Micro-CT Imaging of Tumor Angiogenesis

Ehling, Josef; Theek, Benjamin; Gremse, Felix; Baetke, Sarah C.; Möckel, Diana; Maynard, Juliana; Ricketts, Sally‐Ann; Grüll, Holger; Neeman, Michal; Knuechel, Ruth; Lederle, Wiltrud; Kießling, Fabian; Lammers, Twan

doi:10.1016/j.ajpath.2013.10.014

Cited by 136 publications

(98 citation statements)

References 41 publications

(39 reference statements)

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“…The relative blood volume (rBV) of these organs was determined based on the ratio between organ and blood enhancement created by the µCT blood pool agent 37,38. For these organs, an average absorption value was estimated from the rBV, the absorption of mixed blood (Table 1) and assuming negligible absorption for unperfused tissue 19.…”

Section: Methodsmentioning

confidence: 99%

Absorption Reconstruction Improves Biodistribution Assessment of Fluorescent Nanoprobes Using Hybrid Fluorescence-mediated Tomography

et al. 2014

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Aim: Fluorescence-mediated tomography (FMT) holds potential for accelerating diagnostic and theranostic drug development. However, for proper quantitative fluorescence reconstruction, knowledge on optical scattering and absorption, which are highly heterogeneous in different (mouse) tissues, is required. We here describe methods to assess these parameters using co-registered micro Computed Tomography (µCT) data and nonlinear whole-animal absorption reconstruction, and evaluate their importance for assessment of the biodistribution and target site accumulation of fluorophore-labeled drug delivery systems.Methods: Besides phantoms with varying degrees of absorption, mice bearing A431 tumors were imaged 15 min and 48 h after i.v. injection of a fluorophore-labeled polymeric drug carrier (pHPMA-Dy750) using µCT-FMT. The outer shape of mice and a scattering map were derived using automated segmentation of the µCT data. Furthermore, a 3D absorption map was reconstructed from the trans-illumination data. We determined the absorption of five interactively segmented regions (heart, liver, kidney, muscle, tumor). Since blood is the main near-infrared absorber in vivo, the absorption was also estimated from the relative blood volume (rBV), determined by contrast-enhanced µCT. We compared the reconstructed absorption with the rBV-based values and analyzed the effect of using the absorption map on the fluorescence reconstruction.Results: Phantom experiments demonstrated that absorption reconstruction is possible and necessary for quantitative fluorescence reconstruction. In vivo, the reconstructed absorption showed high values in strongly blood-perfused organs such as the heart, liver and kidney. The absorption values correlated strongly with the rBV-based absorption values, confirming the accuracy of the absorption reconstruction. Usage of homogenous absorption instead of the reconstructed absorption map resulted in reduced values in the heart, liver and kidney, by factors of 3.5, 2.1 and 1.4, respectively. For muscle and subcutaneous tumors, which have a much lower rBV and absorption, absorption reconstruction was less important.Conclusion: Quantitative whole-animal absorption reconstruction is possible and can be validated in vivo using the rBV. Usage of an absorption map is important when quantitatively assessing the biodistribution of fluorescently labeled drugs and drug delivery systems, to avoid a systematic underestimation of fluorescence in strongly absorbing organs, such as the heart, liver and kidney.

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Section: Methodsmentioning

confidence: 99%

Absorption Reconstruction Improves Biodistribution Assessment of Fluorescent Nanoprobes Using Hybrid Fluorescence-mediated Tomography

et al. 2014

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“…For example, highly detailed anatomical information obtained at high-resolution by ex vivo microCT has been used to quantitatively analyze the three-dimensional (3D) micromorphology of tumor blood vessels (12) (13). However, a review of the literature revealed no high-resolution ex vivo microCT studies that investigated the dynamic regulation of wound vessels over time.…”

Section: Introductionmentioning

confidence: 99%

MicroCT angiography detects vascular formation and regression in skin wound healing

Urao

Okonkwo

Fang

et al. 2016

Microvascular Research

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Properly regulated angiogenesis and arteriogenesis are essential for effective wound healing. Tissue injury induces robust new vessel formation and subsequent vessel maturation, which involves vessel regression and remodeling. Although formation of functional vasculature is essential for healing, alterations in vascular structure over the time course of skin wound healing are not well understood. Here, using high-resolution ex vivo X-ray micro-computed tomography (microCT), we describe the vascular network during healing of skin excisional wounds with highly detailed three-dimensional (3D) reconstructed images and associated quantitative analysis. We found that relative vessel volume, surface area and branching number are significantly decreased in wounds from day 7 to day 14 and 21. Segmentation and skeletonization analysis of selected branches from high-resolution images as small as 2.5 μm voxel size show that branching orders are decreased in the wound vessels during healing. In histological analysis, we found that the contrast agent fills mainly arterioles, but not small capillaries nor large veins. In summary, high-resolution microCT revealed dynamic alterations of vessel structures during wound healing. This technique may be useful as a key tool in the study of the formation and regression of wound vessels.

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“…Micro-computed tomography (CT) and micro-digital subtraction angiography (DSA) with contrast agents have reported in-plane spatial resolutions less than 20 μm in mapping small animal vasculature (Figueiredo et al 2012; Ehling et al 2014). Magnetic resonance (MR) images of vasculature having spatial resolutions as fine as 130 μm in a single direction have also been reported (Zwick et al 2009).…”

Section: Introductionmentioning

confidence: 99%

Optimization of Contrast-to-Tissue Ratio Through Pulse Windowing in Dual-Frequency “Acoustic Angiography” Imaging

Lindsey

Shelton

Dayton

2015

Ultrasound in Medicine & Biology

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Early-stage tumors in many cancers are characterized by vascular remodeling, indicative of transformations in cell function. We have previously presented a high-resolution ultrasound imaging approach for detecting these changes which is based on microbubble contrast agents. In this technique, images are formed from only the higher harmonics of microbubble contrast agents, producing images of vasculature alone with 100–200 μm resolution. In this article, shaped transmit pulses are applied to imaging the higher broadband harmonic echoes of microbubble contrast agents, and the effects of varying pulse window and phasing on microbubble and tissue harmonic echoes are evaluated using a dual-frequency transducer in vitro and in vivo. An increase in contrast-to-tissue ratio of 6.8 ± 2.3 dB was observed in vitro by using an inverted pulse with a cosine window relative to a non-inverted pulse with a rectangular window. The increase in mean image intensity due to contrast enhancement in vivo in five rodents was 13.9 ± 3.0 dB greater for an inverted cosine-windowed pulse and 17.8 ± 3.6 dB greater for a non-inverted Gaussian-windowed relative to a non-inverted pulse with a rectangular window. Implications for pre-clinical and diagnostic imaging are also discussed.

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Micro-CT Imaging of Tumor Angiogenesis

Cited by 136 publications

References 41 publications

Absorption Reconstruction Improves Biodistribution Assessment of Fluorescent Nanoprobes Using Hybrid Fluorescence-mediated Tomography

Absorption Reconstruction Improves Biodistribution Assessment of Fluorescent Nanoprobes Using Hybrid Fluorescence-mediated Tomography

MicroCT angiography detects vascular formation and regression in skin wound healing

Optimization of Contrast-to-Tissue Ratio Through Pulse Windowing in Dual-Frequency “Acoustic Angiography” Imaging

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