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Anatomical imaging of orthotopic glioblastoma in mice using MSOT. (A) In vivo single wavelength (800 nm) optoacoustic image depicting the anatomy of an intact mouse brain with U87MG glioblastoma. The slice is at bregma +2 mm. Brain structures such as superior sagittal sinus (SSS, 1), middle cerebral artery (MCA, 2), superficial temporal arteries (TA, 3) and posterior communicating artery (PCA, 4) and altered symmetry at the right MCA (red arrow) are visible. (B) Difference of the optoacoustic images acquired at 850 and 800 nm, highlighting the tumor location and shape (red arrow). (C) T2 weighted MRI anatomy image of the corresponding brain slice with the hyperintense lesion (red arrow) representing the tumor. (D) Graph showing increase in tumor volume across different days post tumor inoculation calculated using the difference in OA signals at 850 and 800 nm (n = 3).
Source publication
Purpose:
Here we demonstrate the potential of multispectral optoacoustic tomography (MSOT), a new non-invasive structural and functional imaging modality, to track the growth and changes in blood oxygen saturation (sO2) in orthotopic glioblastoma (GBMs) and the surrounding brain tissues upon administration of a vascular disruptive agent (VDA).
Me...
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Context 1
... nCr nude mice with orthotopic U87 glioblastoma on the right cortex were used to examine the performance of MSOT to track the tumor growth and development. Strong optoacoustic signals were seen clearly in major blood vessels, such as superior sagittal sinus (SSS, 1), middle cerebral artery (MCA, 2), superficial temporal arteries (TA, 3) and posterior communicating artery (PCA, 4) in the brain cross- sectional image at bregma +2 mm recorded at a wavelength of 800 nm ( Figure 1A), the isosbestic point of hemoglobin absorption in the NIR region. Apart from the major blood vessels, strong optoacoustic signals could be seen from the cortex, in particular the right cortex and altered symmetry in right MCA (red arrow) suggesting the presence of tumor. The difference between the single-wavelength optoacoustic images acquired at 850 and 800 nm ((Diff 850-800 nm ) clearly revealed the tumor location ( Figure 1B). Interestingly, the shape of the hyperintense signals was similar to shape of the tumor observed on MRI anatomy scan ( Figure 1C). Moreover, the tumor dimensions measured by MSOT across the largest cross section were similar to those measured by the T2-weighted MRI anatomical images ( Figure S1). The same strategy was applied to images acquired pre and 3, 6 and 11 days post tumor cell inoculation ( Figure S2) to track the tumor growth and calculate the increase in the tumor volume ( Figure ...
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... nCr nude mice with orthotopic U87 glioblastoma on the right cortex were used to examine the performance of MSOT to track the tumor growth and development. Strong optoacoustic signals were seen clearly in major blood vessels, such as superior sagittal sinus (SSS, 1), middle cerebral artery (MCA, 2), superficial temporal arteries (TA, 3) and posterior communicating artery (PCA, 4) in the brain cross- sectional image at bregma +2 mm recorded at a wavelength of 800 nm ( Figure 1A), the isosbestic point of hemoglobin absorption in the NIR region. Apart from the major blood vessels, strong optoacoustic signals could be seen from the cortex, in particular the right cortex and altered symmetry in right MCA (red arrow) suggesting the presence of tumor. The difference between the single-wavelength optoacoustic images acquired at 850 and 800 nm ((Diff 850-800 nm ) clearly revealed the tumor location ( Figure 1B). Interestingly, the shape of the hyperintense signals was similar to shape of the tumor observed on MRI anatomy scan ( Figure 1C). Moreover, the tumor dimensions measured by MSOT across the largest cross section were similar to those measured by the T2-weighted MRI anatomical images ( Figure S1). The same strategy was applied to images acquired pre and 3, 6 and 11 days post tumor cell inoculation ( Figure S2) to track the tumor growth and calculate the increase in the tumor volume ( Figure ...
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... nCr nude mice with orthotopic U87 glioblastoma on the right cortex were used to examine the performance of MSOT to track the tumor growth and development. Strong optoacoustic signals were seen clearly in major blood vessels, such as superior sagittal sinus (SSS, 1), middle cerebral artery (MCA, 2), superficial temporal arteries (TA, 3) and posterior communicating artery (PCA, 4) in the brain cross- sectional image at bregma +2 mm recorded at a wavelength of 800 nm ( Figure 1A), the isosbestic point of hemoglobin absorption in the NIR region. Apart from the major blood vessels, strong optoacoustic signals could be seen from the cortex, in particular the right cortex and altered symmetry in right MCA (red arrow) suggesting the presence of tumor. The difference between the single-wavelength optoacoustic images acquired at 850 and 800 nm ((Diff 850-800 nm ) clearly revealed the tumor location ( Figure 1B). Interestingly, the shape of the hyperintense signals was similar to shape of the tumor observed on MRI anatomy scan ( Figure 1C). Moreover, the tumor dimensions measured by MSOT across the largest cross section were similar to those measured by the T2-weighted MRI anatomical images ( Figure S1). The same strategy was applied to images acquired pre and 3, 6 and 11 days post tumor cell inoculation ( Figure S2) to track the tumor growth and calculate the increase in the tumor volume ( Figure ...
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... nCr nude mice with orthotopic U87 glioblastoma on the right cortex were used to examine the performance of MSOT to track the tumor growth and development. Strong optoacoustic signals were seen clearly in major blood vessels, such as superior sagittal sinus (SSS, 1), middle cerebral artery (MCA, 2), superficial temporal arteries (TA, 3) and posterior communicating artery (PCA, 4) in the brain cross- sectional image at bregma +2 mm recorded at a wavelength of 800 nm ( Figure 1A), the isosbestic point of hemoglobin absorption in the NIR region. Apart from the major blood vessels, strong optoacoustic signals could be seen from the cortex, in particular the right cortex and altered symmetry in right MCA (red arrow) suggesting the presence of tumor. The difference between the single-wavelength optoacoustic images acquired at 850 and 800 nm ((Diff 850-800 nm ) clearly revealed the tumor location ( Figure 1B). Interestingly, the shape of the hyperintense signals was similar to shape of the tumor observed on MRI anatomy scan ( Figure 1C). Moreover, the tumor dimensions measured by MSOT across the largest cross section were similar to those measured by the T2-weighted MRI anatomical images ( Figure S1). The same strategy was applied to images acquired pre and 3, 6 and 11 days post tumor cell inoculation ( Figure S2) to track the tumor growth and calculate the increase in the tumor volume ( Figure ...
Context 5
... nCr nude mice with orthotopic U87 glioblastoma on the right cortex were used to examine the performance of MSOT to track the tumor growth and development. Strong optoacoustic signals were seen clearly in major blood vessels, such as superior sagittal sinus (SSS, 1), middle cerebral artery (MCA, 2), superficial temporal arteries (TA, 3) and posterior communicating artery (PCA, 4) in the brain cross- sectional image at bregma +2 mm recorded at a wavelength of 800 nm ( Figure 1A), the isosbestic point of hemoglobin absorption in the NIR region. Apart from the major blood vessels, strong optoacoustic signals could be seen from the cortex, in particular the right cortex and altered symmetry in right MCA (red arrow) suggesting the presence of tumor. The difference between the single-wavelength optoacoustic images acquired at 850 and 800 nm ((Diff 850-800 nm ) clearly revealed the tumor location ( Figure 1B). Interestingly, the shape of the hyperintense signals was similar to shape of the tumor observed on MRI anatomy scan ( Figure 1C). Moreover, the tumor dimensions measured by MSOT across the largest cross section were similar to those measured by the T2-weighted MRI anatomical images ( Figure S1). The same strategy was applied to images acquired pre and 3, 6 and 11 days post tumor cell inoculation ( Figure S2) to track the tumor growth and calculate the increase in the tumor volume ( Figure ...
Citations
... For instance, melanin and hemoglobin can be differentiated one from another using 584 and 764 nm. 115,116,120 MPAI has been used to study numerous diseases, including prostate cancer, 121 glioblastoma, 122,123 ovarian cancer, 124 thyroid disease, 125,126 Crohn's disease, 86 liver disease, 127 cardiac injury, 128 systemic sclerosis, 129 and cutaneous tumors. 130,131 In terms of applications, PAI can also be categorized with regards to the type of questions that the imaging modality can be used to answer, namely, fitness of each PAI system to determine: (a) melanoma detection and depth measurement, (b) tumor angiogenesis, (c) lymph node metastases, (d) CTCs, and (e) virtual histology (see Fig. 2). ...
Significance
Cutaneous melanoma (CM) has a high morbidity and mortality rate, but it can be cured if the primary lesion is detected and treated at an early stage. Imaging techniques such as photoacoustic (PA) imaging (PAI) have been studied and implemented to aid in the detection and diagnosis of CM.
Aim
Provide an overview of different PAI systems and applications for the study of CM, including the determination of tumor depth/thickness, cancer-related angiogenesis, metastases to lymph nodes, circulating tumor cells (CTCs), virtual histology, and studies using exogenous contrast agents.
Approach
A systematic review and classification of different PAI configurations was conducted based on their specific applications for melanoma detection. This review encompasses animal and preclinical studies, offering insights into the future potential of PAI in melanoma diagnosis in the clinic.
Results
PAI holds great clinical potential as a noninvasive technique for melanoma detection and disease management. PA microscopy has predominantly been used to image and study angiogenesis surrounding tumors and provide information on tumor characteristics. Additionally, PA tomography, with its increased penetration depth, has demonstrated its ability to assess melanoma thickness. Both modalities have shown promise in detecting metastases to lymph nodes and CTCs, and an all-optical implementation has been developed to perform virtual histology analyses. Animal and human studies have successfully shown the capability of PAI to detect, visualize, classify, and stage CM.
Conclusions
PAI is a promising technique for assessing the status of the skin without a surgical procedure. The capability of the modality to image microvasculature, visualize tumor boundaries, detect metastases in lymph nodes, perform fast and label-free histology, and identify CTCs could aid in the early diagnosis and classification of CM, including determination of metastatic status. In addition, it could be useful for monitoring treatment efficacy noninvasively.
... The reconstruction-unmixing processing steps are described in the methods section. The enhanced quantitative performance achieved with the NNMB method has been previously demonstrated in phantom studies [47] and in brain imaging data (orthotopic glioblastoma model) [49]. ...
Emerging evidence indicates crosstalk between the brain and hematopoietic system following cerebral ischemia. Here, we investigated metabolism and oxygenation in the spleen and spinal cord in a transient middle cerebral artery occlusion (tMCAO) model. Sham-operated and tMCAO mice underwent [ 18 F]fluorodeoxyglucose (FDG)-positron emission tomography (PET) to assess glucose metabolism. Naïve, sham-operated and tMCAO mice underwent multispectral optoacoustic tomography (MSOT) assisted by quantitative model-based reconstruction and unmixing algorithms for accurate mapping of oxygenation patterns in peripheral tissues at 24 h after reperfusion. We found increased [ 18 F]FDG uptake and reduced MSOT oxygen saturation, indicating hypoxia in the thoracic spinal cord of tMCAO mice compared with sham-operated mice but not in the spleen. Reduced spleen size was observed in tMCAO mice compared with sham-operated mice ex vivo. tMCAO led to an increase in the numbers of mature T cells in femoral bone marrow tissues, concomitant with a stark reduction in these cell subsets in the spleen and peripheral blood. The combination of quantitative PET and MSOT thus enabled observation of hypoxia and increased metabolic activity in the spinal cord of tMCAO mice at 24 h after occlusion compared to sham-operated mice.
... Recently, hand-held systems have also been used in a number of clinical trials further demonstrating the powerful capabilities of this imaging technology for diagnosis of medically-relevant conditions [4][5][6]. The optical-absorption-based contrast of OAT provides unique advantages for resolving spectrally-distinctive functional contrast from tissue chromophores [7,8], retrieving molecular information from targeted and genetically-encoded agents [9][10][11][12], sensing local temperature changes [13][14][15], as well as high-resolution imaging of rapid biological dynamics [16][17][18][19][20][21][22]. However, the use of OAT by biomedical researchers and physicians is largely hampered by the bulky and costly solutions associated with conventional nanosecond laser pulsing technologies. ...
Optoacoustic tomography is commonly performed with bulky and expensive short-pulsed solid-state lasers providing high per-pulse energies in the millijoule range. Light emitting diodes (LEDs) represent a cost-effective and portable alternative for optoacoustic signal excitation that can additionally provide excellent pulse-to-pulse stability. Herein, we introduce a full-view LED-based optoacoustic tomography (FLOAT) system for deep tissue in vivo imaging. It is based on a custom-made electronic unit driving a stacked array of LEDs, which attains 100 ns pulse width and highly stable (0.62 % standard deviation) total per-pulse energy of 0.48 mJ. The illumination source is integrated into a circular array of cylindrically-focused ultrasound detection elements to result in a full-view tomographic configuration, which plays a critical role in circumventing limited-view effects, enhancing the effective field-of-view and image quality for cross-sectional (2D) imaging. We characterized the FLOAT performance in terms of pulse width, power stability, excitation light distribution, signal-to-noise and penetration depth. FLOAT of the human finger revealed a comparable imaging performance to that achieved with the standard pulsed Nd:YAG laser. It is anticipated that this compact, affordable and versatile illumination technology will facilitate optoacoustic imaging developments in resource-limited settings for biological and clinical applications.
... In the malignant progression of GBM, tumor angiogenesis destroys the original microcirculation system [38,39]. Previous in vivo brain multispectral optoacoustic tomography (MSOT) studies have visualized brain features and deoxygenated hemoglobin in the growing brain tumor [40,41]. They demonstrated the potential of PACT to track the growth and changes in blood oxygen saturation (sO 2 ) in orthotopic GBMs and the surrounding brain tissues. ...
Simultaneous spatio-temporal description of tumor microvasculature, blood-brain barrier, and immune activity is pivotal to understanding the evolution mechanisms of highly aggressive glioblastoma, one of the most common primary brain tumors in adults. However, the existing intravital imaging modalities are still difficult to achieve it in one step. Here, we present a dual-scale multi-wavelength photoacoustic imaging approach cooperative with/without unique optical dyes to overcome this dilemma. Label-free photoacoustic imaging depicted the multiple heterogeneous features of neovascularization in tumor progression. In combination with classic Evans blue assay, the microelectromechanical system based photoacoustic microscopy enabled dynamic quantification of BBB dysfunction. Concurrently, using self-fabricated targeted protein probe (αCD11b-HSA@A1094) for tumor-associated myeloid cells, unparalleled imaging contrast of cells infiltration associated with tumor progression was visualized by differential photoacoustic imaging in the second near-infrared window at dual scale. Our photoacoustic imaging approach has great potential for tumor-immune microenvironment visualization to systematically reveal the tumor infiltration, heterogeneity, and metastasis in intracranial tumors.
... To avoid negative-value artifacts present in the images reconstructed with standard back projection algorithms [26]. MSOT images were processed with a dedicated non-negative constrained model-based (NNMB) reconstruction-unmixing framework [41], which is also known to facilitate quantification of oxygenation values in the images [43]. Specifically, images corresponding to different excitation wavelengths were first reconstructed with an NNMB algorithm. ...
... The copyright holder for this preprint this version posted August 14, 2022. ; https://doi.org/10.1101/2022.08.11.503550 doi: bioRxiv preprint viously demonstrated in phantom studies [41] and in brain imaging data (orthotopic glioblastoma model) [43]. We compared the signal intensities of the images obtained with the custom-made NNMB reconstruction-unmixing framework with those of the images obtained with the standard MB approach integrated in the MSOT software package (Figs. ...
Emerging evidence indicates crosstalk between the brain and the hematopoietic system follow-ing cerebral ischemia. Here, we investigated metabolism and oxygenation in the spleen and spinal cord in a transient middle cerebral artery occlusion (tMCAO) mouse model that is wide-ly used in focal cerebral ischemia research. Naive, sham and tMCAO mice underwent positron emission tomography (PET) using [18F]fluorodeoxyglucose (FDG) for assessing glucose me-tabolism and multispectral optoacoustic tomography (MSOT) assisted with quantitative model-based reconstruction and unmixing algorithms for accurate mapping of oxygenation patterns in the peripheral tissues at 24 h after reperfusion. We found increased levels of [18F]FDG uptake and reduced MSOT oxygen saturation, indicating hypoxia in the thoracic spinal cord of tMCAO mice compared with sham-operated mice but not in the spleen. A positive correlation was observed between splenic and ipsilateral striatal [18F]FDG uptake. Reduced spleen size was observed in tMCAO mice compared with sham-operated mice ex vivo. tMCAO led to a significant increase in the numbers of mature T cells (CD4 and CD8) in femoral bone marrow tissues, concomitant with a stark reduction in these cell subsets in the spleen and their decrease in periph-eral blood. The numbers of mature granulocytes (determined as CD11b+Gr1hi cells) decreased in bone marrow tissues and blood but increased in the spleen. The combination of quantitative PET and MSOT thus enabled the observation of hypoxia and increased metabolic activity in the spinal cord of tMCAO mice at 24 h after occlusion compared to sham-operated mice.
... In particular, its five-dimensional (real-time spectroscopic three-dimensional) imaging capability enabled new insights into large-scale neuronal activity and the accompanying hemodynamic changes [14][15][16]. Moreover, MSOT imaging of optical probes targeting amyloid-beta deposits and tau fibrils has enabled visualizing specific accumulation of aggregates in animal models of AD, multiparametric characterization of glioblastoma tumors, and neuroinflammation in ischemic stroke [17][18][19][20][21][22][23][24], which may serve to define new diagnostic biomarkers. MSOT imaging, however, faces similar transcranial imaging challenges as fUS. ...
... In particular, its five-dimensional (real-time spectroscopic three-dimensional) imaging capability enabled new insights into large-scale neuronal activity and the accompanying hemodynamic changes [14][15][16]. Moreover, MSOT imaging of optical probes targeting amyloid-beta deposits and tau fibrils has enabled visualizing specific accumulation of aggregates in animal models of AD, multiparametric characterization of glioblastoma tumors, and neuroinflammation in ischemic stroke [17][18][19][20][21][22][23][24], which may serve to define new diagnostic biomarkers. MSOT imaging, however, faces similar transcranial imaging challenges as fUS. ...
Imaging modalities capable of visualizing the human brain have led to major advances in neurology and brain research. Multi-spectral optoacoustic tomography (MSOT) has gained importance for studying cerebral function in rodent models due to its unique capability to map changes in multiple hemodynamic parameters and to directly visualize neural activity within the brain. The technique further provides molecular imaging capabilities that can facilitate early disease diagnosis and treatment monitoring. However, transcranial imaging of the human brain is hampered by acoustic attenuation and other distortions introduced by the skull. Here, we demonstrate noninvasive transcranial MSOT angiography through the temporal bone of an adult healthy volunteer. Time-of-flight (TOF) magnetic resonance angiography (MRA) and T 1 -weighted structural MRI were further acquired to facilitate anatomical registration and interpretation. The superior middle cerebral vein in the temporal cortex was identified in the MSOT images, matching its location observed in the TOF-MRA images. These initial results pave the way toward the application of MSOT in clinical brain imaging.
... d Time traces of the normalized FONT data. Gray traces represent tetrodotoxin (TTX) injected 180 s before PTZ (t = 0 s), abolishing the activation; e no signal change due to PTZ injection are detected in a control isolated CD-1 mouse brain not expressing GCaMP6f proteins; f temporal evolution of the relative signal changes (ΔOA/OA 0 ) in slices at depths of 0.7 mm and 1.1 mm in a GCaMP6f-expressing brain [111]. They showed in a glioblastoma model that the tumor has a hyperoxic and hypoxic phase during growth. ...
... The arcAβ model of amyloidosis exhibits strong vascular dysfunction [136][137][138]. Tissue oxygenation and CBF were respectively measured in arcAβ mice by means of MSOT and MRI [111]. Cerebral metabolic rate of oxygen was subsequently calculated based on these metrics, which was found significantly lower in aged arcAβ mice versus young mice and wild type controls. ...
The ability to non-invasively visualize endogenous chromophores and exogenous probes and sensors across the entire rodent brain with the high spatial and temporal resolution has empowered optoacoustic imaging modalities with unprecedented capacities for interrogating the brain under physiological and diseased conditions. This has rapidly transformed optoacoustic microscopy (OAM) and multi-spectral optoacoustic tomography (MSOT) into emerging research tools to study animal models of brain diseases. In this review, we describe the principles of optoacoustic imaging and showcase recent technical advances that enable high-resolution real-time brain observations in preclinical models. In addition, advanced molecular probe designs allow for efficient visualization of pathophysiological processes playing a central role in a variety of neurodegenerative diseases, brain tumors, and stroke. We describe outstanding challenges in optoacoustic imaging methodologies and propose a future outlook.
... In particular, a 3D optoacoustic technique known as multispectral optoacoustic tomography (MSOT) provides robust, real-time assessment of vascular function and blood oxygenation at several centimeters of tissue depth, in addition to anatomical information, by acquiring data at multiple wavelengths [26]. To date, the technique has been applied in various preclinical therapeutic studies of engrafted tumors in mice [27][28][29][30][31][32] and is currently in clinical trials [33][34][35]. Nonetheless, the dependence of optical fluence on tissue composition, depth and wavelength (an effect known as "spectral coloring") poses a major challenge to spectral unmixing and confounds quantification of hemoglobin oxygen saturation (sO2), especially with increasing imaging depth. ...
Non-invasive monitoring of hemodynamic tumor responses to chemotherapy could provide unique insights into the development of therapeutic resistance and inform therapeutic decision-making in the clinic.
Methods: Here, we examined the longitudinal and dynamic effects of the common chemotherapeutic drug Taxotere on breast tumor (KPL-4) blood volume and oxygen saturation using eigenspectra multispectral optoacoustic tomography (eMSOT) imaging over a period of 41 days. Tumor vascular function was assessed by dynamic oxygen-enhanced eMSOT (OE-eMSOT). The obtained in vivo optoacoustic data were thoroughly validated by ex vivo cryoimaging and immunohistochemical staining against markers of vascularity and hypoxia.
Results: We provide the first preclinical evidence that prolonged treatment with Taxotere causes a significant drop in mean whole tumor oxygenation. Furthermore, application of OE-eMSOT showed a diminished vascular response in Taxotere-treated tumors and revealed the presence of static blood pools, indicating increased vascular permeability.
Conclusion: Our work has important translational implications and supports the feasibility of eMSOT imaging for non-invasive assessment of tumor microenvironmental responses to chemotherapy.
... We acquired PAUS data of the patients in real time and postprocessed the data for off-line multispectral analysis ( Supplementary Fig. S1). When the system was switched to the data acquisition mode, the laser system consecutively produced five wavelengths (700, 756, 796, 866, and 900 nm, Supplementary Fig. S2) for multispectral analysis (41)(42)(43)(44), and the US machine stored the acquired PAUS data for each wavelength in the order of the wavelength series. We defined the acquired PA data from one series of wavelengths as a packet. ...
Thyroid cancer is one of the most common cancers, with a global increase in incidence rate for both genders. Ultrasound-guided fine-needle aspiration is the current gold standard to diagnose thyroid cancers, but the results are inaccurate, leading to repeated biopsies and unnecessary surgeries. To reduce the number of unnecessary biopsies, we explored the use of multiparametric photoacoustic (PA) analysis in combination with the American Thyroid Association (ATA) Guideline (ATAP). In this study, we performed in vivo multispectral PA imaging on thyroid nodules from 52 patients, comprising 23 papillary thyroid cancer (PTC) and 29 benign cases. From the multispectral PA data, we calculated hemoglobin oxygen saturation level in the nodule area, then classified the PTC and benign nodules with multiparametric analysis. Statistical analyses showed that this multiparametric analysis of multispectral PA responses could classify PTC nodules. Combining the photoacoustically indicated probability of PTC and the ATAP led to a new scoring method that achieved a sensitivity of 83% and a specificity of 93%. This study is the first multiparametric analysis of multispectral PA data of thyroid nodules with statistical significance. As a proof of concept, the results show that the proposed new ATAP scoring can help physicians examine thyroid nodules for fine-needle aspiration biopsy, thus reducing unnecessary biopsies.
Significance
This report highlights a novel photoacoustic scoring method for risk stratification of thyroid nodules, where malignancy of the nodules can be diagnosed with 83% sensitivity and 93% specificity.
