Photoacoustic Imaging Research Articles

Immunoregulatory Engineering of Semiconducting Charge-Reversal Nanoantioxidant for Ameliorating Cancer Radioimmunotheranostics.

Radiotherapy (RT) is a crucial clinical modality for cancer. However, nonselectivity, toxicity to normal tissues, and radio-resistance severely limit RT applications. This study develops a versatile X-ray theranostic nano-antioxidant (XTN) to prevent normal tissues from oxidative damage and induce systematic and robust anticancer immunity. XTN owns NIR-II photoacoustic (PA) imaging properties for precise discrimination of the tumor margin through, thereby improving the accuracy of RT. Additionally, XTN is a nano-antioxidant to enhance the cell viability of normal cells after irradiation. Most importantly, XTN scavenges reactive oxygen species (ROS) in the TME to preserve the stimulatory activity of released high mobility group protein B1 to dendritic cells (DCs) and recover T cells' immune function. Meanwhile, XTN achieves charge-reversal specifically releasing an immunomodulator (demethylcantharidin, DMC) in the acidic TME. Moreover, the specifically released DMC inhibits protein phosphatase-2A activity and reduces regulatory T cell (Treg) differentiation. In the bilateral 4T1 tumor model, XTN-mediated radioimmunotherapy remarkably boosts a systemic antitumor immune response and induces durable immunological memory against tumor growth.

Xanthene-Based Dyes for Photoacoustic Imaging and their Use as Analyte-Responsive Probes.

Developing imaging tools that can report on the presence of disease-relevant analytes in multicellular organisms can provide insight into fundamental disease mechanisms as well as provide diagnostic tools for the clinic. Photoacoustic imaging (PAI) is a light-in, sound-out imaging technique that allows for high resolution, deep-tissue imaging with applications in pre-clinical and point-of-care settings. The continued development of near-infrared (NIR) absorbing small-molecule dyes promises to improve the capabilities of this emerging imaging modality. For example, new dye scaffolds bearing chemoselective functionalities are enabling the detection and quantification of disease-relevant analytes through activity-based sensing (ABS) approaches. Recently described strategies to engineer NIR absorbing xanthenes have enabled development of analyte-responsive PAI probes using this classic dye scaffold. Herein, we present current strategies for red-shifting the spectral properties of xanthenes via bridging heteroatom or auxochrome modifications. Additionally, we explore how these strategies, coupled with chemoselective spiroring-opening approaches, have been employed to create ABS probes for in vivo detection of hypochlorous acid, nitric oxide, copper (II), human NAD(P)H: quinone oxidoreductase isozyme 1, and carbon monoxide. Given the versatility of the xanthene scaffold, we anticipate continued growth and development of analyte-responsive PAI imaging probes based on this dye class.

Nanostructured cruciform phototheranostic agents for efficient multimodal imaging-guided type I photodynamic/photothermal synergistic therapy

One-component multimodel imaging-guided synergistic platform provides an attracting strategy for the precise cancer therapy. However, the construction of single molecules integrating near-infrared (NIR) II emission, multimodel-imaging and multiple therapeutic modalities still remains a great challenge. In this study, a series of organic phototheranostic agents (named PMY, MePMY and TPMY) based on a cross-shaped D-π-A framework were designed and synthesized, and their corresponding nanoparticles (NPs) were facilely fabricated by encapsulating them with an amphiphilic polymer. The twisted structure and lower band gaps of these compounds extended their emissions deep into the NIR-II region, and the narrow singlet-triplet energy gaps endowed them with highly efficient intersystem crossing from S1 to T1 state. Specifically, TPMY NPs exhibit NIR-II emission at 1022 nm, efficient generation of type I reactive oxygen species, and high photothermal conversion efficiency (37.8 %), as well as good photostability and biocompatibility. In vitro and in vivo experiments further revealed the excellent photoacoustic and photothermal imaging ability and superior tumoricidal activity of TPMY NPs, in which the tumor growth was effectively inhibited or even completely eradicated upon single administration and once light irradiation. This study thus provides a new insight into the design and development of intelligent phototheranostic agents for multimodel imaging-guided synergistic therapy which has potential in future practical applications.

Deep Learning Realizes Photoacoustic Imaging Artifact Removal

Photoacoustic imaging integrates the strengths of optics and ultrasound, offering high resolution, depth penetration, and multimodal imaging capabilities. Practical considerations with instrumentation and geometry limit the number of available acoustic sensors and their “view” of the imaging target, which result in image reconstruction artifacts degrading image quality. To address this problem, YOLOv8-Pix2Pix is proposed as a hybrid artifact-removal algorithm, which is advantageous in comprehensively eliminating various types of artifacts and effectively restoring image details compared to existing algorithms. The proposed algorithm demonstrates superior performance in artifact removal and segmentation of photoacoustic images of brain tumors. For the purpose of further expanding its application fields and aligning with actual clinical needs, an experimental system for photoacoustic detection is designed in this paper to be verified. The experimental results show that the processed images are better than the pre-processed images in terms of reconstruction metrics PSNR and SSIM, and also the segmentation performance is significantly improved, which provides an effective solution for the further development of photoacoustic imaging technology.

Tumor-specific enhanced NIR-II photoacoustic imaging via photothermal and low-pH coactivated AuNR@PNIPAM-VAA nanogel

BackgroundProperly designed second near-infrared (NIR-II) nanoplatform that is responsive tumor microenvironment can intelligently distinguish between normal and cancerous tissues to achieve better targeting efficiency. Conventional photoacoustic nanoprobes are always “on”, and tumor microenvironment-responsive nanoprobe can minimize the influence of endogenous chromophore background signals. Therefore, the development of nanoprobe that can respond to internal tumor microenvironment and external stimulus shows great application potential for the photoacoustic diagnosis of tumor.ResultsIn this work, a low-pH-triggered thermal-responsive volume phase transition nanogel gold nanorod@poly(n-isopropylacrylamide)-vinyl acetic acid (AuNR@PNIPAM-VAA) was constructed for photoacoustic detection of tumor. Via an external near-infrared photothermal switch, the absorption of AuNR@PNIPAM-VAA nanogel in the tumor microenvironment can be dynamically regulated, so that AuNR@PNIPAM-VAA nanogel produces switchable photoacoustic signals in the NIR-II window for tumor-specific enhanced photoacoustic imaging. In vitro results show that at pH 5.8, the absorption and photoacoustic signal amplitude of AuNR@PNIPAM-VAA nanogel in NIR-II increases up obviously after photothermal modulating, while they remain slightly change at pH 7.4. Quantitative calculation presents that photoacoustic signal amplitude of AuNR@PNIPAM-VAA nanogel at 1064 nm has ~ 1.6 folds enhancement as temperature increases from 37.5 °C to 45 °C in simulative tumor microenvironment. In vivo results show that the prepared AuNR@PNIPAM-VAA nanogel can achieve enhanced NIR-II photoacoustic imaging for selective tumor detection through dynamically responding to thermal field, which can be precisely controlled by external light.ConclusionsThis work will offer a viable strategy for the tumor-specific photoacoustic imaging using NIR light to regulate the thermal field and target the low pH tumor microenvironment, which is expected to realize accurate and dynamic monitoring of tumor diagnosis and treatment.

Glutathione-activated biotin-targeted dual-modal imaging probe with improved PDT/PTT synergistic therapy

BackgroundGlutathione (GSH), a highly abundant thiol compound within cells, plays a critical role in physiological processes and exhibits close correlation with cancer. Among molecular imaging technologies, most probes have relatively short emission wavelengths and lack photoacoustic imaging (PA) capability, resulting in the inability to obtain tissue images with high penetration depth. The presence of GSH in the tumor microenvironment neutralizes ROS, diminishing the therapeutic effect of PDT, thus resulting in often unsatisfactory therapeutic efficacy. Therefore, it is imperative to develop a dual-modal probe for the detection of GSH and the diagnosis and treatment of cancer. ResultsIn this study, we synthesized a novel dual-modal probe, Cy-Bio-GSH, utilizing near-infrared fluorescence (NIRF) and photoacoustic (PA) imaging techniques for GSH detection. The probe integrates cyanine dye as the fluorophore, nitroazobenzene as the recognition moiety, and biotin as the tumor-targeting moiety. Upon reacting with GSH, the probe emits NIR fluorescence at 820 nm and generates a PA signal. Significantly, this reaction activates the photodynamic and photothermal properties of the probe. By depleting GSH and employing a synergistic photothermal therapy (PTT) treatment, the therapeutic efficacy of photodynamic therapy (PDT) is remarkably enhanced. In-vivo experiments confirm the capability of the probe to detect GSH via NIRF and PA imaging. Notably, the combined tumor-targeting ability and PDT/PTT synergistic therapy enhance therapeutic outcomes for tumors and facilitate their ablation. SignificanceA novel tumor-targeting and dual-modal imaging probe (Cy-Bio-GSH) is synthesized, exhibiting remarkable sensitivity and selectivity to GSH, enabling the visualization of GSH in cells and the differentiation between normal and cancer cells. Cy-Bio-GSH enhances PDT/PTT with effective killing of cancer cells and makes the ablation of tumors in mice. This work represents the first tumor-targeting probe for GSH detection, and provides crucial tool for cancer diagnosis and treatment by dual-modal imaging with improved PDT/PTT synergistic therapy.

A Platinum-Protein hybrid nanostructure enables both targeted cancer theragnosis and platinum clearance

Considering the fundamental advantages of photothermal therapy (PTT) and photoacoustic imaging (PAI) of cancer such as precise spatiotemporal control-based, non-invasive therapy with negligible drug resistance and side effects and sensitive, specific diagnosis with high spatial resolution at substantial depth, an advanced, or clinically feasible material that enables both PTT and PAI surely needs to be developed but remains a major challenge yet. Here we developed a hybrid nanostructure (PtNC@ABP-HBVC) between plasmonic platinum nanocluster (PtNC) comprised of many tiny Pt nanoparticles (PtNPs, ∼ 3 nm that is small enough to pass through glomerular filtration in kidney) and a specially designed protein scaffold (ABP-HBVC) capable of binding to human serum albumin (HSA). PtNC is beneficial for efficient light-to-heat conversion and acoustic wave generation due to plasmonic coupling effect among the small PtNPs, and the HSA binding to ABP-HBVC significantly lowers immunogenicity and enables PtNC to be effectively delivered to tumor. Using human breast cancer-bearing xenograft mice, we demostrated that PtNC@ABP-HBVC has the superior efficacy in targeted cancer theragnosis (PTT + PAI) and is rapidly cleared from the body through urinary excretion, which shows its great potential as a promising, clinically attractive agent for cancer theragnosis.

In Vivo Combined Photoacoustic Imaging and Photothermal Treatment of HPV‐Negative Head and Neck Carcinoma with NIR‐Responsive Non‐Persistent Plasmon Nano‐Architectures

AbstractThe combination of photoacoustic imaging (PAI) and photothermal therapy (PTT) is an attractive approach in cancer management due to the non‐invasive features combined with real‐time imaging and selective tissue damage by non‐ionizing radiation. This approach is especially appealing for Head and Neck Squamous Cell Carcinoma (HNSCC) management, where up to 40% of patients require modifications of the treatment regimen. On the other hand, most of the agents developed for PAI/PTT suffer from persistence or re‐shaping issues. Here, a unique non‐persistent plasmon nano‐architecture (tNAs‐IRDye) is presented that simultaneously acts as a contrast agent for PAI and as a photothermal transducer for PTT. The tNAs‐IRDye are fully characterized and evaluated in vitro and ex vivo, and their performance as theranostic agents is assessed in HPV‐negative HNSCC murine models. A significant modulation of tumor growth is obtained in vivo upon intratumoral injection of tNAs‐IRDye and subsequent NIR irradiation compared to the solely irradiated control. The outcomes of this study exhibit a noteworthy potential to foster the development of innovative clinical strategies for the management of HPV‐negative head and neck carcinoma.

Shape and location recovery of laser excitation sources in photoacoustic imaging using topological gradient optimization

This study focuses on source term inversion in fractional partial differential equations, specifically applied to photoacoustic imaging. This work contributes to advancing imaging techniques and provides practical insights for medical diagnostics and materials characterization. Our aim in this paper is to develop an accurate method for recovering the location and the shape of a laser excitation source from partial boundary data. To achieve this, we reformulate our inverse problem as an optimization challenge. We utilize topological sensitivity analysis to establish an asymptotic expansion of a relevant shape function. These theoretical findings form the basis for a rapid and precise detection algorithm. Additionally, we present several numerical experiments that demonstrate the effectiveness and accuracy of our proposed approach.

Distribution-informed and wavelength-flexible data-driven photoacoustic oximetry.

Photoacoustic imaging (PAI) promises to measure spatially resolved blood oxygen saturation but suffers from a lack of accurate and robust spectral unmixing methods to deliver on this promise. Accurate blood oxygenation estimation could have important clinical applications from cancer detection to quantifying inflammation. We address the inflexibility of existing data-driven methods for estimating blood oxygenation in PAI by introducing a recurrent neural network architecture. We created 25 simulated training dataset variations to assess neural network performance. We used a long short-term memory network to implement a wavelength-flexible network architecture and proposed the Jensen-Shannon divergence to predict the most suitable training dataset. The network architecture can flexibly handle the input wavelengths and outperforms linear unmixing and the previously proposed learned spectral decoloring method. Small changes in the training data significantly affect the accuracy of our method, but we find that the Jensen-Shannon divergence correlates with the estimation error and is thus suitable for predicting the most appropriate training datasets for any given application. A flexible data-driven network architecture combined with the Jensen-Shannon divergence to predict the best training data set provides a promising direction that might enable robust data-driven photoacoustic oximetry for clinical use cases.

A high contrast and resolution reconstruction algorithm in quantitative photoacoustic tomography

A framework for reconstruction of optical diffusion and absorption coefficients in quantitative photoacoustic tomography is presented. This framework is based on a Tikhonov-type functional with a regularization term promoting sparsity of the absorption coefficient and a prior involving a Kubelka–Munk absorption–diffusion relation that allows to obtain superior reconstructions. The reconstruction problem is formulated as the minimization of this functional subject to the differential constraint given by a photon-propagation model. The solution of this problem is obtained by a fast and robust sequential quadratic hamiltonian algorithm based on the Pontryagin maximum principle. Results of several numerical experiments demonstrate that the proposed computational strategy is able to obtain reconstructions of the optical coefficients with high contrast and resolution for a wide variety of objects.

A Novel Multi-Effect Photosensitizer for Tumor Destruction via Multimodal Imaging Guided Synergistic Cancer Phototherapy.

How to ingeniously design multi-effect photosensitizers (PSs), including multimodal imaging and multi-channel therapy, is of great significance for highly spatiotemporal controllable precise phototherapy of malignant tumors. Herein, a novel multifunctional zinc(II) phthalocyanine-based planar micromolecule amphiphile (ZnPc 1) was successfully designed and synthesized, in which N atom with photoinduced electron transfer effect was introduced to enhance the near-infrared absorbance and nonradiative heat generation. After simple self-assembling into nanoparticles (NPs), ZnPc 1 NPs would exhibit enhanced multimodal imaging properties including fluorescence (FL) imaging (FLI) /photoacoustic (PA) imaging (PAI) /infrared (IR) thermal imaging, which was further used to guide the combined photodynamic therapy (PDT) and photothermal therapy (PTT). It was that under the self-guidance of the multimodal imaging, ZnPc 1 NPs could precisely pinpoint the tumor from the vertical and horizontal boundaries achieving highly efficient and accurate treatment of cancer. Accordingly, the integration of FL/PA/IR multimodal imaging and PDT/PTT synergistic therapy pathway into one ZnPc 1 could provide a blueprint for the next generation of phototherapy, which offered a new paradigm for the integration of diagnosis and treatment in tumor and a promising prospect for precise cancer therapy.

Image reconstruction of multispectral sparse sampling photoacoustic tomography based on deep algorithm unrolling

Photoacoustic tomography (PAT), as a novel medical imaging technology, provides structural, functional, and metabolism information of biological tissue in vivo. Sparse Sampling PAT, or SS-PAT, generates images with a smaller number of detectors, yet its image reconstruction is inherently ill-posed. Model-based methods are the state-of-the-art method for SS-PAT image reconstruction, but they require design of complex handcrafted prior. Owing to their ability to derive robust prior from labeled datasets, deep-learning-based methods have achieved great success in solving inverse problems, yet their interpretability is poor. Herein, we propose a novel SS-PAT image reconstruction method based on deep algorithm unrolling (DAU), which integrates the advantages of model-based and deep-learning-based methods. We firstly provide a thorough analysis of DAU for PAT reconstruction. Then, in order to incorporate the structural prior constraint, we propose a nested DAU framework based on plug-and-play Alternating Direction Method of Multipliers (PnP-ADMM) to deal with the sparse sampling problem. Experimental results on numerical simulation, in vivo animal imaging, and multispectral un-mixing demonstrate that the proposed DAU image reconstruction framework outperforms state-of-the-art model-based and deep-learning-based methods.

Vascular regional analysis unveils differential responses to anti-angiogenic therapy in pancreatic xenografts through macroscopic photoacoustic imaging.

Pancreatic cancer (PC) is a highly lethal malignancy and the third leading cause of cancer deaths in the U.S. Despite major innovations in imaging technologies, there are limited surrogate radiographic indicators to aid in therapy planning and monitoring. Amongst the various imaging techniques Ultrasound-guided photoacoustic imaging (US-PAI) is a promising modality based on endogenous blood (hemoglobin) and blood oxygen saturation (StO 2 ) contrast to monitor response to anti-angiogenic therapies. Adaptation of US-PAI to the clinical realm requires macroscopic configurations for adequate depth visualization, illuminating the need for surrogate radiographic markers, including the tumoral microvessel density (MVD). In this work, subcutaneous xenografts with PC cell lines AsPC-1 and MIA-PaCa-2 were used to investigate the effects of receptor tyrosine kinase inhibitor (sunitinib) treatment on MVD and StO 2 . Through histological correlation, we have shown that regions of high and low vascular density (HVD and LVD) can be identified through frequency domain filtering of macroscopic PA images which could not be garnered from purely global analysis. We utilized vascular regional analysis (VRA) of treatment-induced StO 2 and total hemoglobin (HbT) changes. VRA as a tool to monitor treatment response allowed us to identify potential timepoints of vascular remodeling, highlighting its ability to provide insights into the TME not only for sunitinib treatment but also other anti-angiogenic therapies.

Thin-Film Piezoelectric Micromachined Ultrasound Transducers in Biomedical Applications: A Review.

Thin-film piezoelectric micromachined ultrasound transducers (PMUTs) are an increasingly relevant and well-researched field, and their biomedical importance has been growing as the technology continues to mature. This review article briefly discusses their history in biomedical use, provides a simple explanation of their principles for newer readers, and sheds light on the materials selection for these devices. Primarily, it discusses the significant applications of PMUTs in the biomedical industry and showcases recent progress that has been made in each application. The biomedical applications covered include common historical uses of ultrasound such as ultrasound imaging, ultrasound therapy, and fluid sensing, but additionally new and upcoming applications such as drug delivery, photoacoustic imaging, thermoacoustic imaging, biometrics, and intrabody communication. By including a device comparison chart for different applications, this review aims to assist microelectromechanical systems (MEMS) designers that work with PMUTs by providing a benchmark for recent research works. Furthermore, it puts forth a discussion on the current challenges being faced by PMUTs in the biomedical field, current and likely future research trends, and opportunities for PMUT development areas, as well as sharing the opinions and predictions of the authors on the state of this technology as a whole. The review aims to be a comprehensive introduction to these topics without diving excessively deep into existing literature.

Inside Front Cover: Supramolecular phthalocyanine assemblies‐enhanced synergistic photodynamic and photothermal therapy guided by photoacoustic imaging

Inside Front Cover: Supramolecular phthalocyanine assemblies‐enhanced synergistic photodynamic and photothermal therapy guided by photoacoustic imaging

Non-invasive optoacoustic imaging of dermal microcirculatory revascularization in diet-induced obese mice undergoing exercise intervention

Microcirculatory dysfunction has been observed in the dermal white adipose tissue (dWAT) and subcutaneous white adipose tissue (scWAT) of obese humans and has been proposed as an early prediction marker for cardio-metabolic disease progression. In-vivo visualization and longitudinal monitoring of microvascular remodeling in these tissues remains challenging. We compare the performance of two optoacoustic imaging methods, i.e. multi-spectral optoacoustic tomography (MSOT) and raster-scanning optoacoustic mesoscopy (RSOM) in visualizing lipid and hemoglobin contrast in scWAT and dWAT in a mouse model of diet-induced obesity (DIO) undergoing voluntary wheel running intervention for 32 weeks. MSOT visualized lipid and hemoglobin contrast in murine fat depots in a quantitative manner even at early stages of DIO. We show for the first time to our knowledge that RSOM allows precise visualization of the dWAT microvasculature and provides quantitative readouts of skin layer thickness and vascular density in dWAT and dermis. Combination of MSOT and RSOM resolved exercise-induced morphological changes in microvasculature density, tissue oxygen saturation, lipid and blood volume content in dWAT and scWAT. The combination of MSOT and RSOM may allow precise monitoring of microcirculatory dysfunction and intervention response in dWAT and scWAT in a mouse model for DIO. Our findings have laid out the foundation for future clinical studies using optoacoustic-derived vascular readouts from adipose tissues as a biomarker for monitoring microcirculatory function in metabolic disease.

Application of $L_{1}-L_{2}$ Regularization in Sparse-View Photoacoustic Imaging Reconstruction

Application of $L_{1}-L_{2}$ Regularization in Sparse-View Photoacoustic Imaging Reconstruction

Isoindigo nanoparticles for photoacoustic imaging-guided tumor photothermal therapy

The key factor in photothermal therapy lies in the selection of photothermal agents. Traditional photothermal agents generally have problems such as poor photothermal stability and low photothermal conversion efficiency. Herein, we have designed and synthesized an isoindigo (IID) dye. We used isoindigo as the molecular center and introduced common triphenylamine and methoxy groups as rotors. In order to improve the photothermal stability and tumor targeting ability, we encapsulated IID into nanoparticles. As a result, the nanoparticles exhibited high photothermal stability and photothermal conversion efficiency (67%) upon 635 nm laser irradiation. Thus, the nanoparticles demonstrated a significant inhibitory effect on live tumors in photothermal therapy guided by photoacoustic imaging and provided a viable strategy to overcome the treatment challenges.

Ultrasound and Photoacoustic Imaging for the Guidance of Laser Ablation Procedures.

The accuracy and efficacy of laser ablation procedures depend on the accurate placement of the laser applicator within the diseased tissue, monitoring the real-time temperature during the ablation procedure, and mapping the extent of the ablated region. Ultrasound (US) imaging has been widely used to guide ablation procedures. While US imaging offers significant advantages for guiding ablation procedures, its limitations include low imaging contrast, angular dependency, and limited ability to monitor the temperature. Photoacoustic (PA) imaging is a relatively new imaging modality that inherits the advantages of US imaging and offers enhanced capabilities for laser-guided ablations, such as accurate, angle-independent tracking of ablation catheters, the potential for quantitative thermometry, and monitoring thermal lesion formation. This work provides an overview of ultrasound-guided procedures and how different US-related artifacts limit their utility, followed by introducing PA as complementary to US as a solution to address the existing limitations and improve ablation outcomes. Furthermore, we highlight the integration of PA-driven features into existing US-guided laser ablation systems, along with their limitations and future outlooks. Integrated US/PA-guided laser ablation procedures can lead to safer and more precise treatment outcomes.