Browsing by Author "Simon, Alex"

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    Ablative and Immunostimulatory Effects of Histotripsy Ablation in a Murine Osteosarcoma Model
    Hay, Alayna N.; Imran, Khan Mohammad; Hendricks-Wenger, Alissa; Gannon, Jessica M.; Sereno, Jacqueline; Simon, Alex; Lopez, Victor A.; Coutermarsh-Ott, Sheryl; Vlaisavljevich, Eli; Allen, Irving C.; Tuohy, Joanne L. (MDPI, 2023-10-09)
    Background: Osteosarcoma (OS) is the most frequently occurring malignant bone tumor in humans, primarily affecting children and adolescents. Significant advancements in treatment options for OS have not occurred in the last several decades, and the prognosis remains grim with only a 70% rate of 5-year survival. The objective of this study was to investigate the focused ultrasound technique of histotripsy as a novel, noninvasive treatment option for OS. Methods: We utilized a heterotopic OS murine model to establish the feasibility of ablating OS tumors with histotripsy in a preclinical setting. We investigated the local immune response within the tumor microenvironment (TME) via immune cell phenotyping and gene expression analysis. Findings: We established the feasibility of ablating heterotopic OS tumors with ablation characterized microscopically by loss of cellular architecture in targeted regions of tumors. We observed greater populations of macrophages and dendritic cells within treated tumors and the upregulation of immune activating genes 72 h after histotripsy ablation. Interpretation: This study was the first to investigate histotripsy ablation for OS in a preclinical murine model, with results suggesting local immunomodulation within the TME. Our results support the continued investigation of histotripsy as a novel noninvasive treatment option for OS patients to improve clinical outcomes and patient prognosis.
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    Focused ultrasound for the remote modulation of nitric oxide release from injectable PEG-fibrinogen hydrogels for tendon repair
    Meyers, Kaylee M.; Simon, Alex; Khan, Zerin M.; Rajachar, Rupak M.; Vlaisavljevich, Eli (Frontiers, 2023-04)
    Introduction: Tendon disorders such as tendinosis, the degradation of collagen in tendon, or tendonitis, inflammation of tendon tissue, contribute to 30% of musculoskeletal complaints. To address the limitations of currently available treatments for tendon repair, an injectable polyethylene glycol (PEG)fibrinogen hydrogel encompassing nitric oxide (NO) releasing mu-particles was generated. The release of nitric oxide, a therapeutic molecule that modulates many wound healing processes, from the hydrogel can be modified with thermal and mechanical stimulus. To achieve remote control over NO release from hydrogels after deployment, focused ultrasound (FUS) was explored as it provides highly controlled thermal and mechanical stimulus non-invasively. Methods: In this work, the ability of FUS to remotely elicit on-demand NO generation from acoustically active composite hydrogels via thermal and/or mechanical stimulus was explored. Specifically, the temperature and timedependent release of NO was simulated and characterized when applying FUS to composite hydrogels. Results: Results from acoustic simulations as well as thermocouple heating studies indicated that high spatial and temporal control over hydrogel warming could be achieved non-invasively with a 3.5 MHz FUS transducer. FUS was also able to remotely control NO release from hydrogels with various thermal magnitudes and durations. Additionally, no apparent changes in the mechanical properties of hydrogels were observed with FUS treatment. Discussion: Utilizing FUS thermal and mechanical stimulus provides a potential method of remotely controlling NO release from hydrogels at a wound site to aid in tendon repair.
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    Histotripsy Ablation in Preclinical Animal Models of Cancer and Spontaneous Tumors in Veterinary Patients: A Review
    Hendricks-Wenger, Alissa; Arnold, Lauren; Gannon, Jessica; Simon, Alex; Singh, Neha; Sheppard, Hannah; Nagai-Singer, Margaret A.; Imran, Khan Mohammed; Lee, Kiho; Clark-Deener, Sherrie; Byron, Christopher R.; Edwards, Michael R.; Larson, Martha M.; Rossmeisl, John H. Jr.; Coutermarsh-Ott, Sheryl; Eden, Kristin; Dervisis, Nikolaos G.; Klahn, Shawna L.; Tuohy, Joanne L.; Allen, Irving C.; Vlaisavljevich, Eli (IEEE, 2021-09-03)
    New therapeutic strategies are direly needed in the fight against cancer. Over the last decade, several tumor ablation strategies have emerged as stand-alone or combination therapies. Histotripsy is the first completely noninvasive, nonthermal, and nonionizing tumor ablation method. Histotripsy can produce consistent and rapid ablations, even near critical structures. Additional benefits include real-time image guidance, high precision, and the ability to treat tumors of any predetermined size and shape. Unfortunately, the lack of clinically and physiologically relevant preclinical cancer models is often a significant limitation with all focal tumor ablation strategies. The majority of studies testing histotripsy for cancer treatment have focused on small animal models, which have been critical in moving this field forward and will continue to be essential for providing mechanistic insight. While these small animal models have notable translational value, there are significant limitations in terms of scale and anatomical relevance. To address these limitations, a diverse range of large animal models and spontaneous tumor studies in veterinary patients have emerged to complement existing rodent models. These models and veterinary patients are excellent at providing realistic avenues for developing and testing histotripsy devices and techniques designed for future use in human patients. Here, we provide a review of animal models used in preclinical histotripsy studies and compare histotripsy ablation in these models using a series of original case reports across a broad spectrum of preclinical animal models and spontaneous tumors in veterinary patients.
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    Histotripsy for the Treatment of Cholangiocarcinoma Liver Tumors: In Vivo Feasibility and Ex Vivo Dosimetry Study
    Hendricks-Wenger, Alissa; Weber, Peter; Simon, Alex; Saunier, Sofie; Coutermarsh-Ott, Sheryl; Grider, Douglas; Vidal-Jove, Joan; Allen, Irving C.; Luyimbazi, David; Vlaisavljevich, Eli (IEEE, 2021-09-01)
    Histotripsy is a noninvasive, nonionizing, and nonthermal 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 its 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. The 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 that 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.