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Preclinical imaging
Preclinical imaging is the visualization of living animals for research purposes, such as drug development. Imaging modalities have long been crucial to the researcher in observing changes, either at the organ, tissue, cell, or molecular level, in animals responding to physiological or environmental changes. Imaging modalities that are non-invasive and in vivo have become especially important to study animal models longitudinally. Broadly speaking, these imaging systems can be categorized into primarily morphological/anatomical and primarily 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, many manufacturers provide multi-modal systems combining the advantages of anatomical modalities such as CT and MR with the functional imaging of PET and SPECT. As in the clinical market, common combinations are SPECT/CT, PET/CT and PET/MR.[citation needed]
Principle: High-frequency micro-ultrasound works through the generation of harmless sound waves from transducers into living systems. As the sound waves propagate through tissue, they are reflected back and picked up by the transducer, and can then be translated into 2D and 3D images. Micro-ultrasound is specifically developed for small animal research, with frequencies ranging from 15 MHz to 80 MHz.
Strengths: Micro-ultrasound is the only real-time imaging modality per se, capturing data at up to 1000 frames per second. This means that not only is it more than capable of visualizing blood flow in vivo, it can even be used to study high speed events such as blood flow and cardiac function in mice. Micro-ultrasound systems are portable, do not require any dedicated facilities, and is extremely cost-effective compared to other systems. It also does not run the risk of confounding results through side-effects of radiation. Currently, imaging of up to 30 μm is possible, allowing the visualization of tiny vasculature in cancer angiogenesis. To image capillaries, this resolution can be further increased to 3–5 μm with the injection of microbubble contrast agents. Furthermore, microbubbles can be conjugated to markers such as activated glycoprotein IIb/IIIa (GPIIb/IIIa) receptors on platelets and clots, αvβ3 integrin, as well as vascular endothelial growth factor receptors (VEGFR), in order to provide molecular visualization. Thus, it is capable of a wide range of applications that can only be achieved through dual imaging modalities such as micro-MRI/PET. Micro-ultrasound devices have unique properties pertaining to an ultrasound research interface, where users of these devices get access to raw data typically unavailable on most commercial ultrasound (micro and non-micro) systems.
Weaknesses: Unlike micro-MRI, micro-CT, micro-PET, and micro-SPECT, 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 of around 3 cm below the skin, and this is more than sufficient for small animals such as mice. The performance of ultrasound imaging is often perceived as to be linked with the experience and skills of the operator. However, this is changing rapidly as systems are being designed into user-friendly devices that produce highly reproducible results. One other potential disadvantage of micro-ultrasound is that the targeted microbubble contrast agents cannot diffuse out of vasculature, even in tumors. However, this may actually be advantageous for applications such as tumor perfusion and angiogenesis imaging.
Cancer Research: The advances in micro-ultrasound has been able to aid cancer research in a plethora of ways. For example, researchers can easily quantify tumor size in two and three dimensions. Not only so, blood flow speed and direction can also be observed through ultrasound. Furthermore, micro-ultrasound can be used to detect and quantify cardiotoxicity in response to anti-tumor therapy, since it is the only imaging modality that has instantaneous image acquisition. Because of its real-time nature, micro-ultrasound can also guide micro-injections of drugs, stem cells, etc. into small animals without the need for surgical intervention. Contrast agents can be injected into the animal to perform real-time tumor perfusion and targeted molecular imaging and quantification of biomarkers. Recently[when?], micro-ultrasound has even been shown to be an effective method of gene delivery.
Unlike conventional micro-ultrasound device with limited blood-flow sensitivity, dedicated real-time ultra fast ultrasound scanners with appropriate sequence and processing have been shown to be able to capture very subtle hemodynamic changes in the brain of small animals in real-time. This data can then be used to infer neuronal activity through the neurovascular coupling. The functional ultrasound imaging (fUS) technique can be seen as an analogue to functional magnetic resonance imaging (fMRI). fUS can be used for brain angiography, brain functional activity mapping, brain functional connectivity from mice to primates including awake animals.
Principle: Photoacoustic tomography (PAT) works on the natural phenomenon of tissues to thermalelastically expand when stimulated with externally applied electromagnetic waves, such as short laser pulses. This causes ultrasound waves to be emitted from these tissues, which can then be captured by an ultrasound transducer. The thermoelastic expansion and the resulting ultrasound wave is dependent on the wavelength of light used. PAT allows for complete non-invasiveness when imaging the animal. This is especially important when working with brain tumor models, which are notoriously hard to study.
Hub AI
Preclinical imaging AI simulator
(@Preclinical imaging_simulator)
Preclinical imaging
Preclinical imaging is the visualization of living animals for research purposes, such as drug development. Imaging modalities have long been crucial to the researcher in observing changes, either at the organ, tissue, cell, or molecular level, in animals responding to physiological or environmental changes. Imaging modalities that are non-invasive and in vivo have become especially important to study animal models longitudinally. Broadly speaking, these imaging systems can be categorized into primarily morphological/anatomical and primarily 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, many manufacturers provide multi-modal systems combining the advantages of anatomical modalities such as CT and MR with the functional imaging of PET and SPECT. As in the clinical market, common combinations are SPECT/CT, PET/CT and PET/MR.[citation needed]
Principle: High-frequency micro-ultrasound works through the generation of harmless sound waves from transducers into living systems. As the sound waves propagate through tissue, they are reflected back and picked up by the transducer, and can then be translated into 2D and 3D images. Micro-ultrasound is specifically developed for small animal research, with frequencies ranging from 15 MHz to 80 MHz.
Strengths: Micro-ultrasound is the only real-time imaging modality per se, capturing data at up to 1000 frames per second. This means that not only is it more than capable of visualizing blood flow in vivo, it can even be used to study high speed events such as blood flow and cardiac function in mice. Micro-ultrasound systems are portable, do not require any dedicated facilities, and is extremely cost-effective compared to other systems. It also does not run the risk of confounding results through side-effects of radiation. Currently, imaging of up to 30 μm is possible, allowing the visualization of tiny vasculature in cancer angiogenesis. To image capillaries, this resolution can be further increased to 3–5 μm with the injection of microbubble contrast agents. Furthermore, microbubbles can be conjugated to markers such as activated glycoprotein IIb/IIIa (GPIIb/IIIa) receptors on platelets and clots, αvβ3 integrin, as well as vascular endothelial growth factor receptors (VEGFR), in order to provide molecular visualization. Thus, it is capable of a wide range of applications that can only be achieved through dual imaging modalities such as micro-MRI/PET. Micro-ultrasound devices have unique properties pertaining to an ultrasound research interface, where users of these devices get access to raw data typically unavailable on most commercial ultrasound (micro and non-micro) systems.
Weaknesses: Unlike micro-MRI, micro-CT, micro-PET, and micro-SPECT, 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 of around 3 cm below the skin, and this is more than sufficient for small animals such as mice. The performance of ultrasound imaging is often perceived as to be linked with the experience and skills of the operator. However, this is changing rapidly as systems are being designed into user-friendly devices that produce highly reproducible results. One other potential disadvantage of micro-ultrasound is that the targeted microbubble contrast agents cannot diffuse out of vasculature, even in tumors. However, this may actually be advantageous for applications such as tumor perfusion and angiogenesis imaging.
Cancer Research: The advances in micro-ultrasound has been able to aid cancer research in a plethora of ways. For example, researchers can easily quantify tumor size in two and three dimensions. Not only so, blood flow speed and direction can also be observed through ultrasound. Furthermore, micro-ultrasound can be used to detect and quantify cardiotoxicity in response to anti-tumor therapy, since it is the only imaging modality that has instantaneous image acquisition. Because of its real-time nature, micro-ultrasound can also guide micro-injections of drugs, stem cells, etc. into small animals without the need for surgical intervention. Contrast agents can be injected into the animal to perform real-time tumor perfusion and targeted molecular imaging and quantification of biomarkers. Recently[when?], micro-ultrasound has even been shown to be an effective method of gene delivery.
Unlike conventional micro-ultrasound device with limited blood-flow sensitivity, dedicated real-time ultra fast ultrasound scanners with appropriate sequence and processing have been shown to be able to capture very subtle hemodynamic changes in the brain of small animals in real-time. This data can then be used to infer neuronal activity through the neurovascular coupling. The functional ultrasound imaging (fUS) technique can be seen as an analogue to functional magnetic resonance imaging (fMRI). fUS can be used for brain angiography, brain functional activity mapping, brain functional connectivity from mice to primates including awake animals.
Principle: Photoacoustic tomography (PAT) works on the natural phenomenon of tissues to thermalelastically expand when stimulated with externally applied electromagnetic waves, such as short laser pulses. This causes ultrasound waves to be emitted from these tissues, which can then be captured by an ultrasound transducer. The thermoelastic expansion and the resulting ultrasound wave is dependent on the wavelength of light used. PAT allows for complete non-invasiveness when imaging the animal. This is especially important when working with brain tumor models, which are notoriously hard to study.