Doug Yeager

Biomedical Applications of Photoacoustic Imaging with Exogenous Contrast Agents

Photoacoustic imaging is a biomedical imaging modality that provides functional information, and, with the help of exogenous contrast agents, cellular and molecular signatures of tissue. In this article, we review the biomedical applications of photoacoustic imaging assisted with exogenous contrast agents. Dyes, noble metal nanoparticles, and other constructs are contrast agents which absorb strongly in the near-infrared band of the optical spectrum and generate strong photoacoustic response. These contrast agents, which can be specifically targeted to molecules or cells, have been coupled with photoacoustic imaging for preclinical and clinical applications ranging from detection of cancer cells, sentinel lymph nodes, and micrometastasis to angiogenesis to characterization of atherosclerotic plaques. Multi-functional agents have also been developed, which can carry drugs or simultaneously provide contrast in multiple imaging modalities. Furthermore, contrast agents were used to guide and monitor the therapeutic procedures. Overall, photoacoustic imaging shows significant promise in its ability to assist in diagnosis, therapy planning, and monitoring of treatment outcome for cancer, cardiovascular disease, and other pathologies.

Intravascular photoacoustic imaging of lipid in atherosclerotic plaques in the presence of luminal blood

Intravascular photoacoustic (IVPA) imaging can characterize atherosclerotic plaque composition on the basis of the optical absorption contrast between different tissue types. Given the high optical absorption of lipid at 1720 nm wavelength, an atherosclerotic rabbit aorta was imaged at this wavelength ex vivo using an integrated intravascular ultrasound (IVUS) and IVPA imaging catheter in the presence of luminal blood. Strong optical absorption of lipid combined with low background signal from other tissues provides a high-contrast, depth-resolved IVPA image of lipid. The ability to image lipid at a single wavelength without removing luminal blood suggests that in vivo detection of lipid in atherosclerotic plaques using combined IVUS/IVPA imaging is possible.

In vivo intravascular ultrasound-guided photoacoustic imaging of lipid in plaques using an animal model of atherosclerosis.

We present a preliminary study demonstrating the capability of ultrasound-guided intravascular photoacoustic (IVPA) imaging to visualize the depth-resolved distribution of lipid deposits in atherosclerotic plaques in vivo. Based on the characteristic optical absorption of lipid in the near infrared wavelength range, IVPA imaging at a single, 1720 nm, wavelength was used to provide a spatially-resolved, direct measurement of lipid content in atherosclerotic arteries. By overlaying an IVPA image with a spatially co-registered intravascular ultrasound (IVUS) image, the combined IVPA/IVUS image was used to visualize lipid distribution within the vessel wall. Ultrasound-guided IVPA imaging was performed in vivo in the abdominal aorta of a Watanabe heritable hyperlipidemic (WHHL) rabbit. Subsequently, the excised rabbit aorta filled with a solution of red blood cells (RBC) was then imaged ex vivo, and histology was obtained in the section adjacent to the imaged cross-section. To demonstrate the potential for future clinical application of IVPA/IVUS imaging, a sample of diseased human right coronary artery (RCA) was also imaged. Both in vivo and ex vivo IVPA images clearly showed the distribution of lipid in the atherosclerotic vessels. In vivo IVPA imaging was able to identify diffuse, lipid-rich plaques in the WHHL rabbit model of atherosclerosis. Furthermore, IVPA imaging at a single wavelength was able to identify the lipid core within the human RCA ex vivo. Our results demonstrate that ultrasound-guided IVPA imaging can identify lipid in atherosclerotic plaques in vivo. Importantly, the IVPA/IVUS images were obtained in presence of luminal blood and no saline flush or balloon occlusion was required. Overall, our studies suggest that ultrasound-guided IVPA imaging can potentially be used for depth-resolved visualization of lipid deposits within the anatomical context of the vessel wall and lumen. Therefore, IVUS/IVPA imaging may become an important tool for the detection of rupture-prone plaques.

Intravascular Photoacoustics for Image-Guidance and Temperature Monitoring During Plasmonic Photothermal Therapy of Atherosclerotic Plaques: A Feasibility Study

Recently, combined intravascular ultrasound and photoacoustic (IVUS/IVPA) imaging has been demonstrated as a novel imaging modality capable of visualizing both morphology (via IVUS) and cellular/molecular composition (via IVPA) of atherosclerotic plaques, using both endogenous tissue absorbers and exogenous contrast agents. Plasmonic gold nanoparticles were previously utilized as IVPA contrast agents which co-localize with atherosclerotic plaques, particularly phagocytically active macrophages. The present work demonstrates the use of IVUS/IVPA imaging as a tool for localized temperature monitoring during laser heating. The temperature dependent change in IVPA signal intensity of silica-coated gold nanorod contrast agents absorbing within the near-infrared optical wavelength range is evaluated and shown to have a linear relationship, with a slope greater than that of endogenous tissue. A continuous wave laser was subsequently incorporated into the IVUS/IVPA integrated catheter and utilized to selectively heat the nanoparticles with simultaneous IVPA temperature monitoring. IVUS/IVPA, therefore, provides a platform for detection and temperature monitoring of atherosclerotic plaques through the selective heating of plasmonic gold nanoparticle contrast agents.

Methodical Study on Plaque Characterization using Integrated Vascular Ultrasound, Strain and Spectroscopic Photoacoustic Imaging

Carotid atherosclerosis has been identified as a potential risk factor for cerebrovascular events, but information about its direct effect on the risk of recurrent stroke is limited due to incomplete diagnosis. The combination of vascular ultrasound, strain rate and spectroscopic photoacoustics could improve the timely diagnosis of plaque status and risk of rupturing. Current ultrasound techniques can noninvasively image the anatomy of carotid arteries. The spatio-temporal variation in displacement of different regions within the arterial wall can be derived from ultrasound radio frequency data; therefore an ultrasound based strain rate imaging modality can be used to reveal changes in arterial mechanical properties. Additionally, spectroscopic photoacoustic imaging can provide information on the optical absorption properties of arterial tissue and it can be used to identify the location of specific tissue components, such as lipid pools. An imaging technique combining ultrasound, strain rate and spectroscopic photoacoustics was tested on an excised atherosclerotic rabbit aorta. The ultrasound image illustrates inhomogeneities in arterial wall thickness, the strain rate indicates the arterial segment with reduced elasticity and the spectroscopic photoacoustic image illustrates the accumulation of lipids. The results demonstrated that ultrasound, strain rate and spectroscopic photoacoustic imaging are complementary. Thus the integration of the three imaging modalities advances the characterization of atherosclerotic plaques.

Real-Time Intravascular Ultrasound and Photoacoustic Imaging

Combined intravascular ultrasound and intravascular photoacoustic (IVUS/IVPA) imaging is an emerging hybrid modality being explored as a means of improving the characterization of atherosclerotic plaque anatomical and compositional features. While initial demonstrations of the technique have been encouraging, they have been limited by catheter rotation and data acquisition, displaying, and processing rates on the order of several seconds per frame as well as the use of off-line image processing. Herein, we present a complete IVUS/IVPA imaging system and method capable of real-time IVUS/IVPA imaging, with online data acquisition, image processing, and display of both IVUS and IVPA images. The integrated IVUS/IVPA catheter is fully contained within a 1-mm outer diameter torque cable coupled on the proximal end to a custom-designed spindle enabling optical and electrical coupling to system hardware, including a nanosecond-pulsed laser with a controllable pulse repetition frequency capable of greater than 10 kHz, motor and servo drive, a US pulser/receiver, and a 200-MHz digitizer. The system performance is characterized and demonstrated on a vessel-mimicking phantom with an embedded coronary stent intended to provide IVPA contrast within content of an IVUS image.

Intravascular Photoacoustic and Ultrasound Imaging: From Tissue Characterization to Molecular Imaging to Image-Guided Therapy

Successful diagnosis and treatment of atherosclerosis demands imaging modalities that can characterize the composition of atherosclerotic plaques, stage the disease, and guide interventional therapy. In this chapter, combined intravascular photoacoustic (IVPA) and intravascular ultrasound (IVUS) imaging is used to address these issues. Based on the difference in optical absorption spectra, lipid-rich tissues can be differentiated using spectroscopic IVPA imaging. Using gold nanoparticles as contrast agent, events happening at the molecular and cellular levels may be visualized in IVPA images. IVPA imaging can also monitor stent deployment during interventional therapy procedures. Design of integrated IVUS/IVPA catheters is discussed. Based on the structural information provided by IVUS images, IVPA images may add further clinically relevant information, helping the management of atherosclerosis.

Intravascular photoacoustic imaging of gold-nanorod labeled atherosclerotic plaques

Combined intravascular photoacoustic (IVPA) and intravascular ultrasound (IVUS) imaging has been previously established as a viable means for imaging atherosclerotic plaques using both endogenous and exogenous contrast. In this study, IVUS/IVPA imaging of an atherosclerotic rabbit aorta following injection of gold nanorods (AuNR) with peak absorbance within the tissue optical window was performed. Ex-vivo imaging results revealed high photoacoustic signal from localized AuNR. Corresponding histological cross-sections and digital photographs of the artery lumen confirmed the presence of AuNR preferentially located at atherosclerotic regions and in agreement with IVPA signal. Furthermore, an integrated IVUS/IVPA imaging catheter was used to image the AuNR in the presence of luminal blood. The results suggest that AuNR allow for IVPA imaging of exogenously labeled atherosclerotic plaques with a comparatively low background signal and without the need for arterial flushing.

System and integrated catheter for real-time intravascular ultrasound and photoacoustic imaging

Combined intravascular ultrasound and photoacoustic imaging (IVUS/IVPA) is an emerging modality for the improved characterization of atherosclerotic plaques including anatomical features of the imaged vessel and tissue composition. Encouraging initial demonstrations of the technique, however, have been limited by slow catheter rotation and data acquisition rates on the order of several seconds per frame, with off-line image processing. Herein, we present both a system and an integrated catheter capable of real-time IVUS/IVPA imaging with online image processing and display of both IVUS and IVPA images. The integrated IVUS/IVPA catheter is fully contained within a 1 mm outer diameter torque cable with the electrical signals transmitted at the proximal end using a slip ring rotary joint. Additional components include a pulsed laser operating at 10 kHz pulse repetition frequency, motor and servo drive, an ultrasound pulser/receiver, and a 200 MHz digitizer coupled to a system capable of real-time IVUS/IVPA imaging. The system performance was validated on a vessel-mimicking phantom with an embedded coronary stent intended to provide IVPA contrast within content of an IVUS image.

Photoacoustic Imaging for Cancer Diagnosis and Therapy Guidance

Photoacoustic imaging uses light as an excitation source and ultrasound imaging to detect sound waves generated by the optically-excited targets and to form images of optical absorption. With the nonionization nature of light waves and the well-established, portable, and cost-effective ultrasound imaging devices, photoacoustic imaging is capable of real-time imaging and is especially suitable for continuous and repetitive imaging of disease sites for long-term monitoring of disease progression or therapeutic outcome. This imaging technique typically offers the submillimeter imaging resolution of tissue at centimeter depths, although, by sacrificing imaging depth, the resolution could be further scaled down to the submicrometer range to reveal the organelle. Because of these advantages, photoacoustic imaging is capable of monitoring blood flow speed, detecting metabolic blood oxygen level of tumors, producing angiography of tumor vasculature networks, and tracing molecular probes to visualize the molecular pathology of cancer in vivo. Furthermore, it can also be used to noninvasively map the change of temperature distribution during thermal cancer therapy. This chapter introduces the physical mechanisms of photoacoustic signal generation in both homogenous and heterogeneous mediums, discusses the recent development of photoacoustic imaging, highlights its abilities to provide functional and molecular information about the tissue, and reviews its diagnostic use in thermal imaging. Finally, the applications of photoacoustic imaging in cancer therapies are reviewed and future outlooks for this promising translational imaging modality are considered.