Pharmacological treatment of gliomas and other brain-infiltrating tumors remains challenging due to limited delivery of most therapeutics across the blood–brain barrier (BBB). Transcranial MRI-guided focused ultrasound (FUS), an emerging technology for noninvasive brain treatments, enables transient opening of the BBB through acoustic activation of circulating microbubbles. Here, we evaluate the safety and utility of transcranial microbubble-enhanced FUS (MB-FUS) for spatially targeted BBB opening in patients with infiltrating gliomas. In this Phase 0 clinical trial (NCT03322813), we conducted comparative and quantitative analyses of FUS exposures (sonications) and their effects on gliomas using MRI, histopathology, microbubble acoustic emissions (harmonic dose [HD]), and fluorescence-guided surgery metrics. Contrast-enhanced MRI and histopathology indicated safe and reproducible BBB opening in all patients. These observations occurred using a power cycling closed feedback loop controller, with the power varying by nearly an order of magnitude on average. This range underscores the need for monitoring and titrating the exposure on a patient-by-patient basis. We found a positive correlation between microbubble acoustic emissions (HD) and MR-evident BBB opening (P = 0.07) and associated interstitial changes (P < 0.01), demonstrating the unique capability to titrate the MB-FUS effects in gliomas. Importantly, we identified a 2.2-fold increase of fluorescein accumulation in MB-FUS–treated compared to untreated nonenhancing tumor tissues (P < 0.01) while accounting for vascular density. Collectively, this study demonstrates the capabilities of MB-FUS for safe, localized, controlled BBB opening and highlights the potential of this technology to improve the surgical and pharmacologic treatment of brain tumors. Significance The blood–brain barrier (BBB) is a critical obstacle to delivering most therapeutics into the brain. In this study, we report combined MRI, histological, and real-time acoustic emissions monitoring findings from a Phase 0 clinical trial examining microbubble-enhanced transcranial focused ultrasound for controlled BBB opening in patients with infiltrating gliomas. The data revealed the capability of this technology to provide safe, controlled, and tightly monitored BBB opening through the intact skull. Our findings demonstrate the capability of this technology to tune BBB opening in real-time, creating opportunities for improved treatment of brain tumors.

Infiltrating gliomas are challenging to treat, as the blood-brain barrier significantly impedes the success of therapeutic interventions. While some clinical trials for high-grade gliomas have shown promise, patient outcomes remain poor. Microbubble-enhanced focused ultrasound (MB-FUS) is a rapidly evolving technology with demonstrated safety and efficacy in opening the blood-brain barrier across various disease models, including infiltrating gliomas. Initially recognized for its role in augmenting drug delivery, the potential of MB-FUS to augment liquid biopsy and immunotherapy is gaining research momentum. In this review, we will highlight recent advancements in preclinical and clinical studies that utilize focused ultrasound to treat gliomas and discuss the potential future uses of image-guided precision therapy using focused ultrasound.

High-frequency focused ultrasound has emerged as a powerful modality for both biomedical imaging and elastography. It is gaining more attention due to its capability to outperform many other imaging modalities at a submicron resolution. Besides imaging, high-frequency ultrasound or acoustic biomicroscopy has been used in a wide range of applications to assess the elastic and mechanical properties at the tissue and single cell level. The interest in acoustic microscopy stems from the awareness of the relationship between biomechanical and the underlying biochemical processes in cells and the vast impact these interactions have on the onset and progression of disease. Furthermore, ultrasound biomicroscopy is characterized by its non-invasive and non-destructive approach. This, in turn, allows for spatiotemporal studies of dynamic processes without the employment of histochemistry that can compromise the integrity of the samples. Numerous techniques have been developed in the field of acoustic microscopy. This review paper discusses high-frequency ultrasound theory and applications for both imaging and elastography.

The clinical applications of transcranial focused ultrasound continue to expand and include ablation as well as drug delivery applications in the brain, where treatments are typically guided by MRI. Although MRI-guided focused ultrasound systems are also preferred for many preclinical investigations, they are expensive to purchase and operate, and require the presence of a nearby imaging center. For many basic mechanistic studies, however, MRI is not required. The purpose of this study was to design, construct, characterize and evaluate a portable, custom, laser-guided focused ultrasound system for noninvasive, transcranial treatments in small rodents. The system comprised an off-the-shelf focused ultrasound transducer and amplifier, with a custom cone fabricated for direct coupling of the transducer to the head region. A laser-guidance apparatus was constructed with a 3D stage for accurate positioning to 1 mm. Pressure field simulations were performed to demonstrate the effects of the coupling cone and the sealing membrane, as well as for determining the location of the focus and acoustic transmission across rat skulls over a range of sizes. Hydrophone measurements and exposures in hydrogels were used to assess the accuracy of the simulations. In vivo treatments were performed in rodents for opening the blood–brain barrier and to assess the performance and accuracy of the system. The effects of varying the acoustic pressure, microbubble dose and animal size were evaluated in terms of efficacy and safety of the treatments. The simulation results were validated by the hydrophone measurements and exposures in the hydrogels. The in vivo treatments demonstrated the ability of the system to open the blood–brain barrier. A higher acoustic pressure was required in larger-sized animals, as predicted by the simulations and transmission measurements. In a particular sized animal, the degree of blood–brain barrier opening, and the safety of the treatments were directly associated with the microbubble dose. The focused ultrasound system that was developed was found to be a cost-effective alternative to MRI-guided systems as an investigational device that is capable of accurately providing noninvasive, transcranial treatments in rodents.

Objective: The goal of this work was to develop a novel modular focused ultrasound hyperthermia (FUS-HT) system for preclinical applications with the following characteristics: MR-compatible, compact probe for integration into a PET/MR small animal scanner, 3D-beam steering capabilities, high resolution focusing for generation of spatially confined FUS-HT effects. Methods: For 3D-beam steering capabilities, a matrix array approach with 11 × 11 elements was chosen. For reaching the required level of integration, the array was mounted with a conductive backing directly on the interconnection PCB. The array is driven by a modified version of our 128 channel ultrasound research platform DiPhAS. The system was characterized using sound field measurements and validated using tissue-mimicking phantoms. Preliminary MR-compatibility tests were performed using a 7T Bruker MRI scanner. Results: Four 11 × 11 arrays between 0.5 and 2 MHz were developed and characterized with respect to sound field properties and HT generation. Focus sizes between 1 and 4 mm were reached depending on depth and frequency. We showed heating by 4 °C within 60 s in phantoms. The integration concept allows a probe thickness of less than 12 mm. Conclusion: We demonstrated FUS-HT capabilities of our modular system based on matrix arrays and a 128 channel electronics system within a 3D-steering range of up to ±30°. The suitability for integration into a small animal MR could be demonstrated in basic MR-compatibility tests. Significance: The developed system presents a new generation of FUS-HT for preclinical and translational work providing safe, reversible, localized, and controlled HT.