Publications

Compositional changes in relation to musculoskeletal injuries are difficult to measure non-invasively. This study aims to use non-invasive label-free imaging with Multispectral Optoacoustic Tomography (MSOT) to evaluate compositional changes with injury. Five different patient groups were examined, covering diagnoses of Achilles or patellar tendinopathy, Achilles tendon rupture and gastrocnemius muscle strain injury. Injured and contralateral limbs were imaged using a commercial MSOT device. Hemoglobin, collagen, and lipid contents were estimated. Some patients were examined before and after exercise. Hemoglobin measures had high reproducibility and displayed systematic changes in response to exercise. The content and exercise response of hemoglobin was equal on both limbs. In contrast, collagen and lipid measures were inconsistent and did not display the expected distribution. In conclusion, MSOT is applicable to imaging of hemoglobin in musculoskeletal injuries, providing complimentary information to conventional ultrasound, but applicability to other components like collagen and lipids could not be shown.

Nanoprobes with NIR-II fluorescence and a large Stokes shift are highly desirable for high-quality bioimaging applications. However, designing NIR-II fluorescent nanoprobes with the desired photophysical properties based on small organic molecules remains a significant challenge. Herein, we report a naphthalimide (NMI)-based NIR-II fluorescent molecule, NMI-BF2, by further enhancing the electron affinity of NMI through the incorporation of boron difluoride formazanate. NMI-BF2 exhibits a sufficient NIR-II quantum yield (QY) of 0.53%, a large Stokes shift of 263 nm, and excellent photostability. For biological applications, NMI-BF2 is coassembled with fetal bovine serum (FBS) to prepare a biocompatible nanoprobe, NMI-BF2/FBS, which maintains a good NIR-II QY of 0.21% and a photothermal conversion efficiency of 32.5%. In vitro and in vivo studies verified that the NMI-BF2/FBS nanoprobe shows an excellent photothermal antitumor therapeutic effect, guided by NIR-II fluorescence and photoacoustic imaging.

Oxidative stress plays a key role in aging and related diseases, including neurodegeneration, cancer, and organ failure. Copper (Cu), a redox-active metal ion, generates reactive oxygen species (ROS), and its dysregulation contributes to aging. Here, we develop activity-based imaging probes for the sensitive detection of Cu(I) and show that labile hepatic Cu activity increases with age, paralleling a decline in ALDH1A1 activity, a protective hepatic enzyme. We also observe an age-related decrease in hepatic glutathione (GSH) activity through noninvasive photoacoustic imaging. Using these probes, we perform longitudinal studies in aged mice treated with ATN-224, a Cu chelator, and demonstrate that this treatment improves Cu homeostasis and preserves ALDH1A1 activity. Our findings uncover a direct link between Cu dysregulation and aging, providing insights into its role and offering a therapeutic strategy to mitigate its effects.

In practical applications within the human body, it is often challenging to fully encompass the target tissue or organ, necessitating the use of limited-view arrays, which can lead to the loss of crucial information. Addressing the reconstruction of photoacoustic sensor signals in limited-view detection spaces has become a focal point of current research. In this study, we introduce a self-supervised network termed HIgh-quality Self-supervised neural representation (HIS), which tackles the inverse problem of photoacoustic imaging to reconstruct high-quality photoacoustic images from sensor data acquired under limited viewpoints. We regard the desired reconstructed photoacoustic image as an implicit continuous function in 2D image space, viewing the pixels of the image as sparse discrete samples. The HIS’s objective is to learn the continuous function from limited observations by utilizing a fully connected neural network combined with Fourier feature position encoding. By simply minimizing the error between the network’s predicted sensor data and the actual sensor data, HIS is trained to represent the observed continuous model. The results indicate that the proposed HIS model offers superior image reconstruction quality compared to three commonly used methods for photoacoustic image reconstruction.

Photoacoustic imaging (PAI) shows promise for skin cancer diagnosis by detecting chromophores like melanin, hemoglobin, lipids, and collagen. While most studies focus on malignant lesions, understanding normal skin variability across anatomical regions is crucial for validating PAI’s clinical application and its use in melanoma diagnosis. We assessed normal skin in 20 healthy volunteers from three different body locations using a clinical PAI system and compared suspicious looking pigmented skin lesions, including melanomas, to adjacent normal skin (n = 74). Higher deoxyhemoglobin levels were observed in the ankle compared to the cheek and volar forearm, while melanin, lipids, and collagen showed minimal variation. Patients with malignant lesions had significantly higher deoxyhemoglobin levels (p = 0.001) than adjacent normal skin, a difference not seen in benign lesions. These findings suggest that PAI may help diagnose malignancies by identifying increased vascularity in skin cancers, while anatomical differences should be considered during diagnostic work-up.

Despite its introduction in the 1970’s, it is only recent technology advances that have propelled growth in clinical optoacoustic (photoacoustic) imaging over the past decade. We analytically present the broad landscape of clinical optoacoustic applications in the context of these key technology advances, the unique contrast achieved, and the tissue biomarkers resolved. We then discuss current challenges and future opportunities to address the unmet clinical needs.

Purpose: Basal Cell Carcinoma (BCC), the most common subtype of non-melanoma skin cancers (NMSC), is prevalent worldwide and poses significant challenges due to their increasing incidence and complex treatment considerations. Existing clinical approaches, such as Mohs micrographic surgery, are time-consuming and labour-intensive, requiring meticulous layer-by-layer excision and examination, which can significantly extend the duration of the procedure. Current optical imaging solutions also lack the necessary spatial resolution, penetration depth, and contrast for effective clinical use.
Methods: Here, we introduce photoacoustic imaging, also known as optoacoustic imaging, based Multispectral Optoacoustic Tomography (MSOT) as a promising solution for non-invasive, high-resolution imaging in dermatology, which also measures hemodynamic changes. MSOT offers high isotropic resolution (80 μm), increased tissue penetration, and contrast-enhanced 3D spatial imaging map. For the first time, we integrated an automated level set image segmentation methodology on optoacoustic images to further enhance the precision in delineating tumor boundaries. Through this proof-of-concept study in 30 subjects, we demonstrate that this segmentation allows for precise measurement of tumor width, depth, and volume, aiding in preoperative tumor mapping and surgical planning.
Results: The MSOT measurements, validated against histology, achieved a correlation coefficient of 0.84 and 0.81 for width and depth respectively, ensuring reliable tumor metrics with a low margin of error.
Conclusion: Clinicians can use these tumor metrics to optimize treatment efficacy, while preserving healthy tissue and cosmetic outcomes. This advancement has the potential to revolutionize diagnostics and treatment, significantly improving the patient outcomes in managing NMSC.

Multispectral optoacoustic tomography is a promising medical imaging modality that combines light and sound to provide molecular imaging information at depths of several centimeters, based on the optical absorption of endogenous chromophores, such as hemoglobin. Assessment of inflammatory bowel disease has emerged as a promising clinical application of optoacoustic tomography. In this context, preclinical studies in animal models are essential to identify novel disease-specific imaging biomarkers and understand findings from emerging clinical pilot studies, however to-date, these studies have been limited by the precise identification of the bowel wall. Herein, a transrectal-absorber guide is applied, serving as a high-contrast landmark for 3D optoacoustic tomography of the colon. This study shows that guided multispectral optoacoustic tomography is able to measure changes in blood oxygenation status over the course of acute, chemically-induced colitis in mice and correlates with standard disease activity scores. This novel approach depicts intestinal hemoglobin composition non-invasively during murine inflammation. These results underscore the potential for optoacoustic imaging in translational inflammatory bowel disease research.

The use of combination therapies that employ a variety of cell death mechanisms has emerged as a promising avenue of research in the treatment of cancer. However, the optimization of therapeutic synergies when integrating different modes remains a significant challenge. To this end, we developed a multifunctional intelligent drug-carrying nanoparticle (DFMTCH NPs) based on the metal-organic framework MIL-100, loaded with doxorubicin (DOX) and disulfiram (DSF), coated with a Cu-tannic acid (Cu-TA) network and hyaluronic acid (HA), for the purpose of combined chemotherapy/chemodynamic/photothermal anti-cancer therapy. On the one hand, the DFMTCH NPs exhibited a range of therapeutic capabilities, including chemotherapy, photothermal therapy (PTT), and chemodynamic therapy (CDT), which collectively enhanced the anti-tumor efficacy of chemotherapeutic agents. In addition, DFMTCH NPs proved sensitive photoacoustic imaging (PAI) in image-guided therapy. On the other hand, DFMTCH NPs could produce reactive oxygen species (ROS) and consume glutathione (GSH) by amplifying cellular oxidative stress, while causing intracellular mitochondrial dysfunction, inducing effective cuproptosis/ferroptosis/apoptosis to inhibit tumor growth. Collectively, this work provided an innovative strategy for designing multifunctional nanoparticles for effective combination therapies to combat colorectal cancer (CRC).

Photoacoustic tomography (PAT) enables non-invasive cross-sectional imaging of biological tissues, but it fails to map the spatial variation of speed-of-sound (SOS) within tissues. While SOS is intimately linked to density and elastic modulus of tissues, the imaging of SOS distribution serves as a complementary imaging modality to PAT. Moreover, an accurate SOS map can be leveraged to correct for PAT image degradation arising from acoustic heterogeneities. Herein, we propose a method for SOS imaging using scanned photoacoustic beacons excited by short laser pulse with inversion reconstruction. Our method is based on photoacoustic reversal beacons (PRBs), which are small light-absorbing targets with strong photoacoustic contrast. We excite and scan a number of PRBs positioned at the periphery of the target, and the generated photoacoustic waves propagate through the target from various directions, thereby achieve spatial sampling of the internal SOS. By picking up the PRB signal using a graph-based dynamic programing algorithm, we formulate a linear inverse model for pixel-wise SOS reconstruction and solve it with iterative optimization technique. We validate the feasibility of the proposed method through simulations, phantoms, and ex vivo biological tissue tests. Experimental results demonstrate that our approach can achieve accurate reconstruction of SOS distribution. Leveraging the obtained SOS map, we further demonstrate significantly enhanced PAT image reconstruction with acoustic correction.