Rupture of vulnerable plaques with thrombosis is one of the major causes of most acute coronary syndromes. Plaque vulnerability is highly correlated with plaque structure, composition, and mechanical properties, which are typically characterized by thin fibrous caps, lipid-rich necrotic cores, and severe stenosis; in addition, plaque vulnerability is also influenced by the mechanomechanical properties of the vessel wall and plaque. Intravascular photoacoustic (IVPA) imaging is an emerging intravascular imaging modality that can provide submillimeter resolution at penetration depths up to several centimeters and is capable of localizing and imaging lipids with high sensitivity and specificity. Simultaneously, plaque elastography can be performed through the IVPA signals without additional excitation; subsequently, the elastic mechanical properties of plaque can be evaluated. Although intravascular ultrasonography (IVUS) and intravascular optical coherence tomography (IVOCT) have been widely used in the clinical evaluation of plaque diagnosis, the current single intravascular imaging technology cannot assess the vulnerability of atherosclerotic plaques. For a comprehensive diagnosis, the clinicians need to obtain multiple features to fully identify and evaluate plaques. In this study, we proposed and developed an intravascular multimodal system that integrates four imaging modalities, namely, PA, US, OCT, and PAE. The information on plaque based on these four modalities can be obtained from a single probe via 360° rotation and synchronous retraction in one time, which is expected to provide a new interventional imaging method and tools for the understanding, diagnosis, and treatment of atherosclerotic plaques.

The intravascular PA-US-OCT-PAE imaging system, which integrates the four subsystems of photoacoustic imaging, ultrasonic imaging, OCT, and photoacoustic elasticity, can be used to analyze the macroscopic and microscopic structural information of the blood vessel wall and to specifically identify the lipid components and to perform the elastic mechanics information diagnosis of lipid plaques. The software and hardware designs of each subimaging system and the timing control between the four modalities are shown in Fig. 1 and Fig. 2. The four-modality imaging results are obtained from the only imaging probe by a single-rotation scanning. The structural design of the integrated probe is shown in Fig. 1(b). As shown in the figure, the optical and acoustic paths are placed in parallel, and a miniature ultrasonic transducer with a main frequency of 30 MHz is used for PA signal reception and US signal excitation and reception. A single-mode fiber with an 8° angle end face is used to transmit PA excitation light and OCT detection light and receive the backscattered light of the OCT. A C-lens and coated mirror with a diameter of 0.5 mm are used to focus and deflect the beam so that the focal point of the light is located approximately 2 mm above the ultrasound transducer. The probe house is connected to the torsion coil for torque conduction. The imaging probe assembled with the above design scheme has only a rigid length of 3.6 mm and a diameter of 0.97 mm; this design improves the passability of the probe in tortuous blood vessels. In vitro experiments with simulated samples and in vivo imaging of rabbit abdominal aorta were conducted using the four-modality system with an integrated probe to demonstrate the feasibility of plaque analysis.

The resolution of the PA-US-OCT-PAE imaging system was tested by using eight tungsten wires each with a diameter of 6 μm; the wires were arranged in a spiral form. As shown in Fig. 4, the lateral resolutions of OCT, PA, and US are 20.5, 61.3, and 122.2 μm, respectively. The axial resolutions of OCT, PA, and US are 15.8, 57.4, and 72.5 μm, respectively. The PAE signal, which is attributed to the rising edge of the PA signal, does not contain depth information. Hence, there is no axial resolution, and its lateral resolution is consistent with the PA modality. Further, in vitro experiments on simulated samples of porcine arterial vessels mixed with stents and lipid demonstrate the imaging capabilities of vascular structure identification, lipid detection, and elasticity measurement (Fig. 5). Finally, the in vivo experimental results of atherosclerosis model rabbits show clear vascular PA-US merged three-dimensional (3D) images, OCT 3D images, and PAE results of different sections (Fig. 6). The above results demonstrate the in vivo imaging capability of the intravascular four-modality system, thereby laying the foundation for its clinical translation. However, the system still has some limitations: the PAE signal cannot be extracted from the site where the PA signal is not generated, resulting in the partial absence of the elastic image; in addition, in vivo imaging experiments were only carried on animal models with lipid plaques, and trial data for other types of plaques are lacking.

In this study, a intravascular multimodal PA-US-OCT-PAE imaging system with an integrated imaging probe were developed for the first time. The resolution of the multimodal system was tested by the ultrasonic echo method, and the excellent imaging capabilities of the system were demonstrated. The results of in vitro simulated samples and in vivo rabbit abdominal aorta imaging experiments showed that the PA modality can provide high-contrast images of the lipid distribution in the depth direction. The US modality can reveal the complete vascular structure. The OCT modality can not only evaluate the adherence of the stent but also provide the fine structure of the vessel wall. The PAE modality can provide the elastic mechanics information of the plaque. The information based on the four modalities, which is obtained by only one pullback imaging, is sufficient for comprehensively evaluating the structure, composition, and mechanical properties of the plaques. In conclusion, the intravascular multimodal imaging system is expected to provide a new and comprehensive method for research on plaque vulnerability and help clinicians to effectively diagnose and treat patients with atherosclerotic problems.