Xiaojing Gong

Intravascular optical-resolution photoacoustic tomography with a 1.1 mm diameter catheter.

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.

High-speed intravascular spectroscopic photoacoustic imaging at 1000 A-lines per second with a 0.9-mm diameter catheter

Abstract. 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.

Reflection-mode in vivo photoacoustic microscopy with subwavelength lateral resolution.

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.

Advances in Imaging Techniques and Genetically Encoded Probes for Photoacoustic Imaging.

Photoacoustic (PA) imaging is a rapidly emerging biomedical imaging modality that is capable of visualizing cellular and molecular functions with high detection sensitivity and spatial resolution in deep tissue. Great efforts and progress have been made on the development of various PA imaging technologies with improved resolution and sensitivity over the past two decades. Various PA probes with high contrast have also been extensively developed, with many important biomedical applications. In comparison with chemical dyes and nanoparticles, genetically encoded probes offer easier labeling of defined cells within tissues or proteins of interest within a cell, have higher stability in vivo, and eliminate the need for delivery of exogenous substances. Genetically encoded probes have thus attracted increasing attention from researchers in engineering and biomedicine. In this review, we aim to provide an overview of the existing PA imaging technologies and genetically encoded PA probes, and describe further improvements in PA imaging techniques and the near-infrared photochromic protein BphP1, the most sensitive genetically encoded probe thus far, as well as the potential biomedical applications of BphP1-based PA imaging in vivo.

Hybrid MoSe2–indocyanine green nanosheets as a highly efficient phototheranostic agent for photoacoustic imaging guided photothermal cancer therapy

Phototheranostic technology based on photoacoustic imaging (PAI) and photothermal therapy (PTT) is emerging as a powerful tool for tumor theranostic applications. For effective tumor eradication, a novel PAI/PTT theranostic nanoagent with an excellent optical absorption and photothermal capability is highly desired. Herein, we present a new PAI/PTT nanohybrid named sMoSe2-ICG NSs by covalently conjugating aminated indocyanine green (ICG) onto a single layer of molybdenum selenide nanosheets (sMoSe2 NSs). We first validate the sMoSe2-ICG NS agent for the PAI and PTT effect in vitro and then use it for highly-sensitive PAI guided highly efficient tumor PTT in vivo. The sMoSe2-ICG NS hybrid possesses several advantages for PAI/PTT applications: (1) the sMoSe2-ICG NSs have strong absorbance in the broad near-infrared (NIR) region, enabling a highly efficient PAI/PTT theranostic effect and the selection of the most widely used excitation wavelength of 808 nm for PTT; (2) the photothermal ability of ICG in sMoSe2-ICG NSs is augmented due to ICG aggregation induced fluorescence quenching and the re-absorbance of ICG fluorescence by sMoSe2 NSs, which further enhances the PAI/PTT theranostic effect. (3) The characteristic absorption peak of sMoSe2-ICG NSs is red-shifted compared to free ICG, resulting in a higher PAI signal-to-noise ratio (SNR) in vivo. Thus, combined with the good stability, high biocompatibility and minimal toxicity properties, the obtained sMoSe2-ICG NSs hybrid has bright prospects for use in future PAI/PTT clinical applications.

In vivo photoacoustic/ultrasonic dual-modality endoscopy with a miniaturized full field-of-view catheter

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.

Three-dimensional Hessian matrix-based quantitative vascular imaging of rat iris with optical-resolution photoacoustic microscopy in vivo

Abstract. For the diagnosis and evaluation of ophthalmic diseases, imaging and quantitative characterization of vasculature in the iris are very important. The recently developed photoacoustic imaging, which is ultrasensitive in imaging endogenous hemoglobin molecules, provides a highly efficient label-free method for imaging blood vasculature in the iris. However, the development of advanced vascular quantification algorithms is still needed to enable accurate characterization of the underlying vasculature. We have developed a vascular information quantification algorithm by adopting a three-dimensional (3-D) Hessian matrix and applied for processing iris vasculature images obtained with a custom-built optical-resolution photoacoustic imaging system (OR-PAM). For the first time, we demonstrate in vivo 3-D vascular structures of a rat iris with a the label-free imaging method and also accurately extract quantitative vascular information, such as vessel diameter, vascular density, and vascular tortuosity. Our results indicate that the developed algorithm is capable of quantifying the vasculature in the 3-D photoacoustic images of the iris in-vivo, thus enhancing the diagnostic capability of the OR-PAM system for vascular-related ophthalmic diseases in vivo.

Highly Sensitive Fluorescence and Photoacoustic Detection of Metastatic Breast Cancer in Mice Using Dual-Modal Nanoprobes

The biomedical imaging of metastatic breast cancer, especially in lymphatic and lung metastasis, is highly significant in cancer staging as it helps assess disease prognosis and treatment. Using an albumin-indocyanine green dual-modal nanoprobe developed in our laboratory, in vivo fluorescence imaging and photoacoustic imaging of metastatic breast cancer tumors were performed separately. Fluorescence imaging at the near-infrared window features high imaging sensitivity but is generally limited by a low imaging depth. Thus, tumors can only be observed in situ whereas tumor cells in the lymph nodes and lung cannot be imaged in a precise manner. In contrast, photoacoustic imaging often helps overcome the limitations of imaging depth with high acoustic spatial resolution, which could provide complementary information for imaging cancer metastases. Ex vivo fluorescence and photoacoustic imaging were also performed to verify the tumor metastatic route. This study may not only provide insights into the design of dual-modal nanoprobes for breast cancer diagnosis but may also demonstrate the superiority of combined fluorescence imaging and photoacoustic imaging for guiding, monitoring, and evaluating lymphatic and lung metastatic stages of breast cancer with a high imaging specificity as well as sensitivity.

Integrated intravascular ultrasound and optical-resolution photoacoustic microscopy with a 1-mm-diameter catheter

Intravascular ultrasound (IVUS) plays a vital role in assessing the severity of atherosclerosis and has greatly enriched our knowledge on atherosclerotic plaques. However, it mainly reveals the structural information of plaques. In contrast, spectroscopic and molecular photoacoustic imaging can potentially improve plaque composition identification, inflammation detection, and ultimately the stratification of plaque vulnerability and risk. In this work, we developed an integrated intravascular ultrasound and optical-resolution photoacoustic microscopy (IVUS-PAM) system with a single catheter as small as 1 mm in diameter, comparable to that of existing clinical IVUS catheters. In addition, by using a GRIN lens to focus the excitation laser pulse, the system provides an optical-diffraction limited photoacoustic lateral resolution as fine as 19.6 micrometers, ~10-fold finer than that of conventional intravascular photoacoustic imaging and existing IVUS technology. The system employs a custom-made miniaturized single-element ultrasonic transducer with a dimension of ~0.5 mm, a centre frequency of ~40 MHz, and a fractional bandwidth of ~60%. The IVUS-PAM can simultaneously acquire co-registered IVUS images with an axial resolution of ~40 micrometers and a lateral resolution of ~200 micrometers. In the future, IVUS-PAM may open up new opportunities for improved high-resolution vulnerable plaque imaging and image-guided stent deployment.