Using Low-Intensity Focused Ultrasound To Open The Blood–Brain Barrier

A conversation with Davinder Ramsingh, MD, Chief Medical Officer, Openwater

Low-intensity focused ultrasound is a noninvasive neuromodulation that’s showing promise as a treatment option for neurological diseases. And its promise could even tackle a difficult challenge facing drug developers.

We caught up with Davinder Ramsingh, MD, chief medical officer of Openwater, to talk about the potential of using low-intensity focused ultrasound (LIFU) to open the blood–brain barrier.

The blood–brain barrier remains one of the biggest challenges in developing therapies for neurological diseases. Why has it proven so difficult to overcome, and what research is Openwater doing in that area?

It comes down to the fact that the blood–brain barrier (BBB) is incredibly good at its job. It is, essentially, a tightly sealed layer of cells that acts as the brain’s ultimate security system to protect the central nervous system (CNS) from toxins and pathogens. However, it creates a massive headache for CNS drug development. The BBB is highly selective and is often cited as blocking over 98% of small molecule drugs and nearly all large molecule therapeutics, like modern antibodies and gene therapies, from reaching the brain. Because of this natural bottleneck, many neurological diseases like Alzheimer’s and brain cancers remain difficult to treat, in part because therapeutics may not penetrate the brain in high enough concentrations to be effective.

At Openwater, we are developing Open-LIFU, our portable, noninvasive low-intensity focused ultrasound platform that delivers acoustic energy to targets within the brain and body. We are actively evaluating its potential application to BBB modulation, including ongoing preclinical work using BBB organoid models. More broadly, focused ultrasound combined with microbubbles has been shown in clinical studies to safely and reversibly open the BBB and enhance drug delivery.

The broader research in this area is encouraging. One preclinical study using a mouse model of breast cancer brain metastases found that pairing LIFU with combination chemotherapy significantly extended survival and slowed tumor progression compared to chemotherapy alone. Focused ultrasound increased blood–tumor barrier permeability, supporting the potential for temporary barrier opening to improve therapeutic delivery and treatment outcomes.

That said, opening the barrier is only useful if it can be done safely and predictably, which is where the field is headed next. A multidisciplinary review of strategies for improving drug delivery across the BBB in CNS tumor patients highlighted LIFU as a standout among emerging technologies for its ability to temporarily and safely increase barrier permeability with no surgery required.

There is growing interest in using LIFU to temporarily open the blood–brain barrier. How does this approach work, and what makes it different from other drug delivery strategies?

The mechanics of the LIFU approach are quite fascinating. It combines highly targeted sound waves with microscopic gas-filled bubbles that are injected intravenously into the bloodstream and circulate through brain capillaries, where they act as mechanical amplifiers for the ultrasound. When we direct the ultrasound at a specific area of the brain, the sound waves cause these microbubbles to oscillate, creating mechanical effects on the vessel wall that transiently increase BBB permeability in that region.

What sets LIFU apart from other drug delivery methods is its precision and reversibility. Instead of relying solely on systemic drug exposure or requiring invasive brain procedures, the ultrasound waves create microscopic temporary doorways in the barrier that safely resolve and close on their own within minutes to hours. We can concentrate the effect so only a precise region of the brain opens enough to deliver the therapy, while localizing the effect to the targeted region and minimizing exposure to surrounding tissue. This supports the potential for repeated use in chronic diseases, with early clinical studies demonstrating the feasibility of repeated BBB opening.

What recent advances have been most significant in demonstrating the potential of LIFU-enabled blood–brain barrier modulation?

We’ve seen some compelling data emerge across both oncology and neurodegenerative diseases. Recent clinical studies have demonstrated that focused ultrasound, when paired with intravenously administered microbubbles, can transiently open the BBB in patients with brain tumors and can be repeated over time. Particularly important for drug developers, a study in recurrent glioblastoma showed that ultrasound-mediated BBB opening increased local brain concentrations of systematically administered therapies.

In Alzheimer’s disease, focused ultrasound BBB opening is especially exciting because it may enhance the effects of anti-amyloid therapy. In a first-in-human proof-of-concept study, combining focused ultrasound BBB opening with aducanumab produced greater amyloid reduction in ultrasound-treated regions than in untreated regions. While these findings require validation in larger studies, this remains one of the most compelling areas in the field.

Which therapeutic areas or drug classes do you believe could benefit most from improved delivery across the blood–brain barrier?

The most immediate therapeutic areas are neuro-oncology, such as recurrent glioblastoma and CNS lymphoma, and major neurodegenerative diseases like Alzheimer’s and Parkinson’s. From a pharmaceutical perspective, transiently modulating the BBB could profoundly benefit the CNS drug pipeline. That could create new opportunities to deliver large and complex therapeutics, particularly antibodies, gene therapies, and nanoparticles whose CNS applications may currently be limited by inadequate brain penetration.

What impact could blood–brain barrier modulation have on the future of drug development for neurological disorders?

It has the potential to revitalize the development of CNS drugs. Many promising therapies may have underperformed or failed in part because they couldn’t achieve adequate exposure in the brain. By safely and reproducibly opening the barrier, BBB modulation could allow us to revisit selected therapies and design future CNS trials with regional BBB permeability as a measurement treatment variable alongside drug-specific pharmacokinetic and pharmacodynamic assessments.

Practically speaking, more affordable portable platforms could allow pharmaceutical companies to more easily build focused ultrasound delivery directly into their trials, potentially at substantially lower infrastructure cost. Ultimately, the goal is to move these treatments out of highly specialized hospital centers and into routine outpatient clinics, democratizing access to highly targeted, noninvasive neurological care for patients everywhere.

About The Expert

Davinder (Dave) Ramsingh, MD, is chief medical officer at Openwater. A UCLA-trained cardiac anesthesiologist, he has more than 20 years of experience in ultrasound and sensor technologies. His work focuses on the clinical translation of non-invasive therapeutic and monitoring technologies, including low-intensity focused ultrasound. Before joining Openwater, he held clinical and medical affairs leadership roles at companies developing ultrasound and critical care monitoring technologies.