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Stanford, CA, United States

Castaneda R.T.,Molecular Imaging Program at Stanford
Journal of visualized experiments : JoVE

Stem cell based therapies offer significant potential for the field of regenerative medicine. However, much remains to be understood regarding the in vivo kinetics of transplanted cells. A non-invasive method to repetitively monitor transplanted stem cells in vivo would allow investigators to directly monitor stem cell transplants and identify successful or unsuccessful engraftment outcomes. A wide range of stem cells continues to be investigated for countless applications. This protocol focuses on 3 different stem cell populations: human embryonic kidney 293 (HEK293) cells, human mesenchymal stem cells (hMSC) and induced pluripotent stem (iPS) cells. HEK 293 cells are derived from human embryonic kidney cells grown in culture with sheared adenovirus 5 DNA. These cells are widely used in research because they are easily cultured, grow quickly and are easily transfected. hMSCs are found in adult marrow. These cells can be replicated as undifferentiated cells while maintaining multipotency or the potential to differentiate into a limited number of cell fates. hMSCs can differentiate to lineages of mesenchymal tissues, including osteoblasts, adipocytes, chondrocytes, tendon, muscle, and marrow stroma. iPS cells are genetically reprogrammed adult cells that have been modified to express genes and factors similar to defining properties of embryonic stem cells. These cells are pluripotent meaning they have the capacity to differentiate into all cell lineages. Both hMSCs and iPS cells have demonstrated tissue regenerative capacity in-vivo. Magnetic resonance (MR) imaging together with the use of superparamagnetic iron oxide (SPIO) nanoparticle cell labels have proven effective for in vivo tracking of stem cells due to the near microscopic anatomical resolution, a longer blood half-life that permits longitudinal imaging and the high sensitivity for cell detection provided by MR imaging of SPIO nanoparticles. In addition, MR imaging with the use of SPIOs is clinically translatable. SPIOs are composed of an iron oxide core with a dextran, carboxydextran or starch surface coat that serves to contain the bioreactive iron core from plasma components. These agents create local magnetic field inhomogeneities that lead to a decreased signal on T2-weighted MR images. Unfortunately, SPIOs are no longer being manufactured. Second generation, ultrasmall SPIOs (USPIO), however, offer a viable alternative. Ferumoxytol (FerahemeTM) is one USPIO composed of a non-stoichiometric magnetite core surrounded by a polyglucose sorbitol carboxymethylether coat. The colloidal, particle size of ferumoxytol is 17-30 nm as determined by light scattering. The molecular weight is 750 kDa, and the relaxivity constant at 2T MRI field is 58.609 mM(-1) sec(-1) strength. Ferumoxytol was recently FDA-approved as an iron supplement for treatment of iron deficiency in patients with renal failure. Our group has applied this agent in an "off label" use for cell labeling applications. Our technique demonstrates efficient labeling of stem cells with ferumoxytol that leads to significant MR signal effects of labeled cells on MR images. This technique may be applied for non-invasive monitoring of stem cell therapies in pre-clinical and clinical settings. Source

Prescher J.A.,Molecular Imaging Program at Stanford | Prescher J.A.,Stanford University | Contag C.H.,Molecular Imaging Program at Stanford | Contag C.H.,Stanford University
Current Opinion in Chemical Biology

Bioluminescence imaging (BLI) exploits the light-emitting properties of luciferase enzymes for monitoring cells and biomolecular processes in living subjects. Luciferases can be incorporated into a variety of nonluminescent hosts and used to track cells, visualize gene expression, and analyze collections of biomolecules. This article highlights recent applications of BLI to studies of mammalian biology, along with the development of novel bioluminescent probes to 'see' cells and molecules in action. Collectively, these efforts are expanding our understanding of living systems and shedding light on the molecular underpinnings of disease. © 2009. Source

Zavaleta C.L.,Molecular Imaging Program at Stanford | Kircher M.F.,Sloan Kettering Cancer Center | Gambhir S.S.,Molecular Imaging Program at Stanford | Gambhir S.S.,Stanford University
Journal of Nuclear Medicine

Raman spectroscopy is an optical technique that offers unsurpassed sensitivity and multiplexing capabilities to the field of molecular imaging. In the past, Raman spectroscopy had predominantly been used as an analytic tool for routine chemical analysis, but more recently, researchers have been able to harness its unique properties for imaging and spectral analysis of molecular interactions in cell populations and preclinical animal models. Additionally, researchers have already begun to translate this optical technique into a novel clinical diagnostic tool using various endoscopic strategies. Copyright © 2011 by the Society of Nuclear Medicine, Inc. Source

Vandenbroucke A.,Molecular Imaging Program at Stanford | McLaughlin J.,Stanford University | Levin S.,Molecular Imaging Program at Stanford | Levin S.,Stanford University
Journal of Instrumentation

We evaluate the performance of an 8 × 8 array of 0.9 × 0.9 × 1 mm3 cerium doped lutetium oxyothosilicate (LSO) crystals coupled to a position sensitive avalanche photodiode (PSAPD) as a function of bias voltage and temperature. We use this detector to develop a general methodology to optimize bias voltage, temperature, and gain for PET detectors using semiconductor photodetectors. This detector module will be used in a novel high resolution positron emission tomography (PET) camera dedicated to breast imaging under construction in our lab. Due to the tight packing of many PSAPDs in the system a thermal gradient is expected across the imaging heads. Data were collected for 11 PSAPD temperatures between 5°C and 40°C using a thermo-electric (Peltier) device. At each temperature the bias voltage was varied in steps of 5 V over a 50 V range. We present three methods to predict the optimal bias voltage at every temperature: one based on optimizing the coincidence time resolution, the others based on the relative change in PSAPD gain and leakage current due to the onset of hole multiplication. Optimal gain could also be predicted based on the quality of the flood histogram. At optimal bias voltage, the energy resolution degrades as (10.5±0.1)+((0. 038±0.006)/ °C·T)%. Time resolution stays constant at 2.37±0.02 ns below 15°C. Above this temperature, time resolution deteriorates as (1.67±0.06)+((0.042±0.002)/°C·T)ns. Even at high temperatures, all 64 crystal position peaks in the flood histogram are still clearly visible. The width of the peaks in the flood histogram show a quadratic degradation with temperature: (2.6±0.1)·10 -2+(1.6±0.2)·10-5/(°C) 2·T2. We conclude that both the quality of the flood histogram as well as the coincidence time resolution are better parameters to estimate the optimal bias voltage, than energy resolution. Optimal bias voltage is found to be dependent on the value of k, the ratio between hole and electron multiplication. We achieve optimal bias at a similar gain at all temperatures. The optimal bias voltage changes linearly across the observed range. © 2012 IOP Publishing Ltd and Sissa Medialab srl. Source

Muehe A.M.,Molecular Imaging Program at Stanford | Feng D.,Molecular Imaging Program at Stanford | Luna-Fineman S.,Stanford University | Link M.P.,Stanford University | And 6 more authors.
Investigative Radiology

Objective The aim of this study was to assess the safety profile of ferumoxytol as an intravenous magnetic resonance imaging contrast agent in children. Materials and Methods We prospectively evaluated the safety of ferumoxytol administrations as an "off-label" contrast agent for magnetic resonance imaging in nonrandomized phase 4 clinical trials at 2 centers. From September 2009 to February 2015, 49 pediatric patients (21 female and 28 male, 5-18 years) and 19 young adults (8 female and 11 male, 18-25 years) were reported under an investigator-initiated investigational new drug investigation with institutional review board approval, in health insurance portability and accountability act compliance, and after written informed consent of the child's legal representative or the competent adult patient was obtained. Patients received either a single dose (5 mg Fe/kg) or up to 4 doses of ferumoxytol (0.7-4 mg Fe/kg) intravenously, which were approximately equivalent to one third of the dose for anemia treatment. We monitored vital signs and adverse events directly for up to 1 hour after injection. In addition, we examined weekly vitals, hematologic, renal, and liver serum panels for 1 month after injection in over 20 pediatric patients. At fixed time points before and after ferumoxytol injection, data were evaluated for significant differences by a repeated measures linear mixed model. Results Four mild adverse events, thought to be related to ferumoxytol, were observed within 1 hour of 85 ferumoxytol injections: 2 episodes of mild hypotension and 1 case of nausea in 65 injections in pediatric patients without related clinical symptoms. One young adult patient developed warmness and erythema at the injection site. All adverse events were self-resolving. No spontaneous serious adverse events were reported. At a dose of 5 mg Fe/kg or lower, intravenous ferumoxytol injection had no clinical relevance or statistically significant effect (P > 0.05) on vital signs, hematological parameters, kidney function, or liver enzymes within 1 month of the injection. Conclusions Ferumoxytol was overall well tolerated among 49 pediatric and 19 young adult patients experiencing various tumors or kidney transplants without major adverse events or signs of hematologic and kidney impairment or liver toxicity. Larger studies are needed to determine the incidence of anaphylactic reactions. Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved. Source

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