Mechanical Damage from Cavitation in High Intensity Focused Ultrasound Accelerated Thrombolysis

Stroke is the fourth most common cause of death in the United States (second worldwide), with about 87% of these being ischemic. Recent studies, in vitro and in vivo, have shown that High Intensity Focused Ultrasound (HIFU) accelerates thrombolysis, the dissolution of blood clots, for ischemic stroke. Although the mechanisms are not fully understood, cavitation is thought to play an important role in sonothrombolysis. Acoustic cavitation is typically divided into two categories describing the bubble behavior: stable cavitation describes bubbles undergoing smooth oscillations, while inertial cavitation is characterized by rapid growth followed by violent collapses. Possible mechanisms associated with both stable cavitation (i.e. microstreaming) and inertial cavitation (i.e. microjets) are thought to increase clot lysis by enhancing the delivery of a thrombolytic agent./nThe damage to a blood clot's fibrin fiber network from bubble collapses in a HIFU field is studied. The bubble dynamical model used is the Keller-Miksis equation with a linear Kelvin-Voigt viscoelastic material to account for the clot material outside the bubble. The amount of damage to the fiber network caused by a single bubble collapse is estimated by/ntwo independent approaches. The first method is based on the stretch of individual fibrin fibers of the blood clot, and estimates the number of broken fibers as a bubble embedded in the blood clot grows to its maximum radius. This method estimates that fibrin fibers (the structural matrix of the blood clot) break as the bubble expands, however the bubble dynamical model does not account for this. To account for the breaking of fibrin fibers (and lysing of red blood cells) a term could be added to the Keller-Miksis equation. This motivates the second method, an independent energy based approach. In this method, the equation for the bubble dynamics, as the bubble grows to its maximum radius, is analyzed in the form of a work-energy statement. The energy method is extended to the more important scenario of a bubble outside a blood clot that collapses asymmetrically creating a jet towards the clot. There is significantly more damage from a bubble growing outside the clot compared to a bubble embedded within the clot structure./nNext, the effects of the physical properties of skull bone when a HIFU wave propagates through it are examined. The dynamics of a test bubble placed at the focus is used in understanding of the pressure field. The sound emitted from the bubble is used to classify the type of cavitation present (stable and/or inertial). The amount of damage in the area surrounding the focus is examined for various initial bubble sizes. The maximum amount of energy available to cause damage to a blood clot increases as the density of the calvaria decreases./nThis dissertation is a first step in analyzing potential cavitation mechanisms, which have only been suggested by other authors. The goal is to assess the plausibility of mechanical damage as a mechanism for enhancement of sonothrombolysis with the addition of microbubbles. The methods to estimate mechanical damage derived here offer the first connection between a bubble and the damage it may cause to a blood clot. This work shows that a bubble near but exterior to a blood clot has the potential to cause significant damage. Ultimately, this dissertation contributes to the understanding of how microbubbles can accelerate clot destruction. This understanding will lead to improves design of therapeutic devices.

Advisor: Szeri, Andrew J