טכניון מכון טכנולוגי לישראל
הטכניון מכון טכנולוגי לישראל - בית הספר ללימודי מוסמכים  
M.Sc Thesis
M.Sc StudentZiso Hadas
SubjectDamaging Tumor Blood Vessels using Ultrasound and
Microbubbles
DepartmentDepartment of Biomedical Engineering
Supervisors Professor Eitan Kimmel
Professor Ofer Nativ
Full Thesis textFull thesis text - English Version


Abstract

The overall objective of this study is to utilize Therapeutic Ultrasound (TUS) as a strategy for non-invasive cancer therapy in a mouse tumor model. The target of the treatment is the blood vessels that feed the tumor, in an intention to reduce blood supply to cancerous cells and induce ischemia and necrosis, on one hand; and to open passages in the vessels' walls thereby increasing uptake of anti cancerous drug by the tumor. At this preliminary stage the increased permeability was tested, yet no drug was given. The goal is achieved by the use of Ultrasound Contrast Agents (UCA), encapsulated gas microbubbles that act to locally amplify the ultrasonic field.

The first phase of the study is an assessment of the effect of TUS and UCA
(Optison) on normal skin tissue vasculature. The purpose of this part was to find TUS parameters that enable maximal vasculature damage when applying both TUS and UCA, while minimizing the damage of TUS alone, thus targeting the treatment to blood vessels only. It was also meant to find a small enough duty cycle to keep thermal heating by TUS to minimum. The second part of the work was done on a cancerous tissue in a mouse tumor model, treated based on the TUS parameters that were found in the first part.

Zones of influence of TUS with and without UCA on blood vessels in normal skin and in tumor were defined in terms of Evans Blue dye leakage and cells damage (determined by histology) with respect to TUS intensity. We have found that pulsed ultrasound with a duty cycle of e.g. 15% and a Mechanical Index (MI) of 1.35, caused leakage from the blood vessels in normal skin tissue only in the group of combined TUS and UCA treatment. At lower intensities there was no effect; at higher intensities even TUS alone induced leakage and the added contribution of  UCA was unnoticeable. The total radiation time also affected the results whereas longer exposure time caused more leakage. Results of experiments in subcutaneous tumors were inconclusive, as bleeding and necrotic zones were found in the control samples as well as in the treated ones.

We have shown in this study that there is a potential for making targeted damage to tumor vasculature and subsequently to the tumor tissue itself with the use of TUS and UCA combination.