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Photoacoustic imaging (PAI) is a noninvasive hybrid imaging modality offering rich optical contrast and high depth-to-resolution ratio deep-tissue imaging. Endogenous chromophores present in the body such as hemoglobin, lipid, melanin, and so on provide strong photoacoustic contrast due to their strong light absorption in certain optical window. To enhance the performance of PAI further, researchers have developed several exogenous contrast agents such as metallic nanoparticles, carbon-based nanomaterials, quantum dots, organic small molecules, semiconducting polymer nanoparticles, and so on. These exogenous contrast agents not only help improving the imaging contrast, but also make targeted molecular imaging possible. In this review article, we first discuss the state-of-the-art PAI techniques with endogenous contrast mechanism. Later, we provide an overview of recent progress in the development of exogenous photoacoustic contrast agents for in vivo imaging applications. Finally, we present the pros/cons of the existing PA contrast agents along with future challenges of contrast agent-based PAI for biomedical applications. This article is categorized under: Diagnostic Tools > Diagnostic Nanodevices Diagnostic Tools > In Vivo Nanodiagnostics and Imaging., (© 2020 Wiley Periodicals, Inc.)

Photoacoustic (PA) tomography (PAT) imaging is an emerging biomedical imaging modality useful in various preclinical and clinical applications. Custom-made circular ring array-based transducers and conventional bulky Nd:YAG/OPO lasers inhibit translation of the PAT system to clinics. Ultra-compact pulsed laser diodes (PLDs) are currently being used as an alternative source of near-infrared excitation for PA imaging. High-speed dynamic in vivo imaging has been demonstrated using a compact PLD-based desktop PAT system (PLD-PAT). A visualized experimental protocol using the desktop PLD-PAT system is provided in this work for dynamic in vivo brain imaging. The protocol describes the desktop PLD-PAT system configuration, preparation of animal for brain vascular imaging, and procedure for dynamic visualization of indocyanine green (ICG) dye uptake and clearance process in rat cortical vasculature.

Tumor phototheranostics in the second near-infrared window (NIR-II, 1000-1700 nm) holds great promise due to high spatiotemporal precision, enhanced penetration depth, and therapeutic efficacy. However, current "always-on" NIR-II phototheranostic agents remain restricted by the inherent nonspecificity from the pseudosignal readout and undesirable treatment-related side effects. To address these challenges, herein we explore an activatable and biocompatible nanotheranostics that generates diagnostic and therapeutic effects only after specific activation and enhancement by tumor microenvironmental redox and acid while keeping silent at normal tissues. Such an intelligent "turn-on" chromogenic nanotheranostics allows in vivo nearly zero-background photoacoustic tomography (PAT) and combined effective photothermal tumor therapy (PTT) both in the NIR-II range with minimal adverse effects. In light of the high sensitivity, superior penetration depth, and biocompatibility, this stimuli-activatable NIR-II photo-nanotheranostics provides broad prospects for the investigation and intervention of deep-tissue redox and acid-associated physiological and pathological events.

Photoacoustic (PA) imaging is an emerging medical imaging modality that combines optical excitation and ultrasound detection. Because ultrasound scatters much less than light in biological tissues, PA generates high-resolution images at centimeters depth. In recent years, wavelengths in the second near-infrared (NIR-II) window (1000 to 1700 nm) have been increasingly explored due to its potential for preclinical and clinical applications. In contrast to the conventional PA imaging in the visible (400 to 700 nm) and the first NIR-I (700 to 1000 nm) window, PA imaging in the NIR-II window offers numerous advantages, including high spatial resolution, deeper penetration depth, reduced optical absorption, and tissue scattering. Moreover, the second window allows a fivefold higher light excitation energy density compared to the visible window for enhancing the imaging depth significantly. We highlight the importance of the second window for PA imaging and discuss the various NIR-II PA imaging systems and contrast agents with strong absorption in the NIR-II spectral region. Numerous applications of NIR-II PA imaging, including whole-body animal imaging and human imaging, are also discussed.

Bulky, expensive Nd:YAG lasers are used in conventional photoacoustic tomography (PAT) systems, making them difficult to translate into clinics. Moreover, real-time imaging is not feasible when a single-element ultrasound transducer is used with these low-pulse-repetition-rate lasers (10-100 Hz). Low-cost pulsed laser diodes (PLDs) can be used instead for photoacoustic imaging due to their high-pulse-repetition rates and compact size. Together with acoustic-reflector-based multiple single-element ultrasound transducers, a portable desktop PAT system was developed. This second-generation PLD-based PAT achieved 0.5 s cross-sectional imaging time with high spatial resolution of ∼165  μm and an imaging depth of 3 cm. The performance of this system was characterized using phantom and in vivo studies. Dynamic in vivo imaging was also demonstrated by monitoring the fast uptake and clearance of indocyanine green in small animal (rat) brain vasculature.

Photoacoustic imaging (PAI) is a fast growing deep-tissue imaging modality. However, light scattering and absorption in biological tissues limit imaging depth. Short near-infrared wavelengths (650 to 950 nm) are widely used for PAI. Using longer near-infrared wavelengths reduces scattering. We demonstrate deep-tissue contrast-enhanced in vivo photoacoustic imaging at a wavelength of 1064 nm. An ultranarrow bandgap semiconducting polymer poly (thienoisoindigo-alt-diketopyrrolopyrrole) (denoted as PIGD) is designed and demonstrated for imaging at 1064 nm. By embedding colloidal nanoparticles (NPs) of PIGD in chicken-breast tissue, an imaging depth of ∼5  cm is achieved. Intravenous injection of PIGD NPs in living rats showed brain vascular images with ∼2 times higher contrast compared with the brain vascular images without any contrast agent. Thus, PIGD NPs as an NIR-II contrast agent opens new opportunities for both preclinical and clinical imaging of deep tissues with enhanced contrast.

Chemo-photothermal nanotheranostics has the advantage of synergistic therapeutic effect, providing opportunities for optimized cancer therapy. However, current chemo-photothermal nanotheranostic systems generally comprise more than three components, encountering the potential issues of unstable nanostructures and unexpected conflicts in optical and biophysical properties among different components. We herein synthesize an amphiphilic semiconducting polymer (PEG-PCB) and utilize it as a multifunctional nanocarrier to simplify chemo-photothermal nanotheranostics. PEG-PCB has a semiconducting backbone that not only serves as the diagnostic component for near-infrared (NIR) fluorescence and photoacoustic (PA) imaging, but also acts as the therapeutic agent for photothermal therapy. In addition, the hydrophobic backbone of PEG-PCB provides strong hydrophobic and π-π interactions with the aromatic anticancer drug such as doxorubicin for drug encapsulation and delivery. Such a trifunctionality of PEG-PCB eventually results in a greatly simplified nanotheranostic system with only two components but multimodal imaging and therapeutic capacities, permitting effective NIR fluorescence/PA imaging guided chemo-photothermal therapy of cancer in living mice. Our study thus provides a molecular engineering approach to integrate essential properties into one polymer for multimodal nanotheranostics., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

We demonstrate dynamic in vivo imaging using a low-cost portable pulsed laser diode (PLD)-based photoacoustic tomography system. The system takes advantage of an 803-nm PLD having high-repetition rate ∼7000  Hz combined with a fast-scanning single-element ultrasound transducer leading to a 5 s cross-sectional imaging. Cortical vasculature is imaged in scan time of 5 s with high signal-to-noise ratio ∼48. To examine the ability for dynamic imaging, we monitored the fast uptake and clearance process of indocyanine green in the rat brain. The system will find applications to study neurofunctional activities, characterization of pharmacokinetic, and biodistribution profiles in the development process of drugs or imaging agents., ((2017) COPYRIGHT Society of Photo-Optical Instrumentation Engineers (SPIE).)

In vivo small-animal imaging has an important role to play in preclinical studies. Photoacoustic tomography (PAT) is an emerging hybrid imaging modality that shows great potential for both preclinical and clinical applications. Conventional optical parametric oscillator-based PAT (OPO-PAT) systems are bulky and expensive and cannot provide high-speed imaging. Recently, pulsed-laser diodes (PLDs) have been successfully demonstrated as an alternative excitation source for PAT. Pulsed-laser diode PAT (PLD-PAT) has been successfully demonstrated for high-speed imaging on photoacoustic phantoms and biological tissues. This work provides a visualized experimental protocol for in vivo brain imaging using PLD-PAT. The protocol includes the compact PLD-PAT system configuration and its description, animal preparation for brain imaging, and a typical experimental procedure for 2D cross-sectional rat brain imaging. The PLD-PAT system is compact and cost-effective and can provide high-speed, high-quality imaging. Brain images collected in vivo at various scan speeds are presented.

Photoacoustic imaging has become an emerging tool for theranostic applications. Not only does it help in

Optical resolution photoacoustic microscopy (ORPAM) is a high-resolution hybrid imaging modality having potential for microscale in vivo imaging. Optical diffraction limits the lateral resolution of ORPAM. A photonic nanojet (PNJ) was used to break this diffraction limit. A single round microsphere can generate a PNJ with subwavelength waist, but its short axial length limits its applications to surface imaging only. We investigate different sphere designs to achieve ultralong nanojets that will make the nanojet more viable in far-field applications, such as photoacoustic imaging. The PNJ properties, including effective length, waist size, working distance, and peak intensity, can be tuned and controlled by changing the sphere design and its refractive index. A truncated multilayer microsphere design could generate an ultraelongated PNJ with length larger than ∼172λ (∼138  μm) while retaining a large working distance ∼32λ (∼26  μm). Through simulation study, we observed ∼11-fold enhancement in lateral resolution with 5  μm round sphere (refractive index 2.2) when used in a conventional ORPAM setup with NA=0.1 and λ=800  nm.

Development of photoacoustic (PA) imaging agents provides opportunities for advancing PA imaging in fundamental biology and medicine. Despite the promise of semiconducting polymer nanoparticles (SPNs) for PA imaging, the molecular guidelines to enhance their imaging performance are limited. In this study, semiconducting polymers (SPs) with self-quenched fluorescence are synthesized and transformed into SPNs for amplified PA imaging in living mice. The self-quenched process is induced by the incorporation of an electron-deficient structure unit into the backbone of SPs, which in turn promotes the nonradiative decay and enhances the heat generation. Such a simple chemical alteration of SP eventually leads to 1.7-fold PA amplification for the corresponding SPN. By virtue of the targeting capability of cyclic-RGD, the amplified SPN can effectively delineate tumor in living mice and increase the PA intensity of tumor by 4.7-fold after systemic administration. Our study thus provides an effective molecular guideline to amplify the PA brightness of organic imaging agents for in vivo PA imaging., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Optical resolution photoacoustic microscopy (ORPAM) is important for various biomedical applications, such as the study of cellular structures, microcirculation systems, and tumor angiogenesis. However, the lateral resolution of a conventional ORPAM is limited by optical diffraction. In this work, we report a simulation study to achieve subdiffraction-limited super-resolution in ORPAM using microspheres. Laser radiation is focused through a microsphere to generate a photonic nanojet, which provides the possibility to break the diffraction limit in ORPAM by reducing the size of the excitation volume. In our simulations using microspheres, we observed improvement in the lateral resolution up to compared to conventional ORPAM. The method is simple, cost effective, and can provide far-field resolution. This approach may provide new opportunities for many biomedical imaging applications that require finer resolution.