Versatile Tiny Bubbles Hold Promise Throughout the Body

Editor's Note: This is the second story in a five-part series about clinical research at the University of Nebraska Medical Center. To learn more what clinical research is and the role it plays at UNMC, read the introduction to this series.

OMAHA - In the hands of Dr. Tom Porter, miniscule bubbles smaller than red blood cells can make the heart beat normally again, test blood flow to that organ, break up blood clots and deliver drug treatments with microscopic precision.

They're called microbubbles, and they're versatile little things. Just four or five millionths of a meter in size, they can carry drugs inside or on their surface. When doctors intentionally break them inside a patient's body with ultrasound waves, their tiny explosions can shear off bits of clots blocking arteries. Not only are they effective, but every application of them is easier on the patient than the standard treatment they may one day replace.

The microbubbles are being used in two human clinical trials at the University of Nebraska Medical Center right now: terminating heart-rhythm disturbances and breaking up clots in renal dialysis grafts. The first use could reduce the need for electric shocks to pace the heart, and the second use could fix a complication patients experience when undergoing kidney hemodialysis.

The bubbles are a protein shell with a gas inside. They first contained air, but Porter and his team determined they'd hold up better filled with denser gases like fluorocarbons. UNMC makes its own bubbles with ultrasound waves.

"Ironically, it's ultrasound that creates the bubbles and that destroys them," Porter said.

This destruction seems to be able to act like a pacemaker to restore normal heart rhythms. There are many different abnormal heart rhythms, which can be dangerous. Some traditional ways of treating abnormal heart rhythms are external shocks and internal pacemaker devices. Patients must be sedated to receive external shocks, while inserting a pacemaker requires surgery. Microbubbles can be injected like medication, and manipulated with harmless ultrasound waves like the ones used to view a developing fetus inside a pregnant woman.

"In essence, it's simplifying the process and making it safer for the patient," Porter said.

Small waves are created when ultrasound makes microbubbles expand and then suddenly collapse. These waves seem to be able to pace the heart into normal rhythm, Porter has found. The waves also can erode the surface of a blood clot in an artery, such as one leading to the heart. One of the traditional ways to deal with arterial blood clots is by inserting a ballon into the artery and inflating it. But this technique can damage the artery, leading to the formation of scar tissue that can just exacerbate the blockage.

If this balloon insertion procedure, called balloon angioplasty, has already occurred, microbubbles can prevent additional blockage from developing. They can carry a special gene therapy to the precise problem area of the artery and at that spot, and only that spot, block a protein that can cause further narrowing of the artery.

"If we give a gene … we only want it to work in one area of the body," Porter said.

Clots can also be troublesome in patients undergoing hemodialysis. In this procedure, a person's blood is filtered through an external machine, instead of by the kidneys. A common way to extract the blood and then reinfuse it is through an arterial-venous graft. In a surgical procedure on the arm, doctors graft together an artery, which takes blood out to the body from the heart, and a vein, which returns blood to the heart. So blood flows into the artery, out into the dialysis machine, and then back into the vein.

Sometimes this graft between the artery and vein can get blocked with a blood clot. That can mean another surgery to create another graft elsewhere on the arm. Because these grafts take a long time to heal before they can be used for hemodialysis, it's more than just a little inconvenient to get a graft clot.

Enter the microbubbles again. Porter has a Phase I clinical trial going to determine whether they can break up clots so patients can continue using the same graft, and don't need more surgery to create a new one. He'll have to overcome some challenges to make this work; one of them is preventing small pieces of clot from traveling into smaller blood vessels and blocking them, which would create new and potentially more serious problems.

Microbubbles' ability to deliver drugs to specific locations could greatly improve chemotherapy for cancer. Chemotherapy drugs are powerful poisons used to kill cancer cells. But they must be used with extreme caution because they're toxic to healthy cells, too. Spilling one kind of chemotherapy on bare skin while trying to inject it into the body, for example, can eat away the skin. But if these poisons were contained inside microbubbles and released only when they reached the tumor, side effects from chemotherapy could be reduced.

Working closely with this cutting-edge research for three years has been Porter's assistant David Kricsfeld, who will take an already bulging resume with him when he starts medical school next month.

"A lot of investigators, when we go to these national meetings … they're amazed at how we have all these applications of microbubbles going on at once," Kricsfeld said.

What makes this possible is Porter's drive and intelligence, Kricsfeld said.

"Who would have thought that this may help break up blood clots, or help deliver drugs?" he said.

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This story originally appeared in Nebraska StatePaper on July 24, 2001.