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Gu J.,Molecular Imaging Program at Stanford MIPS | Wu J.C.,Stanford University
Theranostics | Year: 2012

Being able to self-renew and differentiate into virtually all cell types, both human embryonic stem cells (hESCs) and induced pluripotent stem cells (iPSCs) have exciting therapeutic im-plications for myocardial infarction, neurodegenerative disease, diabetes, and other disorders involving irreversible cell loss. However, stem cell biology remains incompletely understood despite significant advances in the field. Inefficient stem cell differentiation, difficulty in verifying successful delivery to the target organ, and problems with engraftment all hamper the tran-sition from laboratory animal studies to human clinical trials. Although traditional histo-pathological techniques have been the primary approach for ex vivo analysis of stem cell be-havior, these postmortem examinations are unable to further elucidate the underlying mechanisms in real time and in vivo. Fortunately, the advent of molecular imaging has led to unprecedented progress in understanding the fundamental behavior of stem cells, including their survival, biodistribution, immunogenicity, and tumorigenicity in the targeted tissues of interest. This review summarizes various molecular imaging technologies and how they have advanced the current understanding of stem cell survival, biodistribution, immunogenicity, and tumorigenicity. © Ivyspring International Publisher.


Iagaru A.,Stanford University | Mittra E.,Stanford University | Dick D.W.,Molecular Imaging Program at Stanford MIPS | Gambhir S.S.,Stanford University
Molecular Imaging and Biology | Year: 2012

Introduction: Technetium (Tc) methylene diphosphonate (MDP) has been the standard method for bone scintigraphy for three decades. 18F sodiumfluoride ( 18F NaF) positron emission tomography (PET)/computed tomography (CT) has better resolution and is considered superior. The role of 2-deoxy-2-[ 18F]fluoro-D-glucose ( 18F FDG) PET/CT is proven in a variety of cancers, for which it has changed the practice of oncology. There are fewprospective studies comparing these threemethods of detection of skeletal metastases. Thus, we were prompted to initiate this prospective pilot trial. Methods: This is a prospective study (Sep 2007-Dec 2010) of 52 patients with proven malignancy referred for evaluation of skeletal metastases. There were 37 men and 15 women, 19-84 years old (average, 55.6±15.9). Technetium-99m ( 99mTc) MDP bone scintigraphy, 18F NaF PET/CT, and 18F FDG PET/CT were subsequently performed within 1 month. Results: Skeletal lesions were detected by 99mTc MDP bone scintigraphy in 22 of 52 patients, by 18F NaF PET/CT in 24 of 52 patients, and by 18F FDG PET/CT in 16 of 52 patients. The image quality and evaluation of extent of disease were superior by 18F NaF PET/CT over 99mTc MDP scintigraphy in all 22 patients with skeletal lesions on both scans and over 18F FDG PET/CT in 11 of 16 patients with skeletal metastases on 18F FDG PET/CT. In two patients, 18F NaF PET/CT showed skeletal metastases not seen on either of the other two scans. Extraskeletal lesions were identified by 18F FDG PET/CT in 28 of 52 subjects. Conclusion: Our prospective pilot-phase trial demonstrates superior image quality and evaluation of skeletal disease extent with 18F NaF PET/CT over 99mTc MDP scintigraphy and 18F FDG PET/CT. At the same time, 18F FDG PET detects extraskeletal disease that can significantly change disease management. As such, a combination of 18F FDG PET/CT and 18F NaF PET/CT may be necessary for cancer detection. Additional evaluation with larger cohorts is required to confirm these preliminary findings. © Academy of Molecular Imaging and Society for Molecular Imaging, 2011.


Virk M.S.,University of Connecticut Health Center | Sugiyama O.,University of Connecticut Health Center | Park S.H.,University of California at Los Angeles | Gambhir S.S.,Molecular Imaging Program at Stanford MIPS | And 3 more authors.
Molecular Therapy | Year: 2011

Ex-vivo regional gene therapy with bone marrow cells (BMCs) overexpressing bone morphogenetic protein-2 (BMP-2) has demonstrated efficacy in healing critical sized bone defects in preclinical studies. The purpose of this preclinical study was to compare the osteoinductive potential of a novel same day ex-vivo regional gene therapy versus a traditional two-step approach, which involves culture expansion of the donor cells before implantation. In the same day strategy buffy coat cells were harvested from the rat bone marrow, transduced with a lentiviral vector-expressing BMP-2 for 1 hour and implanted into a rat femoral defect in the same sitting. There was no significant difference (P = 0.22) with respect to the radiographic healing rates between the femoral defects treated with the same day strategy (13/13; 100%) versus the traditional two-step approach (11/14; 78%). However, the femoral defects treated with the same day strategy induced earlier radiographic bone healing (P = 0.004) and higher bone volume (BV) micro-computed tomography (micro-CT); P 0.001. The same day strategy represents a significant advance in the field of ex-vivo regional gene therapy because it offers a solution to limitations associated with the culture expansion process required in the traditional ex vivo approach. This strategy should be cost-effective when adapted for human use. © The American Society of Gene and Cell Therapy.


Habte F.,Molecular Imaging Program at Stanford MIPS | Ren G.,Molecular Imaging Program at Stanford MIPS | Ren G.,CA Technologies | Doyle T.C.,Molecular Imaging Program at Stanford MIPS | And 4 more authors.
Molecular Imaging and Biology | Year: 2013

Purpose: The aim of this study is to evaluate the impact of scanning multiple mice simultaneously on image quantitation, relative to single mouse scans on both a micro-positron emission tomography/computed tomography (microPET/CT) scanner (which utilizes CT-based attenuation correction to the PET reconstruction) and a dedicated microPET scanner using an inexpensive mouse holder "hotel." Methods: We developed a simple mouse holder made from common laboratory items that allows scanning multiple mice simultaneously. It is also compatible with different imaging modalities to allow multiple mice and multi-modality imaging. For this study, we used a radiotracer ( 64Cu-GB170) with a relatively long half-life (12.7 h), selected to allow scanning at times after tracer uptake reaches steady state. This also reduces the effect of decay between sequential imaging studies, although the standard decay corrections were performed. The imaging was also performed using a common tracer, 2-deoxy-2-[18 F]fluoro-d-glucose (FDG), although the faster decay and faster pharmacokinetics of FDG may introduce greater biological variations due to differences in injection-to-scan timing. We first scanned cylindrical mouse phantoms (50 ml tubes) both in a groups of four at a time (multiple mice mode) and then individually (single mouse mode), using microPET/CT and microPET scanners to validate the process. Then, we imaged a first set of four mice with subcutaneous tumors (C2C12Ras) in both single- and multiple-mice imaging modes. Later, a second set of four normal mice were injected with FDG and scanned 1 h post-injection. Immediately after completion of the scans, ex vivo biodistribution studies were performed on all animals to provide a "gold-standard" to compare quantitative values obtained from PET. A semi-automatic threshold-based region of interest tool was used to minimize operator variability during image analysis. Results: Phantom studies showed less than 4.5 % relative error difference between the single- and multiple-mice imaging modes of PET imaging with CT-based attenuation correction and 18.4 % without CT-based attenuation correction. In vivo animal studies (n = 4) showed <5 % (for 64Cu, p > 0.686) and <15 % (for FDG, p > 0.4 except for brain image data p = 0.029) relative mean difference with respect to percent injected dose per gram (%ID/gram) between the single- and multiple-mice microPET imaging mode when CT-based attenuation correction is performed. Without CT-based attenuation correction, we observed relative mean differences of about 11 % for 64Cu and 15 % for FDG. Conclusion: Our results confirmed the potential use of a microPET/CT scanner for multiple mice simultaneous imaging without significant sacrifice in quantitative accuracy as well as in image quality. Thus, the use of the mouse "hotel" is an aid to increasing instrument throughput on small animal scanners with minimal loss of quantitative accuracy. © 2013 World Molecular Imaging Society.


Ziv K.,Molecular Imaging Program at Stanford MIPS | Nuhn H.,Stanford University | Ben-Haim Y.,Molecular Imaging Program at Stanford MIPS | Sasportas L.S.,Molecular Imaging Program at Stanford MIPS | And 8 more authors.
Biomaterials | Year: 2014

One of the major challenges in regenerative medicine is the ability to recreate the stem cell niche, which is defined by its signaling molecules, the creation of cytokine gradients, and the modulation of matrix stiffness. A wide range of scaffolds has been developed in order to recapitulate the stem cell niche, among them hydrogels. This paper reports the development of a new silk-alginate based hydrogel with a focus on stem cell culture. This biocomposite allows to fine tune its elasticity during cell culture, addressing the importance of mechanotransduction during stem cell differentiation. The silk-alginate scaffold promotes adherence of mouse embryonic stem cells and cell survival upon transplantation. In addition, it has tunable stiffness as function of the silk-alginate ratio and the concentration of crosslinker - a characteristic that is very hard to accomplish in current hydrogels.The hydrogel and the presented results represents key steps on the way of creating artificial stem cell niche, opening up new paths in regenerative medicine. © 2014 Elsevier Ltd.

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