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Simple Summary: Glioblastoma (GBM) is a common primary brain tumor with a short median overall survival despite aggressive treatment with resection, chemotherapy, and radiation therapy. Focused ultrasound (FUS) represents a promising new therapeutic approach for treatment of GBM. Unlike imaging forms of ultrasound, FUS can successfully penetrate the skull surrounding the brain, allowing for non-invasive ablation of tumor tissue. FUS can also temporarily disrupt the blood–brain barrier, a microvascular network that prohibits diffusion of most therapeutic agents, allowing chemotherapeutic drugs to penetrate the tumor. Other modalities are under investigation and include means of stimulating the immune system and sensitizing tumors to radiation therapy. The feasibility and safety of transcranial FUS has been illustrated in animal models and clinical trials. Precise results can be obtained under guidance from magnetic resonance imaging, limiting side effects. Successful outcomes from clinical trials will likely continue to motivate investigation and innovation of FUS technology for GBM. Glioblastoma (GBM) is an aggressive primary astrocytoma associated with short overall survival. Treatment for GBM primarily consists of maximal safe surgical resection, radiation therapy, and chemotherapy using temozolomide. Nonetheless, recurrence and tumor progression is the norm, driven by tumor stem cell activity and a high mutational burden. Focused ultrasound (FUS) has shown promising results in preclinical and clinical trials for treatment of GBM and has received regulatory approval for the treatment of other neoplasms. Here, we review the range of applications for FUS in the treatment of GBM, which depend on parameters, including frequency, power, pulse duration, and duty cycle. Low-intensity FUS can be used to transiently open the blood–brain barrier (BBB), which restricts diffusion of most macromolecules and therapeutic agents into the brain. Under guidance from magnetic resonance imaging, the BBB can be targeted in a precise location to permit diffusion of molecules only at the vicinity of the tumor, preventing side effects to healthy tissue. BBB opening can also be used to improve detection of cell-free tumor DNA with liquid biopsies, allowing non-invasive diagnosis and identification of molecular mutations. High-intensity FUS can cause tumor ablation via a hyperthermic effect. Additionally, FUS can stimulate immunological attack of tumor cells, can activate sonosensitizers to exert cytotoxic effects on tumor tissue, and can sensitize tumors to radiation therapy. Finally, another mechanism under investigation, known as histotripsy, produces tumor ablation via acoustic cavitation rather than thermal effects. [ABSTRACT FROM AUTHOR]

• An ultrasound-guided, focused ultrasound prototype was developed and validated. • The therapeutic transducer (1.5 MHz) consisted of three 8-mm circular elements. • Elements were placed on a 9 × 32mm curved rectangular aperture: 45 mm radius curvature. • Functionality was examined on tissue-mimicking phantoms. • 2.5 × 1.2 × 6.5 mm and 3.4 × 3.25 × 9.36 mm lesions were seen for 10 and 30 s sonification. To improve patient outcomes (eg, reducing blood loss and infection), practitioners have gravitated toward noninvasive and minimally invasive surgeries (MIS), which demand specialized toolkits. Focused ultrasound, for example, facilitates thermal ablation from a distance, thereby reducing injury to surrounding tissue. Focused ultrasound can often be performed noninvasively; however, it is more difficult to carry out in neuro-oncological tumors, as ultrasound is dramatically attenuated while propagating through the skull. This shortcoming has prompted exploration of MIS options for intracranial placement of focused ultrasound probes, such as within the BrainPath™ (NICO Corporation, Indianapolis, IN). Herein, we present the design, development, and in vitro testing of an image-guided, focused ultrasound prototype designed for use in MIS procedures. This probe can ablate neuro-oncological lesions despite its small size. Preliminary prototypes were iteratively designed, built, and tested. The final prototype consisted of three 8-mm-diameter therapeutic elements guided by an imaging probe. Probe functionality was validated on a series of tissue-mimicking phantoms. Lesions were created in tissue-mimicking phantoms with average dimensions of 2.5 × 1.2 × 6.5 mm and 3.4 × 3.25 × 9.36 mm after 10- and 30-second sonification, respectively. 30 s sonification with 118 W power at 50% duty cycle generated a peak temperature of 68 °C. Each ablation was visualized in real time by the built-in imaging probe. We developed and validated an ultrasound-guided focused ultrasound probe for use in MIS procedures. The dimensional constraints of the prototype were designed to reflect those of BrainPath trocars, which are MIS tools used to create atraumatic access to deep-seated brain pathologies. [ABSTRACT FROM AUTHOR]