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Published On May 10, 2019

TECHNOLOGY

Riding a Wave of Sound

One way to get drugs through the blood-brain barrier: smuggle them across using sound waves.

The blood-brain barrier, a name given to the tightly packed vascular cells in the brain’s capillaries, keeps the central nervous system remarkably free of most pathogens. But that defense is a major challenge for delivering drugs that treat brain disorders. One reason glioblastoma, an aggressive brain cancer, is so lethal is that treatments can’t get across the barrier to reach tumors.

A growing number of researchers see promise in focused ultrasound (FUS), a technique that uses sound waves to cause a targeted breach. During the past year, the first trials of FUS for patients with Alzheimer’s disease have taken place, with encouraging results that suggest the technology may be safe and technically feasible for other hard-to-treat brain diseases, as well.

Sounds in the ultrasound range have a frequency higher than 20kHz, which is the limit of most human hearing. In the 1930s and 1940s, researchers realized that these quickly oscillating waves could be focused on a fixed point to create an intense heat, a discovery that was first tested therapeutically in 1954 as a non-surgical alternative to lobotomies. The technology was tested by directing sound waves into the brain.

The idea of using focused ultrasound to breach the blood-brain barrier has been around for decades, but the challenge has been to keep the disruption temporary and not cause permanent damage. Some investigations have looked at a powerful form of FUS, high-frequency focused ultrasound (HiFU), which can burn away cells and is currently used to destroy tumors and reduce painful bone metastases from cancer. 

A study on rabbits published in 2001 led the way to a new method of using lower-frequency focused ultrasound, guided by MRI, to temporarily open the capillary walls. It was the first nondestructive approach to opening the blood-brain barrier, and laid the groundwork for new experimental ways to help targeted chemotherapies, beneficial viruses, stem cells and nanoparticles get past the barrier to the brain, though studies to date have been almost exclusively in animals.

Medications are first encased in a gas-filled microbubble, made of lipids or polymers and about the size of a red blood cell, then injected into the bloodstream. Energy from focused ultrasound beams "vibrates" or "oscillates" the microbubbles, causing the gas inside to expand and contract with the wave pulses. That makes the whole bubble pulse. “As the bubble goes through a capillary, it will push and pull on the surrounding blood vessel wall,” says biomedical engineer Richard Price, of the University of Virginia in Charlottesville, who uses FUS in animal models of Parkinson’s disease. That ultrasound-driven pushing and pulling actually physically loosens the tight junctions between the cells and allows the therapeutic particles to squeeze through the gaps.

Early results from human trials look promising. Last year, researchers at Sunnybrook Health Sciences Centre in Toronto completed a phase 1 clinical trial testing the safety of combining focused ultrasound with microbubbles to treat Alzheimer’s disease.

Trial participants, in the early stages of the disease, wore helmets with more than 1,000 ultrasound transducers. An MRI pinpointed a target where the sound waves would meet and vibrate the microbubble, which contained no medication in this phase of the trial. Patients received the treatments twice in a spot on their brains’ right frontal lobes, which had low activity.

“We chose that part of the brain because we wanted to show that focused ultrasound would be safe,” says neurosurgeon Nir Lipsman, who led the study. But patients had no complications, and in every case the blood-brain barrier completely sealed itself within 24 hours. Encouraged by those findings, Lipsman has moved on to a phase 2 study, which will involve targeting a larger number of brain regions to open the blood-brain barrier, while another study on Alzheimer’s is also underway in France. A third small trial began recruiting subjects in New York, West Virginia and Ohio last September.

Lipsman also recently launched a phase 2 clinical trial on patients with glioblastoma. After undergoing surgery, chemotherapy and radiation, the patients will receive FUS designed to help deliver maintenance doses of chemotherapy get to affected areas of the brain. This follows a 2018 trial on glioblastoma at the University of Maryland, the first in the United States.

Price at the University of Virginia also sees potential in combining FUS with gene therapy, using bioengineered nanoparticles to carry new genes past the blood-brain barrier to cellular pathways in the brains of people with Parkinson’s disease. “Gene therapy could block the degeneration of those pathways,” Price says.

Price’s research team has used gene therapy in combination with focused ultrasound successfully in rats, but he doesn’t know whether it will work in people. That’s a question also facing some other uses of focused ultrasound. But the past two years have seen a dramatic uptick in proposed uses and clinical trials for FUS and a growing number of manufacturers now make FUS devices, according to neurosurgeon Neal Kassell, chairman of the Focused Ultrasound Foundation, a research organization in Charlottesville. “We know we can open the blood-brain barrier for Alzheimer's, Parkinson's and brain tumors,” Kassell says. “We’re just at the beginning of a long path to widespread use of this technology, but the initial steps have been really encouraging.”