Shake, But No Bake: New Ultrasound Technique Enhances Drug Delivery Without Cooking the Clots in Stroke Victims

Christy K. Holland, PhD- Christy.holland@uc.edu
Department of Biomedical Engineering, Colleges of Engineering and Medicine
University of Cincinnati
Cincinnati, Ohio 45221

Sauraubh Datta, MS
Sampada S. Vaidya, MBBS
George J. Shaw, MD, PhD
Department of Biomedical Engineering, Colleges of Engineering and Medicine, University of Cincinnati, Cincinnati, Ohio 45221

Jason M. Meunier, PhD
Department of Emergency Medicine, College of Medicine, University of Cincinnati, Cincinnati, Ohio 45221

Constantin-C. Coussios, PhD (Cantab)
Department of Engineering Science, University of Oxford, Oxford, UK OX1 2JD

Popular version of paper 1aBB5
Presented Tuesday morning, November 28, 2006
4th ASA/ASJ Joint Meeting, Honolulu, HI

Recombinant tissue plasminogen activator (rt-PA) is the only scientifically proven and FDA-approved treatment for acute ischemic stroke. Unfortunately, this drug can also cause bleeding in the brain. Improved effectiveness or greater safety would provide a powerful impetus for physicians to administer rt-PA to a larger portion of the patients with ischemic stroke. Our research is offering hope that ultrasound will assist rt-PA speed the restoration of blood flow and minimize the risk of bleeding in the brain in the early stages of stroke.

How could the outcomes for acute ischemic stroke victims be improved? Quality outcomes would improve if the medication efficacy could be increased or if the risk of side effects could be decreased. A therapy that could lower the administered dose of rt-PA or that could increase its efficacy would represent a significant breakthrough.

Recent studies undertaken at the University of Cincinnati have shown that dramatic enhancement of (rt-PA) thrombolysis can be achieved with ultrasound, suggesting its use to complement rt-PA stroke therapy. Viewing through a microscope, we measured the lysis of a human blood clot. In the videos below, the clot on the left was treated with rt-PA alone. The clot in the video on the right was treated with rt-PA and 120-kHz pulsed ultrasound.

Ultrasound treatment significantly enhanced the average rate of clot dissolution. Faster lysis would lead to faster recanalization times and potentially a more successful stroke therapy. Studies of the mechanisms of the enhancement have revealed the formation of tiny gently pulsating bubbles (stable cavitation) as playing an important role in the enhancement of the drug. The stable cavitation bubbles near the surface may act as micropumps to help rt-PA penetrate the clot surface and to facilitate the removal of fibrin degradation products away from the clot, not unlike a stirring mechanism.

More importantly, the enhancement due to stable cavitation inside the clot may be due to the mechanical effects of oscillating microbubbles near the fibrin mesh. The role of ultrasound heating the clot has been ruled out as a contributing mechanism to the enhanced thrombolysis.

Our observed correlation with stable cavitation suggests that bubble activity is important for enhanced thrombolysis.

Some helpful definitions.
Ultrasound refers to vibrations or sound waves whose frequencies are above the range of human hearing.
• Sound wave frequency is measured in Hertz, where 1 Hz = 1 cycle/second.
• Ultrasound refers to those waves with frequencies above 20,000 Hz (or 20 kHz).
• Although humans cannot hear ultrasound waves, bats can hear and emit in the ultrasound frequency range.
Thrombolysis is the destroying or breaking up of a blood clot within a blood vessel.
An ischemic stroke is one caused by blood clots or other obstruction in the blood vessels of the brain.
Stable cavitation is gently pulsating microscopic bubbles.
Recanalization is the process of restoring flow to an artery.
Fibrin is a fibrous protein that forms the scaffold of a blood clot.