Photoacoustic imaging is an emerging technology that can provide anatomic, functional, and molecular information about biological tissue. Intravascular spectroscopic and molecular photoacoustic imaging can potentially improve the identification of atherosclerotic plaque composition, the detection of inflammation, and ultimately the risk stratification of atherosclerosis. In this study, a first-of-its-kind intravascular optical-resolution photoacoustic tomography (OR-PAT) system with a 1.1 mm diameter catheter is developed, offering optical-diffraction limited transverse resolution as fine as 19.6 μm, ∼10-fold finer than that of conventional intravascular photoacoustic and ultrasonic imaging. To offer complementary imaging information and depth, the system also acquires co-registered intravascular ultrasound images in parallel. Imaging of an iliac stent and a lipid phantom shows that the high resolution and contrast of OR-PAT can enable improved stent implantation guidance and lipid identification. In the future, these capabilities may ultimately improve the diagnosis and interventional treatment of vulnerable atherosclerotic plaques, which are prone to cause thrombotic complications such as myocardial infarction and stroke.
Optical-resolution photoacoustic microscopy (OR-PAM) is becoming a vital tool for studying the microcirculation system in vivo. By increasing the numerical aperture of optical focusing, the lateral resolution of OR-PAM can be improved; however, the depth of focus and thus the imaging range will be sacrificed correspondingly. In this work, we report our development of blind-deconvolution optical-resolution photoacoustic microscopy (BD-PAM) that can provide a lateral resolution ~2-fold finer than that of conventional OR-PAM (3.04 vs. 5.78μm), without physically increasing the system's numerical aperture. The improvement achieved with BD-PAM is demonstrated by imaging graphene nanoparticles and the microvasculature of mice ears in vivo. Our results suggest that BD-PAM may become a valuable tool for many biomedical applications that require both fine spatial resolution and extended depth of focus.
Endoscopy is an essential clinical tool for the diagnosis of gastrointestinal (GI) tract cancer. A photoacoustic system that elegantly combines optical and ultrasound endoscopy advantages by providing high-sensitivity functional information and large imaging depth is a potentially powerful tool for GI tract imaging. Recently, several photoacoustic endoscopic imaging systems have been proposed and developed. However, the relatively large size and rigid length of the catheter make it difficult to translate them into wide clinical applications; while the existing system of a relatively small catheter, capable of in vivo animal imaging, is unable to acquire full (360°) field-of-view cross-section images. In this study, we developed a photoacoustic/ultrasonic dual-modality endoscopic system and a corresponding miniaturized, encapsulated imaging catheter, which provides a full 360° field-of-view. The diameter of the catheter is 2.5 mm, which is compatible with the 2.8-mm instrumental channel of a conventional clinical optical endoscope. Using this system, we demonstrate in vivo 3-dimensional endoscopic photoacoustic/ultrasonic imaging of the colorectum of a healthy Sprague Dawley rat, by depicting vasculature and morphology of the GI tract. The significantly improved imaging field of view, reduced catheter size, high-quality imaging results suggest that the developed photoacoustic/ultrasonic dual-modality endoscopy has a great potential to be translated into a broad range of clinical applications in gastroenterology.
Intravascular spectroscopic photoacoustic technology can image atherosclerotic plaque composition with high sensitivity and specificity, which is critical for identifying vulnerable plaques. Here, we designed and engineered a catheter of 0.9 mm in diameter for intravascular photoacoustic (IVPA) imaging, smaller than the critical size of 1 mm required for clinical translation. Further, a quasifocusing photoacoustic excitation scheme was developed for the catheter, producing well-detectable IVPA signals from stents and lipids with a laser energy as low as ~30 μJ/pulse. As a result, this design enabled the use of a low-energy, high-repetition rate, ns-pulsed optical parametric oscillator laser for high-speed spectroscopic IVPA imaging at both the 1.2-μm and 1.7-μm spectral bands for lipid detection. Specifically, for each wavelength, a 1-kHz IVPA A-line rate was achieved, ~100-fold faster than previously reported IVPA systems offering a similar wavelength tuning range. Using the system, spectroscopic IVPA imaging of peri-adventitial adipose tissue from a porcine aorta segment was demonstrated. The significantly improved imaging speed, together with the reduced catheter size and multiwavelength spectroscopic imaging ability, suggests that the developed high-speed IVPA technology is of great potential to be further translated for in vivo applications.
We developed a linear ultrasound array-based real-time photoacoustic imaging system with a compact coaxial excitation handheld photoacoustic imaging probe for guiding sentinel lymph node (SLN) needle biopsy. Compared with previous studies, our system and probe have the following advantages: (1) the imaging probe is quite compact and user-friendly; (2) laser illumination and ultrasonic detection are achieved coaxially, enabling high signal-to-noise ratio; and (3) GPU-based image reconstruction enables real-time imaging and displaying at a frame rate of 20 Hz. With the system and probe, clear visualization of the SLN at the depth of 2 cm (~human SLN depth) was demonstrated on a living rat. A fine needle was pushed towards the SLN based on the guidance of real-time photoacoustic imaging. The proposed photoacoustic imaging system and probe was shown to have great potential to be used in clinics for guiding SLN needle biopsy, which may reduce the high morbidity rate related to the current gold standard clinical SLN biopsy procedure.
Many diseases involve either the formation of new blood vessels (e.g., tumor angiogenesis) or the damage of existing ones (e.g., diabetic retinopathy) at the microcirculation level. Optical-resolution photoacoustic microscopy (OR-PAM), capable of imaging microvessels in 3D in vivo down to individual capillaries using endogenous contrast, has the potential to reveal microvascular information critical to the diagnosis and staging of microcirculation-related diseases. In this study, we have developed a dedicated microvascular quantification (MQ) algorithm for OR-PAM to automatically quantify multiple microvascular morphological parameters in parallel, including the vessel diameter distribution, the microvessel density, the vascular tortuosity, and the fractal dimension. The algorithm has been tested on in vivo OR-PAM images of a healthy mouse, demonstrating high accuracy for microvascular segmentation and quantification. The developed MQ algorithm for OR-PAM may greatly facilitate quantitative imaging of tumor angiogenesis and many other microcirculation related diseases in vivo. M. Arbeit, "VEGF is essential for hypoxia-inducible factor-mediated neovascularization but dispensable for endothelial sprouting," Proc. Natl. Acad. Sci. U. S. A. 108(32), 13264-13269 (2011). 9. J. Folkman, "Angiogenesis in cancer, vascular, rheumatoid and other disease," Nat. Med. 1(1), 27-30 (1995 1182-1186 (1971). 11. J. W. Baish and R. K. Jain, "Cancer, angiogenesis and fractals," Nat. Med. 4(9), 984 (1998). 12. R. K. Jain, "Normalizing tumor vasculature with anti-angiogenic therapy: A new paradigm for combination therapy," Nat. Med. 7(9), 987-989 (2001)
As an optical-acoustic hybrid imaging technology, photoacoustic imaging uniquely combines the advantages of rich optical contrast with high ultrasonic resolution in depth, opening up many new possibilities not attainable with conventional pure optical imaging technologies. To perform photoacoustic molecular imaging, optically absorbing exogenous contrast agents are needed to enhance the signals from specifically targeted disease activity. In this work, we designed and developed folate receptor targeted, indocyanine green dye doped poly(d,l-lactide-co-glycolide) lipid nanoparticles (FA-ICG-PLGA-lipid NPs) for molecular photoacoustic imaging of tumor. The fabricated FA-ICG-PLGA-lipid NPs exhibited good aqueous stability, a high folate-receptor targeting efficiency, and remarkable optical absorption in near-infrared wavelengths, providing excellent photoacoustic signals in vitro. Furthermore, after intravenous administration of FA-ICG-PLGA-lipid NPs, mice bearing MCF-7 breast carcinomas showed significantly enhanced photoacoustic signals in vivo in the tumor regions, compared with those using non-targeted ICG-PLGA-lipid NPs. Given the existing wide clinical use of ICG and PLGA, the developed FA-ICG-PLGA-lipid NPs, in conjunction with photoacoustic imaging technology, offer a great potential to be translated into the clinic for non-ionizing molecular imaging of breast cancer in vivo.
Abstract:We developed a reflection-mode subwavelength-resolution photoacoustic microscopy system capable of imaging optical absorption contrast in vivo. The simultaneous high-resolution and reflection-mode imaging capacity of the system was enabled by delicately configuring a miniature high-frequency ultrasonic transducer tightly under a water-immersion objective with numerical aperture of 1.0. At 532-nm laser illumination, the lateral resolution of the system was measured to be ~320 nm. With this system, subcellular structures of red blood cells and B16 melanoma cells were resolved ex vivo; microvessels, including individual capillaries, in a mouse ear were clearly imaged label-freely in vivo, using the intrinsic optical absorption from hemoglobin. The current study suggests that, the optical-absorption contrast, subwavelength resolution, and reflection-mode ability of the developed photoacoustic microscopy may empower a wide range of biomedical studies for visualizing cellular and/or subcellular structures.
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