Computed tomography of an excised heart following transplantation of mesenchymal stem cells encapsulated with Barium sulfate. Multiple injections of the microcapsules are clearly visible throughout the heart.. Nuclear medicine uses radioactive isotopes to interrogate cellular and sub-cellular biological and metabolic processes. Generally, these radioactive isotopes or radionuclides are chemically bound to complexes designed to specifically target certain physiologic processes. These radioactive complexes, often referred to as tracers, are introduced into the body prior to imaging ie, frequently by intravenous injection.
Based on the design of the tracer, the disease process may either be identified by a large uptake of the radioactive tracer or exclusion of the tracer. PET imaging operates on the following principle.
The PET tracers emit positrons which annihilate with nearby electrons causing 2 gamma photons KeV to be emitted in opposite directions. The coincident detection of these emissions by multiple detectors in the PET scanner allows direct localization of the annihilation events. Specifically, statistical analysis and tomographic reconstruction are used to generate the 3D PET image. Additionally, this short half-life requires that tracers reach their target in a fairly expeditious manner..
The most common tracer molecule is fluorodeoxyglucose FDG , a sugar that is tagged with the 18 F isotope and used to investigate glucose metabolism. In clinical cardiology, [ 18 F]-FDG PET is most frequently used to identify "hibernating myocardium" or viable heart tissue with metabolically reduced function. Clinically, this hibernating myocardium is considered salvageable if revasculation is performed in the near future..
Though used extensively for viability imaging, PET is also capable of measuring perfusion, contractile function, substrate metabolism, oxygen consumption, autonomic innervation, and angio-genesis. Perhaps the strongest case for PET imaging in the context of cellular therapeutics is its capacity for cell tracking. Radiolabeling of cells for PET imaging can be performed directly with the radio-nuclide or by way of a reporter gene. Direct labeling involves incubation of cells with the radiotracer to allow sufficient uptake into the cells.
Recently, [ 18 F]-FDG has shown success in labeling and tracking tissue distribution of autologous bone marrow mononuclear cells and progenitor cells following intracoronary transplantation in post-infarct pig hearts. To date, there has been limited success direct labeling with other longer half-life PET isotopes. Furthermore, similar to magnetic labeling, detection of stem cells directly labeled with radionuclide labeling will be hindered if rapid cell proliferation occurs..
Recent advances in reporter gene-based cell labeling have extended the capabilities of PET imaging beyond short-term monitoring. Reporter genes encode for substances, such as enzymes or receptors, that will bind with a reporter probe. For labeling, a reporter gene is typically transfected exogenously into the cells. Following transplantation, imaging with a PET-specific radionuclide labeled reporter probe enables detection of the cells. More details on reporter gene cell labeling can be found in Bengel et al. Each approach has different advantages and disadvantages as outlined by Zhang et al.
For example, Wu et al 62 have published a study using HSV1-sr39tk as a PET reporter gene to track cell survival following intramyocardial transplantation of embryonic rat cardiomyoblasts. In that study, they demonstrated long-term survival of the cells out to 16 days. In a subsequent study by Cao et al 63 a novel triple fusion reporter gene for fluorescence, bioluminescence, and PET imaging was developed and used to study cell survival, proliferation, and migration of embryonic stem cells after delivery to the rat myocardium.
PET imaging using 9-[4- 18 F-fluoro hydroxymethyl butyl]guanine 18 F-FHBG confirmed survival and proliferation as indicated by an increase in PET signal and bioluminescence throughout the 4 week time course of the study. Figure 4. Endocardial mapping of a pig heart 16 days after myocardial infarction. Normal viability is represented by blue and pink colors.
Yellow and green colors represent decreased viability in the mid-distal anterior wall, and red represents non-viability at the heart apex. B: 13N ammonia PET with a transmission scan of the pig heart supine position 16 days after acute infarction indicating perfusion defect in the anterior wall and apex. No activity is seen in the posterior wall, where the non-transfected MSCs were injected.
Recently, PET reporter genes have been used in a relevant large animal model of reperfused myocar-dial infarction to track biodistribution after direct myocardial injection using an electrical mechanical mapping system. Single Photon Emission Computed Tomography. During a SPECT scan, the gamma camera is rotated around the subject and projection images are acquired.
Filtered back projection and iterative reconstruction are used to create a 3D volume of the 2D projection data. Synchronization of the SPECT acquisition with the electrocardiogram is commonly used when quantifying myocardial perfusion, thickness, contractility, and other measures of ventricular function.
SPECT imaging may also be used to assess viability, substrate metabolism, and cell death, 65 all of which can be important in assessing the efficacy of cell therapy and in understanding the mechanisms by which the cell therapies participate in treating the disease.. Direct labeling involves incubation of the cells with radioisotopes such as In oxine and has been shown to not affect the proliferative capacity of the cells or to negatively affect the surface or intracellular markers.
The cells were delivered intravenously to dogs at 3 days after creation of reperfused myocardial infarctions. SPECT imaging was performed at multiple time points up to 8 days post-injection. Although initial uptake was predominantly in the lungs with significant redistribution to the liver, focal and diffuse uptake to the heart was observed in several of the infarcted animals Figure 5 while no detection was observed in MR images. This study demonstrates the value of SPECT imaging for tracking the biodistribution and fate of the cells after intravenous delivery, and also shows its higher sensitivity for visualizing labeled cells compared to MRI..
Figure 5. Fused volume renderings of single photon emission tomograms red with computed tomograms gray of a dog immediately A , 24 h B , and 5 days C after intravenous administration of Indium oxine-labeled bone marrow-derived mesenchymal stem cells. Initial uptake A is predominantly in the lungs and redistributes to the spleen and heart by 24 h B.
At 5 days post-administration, the cells remain visible in the heart with further redistribution to the liver. Reprinted with permission from Kraitchman et al.
Reporter-gene labeling for SPECT is performed as described for PET imaging by just replacing the substrate label with a single photon emitting radioisotope. By using a dual-isotope approach, they were able to correct for physical effects such as cross-talk, scatter and attenuation, and subsequently obtain a quantitative evaluation of cell expression.
Recently, the research community and companies have begun integrating these nuclear medicine scanners with the CT and MRI scanners for precise image registration. Furthermore, the anatomical images can be used for attenuation correction to provide more accurate quantification of metabolic activity.. By presenting their capabilities in the context of their application to cellular therapeutics, this review has only scratched the surface of their full functionality.
However, it should provide a framework by which to begin to understand their importance. Furthermore, it should be stated that numerous other noninvasive modalities exist or are on the horizon 71 that promise to continue to push imaging capabilities for basic science research.. Section sponsored by Laboratorio Dr Esteve. Home Articles in press Current Issue Archive.
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Kraitchman b. Baltimore, Maryland, USA. Russell H. This item has received. Article information. Show more Show less. Cell therapy continues to be an active area of basic science research with early promise in the treatment of cardiovascular diseases. However, there are many unknowns including the mechanisms by which they work, the most useful cell types, the most efficient delivery strategies, and their safety.
Noninvasive imaging provides a wide array of tools to quantitatively address many of these unknowns. This article reviews echocardiography, magnetic resonance imaging, computed tomography, positron emission tomography and single photon emission tomography in the context of imaging cellular therapeutics to demonstrate how these modalities are being used to answer some of these questions.. Palabras clave:.
In principle, it enables in vivo interrogation of the therapeutic effects on anatomy and physiology while reducing the number of animals needed for experiments, allowing serial evaluation of the progression of disease and treatment response, and oftentimes providing more accurate quantitative measurements or even measurements not possible by any other means. For each modality, a brief description of the technology will be provided followed by examples of how that technology has been used to evaluate cell therapy efficacy and treatment strategy.
In this study, myocardial contrast echocardiography showed smaller infarct sizes and improved micro-vascular flow in ischemic border zones in treated animals; conventional echocardiography demonstrated higher fractional area shortening and improved cardiac synchrony. Intracoronary autologous bone-marrow cell transfer after myocardial infarction: the BOOST randomised controlled clinical trial.. Lancet, , pp. Intracoronary injection of CDpositive enriched bone marrow progenitor cells promotes cardiac recovery after recent myocardial infarction: feasibility and safety..
Circulation, Suppl 9 , pp. Improved clinical outcome after intracoronary administration of bone-marrow-derived progenitor cells in acute myocardial infarction: final 1-year results of the REPAIR-AMI trial.. Eur Heart J, 27 , pp. Intracoronary administration of bone marrow-derived progenitor cells improves left ventricular function in patients at risk for adverse remodeling after acute ST-segment elevation myocardial infarction: results of the reinfusion of enriched progenitor cells and infarct remodeling in acute myocardial infarction study REPAIR-AMI cardiac magnetic resonance imaging substudy..
Am Heart J, , pp. Cell therapy of acute myocardial infarction: Open questions.. Cardiology, , pp.
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Clinical utility of contrast-enhanced echocardiography.. Clin Cardiol, 29 , pp. II25 Medline. Molecular imaging of cardiovascular disease using ultrasound.. J Nucl Cardiol, 15 , pp. Transplantation of mesenchymal stem cells within a poly lactide-co-epsilon-caprolactone scaffold improves cardiac function in a rat myocardial infarction model.. Eur J Heart Fail, 11 , pp. Stem cell therapy improves myocardial perfusion and cardiac synchronicity: new application for echocardiography.. J Am Soc Echocardiogr, 20 , pp. In vivo echocardiographic imaging of transplanted human adult stem cells in the myocardium labeled with clinically applicable CliniMACs nanoparticles..
J Am Soc Echocardiogr, 19 , pp. Visualization of transplanted cells within the myocardium.. Int J Cardiol, , pp. Ultrasound-mediated microbubble destruction enhances the efficacy of bone marrow mesenchymal stem cell transplantation and cardiac function.. Clin Exp Pharmacol Physiol, 36 , pp. Standardized myocardial segmentation and nomenclature for tomographic imaging of the heart: a statement for healthcare professionals from the cardiac imaging committee of the council on clinical cardiology of the American Heart Association.. Circulation, , pp.
Cardiac repair with intramyocardial injection of allogeneic mesenchymal stem cells after myocardial infarction.. Dual in vivo magnetic resonance evaluation of magnetically labeled mouse embryonic stem cells and cardiac function at 1. Magn Reson Med, 55 , pp. Reduction in infarct size, but no functional improvement after bone marrow cell administration in a porcine model of reperfused myocardial infarction..
Forced myocardin expression enhances the therapeutic effect of human mesenchymal stem cells after transplantation in ischemic mouse hearts.. Stem Cells, 26 , pp. A placebo controlled, dose-ranging, safety study of allogenic mesenchymal stem cells injected by endomyocardial delivery after an acute myocardial infarction.. Eur Heart J, 29 , pp. Sustained persistence of transplanted proangiogenic cells contributes to neovascularization and cardiac function after ischemia..
Circ Res, , pp. Human heart: tagging with MR imaging-a method for noninvasive assessment of myocardial motion..
Industrial computed tomography cuts deep for applications beyond just porosity analysis.
Radiology, , pp. MR imaging of motion with spatial modulation of magnetization.. J Magn Reson, , pp. Complementary displacement-encoded MRI for contrast-enhanced infarct detection and quantification of myocardial function in mice.. Magn Reson Med, 51 , pp. Fast determination of regional myocardial strain fields from tagged cardiac images using harmonic phase MRI..
NMR Biomed, 20 , pp. Multimodality noninvasive imaging demonstrates in vivo cardiac regeneration after mesenchymal stem cell therapy.. J Am Coll Cardiol, 48 , pp. Relationship of MRI delayed contrast enhancement to irreversible injury, infarct age, and contractile function.. Simultaneous evaluation of infarct size and cardiac function in intact mice by contrast-enhanced cardiac magnetic resonance imaging reveals contractile dysfunction in noninfarcted regions early after myocardial infarction..
- What is Micro-CT? An Introduction!
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In vivo magnetic resonance imaging of mesenchymal stem cells in myocardial infarction.. Myocardial first-pass perfusion cardiovascular magnetic resonance: history, theory, and current state of the art.. J Cardiovasc Magn Reson, 10 , pp. Early improvement in cardiac tissue perfusion due to mesenchymal stem cells..
Bioenergetic and functional consequences of bone marrow-derived multipotent progenitor cell transplantation in hearts with postinfarction left ventricular remodeling.. Functional and bioenergetic modulations in the infarct border zone following autologous mesenchymal stem cell transplantation..
M, Kraitchman DL.. Monitoring cell therapy using iron oxide MR contrast agents.. Curr Pharm Biotechnol, 5 , pp. Magnetic tagging of therapeutic cells for MRI.. J Nucl Med, 50 , pp. Iron oxide MR contrast agents for molecular and cellular imaging.. Micro-CT is a 3D imaging technique utilizing X-rays to see inside an object, slice by slice. Samples can be imaged with pixel sizes as small as nanometers and objects can be scanned as large as millimeters in diameter. Micro-CT scanners capture a series of 2D planar X-ray images and reconstruct the data into 2D cross-sectional slices.
These slices can be further processed into 3D models and even printed as 3D physical objects for analysis. With 2D X-ray systems you can see through an object, but with the power of 3D micro- CT systems you can see inside the object and reveal its internal features. It provides volumetric information about the microstructure, nondestructively. X-rays are generated in an X-ray source, transmitted through the sample, and recorded by the X-ray detector as a 2D projection image.
The sample is then rotated a fraction of a degree on the rotational stage, and another X-ray projection image is taken. This step is repeated through a degree turn or sometimes degrees, depending on sample type. These slices can be analyzed, further processed into 3D models, made into movies, printed into 3D physical objects, and more. This allows the sample to be preserved for historical record, tested again at a later date, used in another test, or put into final production.
There are several techniques which allow samples to be imaged in their native states, including light microscopy, laser scanning, visible and other spectrum photography, and more. Micro-CT is one such technique where most of the samples studied are scanned in an unaltered state. It can be used to study the interior structure of both material and biological samples without having to cut the samples, preserving the samples or specimens for future studies. The quantitative information obtained from micro-CT scanning can only be obtained from 3D images, and 3D digital models created from micro-CT virtual slices allow scientists to measure any parameters for comparison in before-and-after studies.
What is the difference between medical CT and micro-CT scans? For materials science and small animal imaging, much higher resolution was needed, and micro-CT scanning was introduced in the s. Micro-CT scanners can work at the level of one micron, which is a thousandth of a millimeter, and smaller. What is the difference between in vivo and ex vivo micro-CT scanning? For micro-CT, in vivo typically refers to systems that scan mice and rats and in some cases rabbits, while ex vivo systems typically handle the remainder of the applications.