Researchers from the University of Maryland School of Medicine (UMSOM) , Brigham and Women's Hospital in Boston, and other North American institutions, have provided the first technical description for using focused ultrasound to reliably open the blood-brain barrier. The findings, recently published in Device , pave the way for expanding the use of this experimental device to open the blood-brain barrier to improve treatments and diagnostics for patients with brain tumors and other neurological disorders.
Physicians, scientists, and engineers, led by Graeme Woodworth, MD, Professor and Chair of Neurosurgery at UMSOM and Director of the Brain Tumor Treatment and Research Program at the University of Maryland Marlene and Stewart Greenebaum Comprehensive Cancer Center (UMGCCC) , collected data from 34 glioblastoma patients, each receiving up to six monthly treatment cycles involving a total of 972 individual focused ultrasound sonications to determine the most effective use of focused ultrasound to achieve reliable blood-brain barrier opening. They found that echoing soundwaves, captured as acoustic emissions signals generated by circulating microbubbles, are a reliable measurement to predict blood-brain barrier opening in patients. The methods and analyses described in the study will allow researchers and clinicians to monitor, compare, and prescribe blood-brain barrier opening treatments across different devices, patients, and settings in the future, helping to facilitate and localize drug delivery in the brain.
"Given the expanding availability of multiple ultrasonic energy delivery devices, varying treatment parameters, and differing real-time monitoring and control approaches, a significant, unmet need exists for defining and standardizing blood-brain barrier opening treatments with focused ultrasound," said Dr. Woodworth. "Acoustic emissions monitoring and acoustic emissions-derived dosing regimens offer an opportunity for a unifying concept in focused ultrasound. The data and analysis provided in this study serve to advance this methodological paradigm and the focused ultrasound field."
The blood-brain barrier is a specialized network of vascular and brain cells that acts as the brain's security system to protect against invasion by dangerous toxins and microbes. But it also decreases the effectiveness of treatments in the brain, like chemotherapy drugs. To open the blood-brain barrier using focused ultrasound, microscopic inert gas-filled bubbles are injected into the patient's bloodstream and activated by ultrasound energy in the targeted area, all while being monitored by an MRI to determine effectiveness.
"Upon excitation under low-intensity ultrasound waves, the microbubbles oscillate within the energy field, causing temporary mechanical perturbations in the walls of the brain blood vessels," said Pavlos Anastasiadis, PhD , an Assistant Professor of Neurosurgery at UMSOM and co-author of this study.
"Our study builds on seminal work that began back in the 1990s in the Focused Ultrasound Lab at Brigham and Women's Hospital when microbubbles were first used to open the blood-brain barrier," said senior author Alexandra J. Golby, MD, Director of Image-Guided Neurosurgery at Brigham and Women's Hospital. "Our work builds upon these discoveries, finding a safe and feasible technique that allows us to repeatedly open the blood-brain barrier in patients with glioblastoma prior to chemotherapy."
The data in this study were collected from a subset of glioblastoma patients enrolled in a clinical trial led by Dr. Woodworth where focused ultrasound was used to open the blood-brain barrier to deliver standard-of-care chemotherapy. The researchers are planning to publish their findings on this new trial in the near future.
"Dr. Woodworth and his team continue to lead the way in focused ultrasound research as a treatment method in patients with glioblastoma, and other brain cancers," said Taofeek K. Owonikoko, MD, PhD, Executive Director of UMGCCC. "This work provides the first detailed technical descriptions of acoustic emissions dosing in targeted focused ultrasound and will inform clinical and regulatory advancement of this treatment."
Currently, a larger diagnostics-focused pivotal focused ultrasound trial is underway in glioblastoma patients called LIBERATE ( NCT05383872 ) co-led by Dr. Woodworth in partnership with ReFOCUSED (The Research Consortium for Transcranial Focused Ultrasound-Enhanced Drug Delivery & Diagnostics). ReFOCUSED is a growing group of researchers from over 20 sites across North America whose goal is to use the new opportunities offered by MRI-guided focused ultrasound to improve the clinical outcomes of brain diseases.
This study was funded by the device manufacturer, Insightec Inc. (Miami, FL) and the Focused Ultrasound Foundation.
