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Preclinical small animal imaging

Preclinical imaging is the visualization of living animals for research purposes. Imaging modalities that are non-invasive and in vivo have become very important to study animal models over a longer period of time. Broadly speaking, the imaging systems can be categorized into morphological/anatomical and molecular imaging techniques. Techniques such as high-frequency micro-ultrasound, magnetic resonance imaging (MRI) and computed tomography (CT) are usually used for anatomical imaging, while optical imaging (fluorescence and bioluminescence), positron emission tomography (PET), and single photon emission computed tomography (SPECT) are usually used for molecular visualizations.

These days preclinical research mostly uses multimodal systems, combining the advantages of anatomical modalities such as CT and MR with the functional imaging of PET and SPECT. The most common combinations are SPECT/CT, PET/CT and PET/MR.

Micro-Ultrasound

Vivo 2100Micro-ultrasound is specifically developed by Visualsonics for small animal research. Infinity houses the Vevo 2100 System. Contrast agents in the form of microbubbles, which have different acoustic properties from that of tissues, can be introduced into animal systems to highlight vasculature or be targeted towards specific receptors.

Micro-ultrasound is the only real-time imaging modality. It can visualize blood flow and cardiac function in vivo in mice. Capillaries can be imaged by the injection of microbubble contrast agents. 

As a downside, micro-ultrasound has a limited depth of penetration. As frequency increases (and so does resolution), maximum imaging depth decreases. Typically, micro-ultrasound can image tissue about 3 cm below the skin. This is more than sufficient for small animals such as mice and rats.

Micro MRI

Bruker BioSpin PharmaScanThe advantage of micro-MRI is the good spatial resolution. The Bruker BioSpin PharmaScan available at Infinity has up to 50µm structural resolution for excellent contrast between normal and pathological soft tissue. Micro-MRI can be used in a wide variety of applications, including anatomical, functional, and molecular imaging. It also has a wide range of sequences, making it fit well into a multimodal approach. Additionally, the technique uses no radiation. 

One of the biggest drawbacks of micro-MRI is the cost, both of the purchase and of the maintenance (helium). Furthermore the image acquisition times are long, spanning into minutes and sometimes hours. This may negatively affect animals that are anesthetized for long periods of time. 

Micro-CT

Flex Triumph IIMicro-CT is a good tool for examining tissue composed of elements of a relatively higher atomic number than the tissue surrounding them, such as bone and calcifications (calcium based) within the body (carbon based flesh), or of structures (vessels, bowel). The GE Triumph II CT, available at Infinity, is a high-resolution scanner (50 µm) with a large and variable field of view. 50 µm is about the limit of micro-CT, as the radiation dose to achieve higher resolutions would be lethal to small animals. Image acquisition times are only about 8-30 minutes for small animals. 

One of the major drawbacks of micro-CT is the radiation dosage placed on test animals. Although this is generally not lethal, the radiation is high enough to affect the immune system and other biological pathways. 

Micro-PET

Flex Triumph IIThe strength of micro-PET is that because the radiation source is within the animal, it has practically unlimited depth of imaging. The system at Infinity (GE Triumph II CT) has high sensitivity and a large field of view (axial 7,5cm, transverse 9cm), allowing dynamic imaging of the whole body of a mouse. Also, there is a micro-CT incorporated in the system. The acquisition time is reasonably fast, usually around minutes. Micro-PET is extremely sensitive to molecular details. 

However micro-PET has a few disadvantages. The systems are very expensive and often a cyclotron needs to be in close proximity to produce the radioisotopes (Radioactive isotopes used in micro-PET typically have very short half-lives). Micro-PET also suffers from poor spatial resolution (1,2 mm). In order to conduct a well-rounded research that involves not only molecular imaging but also anatomical imaging, micro-PET needs to be used in conjunction with micro-MRI or micro-CT, which is possible at Infinity.

Micro-SPECT

U-SPECT IIInfinity houses the Milabs U-SPECT II. The benefit of SPECT is that the nuclear isotopes are more readily available, cheaper, and have longer half-lives than micro-PET isotopes (hours or even days). Furthermore, the Infinity scanner has a very good spatial resolution (down to 300 µm) and an attached micro-CT.  

The downside to capturing γ-rays that are produced by the radioisotope is a less accurate prediction of the origin of the radiation, which translates into a lower resolution than micro-PET. Consequently, complementary systems such as micro-SPECT/MRI and micro-SPECT/CT are needed to provide a complete view of the test animals. Micro-SPECT also has a smaller field f view than micro-PET, so only part of the mouse or rat can be imaged.  

Optical Imaging

IVIS LuminaOptical imaging (Perkin Elmer IVIS Lumina II available at Infinity) is fast and easy to perform, and relatively inexpensive compared to many of the other imaging modalities. Furthermore it is in vivo, non-invasive and allows a large field of view. In bioluminescence imaging, a bioluminescent gene (for example from fireflies) is inserted to tumor cells, which in turn become bioluminescent. 

Fluoroscopic imaging involves coupling a fluorophore or fluorochrome to a molecule, which then travels to certain target locations in the body. No ionizing radiation is used in either process. 

A major weakness of optical imaging is the depth of penetration, which is only for a few millimeters. Optical imaging also has inferior spatial resolution compared to other modalities, only reaching from 1 to 10 mm. 

Small Animal radiotherapy

Infinity houses a SARRP (Small Animal Radiation research Platform) for high precision irradiation (1mm beam). The system incorporates CT imaging with precise radiation delivery to enable researchers to pinpoint an exact anatomical target and confidently deliver 0.5 mm beams to that point. Radiation therapy is a very important treatment for cancer patients worldwide. The SARRP enables researchers to assess existing treatment regimes and provide new results that can help to shape the future of radiation therapy. The automatically rotatable specimen stage allows radiation to be delivered at multiple angles without the need to reposition the animal between exposures.  

All the above techniques are available at Infinity in adjacent rooms. The animals are fixated on specially designed multimodal beds that fit in each imaging device, which means that the animal is scanned every time in exactly the same position. Images from different modalities can thus be overlaid accurately. Special hatches exist between the rooms to pass the animal from one device to another.  

Multimodality Imaging

To enable accurate localization of the disease process, functional and molecular imaging techniques are often combined with anatomical imaging systems into multimodality imaging systems. This integration can be achieved at different levels of complexity. Two systems can be relatively easy set up as a sequential system with a common bed so there is minimal interference and images of the patient are acquired in a sequential mode.

In order to scan an animal using two or more imaging modalities, it is important that the animal is kept motionless; so that it is scanned in exactly the same position during the different scans. To ensure this, Infinity has placed the different imaging technologies in adjacent rooms with special hatches between the rooms. The animals are fixated in multimodality beds, created to fit perfectly in every modality. This makes multimodality imaging possible, thus ensuring the most complete, detailed and accurate images. 

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