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The family of Vevo® Imaging Systems from FUJIFILM VisualSonics, Inc. is leading to translational breakthroughs in the understanding of cancer progression and therapy. More specifically, high-frequency ultrasound and photoacoustic imaging of orthotopic and patient-derived xenograft (PDX) models of human cancer have empowered researchers in the past decade, with key translational findings on tumor growth and microenvironment and in response to new and existing cancer therapies. This Application Note focuses on the deep-tissue-imaging capabilities of micro-ultrasound and photoacoustic imaging that contributed to these translational findings. The Vevo Imaging Systems are the world's first commercially available high-frequency linear-array-based micro-ultrasound platforms. The family of products (Vevo 1100, 2100, 3100 and LAZR) has emerged as the gold standard in small animal in vivo imaging. The advanced system, Vevo LAZR, includes photoacoustics, a hybrid imaging modality that couples optical excitation with acoustic detection1. The Vevo ultrasound systems operate at frequencies of 30–70 MHz (compared to frequencies of 3–15 MHz for clinical ultrasound systems), allowing 30-μm spatial resolution, required for detailed imaging of cancer models generated in mice, rats and zebrafish, among others. They are portable systems; do not emit ionizing radiation; and are configured and designed specifically for non-invasive in vivo imaging, quantification and longitudinal-study data analysis. With these systems, cancer researchers are empowered with a composite of anatomical, functional, physiological and molecular data acquired simultaneously and sequentially in real time. Each Vevo imaging system is connected to a series of application-specific transducers that transmit and receive non-invasive ultrasound signals to generate real-time images. The animal under study is anesthetized and maintained on a heated platform, and key physiological parameters such as heart rate, temperature, respiration and electrocardiogram readings are captured in real time and time stamped. An additional accessory is an injection mount that allows for ultrasound-guided precision in gene or drug delivery, as reported in immunotherapy studies of head and neck cancers. Four-week-old female non-obese diabetic (NOD) severe combined immunodeficiency (SCID) mice (n = 2) were used for the surgical generation of orthotopic models of human pancreatic cancer, according to the University Health Network (UHN)-approved protocol for animal care and use. While the mice were under anesthesia, their abdominal skin and muscle were incised from the midline to allow for visualization and positioning of the pancreas lobes for direct implantation of human pancreatic cancer tissue. Successful implantation was confirmed using a dissection microscope, and mice were monitored as per the protocol approved by the Animal Care and Use Committee. Image acquisition and quantitation were performed with the Vevo LAZR Imaging System (FUJIFILM VisualSonics, Inc.). This system combines micro-ultrasound and photoacoustic imaging into a common platform. Light generated from a tunable laser (680–970 nm) was delivered through fiber optic bundles integrated into a linear-array ultrasonic transducer (LZ250, fc = 21 MHz; LZ550, fc = 50 MHz). Mice were imaged under isoflurane after implantation of pancreatic tumors (either 30 d or 15 d post-implantation). In this Application Note, we focus on five different data sets on the tumor and its microenvironment obtained by using the associated imaging modes on the Vevo Imaging Systems. The Vevo LAZR provides all of the various micro-ultrasound and photoacoustic imaging modes required to fully assess the tumor microenvironment. A 2D ultrasound of the abdominal cavity was acquired in brightness (B) mode in the transverse orientation (Fig. 1). The B-mode image is composed of regions of varying brightness or echogenicity. A prepalpable orthotopic pancreas tumor was identified 15 d post-implantation by its characteristic anatomy and size on ultrasound. This anatomy was defined by its depth below the skin line and its echogenicity relative to adjacent abdominal organs. The high frequency of 50 MHz clearly defined the tissue margins for 3D reconstruction of the tumor and adjacent abdominal organs, in vivo and in minutes. Ultrasound of tumors with volumes of up to 300 mm3 has been reported in subcutaneous and orthotopic models in longitudinal studies addressing drug efficacies. Sastra and Olive2 have published a detailed method report on the imaging of orthotopic pancreas tumors in vivo. Additional characterization is accomplished by imaging and quantifying changes in the tumor microenvironment. Tumor vascular density and the functionality of microvessels as small as 3 μm can be assessed using Doppler ultrasound imaging of slow blood flow (not shown) and contrast-enhanced ultrasound using gas-filled microbubbles (MicroMarker®), respectively. In Figure 2a the filling of microbubbles into a pancreas tumor is depicted as a heat map that plots the contrast-enhanced ultrasound signal as a function of the wash-in rate of the microbubbles. Based on these data, it can be inferred that this tumor is well perfused at its periphery and poorly perfused at its core. Figure 2b is a non-invasive characterization of another pancreas tumor in which the microvascular distribution is clearly heterogeneous. As reported recently3, 4, 5, tissue oxygenation—specifically, oxygen saturation consistent with hypoxia in the tumor—can be imaged and quantified in minutes. This characterization exploits the differing optical absorption of a dominant photoacoustic absorber called hemoglobin when it is oxygenated or deoxygenated. In fact, changing tissue vasculature is an aggressive phenotype in cancer progression6. Figure 2c shows an ultrasound image of the anatomy of an orthotopic pancreas tumor, and Figure 2d shows an oxygenation map of that tumor obtained using the Oxyhemo tool on the Vevo LAZR. This map characterizes the tumor as well oxygenated in its periphery and poorly oxygenated at its core. A rim of low oxygenation is evident at the interface of high oxygenation and no oxygenation. This rim was identified as positive for a hypoxic marker, as published in a separate report7. Contrast agents improve imaging by introducing a material into the bloodstream with acoustic or optical properties that differ from those of the tissues to be imaged. One commercially available molecular ultrasound agent is MicroMarker Target-Ready. This agent is coated with streptavidin and is ready for in vivo targeted imaging. Table 1 lists a selection of vascular markers for in vivo imaging with the targeted MicroMarker. The table also includes contrast agents that can be used for photoacoustic imaging of biomarkers such as markers of metastasis and stem cells, to name a few. Figure 3 shows spectrally unmixed molecular data obtained by photoacoustics that contrast with and simultaneously complement the positive nanoparticle signal detected by fluorescence. The Vevo Imaging Systems are the most comprehensive imaging solution in personalized and precision medicine. Many recent scientific insights on the relationship between functional tumor vasculature and onset of hypoxia were made possible by the combination of two or three of the described imaging modes, with high fidelity5, 8. Such insights were obtained through deep-tissue imaging of orthotopic models of the colon and pancreas3, 4, 7. In addition,cancer genetics has recently benefited from photoacoustic imaging of melanin in reporter constructs in investigations of the role of oncogenes or tumor-suppressor genes9. The complexity of cancer research can be addressed by the fusion of all five data sets from one live scan of a cancer model, in real time and at high resolution. Download references We are grateful to Drs. I. Lohse and D. Hedley for their kind gift of orthotopic models of pancreas cancer.

Screening and quantification of the tumor microenvironment with micro-ultrasound and photoacoustic imaging