This proposal describes the synthesis and validation of the first example of a biochemical- responsive ultrasound contrast agent, a potentially groundbreaking advance for deep-tissue imaging of intravascular disease. By improving the power of ultrasound, completion of this multidisciplinary proposal would add value and power to an inexpensive, widespread technique and thus has excellent potential for clinical translation. In addition, this mechanism of activation may be translated to other applications like direct enhancement of sonolytic therapy or site- specific release of therapeutic agents. In this proposal, This proposal describes the synthesis and validation of the first example of a biochemical- responsive ultrasound contrast agent, a potentially groundbreaking advance for deep-tissue imaging of intravascular disease. concern for this country. Acute thrombi may form quickly and develop into worse conditions, potentially leading to patient death if left untreated. Detection is preferably performed using compression ultrasound, a painless, non-invasive outpatient procedure that has good predictive value for symptomatic, proximal vein thrombosis. However, ultrasound cannot differentiate between older clots that should not be treated and acute thrombi that must be treated immediately. The team of PIs has developed a new type of microbubble that remains invisible to ultrasound under normal conditions but becomes detectable only after exposure to certain chemical stimuli. Prior to activation, the microbubble is coated by a rigid, crosslinked polymer shell that dampens the microbubble's response to ultrasound. Treatment with a specific stimulus removes the crosslinks, leaving a flexible, freely oscillating microbubble. The resultant microbubble can be detected via its harmonic oscillations with excellent specificity. Microbubbles will be designed to exhibit sensitivity to thrombin, a protease involved in the coagulation cascade. The microbubbles will be coated with polymer shells crosslinked by DNA aptmaters sensitive to thrombin. Next, their behavior in ultrasound will be examined in real-time on the single bubble level through special equipment previously designed by the PI to create ultrasound pulse programs for optimized signal-to-noise imaging. These thrombin-sensitive ultrasound contrast agents will then be validated in an ex vivo flow model and an in vivo rabbit thrombosis model to detect actual acute thrombi. Thus, a new type of microbubble will be tuned to a medically-relevant system and validated in vivo with excellent chance for translation.

Public Health Relevance

Deep Venous Thrombosis is a rapidly developing, potentially fatal disease that is preferably diagnosed through ultrasound imaging, but current imaging techniques are unable to detect some of its forms. This proposal describes the fabrication and validation of a new type of contrast agent that lays dormant in healthy tissue but becomes strongly detectable by ultrasound in areas of thrombosis. Creation of these contrast agents would greatly improve patient prognosis through early detection and mitigate healthcare costs by empowering a quick and painless procedure that can be performed in operating rooms, clinics, and doctors'offices.

Agency
National Institute of Health (NIH)
Institute
National Institute of Biomedical Imaging and Bioengineering (NIBIB)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21EB012758-02
Application #
8299530
Study Section
Clinical Molecular Imaging and Probe Development (CMIP)
Program Officer
Lopez, Hector
Project Start
2011-07-15
Project End
2013-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
2
Fiscal Year
2012
Total Cost
$257,845
Indirect Cost
$82,845
Name
University of California San Diego
Department
Engineering (All Types)
Type
Schools of Arts and Sciences
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Nakatsuka, Matthew A; Barback, Christopher V; Fitch, Kirsten R et al. (2013) In vivo ultrasound visualization of non-occlusive blood clots with thrombin-sensitive contrast agents. Biomaterials 34:9559-65