Corporate and academic R&D target stroke with ultrasound

Philips is working with contrast agent developer ImaRx to find information that might turn diagnostic ultrasound scanners into weapons against acute ischemic stroke, the companies announced early this month. Research at Oregon Health & Science University may complement Philips' collaboration, providing information to use against a disease with annual medical costs approaching $63 billion.

Every year three million in the U.S. suffer strokes. About 87% of these strokes are ischemic, according to the American Stroke Association, caused by blood clots that obstruct normal blood flow in the brain. Fewer than 6% of stroke victims receive tPA, the only drug approved by the FDA for acute ischemic stroke. Microbubble therapies promise a new means for delivering tPA or for busting up clots themselves.

The collaboration between Philips and ImaRx will make use of Philips' portfolio of scanners and engineers, fine-tuning parameters to produce the best therapeutic outcome possible with the SonoLysis approach from ImaRx.

"We are trying to optimize the parameters in our equipment to use their proprietary technology and to develop treatment paradigms together," said Prahlad Singh, senior director of strategic planning and business development for Philips ultrasound.

ImaRx is testing the approach in a phase I/II study, evaluating the microbubbles and ultrasound for the treatment of acute ischemic stroke. Less than a micron in diameter, the lipid-shelled microbubbles have the potential to infiltrate a blood clot like a microscopic army that, when agitated by ultrasound, can burst the clot from the inside out. The microbubbles may also be able to transport and release tPA in the clot.

The collaboration with Philips is intended to develop a more detailed understanding of the interaction of ultrasound and the MRX-801 microbubble technology. Philips is providing the equipment and expertise that ImaRx will use during laboratory and preclinical studies of the agent.

OHSU investigators are similarly looking at fundamental issues, but they are not focused on just one brand of ultrasound or contrast agent. Dr. Sanjiv Kaul, chief of cardiovascular medicine, and colleagues plan to look at a number of microbubble and ultrasound technologies, including their own.

They will do so in a novel way. Using grant money from the M.J. Murdock Charitable Trust, Kaul and colleagues are custom building a high-definition optical camera that will capture nanosecond changes as microbubbles are pelted by ultrasound. The camera will focus specifically on the compression and relaxation phases that cause these bubbles to explode.

"This might allow us to modify the bubbles or ultrasound to achieve a kind of a maximal bang for the buck," Kaul said.

The research team will look specifically at the interaction between microbubbles and blood clots both in vitro and in vivo.

"No one knows how microbubbles cause thrombus dissolution," he said. "While there are many theories, no one has ever observed the real effect. Once we know the real mechanism, we can amplify it."

They will also investigate what happens when ultrasound bursts microbubbles carrying drugs or genes, which then get dispersed into the surrounding tissue. Determining how this happens may provide important information about the localized microcirculation and endothelium, Kaul said.

The details that emerge from these studies may help Kaul and colleagues develop technologies specifically tuned to certain medical tasks, such as treating ischemic stroke. Early work will require no more expertise than OHSU already has at hand. But corporate collaboration eventually will be needed.

"It is a design issue, and we can design microbubbles in small batches," he said. "But for commercial and clinical applications, we will need to get a company involved."