Intravascular Photoacoustic Imaging of Lipid-Laden Plaque: From Fundamental Concept Towards Clinical Translation

Atherosclerosis is the major form of cardiovascular disease, which has been the number one cause of death in the United States and worldwide for a century. Among the different plaque types, vulnerable plaques account for the majority of fatal acute coronary syndromes due to their rupture and thrombosis. Currently, there are no clinically available imaging tools to reliably and accurately detect vulnerable plaques largely due to the lack of chemical selectivity. This gap, along with the increasing prevalence of coronary artery diseases, highlight an unmet clinical need for an imaging modality with both chemical selectivity and enough depth resolution to advance the detection, understanding, and treatment of lipid-laden vulnerable plaques. During the past decade, intravascular photoacoustic (IVPA) imaging has been demonstrated as a promising approach to meet this pressing need. However, this research direction is confronted with several significant bottlenecks, which have blocked this technology from in vivo applications. Here, this dissertation work is devoted to addressing these bottlenecks and translating this imaging technology towards clinical utility. First, the lipid contrast in IVPA imaging has not been fully explored in this research field. Thus, in Chapter 1, the contrast mechanism in vibration-based photoacoustic imaging was revisited. The lipid-water contrast and optical windows for lipid imaging at 1.2 and 1.7 μm were further validated on a theoretical basis. Second, the slow imaging speed at minute-level per frame is a longstanding challenge in clinical translation of IVPA imaging, as the clinical utility requires real-time video-rate speed to reduce the operation time and to suppress the motion artifacts caused by cardiac pulsation in vivo. In Chapter 2, a first-generation high-speed IVPA imaging system at 1.7 μm was demonstrated. Using KTP-based OPO as optical excitation source, an imaging speed of 1 frame per second was achieved, which is nearly two orders of magnitude faster than previously reported imaging speeds. In Chapter 4, a second-generation high-speed IVPA imaging system at 1.7 μm, capable of imaging at 25 frames per second in real-time display mode was further presented. This unprecedented imaging speed was achieved by concurrent innovations in optical excitation laser source, IVPA catheter design, real-time image processing and display algorithms. Third, an IVPA catheter, which has high detection sensitivity, clinically relevant size, and functional sheath material integrated is another great challenge in clinical translation of IVPA imaging. To meet these requirements, three different catheter designs were prototyped and evaluated in Chapter 2, Chapter 3, and Chapter 5, respectively. Through collinear or quasi-collinear overlapping of the optical and acoustic paths in the catheter, we have significantly improved the detection sensitivity and penetration depth (\u3e5 mm) of IVPA imaging. Through quantitative comparison of multiple sheath candidates, we identified an optically and acoustically transparent sheath material and further integrated it onto IVPA catheter, making it feasible for in vivo validation of IVPA imaging. Finally, with a portable and fully integrated IVPA imaging system, IVPA imaging was successfully performed in vivo on both rabbit and swine models in Chapter 5. In the end, an outlook of IVPA imaging is provided in Chapter 6