Biomedical Photoacoustic Imaging Research Articles

Compressed Sensing for Biomedical Photoacoustic Imaging: A Review.

Photoacoustic imaging (PAI) is a rapidly developing emerging non-invasive biomedical imaging technique that combines the strong contrast from optical absorption imaging and the high resolution from acoustic imaging. Abnormal biological tissues (such as tumors and inflammation) generate different levels of thermal expansion after absorbing optical energy, producing distinct acoustic signals from normal tissues. This technique can detect small tissue lesions in biological tissues and has demonstrated significant potential for applications in tumor research, melanoma detection, and cardiovascular disease diagnosis. During the process of collecting photoacoustic signals in a PAI system, various factors can influence the signals, such as absorption, scattering, and attenuation in biological tissues. A single ultrasound transducer cannot provide sufficient information to reconstruct high-precision photoacoustic images. To obtain more accurate and clear image reconstruction results, PAI systems typically use a large number of ultrasound transducers to collect multi-channel signals from different angles and positions, thereby acquiring more information about the photoacoustic signals. Therefore, to reconstruct high-quality photoacoustic images, PAI systems require a significant number of measurement signals, which can result in substantial hardware and time costs. Compressed sensing is an algorithm that breaks through the Nyquist sampling theorem and can reconstruct the original signal with a small number of measurement signals. PAI based on compressed sensing has made breakthroughs over the past decade, enabling the reconstruction of low artifacts and high-quality images with a small number of photoacoustic measurement signals, improving time efficiency, and reducing hardware costs. This article provides a detailed introduction to PAI based on compressed sensing, such as the physical transmission model-based compressed sensing method, two-stage reconstruction-based compressed sensing method, and single-pixel camera-based compressed sensing method. Challenges and future perspectives of compressed sensing-based PAI are also discussed.

Regulating interparticle proximity in plasmonic nanosphere aggregates to enhance photoacoustic response and photothermal stability.

Designing plasmonic nanoparticles for biomedical photoacoustic (PA) imaging involves tailoring material properties at the nanometer scale. A key in developing plasmonic PA contrast nanoagents is to engineer their enhanced optical responses in the near-infrared wavelength range, as well as heat transfer properties and photostability. This study introduces anisotropic plasmonic nanosphere aggregates with close interparticle proximity as photostable and efficient contrast agent for PA imaging. Silver (Ag), among plasmonic metals, is particularly attractive due to its strongest optical response and highest heat conductivity. Our results demonstrate that close interparticle proximity in silver nanoaggregates (AgNAs), spatially confined within a polymer shell layer, leads to blackbody-like optical absorption, resulting in robust PA signals through efficient pulsed heat generation and transfer. Additionally, our AgNAs exhibit a high photodamage threshold highlighting their potential to outperform conventional plasmonic contrast agents for high-contrast PA imaging over multiple imaging sessions. Furthermore, we demonstrate the capability of the AgNAs for molecular PA cancer imaging in vivo by incorporating a tumor-targeting peptide moiety.

Deep learning-powered biomedical photoacoustic imaging

Photoacoustic Imaging (PAI) is an emerging hybrid imaging modality that combines optical imaging and ultrasound imaging, offering advantages such as high resolution, strong contrast, and safety. Despite demonstrating superior imaging capabilities, PAI still has certain limitations in its clinical application, such as the trade-off between imaging depth and spatial resolution, and the need for further improvement in imaging speed. Deep Learning, as a novel machine learning technique, has gained significant attention for its ability to improve medical image data and has been widely applied in PAI in recent years to overcome these limitations. In this review, we first introduce the principles of photoacoustic imaging, followed by the development and applications of popular deep neural network structures such as U-Net and GAN networks. Furthermore, we comprehensively discuss the recent advancements in the application of deep learning in photoacoustic imaging. Finally, a summary and discussion are provided.

Tunable Interparticle Connectivity in Gold Nanosphere Assemblies for Efficient Photoacoustic Conversion.

Manipulating matter at the nanometer scale to create desired plasmonic nanostructures holds great promise in the field of biomedical photoacoustic (PA) imaging. We demonstrate a strategy for regulating PA signal generation from anisotropic nano-sized assemblies of gold nanospheres (Au NSs) by adjusting the inter-particle connectivity between neighboring Au NSs. The inter-particle connectivity is controlled by modulating the diameter and inter-particle spacing of Au NSs in the nanoassemblies. The results indicate that nanoassemblies with semi-connectivity, i.e., assemblies with a finite inter-particle spacing shorter than the theoretical limit of repulsion between nearby Au NSs, exhibit 3.4-fold and 2.4-fold higher PA signals compared to nanoassemblies with no connectivity and full connectivity, respectively. Furthermore, due to the reduced diffusion of Au atoms, the semi-connectivity Au nanoassemblies demonstrate high photodamage threshold and, therefore, excellent photostability at fluences above the current American National Standards Institute limits. The exceptional photostability of the semi-connectivity nanoassemblies highlights their potential to surpass conventional plasmonic contrast agents for continuing PA imaging. Collectively, our findings indicate that semi-connected nanostructures are a promising option for reliable, high-contrast PA imaging applications over multiple imaging sessions due to their strong PA signals and enhanced photostability.

Biomedical Photoacoustic Imaging With Unknown Spatially Distributed Ultrasound Sensor Array.

With the growth of interest in different medical study on biological function, non-invasive photoacoustic imaging of biological tissue attracts the interests for researchers. To eliminate the limited angle effect of photoacoustic imaging based on ultrasound linear array, spatially distributed ultrasound sensor array is applied. The accurate sensor array position determines the quality of the imaging results. In this study, we proposed three methods based on photoacoustic and ultrasound signals to enhance the imaging quality using a 256-element full-ring array. Groups of photoacoustic and ultrasound signals are used to regress the position of each element sensor. In phantom study and mouse brain study, photoacoustic imaging results can both yield details clearly with average error rate of less than 1% (50 [Formula: see text]). The performance of our three methods have proved that they can be potentially applied to other ultrasound-based medical imaging studies with unknown distributed positions of sensor array to enhance the imaging quality. The proposed methods can contribute to precise biomedical imaging with unknown distributed positions of sensor array in different application scenarios.

Signal and Image Processing in Biomedical Photoacoustic Imaging: A Review

Photoacoustic imaging (PAI) is a powerful imaging modality that relies on the PA effect. PAI works on the principle of electromagnetic energy absorption by the exogenous contrast agents and/or endogenous molecules present in the biological tissue, consequently generating ultrasound waves. PAI combines a high optical contrast with a high acoustic spatiotemporal resolution, allowing the non-invasive visualization of absorbers in deep structures. However, due to the optical diffusion and ultrasound attenuation in heterogeneous turbid biological tissue, the quality of the PA images deteriorates. Therefore, signal and image-processing techniques are imperative in PAI to provide high-quality images with detailed structural and functional information in deep tissues. Here, we review various signal and image processing techniques that have been developed/implemented in PAI. Our goal is to highlight the importance of image computing in photoacoustic imaging.

Progress in biomedical photoacoustic imaging instrumentation toward clinical application

Photoacoustic (optoacoustic) imaging is able to generate highly resolved images of structures with optical absorption contrast in biological tissues. This is made possible by excitation of ultrasound through the absorption of pulsed or rapidly modulated optical radiation. Since the resolution is mainly determined by the ultrasound waves, which are detected at multiple locations outside the tissue, absorbing structures such as blood vessels can be resolved at a depth of several centimeters with sub-millimeter resolution. Furthermore, spectroscopic measurements allow the extraction of functional parameters including blood oxygenation. These favorable properties have generated a lot of hope for improved diagnostics of diseases that involve changes in vasculature, such as breast tumors. After more than two decades of instrumentation development and encouraging clinical trials, photoacoustic imaging techniques are about to enter clinical practice. In this Perspective, we give an overview of recent achievements in the fields of photoacoustic tomography, microscopy, and endoscopy and try to anticipate further developments that will take advantage of the unique properties of this technology on its way to a variety of clinical applications.

Portable and Affordable Light Source-Based Photoacoustic Tomography.

Photoacoustic imaging is a hybrid imaging modality that offers the advantages of optical (spectroscopic contrast) and ultrasound imaging (scalable spatial resolution and imaging depth). This promising modality has shown excellent potential in a wide range of preclinical and clinical imaging and sensing applications. Even though photoacoustic imaging technology has matured in research settings, its clinical translation is not happening at the expected pace. One of the main reasons for this is the requirement of bulky and expensive pulsed lasers for excitation. To accelerate the clinical translation of photoacoustic imaging and explore its potential in resource-limited settings, it is of paramount importance to develop portable and affordable light sources that can be used as the excitation light source. In this review, we focus on the following aspects: (1) the basic theory of photoacoustic imaging; (2) inexpensive light sources and different implementations; and (3) important preclinical and clinical applications, demonstrated using affordable light source-based photoacoustics. The main focus will be on laser diodes and light-emitting diodes as they have demonstrated promise in photoacoustic tomography—the key technological developments in these areas will be thoroughly reviewed. We believe that this review will be a useful opus for both the beginners and experts in the field of biomedical photoacoustic imaging.

High pulse energy fibre laser as an excitation source for photoacoustic tomography.

A custom fibre laser designed as an excitation source for biomedical photoacoustic tomography has been developed. It is based on a custom-drawn large core diameter fibre (200 µm) that enables high pulse energies (∼10 mJ) to be achieved. The system can provide variable pulse durations (10 - 500 ns) and pulse repetition frequencies (100 Hz - 1 kHz), as well as arbitrary pulse bursts according to specific user defined sequences. The system is also compact and does not require external water cooling. This, along with the flexibility in the temporal characteristics of its output that it offers, will aid the translation of photoacoustic imaging to practical application in medicine and biology.

Deep learning in photoacoustic tomography: current approaches and future directions

.Biomedical photoacoustic tomography, which can provide high-resolution 3D soft tissue images based on optical absorption, has advanced to the stage at which translation from the laboratory to clinical settings is becoming possible. The need for rapid image formation and the practical restrictions on data acquisition that arise from the constraints of a clinical workflow are presenting new image reconstruction challenges. There are many classical approaches to image reconstruction, but ameliorating the effects of incomplete or imperfect data through the incorporation of accurate priors is challenging and leads to slow algorithms. Recently, the application of deep learning (DL), or deep neural networks, to this problem has received a great deal of attention. We review the literature on learned image reconstruction, summarizing the current trends and explain how these approaches fit within, and to some extent have arisen from, a framework that encompasses classical reconstruction methods. In particular, it shows how these techniques can be understood from a Bayesian perspective, providing useful insights. We also provide a concise tutorial demonstration of three prototypical approaches to learned image reconstruction. The code and data sets for these demonstrations are available to researchers. It is anticipated that it is in in vivo applications—where data may be sparse, fast imaging critical, and priors difficult to construct by hand—that DL will have the most impact. With this in mind, we conclude with some indications of possible future research directions.

Towards Clinical Translation of LED-Based Photoacoustic Imaging: A Review.

Photoacoustic imaging, with the capability to provide simultaneous structural, functional, and molecular information, is one of the fastest growing biomedical imaging modalities of recent times. As a hybrid modality, it not only provides greater penetration depth than the purely optical imaging techniques, but also provides optical contrast of molecular components in the living tissue. Conventionally, photoacoustic imaging systems utilize bulky and expensive class IV lasers, which is one of the key factors hindering the clinical translation of this promising modality. Use of LEDs which are portable and affordable offers a unique opportunity to accelerate the clinical translation of photoacoustics. In this paper, we first review the development history of LED as an illumination source in biomedical photoacoustic imaging. Key developments in this area, from point-source measurements to development of high-power LED arrays, are briefly discussed. Finally, we thoroughly review multiple phantom, ex-vivo, animal in-vivo, human in-vivo, and clinical pilot studies and demonstrate the unprecedented preclinical and clinical potential of LED-based photoacoustic imaging.

Theoretical and Experimental Study of Photoacoustic Excitation of Silica-Coated Gold Nanospheres in Water

Silica-coated gold nanoparticles are commonly employed in biomedical photoacoustic (PA) imaging applications. We investigate theoretically and experimentally the PA signal generation by silica-coated gold nanospheres in water. Our theoretical model considers thermoelastic expansion in the long-pulse illumination regime, and the PA signals are determined based on a semi-analytical solution to the thermal diffusion equations and a finite-difference in time domain (FDTD) solution to the thermoelastic equations. Both the influence of interfacial thermal (Kapitza) resistance at the gold-water boundary and the influence of the silica coating on PA signal generation were investigated. Our results indicate that for the nanosecond pulses commonly employed in PA imaging, Kapitza resistance has a negligible effect on photoacoustic signal generation. Moreover, our model shows that the presence of a silica coating causes a reduction in the PA signal amplitude, with the level of signal reduction increasing with thicker silica coating. Our theoretical predictions are qualitatively consistent with our experimental results, where suspensions of in-house-synthesized and commercially available silica-coated gold nanosphere suspensions were excited with nanosecond-pulsed laser illumination at 532 nm. The PA signal amplitudes from silica-coated nanospheres were lower than the signal amplitudes for uncoated gold nanospheres of the same core gold diameter. The amount of reduction of the experimentally PA signal amplitude due to the silica coating was found to increase with thicker silica coating, in agreement with our theoretical predictions.

Biomedical Photoacoustic Imaging Optimization with Deconvolution and EMD Reconstruction

A photoacoustic (PA) signal of an ideal optical absorbing particle is a single N-shape wave. PA signals are a combination of several individual N-shape waves. However, the N-shape wave basis leads to aliasing between adjacent micro-structures, which deteriorates the quality of final PA images. In this paper, we propose an image optimization method by processing raw PA signals with deconvolution and empirical mode decomposition (EMD). During the deconvolution procedure, the raw PA signals are de-convolved with a system dependent deconvolution kernel, which is measured in advance. EMD is subsequently adopted to further process the PA signals adaptively with two restrictive conditions: positive polarity and spectrum consistency. With this method, signal aliasing is alleviated, and the micro-structures and detail information, previously buried in the reconstructing images, can now be revealed. To validate our proposed method, numerical simulations and phantom studies are implemented, and reconstructed images are used for illustration.

Simulation Studies of Photoacoustic Response from Gold-Silica Core-Shell Nanoparticles

Metal nanoparticles especially of noble metals are used as an exogenous contrast agent for biomedical photoacoustic (PA) imaging in the tissue transmission window extending from visible to near infrared 700–1100 nm band. Different geometrical configurations of gold and silver nanoparticles like spherical core-shell, nanorod, and nanocages are promising candidates for thermoplasmonics, photothermal therapy, photothermal imaging, and photoacoustic imaging. In the current study, we simulated the photoacoustic response of gold and silica core-shell nanoparticle in water medium. Finite element simulations were carried out to study the spectral absorption response and effect of nanosecond laser pulse excitation on the spatial/temporal temperature as well as photoacoustic pressure variations of different core-shell geometry of nanoparticle. We have optimized the dimensions of gold nanosphere, gold-silica, and silica-gold core-shell geometries for optimum photoacoustic conversion efficiency. Further, the effect of shell thickness on the pulse photoacoustic signals for core-shell gold-silica and silica-gold nanoparticle has been studied. We concluded that silica-gold core-shell nanoparticles possess better photoacoustic conversion efficiency in comparison to gold nanosphere and gold-silica core-shell geometries. The prime aim of this study is to design efficient nano-probes for photoacoustic imaging, photoacoustic tomography, photothermal therapy, and drug delivery.

Photoacoustic reflection artifact reduction using photoacoustic-guided focused ultrasound: comparison between plane-wave and element-by-element synthetic backpropagation approach.

Reflection artifacts caused by acoustic inhomogeneities constitute a major problem in epi-mode biomedical photoacoustic imaging. Photoacoustic transients from the skin and superficial optical absorbers traverse into the tissue and reflect off echogenic structures to generate reflection artifacts. These artifacts cause difficulties in the interpretation of images and reduce contrast and imaging depth. We recently developed a method called PAFUSion (photoacoustic-guided focused ultrasound) to circumvent the problem of reflection artifacts in photoacoustic imaging. We already demonstrated that the photoacoustic signals can be backpropagated using synthetic aperture pulse-echo data for identifying and reducing reflection artifacts in vivo. In this work, we propose an alternative variant of PAFUSion in which synthetic backpropagation of photoacoustic signals is based on multi-angled plane-wave ultrasound measurements. We implemented plane-wave and synthetic aperture PAFUSion in a handheld ultrasound/photoacoustic imaging system and demonstrate reduction of reflection artifacts in phantoms and in vivo measurements on a human finger using both approaches. Our results suggest that, while both approaches are equivalent in terms of artifact reduction efficiency, plane-wave PAFUSion requires less pulse echo acquisitions when the skin absorption is the main cause of reflection artifacts.

Photoacoustic Signal Generation in Gold Nanospheres in Aqueous Solution: Signal Generation Enhancement and Particle Diameter Effects

Gold nanoparticles can be used as an exogenous contrast agent for biomedical photoacoustic (PA) imaging. The generation of PA signals in monodispersed gold nanosphere suspensions (diameters 20–150 nm) from pulsed-laser excitation (5 ns pulse width, wavelength 532 nm) was investigated experimentally and compared to signals measured in solutions of a homogeneous molecular absorber. The PA signal amplitude was found to increase linearly with excitation fluence for the homogeneous absorber and the nanospheres up to 80 nm in diameter. By contrast, the signal amplitude was found to increase quadratically with respect to fluence for larger nanospheres. In the linear regime, the PA signal amplitude in gold nanosphere suspensions was found to be on average 26% higher than that in the homogeneous absorber with identical absorption coefficient, which were measured using an integrating sphere. Furthermore, in suspensions with identical absorption coefficient, no dependence of the PA signal amplitude on nanosphere dia...

Application of scanning acoustic and photoacoustic microscopes in orthopedic surgery

Demands for orthopedic surgery, decreasing pain and disabilities, are increasing in developed countries with older nations. Together with increasing number of patients, its cost is now rising. Among modalities for noninvasive diagnosing techniques, such as plain X-rays, computed tomography, magnetic resonance imaging (MRI), and ultrasonography (US), MRI is a powerful tool for evaluating anatomical abnormalities. However, location and economic limitations for routine use remain. US is quick and inexpensive with a higher resolution than MRI. US plays an important role in assessing musculoskeletal soft tissues. A scanning acoustic microscope (SAM) characterizes biological tissues by estimating the elastic parameters based on sound speed. Biomedical photoacoustic (PA) imaging has the unique capability of combining high optical contrast and high ultrasound resolution in a single modality. Osteoarthritis and frozen shoulder are the major problems in musculoskeletal diseases. Osteoarthritis is a degenerative joint disorder characterized by the progressive degeneration of articular cartilage, osteophyte formation, and subsequent joint space narrowing. Further, frozen shoulder is characterized with severe pain and a decrease in shoulder motion, which is caused by joint capsular stiffness. We applied SAM and PA to animal models for assessing.

Changes of masseter muscle in a rat unilateral occlusal model assessed by photoacoustic imaging system

Biomedical photoacoustic (PA) imaging system has the unique capability of combining high optical contrast with high ultrasound (US) resolution in a single modality. PA imaging system with 532 nm laser and 50 MHz US transducer has been developed. When the laser with the wavelength of 532 nm is used, PA signals are reflected from blood vessels. Patients with unilateral occlusion due to the extraction of unilateral molars are often seen in dental practice. Although the period of the unilateral occlusion induces the changes of masseter muscle (MM), it is not known that how blood vessels and tissue elasticity of MM are affected by the unilateral occlusion. In this study, we aimed to evaluate the sequential changes of MM due to the unilateral occlusion in rats with PA imaging system. PA signals from the MM of the non-occlusal side were significantly lower than that of the occlusal side, and US signals from the MM of the occlusal side were significantly higher than that of the non-occlusal side depending on the period of the unilateral occlusion. Unilateral occlusion affected both the blood vessels and the tissue elasticity. The PA imaging system could evaluate blood circulation and tissue elasticity simultaneously.

In vivo demonstration of reflection artifact reduction in photoacoustic imaging using synthetic aperture photoacoustic-guided focused ultrasound (PAFUSion).

Reflection artifacts caused by acoustic inhomogeneities are a critical problem in epi-mode biomedical photoacoustic imaging. High light fluence beneath the probe results in photoacoustic transients, which propagate into the tissue and reflect back from echogenic structures. These reflection artifacts cause problems in image interpretation and significantly impact the contrast and imaging depth. We recently proposed a method called PAFUSion (Photoacoustic-guided focused ultrasound) to identify such reflection artifacts in photoacoustic imaging. In its initial version, PAFUSion mimics the inward-travelling wavefield from small blood vessel-like PA sources by applying ultrasound pulses focused towards these sources, and thus provides a way to identify the resulting reflection artifacts. In this work, we demonstrate reduction of reflection artifacts in phantoms and in vivo measurements on human volunteers. In view of the spatially distributed PA sources that are found in clinical applications, we implemented an improved version of PAFUSion where photoacoustic signals are backpropagated to imitate the inward travelling wavefield and thus the reflection artifacts. The backpropagation is performed in a synthetic way based on the pulse-echo acquisitions after transmission on each single element of the transducer array. The results provide a direct confirmation that reflection artifacts are prominent in clinical epi-photoacoustic imaging, and that PAFUSion can strongly reduce these artifacts to improve deep-tissue photoacoustic imaging.

Charge transfer NIR dyes for improved photoacoustic effect

A new class of NIR absorbing dyes accessed by a cycloaddition-cycloreversion reaction of alkynes with 2,3,5,6-tetrafluoro-7,7,8,8-tetracyanoquinodimethane is reported. The photoacoustic effect of the new NIR dyes was systematically studied. The results validated the positive correlation between the molar extinction coefficient and the photoacoustic effect. All of the new NIR dyes showed higher photoacoustic intensities compared to indocyanine green dye, which is the standard organic dye widely used as a photoacoustic contrast agent. Finally, the nano-sized liposomes loaded with the NIR dye showed good stabilities and high photoacoustic intensities, and were utilized to image the cells in agarose gels for a long time. The study guides the future design of NIR dyes for photoacoustic molecular materials with high intensities and displays promising applications in biomedical photoacoustic imaging.