Biomedical subjects

Laurence W Hedlund

Publications and source records attributed to Laurence W Hedlund.

14 recordsLinked to original sources

PubMed2006

Imaging alveolar-capillary gas transfer using hyperpolarized 129Xe MRI.

Effective pulmonary gas exchange relies on the free diffusion of gases across the thin tissue barrier separating airspace from the capillary red blood cells (RBCs). Pulmonary pathologies, such as inflammation, fibrosis, and edema, which cause an increased blood-gas barrier thickness, impair the efficiency of this exchange. However, definitive assessment of such gas-exchange abnormalities is challenging, because no methods currently exist to directly image the gas transfer process. Here we exploit the solubility and chemical shift of (129)Xe, the magnetic resonance signal of which has been enhanced by 10(5) with hyperpolarization, to differentially image its transfer from the airspaces into the tissue barrier spaces and RBCs in the gas exchange regions of the lung. Based on a simple diffusion model, we estimate that this MR imaging method for measuring (129)Xe alveolar-capillary transfer is sensitive to changes in blood-gas barrier thickness of approximately 5 microm. We validate the successful separation of tissue barrier and RBC images and show the utility of this method in a rat model of pulmonary fibrosis where (129)Xe replenishment of the RBCs is severely impaired in regions of lung injury.

Animals↗

PubMed2006

Imaging methods for morphological and functional phenotyping of the rodent heart.

Small animal imaging has a critical role in phenotyping, drug discovery, and in providing a basic understanding of mechanisms of disease. Translating imaging methods from humans to small animals is not an easy task. The purpose of this work is to compare two cardiac imaging modalities, i.e., magnetic resonance microscopy (MRM) and microcomputed tomography (CT) for preclinical studies on rodents. We present the two technologies, the parameters that they can measure, the types of alterations that they can detect, and show how these imaging methods compare to techniques available in clinical medicine. While this paper does not refer per se to the cardiac risk assessment for drug or chemical development, we hope that the information will effectively address how MRM and micro-CT might be exploited to measure biomarkers critical for safety assessment.

Animals↗

PubMed2006

A liposomal nanoscale contrast agent for preclinical CT in mice.

OBJECTIVE: The goal of this study was to determine if an iodinated, liposomal contrast agent could be used for high-resolution, micro-CT of low-contrast, small-size vessels in a murine model. MATERIALS AND METHODS: A second-generation, liposomal blood pool contrast agent encapsulating a high concentration of iodine (83-105 mg I/mL) was evaluated. A total of five mice weighing between 20 and 28 g were infused with equivalent volume doses (500 microL of contrast agent/25 g of mouse weight) and imaged with our micro-CT system for intervals of up to 240 min postinfusion. The animals were anesthetized, mechanically ventilated, and vital signs monitored allowing for simultaneous cardiac and respiratory gating of image acquisition. RESULTS: Initial enhancement of about 900 H in the aorta was obtained, which decreased to a plateau level of approximately 800 H after 2 hr. Excellent contrast discrimination was shown between the myocardium and cardiac blood pool (650-700 H). No significant nephrogram was identified, indicating the absence of renal clearance of the agent. CONCLUSION: The liposomal-based iodinated contrast agent shows long residence time in the blood pool, very high attenuation within submillimeter vessels, and no significant renal clearance rendering it an effective contrast agent for murine vascular imaging using a micro-CT scanner.

Animals↗

PubMed2006

Intertumoral differences in hypoxia selectivity of the PET imaging agent 64Cu(II)-diacetyl-bis(N4-methylthiosemicarbazone).

UNLABELLED: Cu-Diacetyl-bis(N(4)-methylthiosemicarbazone) (Cu-ATSM) is a recently developed PET imaging agent for tumor hypoxia. However, its accuracy and reliability for measuring hypoxia have not been fully characterized in vivo. The aim of this study was to evaluate (64)Cu-ATSM as a hypoxia PET marker by comparing autoradiographic distributions of (64)Cu-ATSM with a well-established hypoxia marker drug, EF5. METHODS: R3230 mammary adenocarcinomas (R3230Ac), fibrosarcomas (FSA), and 9L gliomas (9L) were used in the study. EF5 and Hoechst 33342, a vascular perfusion marker, were administered to the animal for immunohistochemical analysis. (64)Cu-ATSM microPET and autoradiography were performed on the same animal. The tumor-to-muscle ratio (T/M ratio) and standardized uptake values (SUVs) were characterized for these 3 different types of tumors. Five types of images-microPET, autoradiography, EF5 immunostaining, Hoechst fluorescence vascular imaging, and hematoxylin-and-eosin histology-were superimposed, evaluated, and compared. RESULTS: A significantly higher T/M ratio and SUV were seen for FSA compared with R3230Ac and 9L. Spatial correlation analysis between (64)Cu-ATSM autoradiography and EF5 immunostained images varied between the 3 tumor types. There was close correlation of (64)Cu-ATSM uptake and hypoxia in R3230Ac and 9L tumors but not in FSA tumors. Interestingly, elevated (64)Cu-ATSM uptake was observed in well-perfused areas in FSA, indicating a correlation between (64)Cu-ATSM uptake and vascular perfusion as opposed to hypoxia. The same relationship was observed with 2 other hypoxia markers, pimonidazole and carbonic anhydrase IX, in FSA tumors. Breathing carbogen gas significantly decreased the hypoxia level measured by EF5 staining in FSA-bearing rats but not the uptake of (64)Cu-ATSM. These results indicate that some other (64)Cu-ATSM retention mechanisms, as opposed to hypoxia, are involved in this type of tumor. CONCLUSION: To our knowledge, this study is the first comparison between (64)Cu-ATSM uptake and immunohistochemistry in these 3 tumors. Although we have shown that (64)Cu-ATSM is a valid PET hypoxia marker in some tumor types, but not for all, this tumor type-dependent hypoxia selectivity of (64)Cu-ATSM challenges the use of (64)Cu-ATSM as a universal PET hypoxia marker. Further studies are needed to define retention mechanisms for this PET marker.

Animals↗

PubMed2005

Effects of breathing and cardiac motion on spatial resolution in the microscopic imaging of rodents.

One can acquire high-resolution pulmonary and cardiac images in live rodents with MR microscopy by synchronizing the image acquisition to the breathing cycle across multiple breaths, and gating to the cardiac cycle. The precision with which one can synchronize image acquisition to the motion defines the ultimate resolution limit that can be attained in such studies. The present work was performed to evaluate how reliably the pulmonary and cardiac structures return to the same position from breath to breath and beat to beat across the prolonged period required for MR microscopy. Radiopaque beads were surgically glued to the abdominal surface of the diaphragm and on the cardiac ventricles of anesthetized, mechanically ventilated rats. We evaluated the range of motion for the beads (relative to a reference vertebral bead) using digital microradiography with two specific biological gating methods: 1) ventilation synchronous acquisition, and 2) both ventilation synchronous and cardiac-gated acquisitions. The standard deviation (SD) of the displacement was < or =100 microm, which is comparable to the resolution limit for in vivo MRI imposed by signal-to-noise ratio (SNR) constraints. With careful control of motion, its impact on resolution can be limited. This work provides the first quantitative measure of the motion-imposed resolution limits for in vivo imaging.

Animals↗

PubMed2005

Morphology of the small-animal lung using magnetic resonance microscopy.

Small-animal imaging with magnetic resonance microscopy (MRM) has become an important tool in biomedical research. When MRM is used to image perfusion-fixed and "stained" whole mouse specimens, cardiopulmonary morphology can be visualized, nondestructively, in exquisite detail in all three dimensions. This capability can be a valuable tool for morphologic phenotyping of different mouse strains commonly used in genomics research. When these imaging techniques are combined with specialized methods for biological motion control and animal support, the lungs of the live, small animal can be imaged. Although in vivo imaging may not achieve the high resolution possible with a fixed specimen, dynamic functional studies and survival studies that follow the progression of pulmonary change related to disease or environmental exposure are possible. By combining conventional proton imaging with gas imaging, using hyperpolarized 3He, it is possible to image the tissue and gas compartments of the lung. This capability is illustrated in studies on an emphysema model in rats and on radiation damage of the lung. With further improvements in imaging and animal handling technology, we will be able to image faster and at higher resolutions, making MRM an even more valuable research tool.

Animals↗

PubMed2004

Proton and hyperpolarized helium magnetic resonance imaging of radiation-induced lung injury in rats.

PURPOSE: To assess the usefulness of hyperpolarized helium (3He) MRI, including apparent diffusion coefficient measurements, in the detection and evaluation of radiation-induced lung injury in rats. METHODS AND MATERIALS: Female Fischer-344 rats were treated to the right lung with fractionated dose of 40 Gy (5 x 8 Gy) using 4-MV photons. Conventional proton (1H) and hyperpolarized (3He) MRI were used to image the lungs 3-6 months after radiation treatment. Apparent diffusion coefficient (ADC) maps of hyperpolarized 3He in the lungs were calculated using a nonlinear, least-squares fitting routine on a pixel-by-pixel basis. After imaging, lungs were processed for histologic assessment of damage. RESULTS: The effect of radiation was time dependent with progressive right lung damage ranging from mild to moderate at 3 months to severe fibrosis with structural deformation at 6 months after radiation. There was a significant decrease in the apparent diffusion coefficient of hyperpolarized 3He gas in radiation-treated lungs. Areas of decreased ADC in the lungs correlated with fibrosis shown by histology. CONCLUSION: This is the first study to show that hyperpolarized 3He MRI can detect radiation-induced lung injury noninvasively. Reduced hyperpolarized 3He ADC values postradiation likely reflect reduced alveolar volumes associated with fibrosis of the interstitium. Future studies at earlier time points may determine whether this noninvasive imaging technique can detect lung damage before clinical symptoms. Development of this new approach of magnetic resonance lung imaging in the rat model of radiation-induced lung injury will increase the ability to develop appropriate algorithms and more accurate models of the normal tissue complication probability.

Animals↗

PubMed2004

Cine magnetic resonance microscopy of the rat heart using cardiorespiratory-synchronous projection reconstruction.

PURPOSE: To tailor a cardiac magnetic resonance (MR) microscopy technique for the rat that combines improvements in pulse sequence design and physiologic control to acquire high-resolution images of cardiac structure and function. MATERIALS AND METHODS: Projection reconstruction (PR) was compared to conventional Cartesian techniques in point-spread function simulations and experimental studies to evaluate its artifact sensitivity. Female Sprague-Dawley rats were imaged at 2.0 T using PR with direct encoding of the free induction decay. Specialized physiologic support and monitoring equipment ensured consistency of biological motion and permitted synchronization of imaging with the cardiac and respiratory cycles. RESULTS: The reduced artifact sensitivity of PR offered improved delineation of cardiac and pulmonary structures. Ventilatory synchronization further increased the signal-to-noise ratio by reducing inter-view variability. High-quality short-axis and long-axis cine images of the rat heart were acquired with 10-msec temporal resolution and microscopic spatial resolution down to 175 microm x 175 microm x 1 mm. CONCLUSION: Integrating careful biological control with an optimized pulse sequence significantly limits both the source and impact of image artifacts. This work represents a novel integration of techniques designed to support measurement of cardiac morphology and function in rodent models of cardiovascular disease.

Animals↗

PubMed2002

Magnetic resonance histology for morphologic phenotyping.

Magnetic resonance histology (MRH) images of the whole mouse have been acquired at 100-micron isotropic resolution at 2.0 T with image arrays of 256 x 256 x 1024. Higher resolution (50 x 50 x 50 microns) of limited volumes has been acquired at 7.1T with image arrays of 512 x 512 x 512. Even higher resolution images (20 x 20 x 20 microns) of isolated organs have been acquired at 9.4 T. The volume resolution represents an increase of 625000 x over conventional clinical MRI. The technological basis is summarized that will allow basic scientists to begin using MRH as a routine method for morphologcic phenotyping of the mouse. MRH promises four unique attributes over conventional histology: 1). MRH is non-destructive; 2). MRH exploits the unique contrast mechanisms that have made MRI so successful clinically; 3). MRH is 3-dimensional; and 4). the data are inherently digital. We demonstrate the utility in morphologic phenotyping a whole C57BL/6J mouse.

Animals↗

PubMed2002

Fiber-optic stethoscope: a cardiac monitoring and gating system for magnetic resonance microscopy.

A fundamental problem associated with using the conventional electrocardiograph (ECG) to monitor a subject's cardiac activity during magnetic resonance imaging (MRI) is the distortion of the ECG due to electromagnetic interference. This problem is particularly pronounced in MR microscopy (MRI of small animals at microscopic resolutions (< 0.03 mm(3))) because the strong, rapidly-switching magnetic field gradients induce artifacts in the animal's ECG that often mimic electrophysiologic activity, impairing the use of the ECG for cardiac monitoring and gating purposes. The fiber-optic stethoscope system offers a novel approach to measuring cardiac activity that, unlike the ECG, is immune to electromagnetic effects. The fiber-optic stethoscope is perorally inserted into the esophagus of small animals to optically detect pulsatile compression of the esophageal wall. The optical system is shown to provide a robust cardiac monitoring and gating signal in rats and mice during routine cardiac MR microscopy.

Animals↗

PubMed2002

Mechanical ventilation for imaging the small animal lung.

This review emphasizes some of the challenges and benefits of in vivo imaging of the small animal lung. Because mechanical ventilation plays a key role in high-quality, high-resolution imaging of the small animal lung, the article focuses particularly on the problems of ventilation support, control of breathing motion and lung volume, and imaging during different phases of the breathing cycle. Solutions for these problems are discussed primarily in relation to magnetic resonance imaging, both conventional proton imaging and the newer, hyperpolarized helium imaging of pulmonary airways. Examples of applications of these imaging solutions to normal and diseased lung are illustrated in the rat and guinea pig. Although difficult to perform, pulmonary imaging in the small animal can be a valuable source of information not only for the normal lung, but also for the lung challenged by disease.

Anatomy, Cross-Sectional↗

PubMed2002

Morphologic phenotyping with MR microscopy: the visible mouse.

A method for rapid morphologic phenotyping is demonstrated by using magnetic resonance microscopy. Whole fixed C57BL/6J mice were imaged at 110-microm isotropic resolution; limited volumes of the intact specimen, at 50-microm isotropic resolution; and isolated organs, at 25-microm isotropic resolution. The three-dimensional imaging technique was applied to uricase knockout mice to demonstrate the method for the evaluation of morphologic phenotype.

Animals↗

PubMedDate not supplied

Tumor imaging in small animals with a combined micro-CT/micro-DSA system using iodinated conventional and blood pool contrast agents.

X-ray based micro-computed tomography (CT) and micro-digital subtraction angiography (DSA) are important non-invasive imaging modalities for following tumorogenesis in small animals. To exploit these imaging capabilities further, the two modalities were combined into a single system to provide both morphological and functional data from the same tumor in a single imaging session. The system is described and examples are given of imaging implanted fibrosarcoma tumors in rats using two types of contrast media: (a) a new generation of blood pool contrast agent containing iodine with a concentration of 130 mg/mL (Fenestratrade mark VC, Alerion Biomedical, San Diego, CA, USA) for micro-CT and (b) a conventional iodinated contrast agent (Isovue(R)-370 mg/mL iodine, trademark of Bracco Diagnostics, Princeton, NJ, USA) for micro-DSA. With the blood pool contrast agent, the 3D vascular architecture is revealed in exquisite detail at 100 microm resolution. Micro-DSA images, in perfect registration with the 3D micro-CT datasets, provide complementary functional information such as mean transit times and relative blood flow through the tumor. This imaging approach could be used to understand tumor angiogenesis better and be the basis for evaluating anti-angiogenic therapies.

Angiography, Digital Subtraction↗

PubMedDate not supplied

4-D micro-CT of the mouse heart.

PURPOSE: Demonstrate noninvasive imaging methods for in vivo characterization of cardiac structure and function in mice using a micro-CT system that provides high photon fluence rate and integrated motion control. MATERIALS AND METHODS: Simultaneous cardiac- and respiratory-gated micro-CT was performed in C57BL/6 mice during constant intravenous infusion of a conventional iodinated contrast agent (Isovue-370), and after a single intravenous injection of a blood pool contrast agent (Fenestra VC). Multiple phases of the cardiac cycle were reconstructed with contrast to noise and spatial resolution sufficient for quantitative assessment of cardiac function. RESULTS: Contrast enhancement with Isovue-370 increased over time with a maximum of approximately 500 HU (aorta) and 900 HU (kidney cortex). Fenestra VC provided more constant enhancement over 3 hr, with maximum enhancement of approximately 620 HU (aorta) and approximately 90 HU (kidney cortex). The maximum enhancement difference between blood and myocardium in the heart was approximately 250 HU for Isovue-370 and approximately 500 HU for Fenestra VC. In mice with Fenestra VC, volumetric measurements of the left ventricle were performed and cardiac function was estimated by ejection fraction, stroke volume, and cardiac output. CONCLUSION: Image quality with Fenestra VC was sufficient for morphological and functional studies required for a standardized method of cardiac phenotyping of the mouse.

Animals↗