Super-Resolution Ultrasound Imaging

Noninvasive detection of molecular markers at high resolution remains an open problem in medicine. We are seeking to achieve this elusive goal by combining the dynamics of new phase-change nanoparticles with advanced image processing techniques. This method - which draws inspiration from recent Nobel-winning advances in optical microscopy - has the potential to dramatically improve our understanding of disease on a molecular level.

We have developed highly dynamic contrast agents - called laser-activated nanodroplets (LANDs) - which consist of a perfluorocarbon core, an encapsulated dye, a stabilizing shell, and targeting antibodies. The dye acts as a fuse and, upon radiation with a pulsed laser, the LANDs can be remotely triggered to undergo a liquid to gas phase transition, forming transient microbubbles. While in their microbubble form, the LANDs generate high ultrasound contrast, enabling single-particle detection sensitivity. The boiling point of the perfluorocarbon core (55 °C) is much higher than the surrounding tissue, resulting in the eventual recondensation of the particles to return to their nanodroplet form. In this manner, the vaporization/recondensation cycle can be repeated tens to hundreds of times for each individual particle.

By capturing high frame rate (kHz) ultrasound images, individual "blinking" LANDs can be isolated and their location can be pinpointed with much greater precision than the resolution of the imaging system. We have used this technique to localize individual nanodroplets to within 5-12 μm in vitro and 7-15 μm in vivo. This will enable high-resolution imaging of the microvasculature. Furthermore, in cancer applications, the small size of the LANDs allows them to escape the vasculature via the enhanced permeability and retention effect, and molecular targeting will enable near-single-cell resolution dynamic molecular profiling. Overall, this technology has the potential to be a valuable new tool in understanding the development, progression, and treatment response of tumors.

1) The tissue is pulsed with a nanosecond laser.  2) Photoabsorbers within the body convert the optical energy to localized heating.  3) Elevated temperature results in a thermoelastic expansion of the tissue., which generates a broadband ultrasound wave centered at the absorber. Image graphic design by Patricio Sarzosa.

1) The tissue is pulsed with a nanosecond laser.  2) Photoabsorbers within the body convert the optical energy to localized heating.  3) Elevated temperature results in a thermoelastic expansion of the tissue., which generates a broadband ultrasound wave centered at the absorber. Image graphic design by Patricio Sarzosa.

Translational Photoacoustic Imaging

Photoacoustic imaging (also known as optoacoustic imaging) is a rapidly emerging biomedical imaging modality which combines optical excitation with acoustic detection. The acoustic detection allows us to circumvent the loss of imaging resolution associated with the diffuse propagation of light in tissue (at depths exceeding 1-2 mm). Therefore, high resolution images with optical contrast can be achieved centimeters deep in tissue.

Photoacoustic imaging can be used to visualize endogenous optical absorbers, including hemoglobin, melanin, and lipids. Furthermore, by tuning the wavelength of laser light, spectroscopic information can be obtained and tissue components can be separated. This makes the technology applicable to a variety of clinical applications, including cancer and cardiovascular disease.

This unique set of features makes photoacoustic imaging a useful tool in the growing field of molecular imaging. In fact, optical contrast agents, including dyes, nanoparticles, and genetically expressed chromophores, can be harnessed to achieve molecular and/or cellular specificity. This is critical as the medical community continues to move towards personalized medicine and highly targeted therapeutics. Despite the promise of this technology and the progress over the last two decades, photoacoustic imaging has not yet made a significant impact on the clinical care of disease.

In the FMI Lab, we are actively working to push photoacoustic imaging into the clinic. We are identifying clinical applications where the technology can yield a significant improvement over the current standard of care. Once we gain a foothold with initial clinical success, we will expand to apply photoacoustic imaging to other promising areas.

Our initial thrust is in the area of detecting lymph node metastasis noninvasively in breast cancer patients. This work is funded by the Department of Defense Breast Cancer Research Program through a Breakthrough Award. We are developing a clinical imaging system which is capable of acquiring and displaying real-time ultrasound and photoacoustic images. We will use this system to analyze the lymph nodes of breast cancer patients undergoing the sentinel lymph node biopsy procedure. Our preclinical results have indicated that metastatic lymph nodes exhibit a large drop in blood oxygenation at very early stages of disease progression. We hope to apply this effect to noninvasively detect micrometastases in breast cancer patients. The end result could be improved diagnosis/staging and reduced need for the invasive sentinel lymph node biopsy procedure.

We plan to expand from this initial project into related clinical applications, including targeting new disease sites, monitoring the outcome of therapy, and leading the effort to bring molecular imaging into the clinic.