Ultrasound and Ultrasound Contrast Agent Induce Small Diameter Blood Vessel Growth: a Survival Study
Chenara A. Johnson - cjohns42@illinois.edu
William D.O'Brien
Univ. of Illinois
405 N Mathews, Urbana, IL 61801
Popular version of the paper 1pBB8
Presented Monday afternoon, October 26, 2009
158th ASA Meeting, San Antonio, TX
Diseases involving poor blood circulation affect millions of people in the United States. Current interventions involve risky, invasive procedures. For this reason, alternative methods of supplying blood flow in muscle are needed. Some cellular, molecular, and genetic therapy techniques that have been investigated failed due to their ineffectiveness or the lack of site specificity. Ultrasound and ultrasound contrast agents provide a way to target blood-deprived tissue by boosting natural responses to poor blood circulation. They have been shown to increase the number of small-diameter blood vessels in muscle tissue. However, a major obstacle to progress is the lack of understanding of the principles and mechanisms underlying this effect.
To determine if ultrasound is a viable option for blood restoration therapy, it is necessary and important to establish guidelines by which optimal growth of collateral blood supply occurs. Most of the current studies apply ultrasound at various pressures to reduced-blood flow models. They assess improvements to the blood supply, such as increases in small diameter blood vessels, for 3 to 27s days later. Some have suggested that these increases in blood vessels are caused by the collapse of ultrasound contrast agents under the pressure of the ultrasound energy. But it is difficult to know what exactly the cause is because studies often use pressures that only cause 50 percent of the contrast agent to collapse.
Therefore, the objectives of this study were to 1) understand the process of induced collateral blood supply in the normal setting, using a method that causes 100 percent collapse and 2) determine the time course of changes to the blood supply.
Understanding how the ultrasound-induced increase in bloody supply occurs is key to discerning how to increase blood flow. Establishing when the boost in the number of small-diameter blood vessels occurs provides a timeline useful for finding factors that are precursors to the increase in blood supply. Using a normal model, the results are not confounded by external processes.
In this study, ultrasound and ultrasound contrast agents were used to improve the blood supply in a model. Then 3 to 27 days later, the number of small-diameter blood vessels was assessed. At low ultrasound pressures, the ultrasound contrast agent oscillates, growing and shrinking in response to the pressure that is applied. However, at sufficiently high ultrasound pressures, ultrasound contrast agents have been shown to collapse. This collapse potentially creates the desired effect.
To determine the extent to which an increase in blood supply occurred, small diameter blood vessels were assessed. Exposure to ultrasound and ultrasound contrast agent initially reduced the amount of small-diameter blood vessels after exposure but gradually increased the number of blood vessels over the subsequent day. This decrease and subsequent increase shows that ultrasound and ultrasound contrast agents are able to increase blood supply.
A model used to explain normal wound healing fit these observations poorly, suggesting that the normal healing processes are altered in the presence of ultrasound and ultrasound contrast agents. It has been speculated that there are numerous contributing factors that are induced by ultrasound exposure not present in normal wound healing. For example, ultrasound has been documented to enhance the activity of cells involved in inflammation. Inflammatory cells are important contributors to increasing the number of small-diameter blood vessels.
In this study, ultrasound and ultrasound contrast agents increased the amount of inflammatory cells found in the tissues after exposure by almost 300 percent when compared to the control! This increase was followed by a rapid decrease to approximately 30 percent more than that of the control by day 3. The number of inflammatory cells remained at this level for up to 27 days.
The drastic increase in inflammatory cells shows that ultrasound and ultrasound contrast agents provide collateral blood supply possibly by boosting the amount of inflammatory cells.