ability of nanodroplets to function as sustainable cavitation nuclei over multiple pulses was investigated, with results revealing that PFH nanodroplets were sustainable cavitation nuclei over 1,000 pulses, whereas PFP nanodroplets were destroyed during the first few pulses (<50 pulses), likely because of the lower boiling point. Finally, tissue phantoms containing a layer of embedded red blood cells were used to compare the damage generated for NMH treatments using PFP and PFH droplets, with results indicating that PFH nanodroplets significantly improved NMH ablation, allowing for well-defined lesions to be generated at all frequencies and PRFs tested. Overall, the results of this study provide significant insight into the role of droplet composition in NMH therapy and provide a rational basis to tailor droplet parameters to improve NMH tissue fractionation.
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http://dx.doi.org/10.1016/j.ultrasmedbio.2015.11.027DOI Listing
April 2016

The role of positive and negative pressure on cavitation nucleation in nanodroplet-mediated histotripsy.

Phys Med Biol 2016 Jan 30;61(2):663-82. Epub 2015 Dec 30.

Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI 48109, USA.

Nanodroplet-mediated histotripsy (NMH) is an ultrasound ablation technique combining histotripsy with acoustically sensitive perfluorocarbon (PFC) nanodroplets that can be selectively delivered to tumor cells for targeted tumor ablation. NMH takes advantage of the significantly reduced cavitation threshold of the nanodroplets, allowing for cavitation to be selectively generated only in regions containing nanodroplets. Understanding the physical mechanisms underlying the nanodroplet cavitation process is essential to the development of NMH. In this study, we hypothesize that cavitation nucleation is caused by the negative pressure (p-) exposed to the PFC, and the NMH cavitation threshold is therefore determined by the incident p-  of the single-cycle pulses commonly used in NMH. This paper reports the first study that separately investigates the effects of negative and positive pressure on the NMH cavitation threshold using near half-cycle ultrasound pulses with dominant negative (negative-polarity pulses) or positive (positive-polarity pulses) pressure phases. Tissue phantoms containing perfluorohexane (PFH) nanodroplets were exposed to negative-polarity and positive-polarity pulses generated by a frequency compounding transducer recently developed in our lab, and the probability of generating cavitation was measured as a function of peak negative (p-) and peak positive (p+) pressure. The results showed close agreement in the p- cavitation threshold for PFH phantoms exposed to negative-polarity (11.4 ± 0.1 MPa) and positive-polarity (11.7 ± 0.2 MPa) pulses. The p+ at the cavitation threshold, in contrast, was measured to be sign ficantly different for the negative-polarity (4.0 ± 0.1 MPa) and positive-polarity (42.6 ± 0.2 MPa) pulses. In the final part of this study, the experimental results were compared to the cavitation threshold predicted by classical nucleation theory (CNT), with results showing close agreement between simulations and experiments. Overall, the results support our hypothesis and provide significant insight into the physical mechanisms underlying NMH.
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http://dx.doi.org/10.1088/0031-9155/61/2/663DOI Listing
January 2016

Noninvasive thrombolysis using microtripsy: a parameter study.

IEEE Trans Ultrason Ferroelectr Freq Control 2015 Dec;62(12):2092-105

Histotripsy fractionates soft tissue by well-controlled acoustic cavitation using microsecond-long, high-intensity ultrasound pulses. The feasibility of using histotripsy as a noninvasive, drug-free, and image-guided thrombolysis method has been shown previously. A new histotripsy approach, termed microtripsy, has recently been investigated for the thrombolysis application to improve treatment accuracy and avoid potential vessel damage. In this study, we investigated the effects of pulse repetition frequency (PRF) on microtripsy thrombolysis. Microtripsy thrombolysis treatments using different PRFs (5, 50, and 100 Hz) and doses (20, 50, and 100 pulses) were performed on blood clots in an in vitro vessel flow model. To quantitatively evaluate the microtripsy thrombolysis effect, the location of focal cavitation, the incident rate of pre-focal cavitation on the vessel wall, the size and location of the resulting flow channel, and the generated clot debris particles were measured. The results demonstrated that focal cavitation was always well confined in the vessel lumen without contacting the vessel wall for all PRFs. Pre-focal cavitation on the front vessel wall was never observed at 5Hz PRF, but occasionally observed at PRFs of 50 Hz (1.2%) and 100 Hz (5.4%). However, the observed pre-focal cavitation was weak and did not significantly affect the focal cavitation. Results further demonstrated that, although the extent of clot fractionation per pulse was the highest at 5 Hz PRF at the beginning of treatment (<20 pulses), 100 Hz PRF generated the largest flow channels with a much shorter treatment time. Finally, results showed fewer large debris particles were generated at a higher PRF. Overall, the results of this study suggest that a higher PRF (50 or 100 Hz) may be a better choice for microtripsy thrombolysis to use clinically due to the larger resulting flow channel, shorter treatment time, and smaller debris particles.
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http://dx.doi.org/10.1109/TUFFC.2015.007268DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4824290PMC
December 2015

Effects of Thermal Preconditioning on Tissue Susceptibility to Histotripsy.

Ultrasound Med Biol 2015 Nov 28;41(11):2938-54. Epub 2015 Aug 28.

Department of Biomedical Engineering, University of Michigan, Ann Arbor, Michigan, USA.

Histotripsy is a non-invasive ablation method that mechanically fractionates tissue by controlling acoustic cavitation. Previous work has revealed that tissue mechanical properties play a significant role in the histotripsy process, with stiffer tissues being more resistant to histotripsy-induced tissue damage. In this study, we propose a thermal pretreatment strategy to precondition tissues before histotripsy. We hypothesize that a thermal pretreatment can be used to alter tissue stiffness by modulating collagen composition, thus changing tissue susceptibility to histotripsy. More specifically, we hypothesize that tissues will soften and become more susceptible to histotripsy when preheated at ∼60°C because of collagen denaturation, but that tissues will rapidly stiffen and become less susceptible to histotripsy when preheated at ∼90°C because of collagen contraction. To test this hypothesis, a controlled temperature water bath was used to heat various ex vivo bovine tissues (tongue, artery, liver, kidney medulla, tendon and urethra). After heating, the Young's modulus of each tissue sample was measured using a tissue elastometer, and changes in tissue composition (i.e., collagen structure/density) were analyzed histologically. The susceptibility of tissues to histotripsy was investigated by treating the samples using a 750-kHz histotripsy transducer. Results revealed a decrease in stiffness and an increase in susceptibility to histotripsy for tissues (except urethra) preheated to 58°C. In contrast, preheating to 90°C increased tissue stiffness and reduced susceptibility to histotripsy for all tissues except tendon, which was significantly softened due to collagen hydrolysis into gelatin. On the basis of these results, a final set of experiments were conducted to determine the feasibility of using high-intensity focused ultrasound to provide the thermal pretreatment. Overall, the results of this study indicate the initial feasibility of a thermal pretreatment strategy to precondition tissue mechanical properties and alter tissue susceptibility to histotripsy. Future work will aim to optimize this thermal pretreatment strategy to determine if this approach is practical for specific clinical applications in vivo without causing unwanted damage to surrounding or overlying tissue.
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http://dx.doi.org/10.1016/j.ultrasmedbio.2015.07.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4648696PMC
November 2015
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