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Contrast Agent Development Application Note

TriTomTM Contrast Agent Develpoment

The development of novel optical imaging contrast agents requires extensive testing in both phantoms and animal models to ensure the safety and utility of the agent for in vivo applications. However, evaluating the biodistribution and clearance of a contrast agent remains challenging in preclinical studies due to limited whole-body real-time imaging technologies. The TriTom is a multimodal imaging platform that provides high-resolution photoacoustic (PA) and fluorescence (FL) images of small animal models. Here, we demonstrate TriTom analysis of a novel photoacoustic agent and highlight the system’s unique advantages for advancing optical contrast agent development.

SYSTEM SPECIFICATIONS

Imaging System        TriTomTM
Excitation Wavelengths   460 – 1300nm
Spatial Resolution    Up to 160 µm(PA)
                                           Up to 70 µm (FL)
Acquisition Time        36 s per scan

Contrast Agent Characterization

A critical step in developing novel photoacoustic contrast agents is determining the wavelength-dependent photoacoustic absorption spectrum. Indocyanine green (ICG) is a popular component of these agents, partly due to the ability to easily form J-aggregates (ICG-JA), which have increased stability and a stronger optical absorption in the NIR window. The TriTom provides high-resolution and high-sensitivity volumetric images of up to ten contrast agent samples in a single scan and requires minimal volumes (< 50 µL), which is beneficial for evaluating expensive or difficult-to-make contrast agents. Additionally, the ability to investigate multiple agents in a single scan allows for direct comparison to controls or other gold-standard references.

Figure 1: (a) Photoacoustic spectrum of ICG and ICG-JA measured with the TriTom. (b, c) 3D TriTom images of a sample phantom containing the same concentration of ICG and ICG-JA acquired with 780 nm (b) and 895 nm (c) laser excitation. Scale bar = 10 mm.
Data reproduced from [1]. 
Figure 2: Reconstructed PA coronal volumes showing the in vivo biodistribution of 0.4 mM ICG (left) compared to ICG-JA (right).  The TriTom’s high-resolution imaging allows for whole-body evaluation of contrast agent dynamics, accumulation, and clearance. (a) thoracic arteries; (b) spleen; (c) intestines; (d) liver (left lobe); (e) liver (median lobe). Scale bar = 10mm. [1] 
Contrast Biodistribution

Preclinical evaluation of the biodistribution and clearance of optical absorbers in healthy animal models are necessary to clinical translation of new contrast agents. However, these studies typically require large sample sizes or indirect measures due to inadequate tools for whole-body imaging. The TriTom provides high-resolution images of large volumes (> 30 cm3), enabling whole-body anatomical and molecular analysis of the contrast agent biodistribution. Further, the fast scan time (< 36 s) allows for functional imaging of the agent’s dynamics, physiologic interaction, and clearance mechanisms. These features allow for the direct, quantitative assessment of the agent in vivo, making the TriTom an ideal tool for developing novel optical contrast agents.

Figure 3: Molecular unmixing of ICG-JA (green) overlaid on the pre-injection anatomical image (black) acquired with 800 nm laser excitation [1]. The 3D TriTom images show the longitudinal accumulation of the targeted ICG-JAs in the vasculature and provide an in vivo molecular analysis of their clearance mechanism. (a) thoracic arteries; (b) CuSO2 fiducial; (c) intestines; (d) liver (left lobe); (e) liver (median lobe); (f) spleen). Scale bar = 5mm. 

References

[1] S. Singh et al., Photoacoustics 29 (100437), doi: 10.1016/j.pacs.2022.100437 (2023).

Anatomical Imaging Application Note

TriTom™ Photoacoustic Imaging Platform: Small Animal Anatomical Imaging

The ability to directly visualize and evaluate anatomical structures and biological processes in small animal models at the whole-body level is critical for understanding the pathophysiology of human diseases. The TriTom™ small animal imaging platform provides noninvasive high-resolution photoacoustic tomography (PAT) images that can be used to extract functional and anatomical information at the molecular level.

Whole Body Anatomical Imaging

Noninvasive whole-body imaging of small animals is crucial for understanding the fundamental relationship between anatomical structure and function. Optical methods have a high spatial resolution but suffer from shallow penetration depth (1-2 mm). Non-optical techniques such as MRI and PET provide the penetration depth but are costly, have long acquisition times, use ionizing radiation, or require exogenous contrast agents. Photoacoustic imaging takes advantage of the intrinsic optical properties of tissue, specifically hemoglobin, to provide high-resolution images of both superficial and deep blood-rich structures in murine models.

SYSTEM SPECIFICATIONS
Imaging System                      TriTomTM
Repetition Rate                       20 Hz
PA Excitation Range               532 nm &                              650-1300
(2300) nm
Figure 1: Whole-body anatomical PAT scan of a nu/nu nude mouse acquired at 800 nm laser excitation with the TriTom™. 
Functional Imaging

In addition to whole-body anatomical imaging, photoacoustic imaging can be utilized for functional imaging of physiological processes, which can include monitoring blood oxygenation, tumor growth, or therapeutic effects. Contrast agents, such as ICG, nanoparticles, etc., can be used to evaluate either blood-flow dynamics or for targeted imaging of vascular biomarkers. Here, we show high-resolution images of vasculature in the kidneys (Figure 2) and liver (Figure 3), demonstrating the ability to detect pathophysiological abnormalities in superficial and deep tissues.

Figure 2: PAT maximum intensity projection of the spine (1), left kidney (2), right kidney (3), and iliac arteries (4) acquired at 750 nm in a female nu/nu nude mouse. Scale bar = 5mm. 
Figure 3: PAT maximum intensity projection of the mouse liver collected with 750 nm laser excitation. ale bar = 5mm. 

Brain Imaging Application Note

Photoacoustic Neuroimaging with the TriTomTM

Brain imaging, or neuroimaging, is used to understand the relationship between brain function and behavior and study the underlying causes of neurological and psychiatric diseases. It is important in helping to understand the relationship between specific areas of the brain and what function they serve. Photoacoustic Imaging (PAI) relies on differential thermoelastic expansion. A pulsed laser light is used to illuminate a tissue of interest where the light is absorbed resulting in local heating and thermoelastic expansion. The produced pressure, or sound waves, are emitted and detected by high-frequency transducers allowing the signals to be processed into high-resolution images. Therefore, PAI combines the temporal and spatial resolution of ultrasound with the contrast and spectral nature of optics PAI is a noninvasive technique that can be used for multiple applications including brain imaging. It allows for an image of the brain with
micrometer-millisecond spatiotemporal resolution with sufficient penetration enabling the structural interrogation of the brain ranging from microscopic to macroscopic.

SYSTEM SPECIFICATIONS
Imaging System                       TriTomTM
Repetition Rate                        20 Hz
PA Excitation Range                532 nm &                                                 650-1300                                             (2300) nm
 
Figure 1: PAT composite image of the upper torso and brain of a female BALB/c mouse acquired post-mortem with 532 nm excitation (orange) and 750 nm (grey).
Photoacoustic Neuroimaging

Neuroimaging, or brain imaging, is a fundamental tool for evaluating and monitoring the structure and function of the brain. However, there is currently no single imaging method capable of accurately mapping the brain’s complex anatomy and physiologic processes. Photoacoustic tomography (PAT) is a noninvasive and non-ionizing imaging modality that can be used as a complementary tool to conventional imaging techniques used in preclinical neuroscience research such as magnetic resonance imaging (MRI), computed tomography (CT), and positron emission tomography (PET). PAT is capable of acquiring high contrast and resolution images of optical absorption with great depths. PAT relies on the detection of acoustic ultrasound waves generated following the optical absorption of laser light by chromophores, i.e., hemoglobin, in biologic tissue. A tissue’s properties are dependent on the tissue’s constituents such as water, fat, melanin, oxy-hemoglobin, and deoxy-hemoglobin. The combination of optical excitation with ultrasonic detection of PAI can provide complementary information to other modalities and offers many advantages such as providing portable technology and no harmful ionizing radiation. PAT can provide high-resolution, high-sensitivity images with or without exogenous contrast.

Figure 2: 2D transverse slices of the 750 nm PAT scans acquired at several vertical displacements. (1) arms, (2) cerebellum, (3) auricular artery, (4) cerebral artery, (5) medulla, (6) outline of brain, (7) transverse sinus, (8) confluence of sinus, (9) sublingual vein, (10) facial vein, (11) superficial temporal vein, (12) subarachnoid space, (13) right eye, (14) left eye, (15) optic track. Scale bar = 5 mm.
Figure 3: 10 mm thick coronal (left) and transverse (right) maximum intensity projection slabs of a PAT volume reconstructed from the 750 nm scan. (1) Superior sagittal sinus, (2) transverse sinus, (3) confluence of sinus, (4) cerebral artery, (5) auricular artery, (6) jugular vein, (7) brachial artery, (8) ophthalmic artery. Scale bar = 5 mm. 
PAT and MRI: Complimentary Imaging Modalities for Brain Imaging

MRI produces detailed images of organs and structures of the body by using large magnetic and radio waves and can acquire high-resolution images of brain structures over large volumes. However, it provides poor temporal resolution and it cannot be used to study fast hemodynamic responses and mechanisms. Optical imaging provides contrast for structural and functional imaging by exploiting diverse biological molecules present in tissues, but the optical scattering of the imaging technique limits the imaging depth.    Utilizing the imaging capability of single or multiple components of noninvasive imaging tools, PAT and MRI can bridge the limitations of conventional brain imaging techniques by compensating the limitations of each imaging modality.

Figure 4: PAT (left) and MRI (right) scans of two female BALB/c mice demonstrating the anatomical and functional information acquired with complementary imaging modalities. Scale bars = 10 mm.

Multifunctional PtCuTe Nanosheets with Strong ROS Scavenging and ROS-Independent Antibacterial Properties Promote Diabetic Wound Healing

Author(s): Yaru Guo, Shuai Ding, Changshuai Shang, Chenguang Zhang, Menggang Li, Qinghua Zhang, Lin Gu, Boon Chin Heng, Shihan Zhang, Feng Mei, Ying Huang, Xuehui Zhang, Mingming Xu, Jiuhui Jiang, Shaojun Guo, Xuliang Deng, Lili Chen

Abstract

Nanozymes, as one of the most efficient reactive oxygen species (ROS)-scavenging biomaterials, are receiving wide attention in promoting diabetic wound healing. Despite recent attempts at improving the catalytic efficiency of Pt-based nanozymes (e.g., PtCu, one of the best systems), they still display quite limited ROS scavenging capacity and ROS-dependent antibacterial effects on bacteria or immunocytes, which leads to uncontrolled and poor diabetic wound healing. Hence, a new class of multifunctional PtCuTe nanosheets with excellent catalytic, ROS-independent antibacterial, proangiogenic, anti-inflammatory, and immuno-modulatory properties for boosting the diabetic wound healing, is reported. The PtCuTe nanosheets show stronger ROS scavenging capacity and better antibacterial effects than PtCu. It is also revealed that the PtCuTe can enhance vascular tube formation, stimulate macrophage polarization toward the M2 phenotype and improve fibroblast mobility, outperforming conventional PtCu. Moreover, PtCuTe promotes crosstalk between different cell types to form a positive feedback loop. Consequently, PtCuTe stimulates a proregenerative environment with relevant cell populations to ensure normal tissue repair. Utilizing a diabetic mouse model, it is demonstrated that PtCuTe significantly facilitated the regeneration of highly vascularized skin, with the percentage of wound closure being over 90% on the 8th day, which is the best among the reported comparable multifunctional biomaterials.

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Cancer Imaging Application Note

Cancer Detection and Monitoring with the TriTomTM

Photoacoustic imaging has become a popular tool in preclinical cancer research as a noninvasive technique for monitoring tumor growth and therapeutic response. Specifically, photoacoustic imaging can provide high-sensitivity images of both superficial and deep vasculature and quantitative assessment of blood oxygen saturation without exogenous contrast. The TriTom small animal imaging platform provides high-resolution photoacoustic tomography (PAT) images, enabling whole-body in vivo anatomical, functional, and molecular analysis for longitudinal cancer studies.

SYSTEM SPECIFICATIONS
Imaging System                   TriTomTM
Excitation Wavelengths     460 – 1300nm
Spatial Resolution               Up to 160 µm (PA)                            
Up to 70 µm (FL)
Acquisition Time                 36 s per scan
Monitoring Microvascular Development

The microvascular network of a tumor not only regulates the supply of nutrients that contribute to growth and metastasis but influences the response to anticancer therapies. Preclinical studies of tumor growth and neovasculature development are, therefore, critical to fundamental cancer research and therapeutic development. The TriTom is a 3D imaging platform that can resolve the complex and size-varying blood vessels supplying the tumor and quantify the local density of microvessels. Further, the TriTom’s superior spatial resolution in all three anatomical planes allows for visualization and monitoring of the microvascular network from any angle. This unique advantage enables longitudinal monitoring of tumor vasculature development and evaluation of therapies targeting cancer blood supply.

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Figure 1: (a) TriTom observation of a tumor-bearing hairless mouse model and (b) corresponding MIP coronal slab constructed from TriTom data acquired with 700 and 1064 nm laser excitation. The high-resolution image shows the local tumor environment (red ROI) and supplying vascular structures (blue arrows). Scale bar = 5 mm.
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Figure 2: MIP coronal slabs encompassing anterior structures up to 10 mm deep in healthy (top) and tumor-bearing (bottom) mice. The reconstructed TriTom volumes show the high-resolution vascular anatomy maps produced by the TriTom without exogenous contrast agents. Additionally, the superior resolution in all three anatomical planes enables in vivo monitoring of tumor (orange ROI) growth and microvascular development (purple arrows). 1. Superficial lateral vein, 2. Intestines, 3. Superficial abdominal arteries, 4. Deep circumflex iliac artery, 5. Common iliac artery, 6. External iliac artery, 7. Lateral caudal vein. Scale bar = 5mm.
Tumor Growth Monitoring

Accurate noninvasive measurements of tumor size and morphology are crucial to evaluating the effects of novel therapies. However, current modalities provide an incomplete picture of the tumor environment due to poor spatial resolution and limited imaging depth. The TriTom is a high-resolution 3D imaging technology with superior molecular sensitivity in deep tissue. As a result, the TriTom images provide a detailed view of the tumor morphology and enable accurate longitudinal assessment of tumor growth. These key features make the TriTom a powerful tool for monitoring tumor growth, metastasis, and therapeutic response in preclinical cancer research.

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Figure 3:  in vivo evaluation of tumor growth. (a) High-resolution MIP of the 700 nm and 1064 nm TriTom volumes showing the tumor and its immediate environment. (b) Axial cross-section of the tumor noted by the dashed line in (a). This region corresponds to the H&E-stained tumor section (c) with corresponding structures (orange and yellow ROIs) and tumor microvasculature (arrows) identified and readily available for quantitative measurements. Scale bar = 1 mm.

Laser-Synthesized Germanium Nanoparticles as Biodegradable Material for Near-Infrared Photoacoustic Imaging and Cancer Phototherapy

Author(s): Iaroslav B. Belyaev, Ivan V. Zelepukin, Polina A. Kotelnikova, Gleb V. Tikhonowski, Anton A. Popov, Alina Yu. Kapitannikova, Jugal Barman, Alexey N. Kopylov, Daniil N. Bratashov, Ekaterina S. Prikhozhdenko, Andrei V. Kabashin, Sergey M. Deyev, Andrei V. Zvyagin

Abstract

Biodegradable nanomaterials can significantly improve the safety profile of nanomedicine. Germanium nanoparticles (Ge NPs) with a safe biodegradation pathway are developed as efficient photothermal converters for biomedical applications. Ge NPs synthesized by femtosecond-laser ablation in liquids rapidly dissolve in physiological-like environment through the oxidation mechanism. The biodegradation of Ge nanoparticles is preserved in tumor cells in vitro and in normal tissues in mice with a half-life as short as 3.5 days. Biocompatibility of Ge NPs is confirmed in vivo by hematological, biochemical, and histological analyses. Strong optical absorption of Ge in the near-infrared spectral range enables photothermal treatment of engrafted tumors in vivo, following intravenous injection of Ge NPs. The photothermal therapy results in a 3.9-fold reduction of the EMT6/P adenocarcinoma tumor growth with significant prolongation of the mice survival. Excellent mass-extinction of Ge NPs (7.9 L g−1 cm−1 at 808 nm) enables photoacoustic imaging of bones and tumors, following intravenous and intratumoral administrations of the nanomaterial. As such, strongly absorbing near-infrared-light biodegradable Ge nanomaterial holds promise for advanced theranostics.

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The development of ionizing radiation acoustic imaging (iRAI) for mapping the dose deep in the patient body during radiation therapy

Author(s): Wei Zhang, Dale Litzenberg, Yaocai Huang, Kai-Wei Chang, Ibrahim Oraiqat, Scott Hadley, Eduardo G. Moros, Man Zhang, Paul L. Carson, Kyle C. Cuneo, Issam EI Naqa, Xueding Wang

Abstract

Ionizing radiation acoustic imaging (iRAI) provides the potential to map the radiation dose during radiotherapy in real time. Described here is the development of iRAI volumetric imaging system in mapping the three-dimensional (3D) radiation dose deposition of clinical radiotherapy treatment plan with patient receiving radiation to liver tumor. The real-time visualizations of radiation dose delivered have been archived in patients with liver tumor under a clinical linear accelerator. This proof-of-concept study demonstrated the potential of iRAI to map the dose distribution in deep body during radiotherapy, potentially leading to personalized radiotherapy with optimal efficacy and safety.

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Toward in vivo dosimetry in external beam radiotherapy using x-ray acoustic computed tomography: A soft-tissue phantom study validation

Author(s): Hao Lei, Wei Zhang, Ibrahim Oraiqat, Zhipeng Liu, Jun Ni, Xueding Wang, Issam El Naqa

Abstract

Purpose: To study, using phantoms made from biological tissues, the feasibility and practical challenges of monitoring the position of the radiation beam and the deposited dose by x-ray acoustic computed tomography (XACT) during external beam radiotherapy delivery.

Material and methods: A prototype XACT system with a single immersion ultrasound transducer, which was positioned around the target sample driven by a motor-controlled rotation stage, was used to acquire the x-ray acoustic (XA) signals produced by a medical linear accelerator (Linac) to form an XACT image of the irradiated phantom. To investigate the feasibility of XACT in tracking the position of radiation dose, a large piece of veal liver with embedded fat tissue was imaged and beam misalignments were measured. Next, we explored the sensitivity of XACT in monitoring and quantifying the delivered dose, in which a block of porcine gel was embedded with equally spaced lard cylinders and imaged. The doses on the lard cylinders modulated by physical wedges were quantified from the XACT image and were verified by comparison to measurements from radiochromic films as the gold standard. Then, to simulate how XACT can perform in a targeted tissue in the human body, a porcine gel phantom with lard cylinders covered by different materials (bone, muscle, and air gap, respectively) was also imaged.

Results: The reconstructed XACT images of the phantoms show congruence with the boundaries of the beam field and the interfaces between the different tissue materials. The beam displacement from the target was tracked properly by the reconstructed XACT images. An intensity difference as small as 2.9% in delivered dose region can be measured from XACT images P = 0.02. The intensities of XACT images were highly correlated to the film measurements with an R2 better than 0.986. The expected variances of dose delivered to different target regions as a result of the difference in attenuation were successfully captured by the XACT images.

Conclusions: This study validated the feasibility of XACT in accurately obtaining relative dose maps of tissue-mimicking phantoms. XACT offers a practical method for verifying the beam position against the target and quantifying the relative dose delivered to the target during external beam radiotherapy.

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Custom Systems & Algorithms

PhotoSounds OEM line of products is an ideal starting point for the development of custom systems where the parallel acquisition of multiple channels is required. All our ADCs are streaming and allow the continuous acquisition of data straight to the receiving computer for processing or storage.

PhotoSound’s ADCs are feature-rich, they have multiple electronic and optical trigger inputs as well as programmable outputs that allow the timing control of additional devices. It is possible to combine multiple ADCs in parallel. Simultaneous acquisition of 4096 channels has been realized routinely.
Access to raw data as well as a user-friendly SDK allows for the easy development of any software and reconstruction algorithms.

PhotoSound Products Used

Legion ADC

Deep Learning Enabled Real-Time Photoacoustic Tomography System via Single Data Acquisition Channel

Y-Net: Hybrid Deep Learning Image Reconstruction for Photoacoustic Tomography In Vivo

Signal-domain speed-of-sound correction for ring-array-based photoacoustic tomography

Enhanced clinical photoacoustic vascular imaging through a skin localization network and adaptive weighting

3D Frequency-Domain Full Waveform Inversion for Whole-Breast Imaging With a Multi-Row Ring Array

Single Wavelength Reconstruction of Optical Absorption Coefficient and Elastic Modulus Utilizing Photoacoustic Tomography

TriTom

Spatiotemporal image reconstruction to enable high-frame-rate dynamic photoacoustic tomography with rotating-gantry volumetric imagers

Probing the photophysical properties of fluorescent proteins using photoacoustic pump-probe spectroscopy and imaging

Flash ADC

Utility of Low-Cost Multichannel Data Acquisition System for Photoacoustic Computed Tomography

GPU-Accelerated 3D Volumetric X-Ray-Induced Acoustic Computed Tomography

Author(s): Donghyun Lee, Eun-Yeong Park, Seongwook Choi, Hyeongsub Kim, Jung-joon Min, Changho Lee, and Chulhong Kim

ABSTRACT

X-ray acoustic imaging is a hybrid biomedical imaging technique that can acoustically monitor X-ray absorption distribution in biological tissues through the X-ray induced acoustic effect. In this study, we developed a 3D volumetric X-ray-induced acoustic computed tomography (XACT) system with a portable pulsed X-ray source and an arc-shaped ultrasound array transducer. 3D volumetric XACT images are reconstructed via the back-projection algorithm, accelerated by a custom-developed graphics processing unit (GPU) software. Compared with a CPU-based software, the GPU software reconstructs an image over 40 times faster. We have successfully acquired 3D volumetric XACT images of various lead targets, and this work shows that the 3D volumetric XACT system can monitor a high-resolution X-ray dose distribution and image X-ray absorbing structures inside biological tissues.

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