Quantitative in vivo micro-computed tomography for assessment of age-dependent changes in murine whole-body composition

Androgen deprivation, a consequence of hypogonadism, certain cancer treatments, or normal aging in men, leads to loss of muscle mass, increased adiposity, and osteoporosis. In the present study, using a soluble chimeric form of activin receptor type IIB (ActRIIB) we sought to offset the adverse effects of androgen deprivation on muscle, adipose tissue, and bone. Castrated (ORX) or sham-operated (SHAM) mice received either TBS [vehicle-treated (VEH)] or systemic administration of ActRIIB-mFc, a soluble fusion protein comprised of a form of the extracellular domain of ActRIIB fused to a murine IgG2aFc subunit. In vivo body composition imaging demonstrated that ActRIIB-mFc treatment results in increased lean tissue mass of 23% in SHAM mice [19.02 ± 0.42 g (VEH) versus 23.43 ± 0.35 g (ActRIIB-mFc), P < 0.00001] and 26% in ORX mice [15.59 ± 0.26 g (VEH) versus 19.78 ± 0.26 g (ActRIIB-mFc), P < 0.00001]. Treatment also caused a decrease in adiposity of 30% in SHAM mice [5.03 ± 0.48 g (VEH) versus 3.53 ± 0.19 g (ActRIIB-mFc), NS] and 36% in ORX mice [7.12 ± 0.53 g (VEH) versus 4.57 ± 0.28 g (ActRIIB-mFc), P < 0.001]. These changes were also accompanied by altered serum levels of leptin, adiponectin, and insulin, as well as by prevention of steatosis (fatty liver) in ActRIIB-mFc-treated ORX mice. Finally, ActRIIB-mFc prevented loss of bone mass in ORX mice as assessed by whole body dual x-ray absorptiometry and micro-computed tomography of proximal tibias. The data demonstrate that treatment with ActRIIB-mFc restored muscle mass, adiposity, and bone quality to normal levels in a mouse model of androgen deprivation, thereby alleviating multiple adverse consequences of such therapy.

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Radiosafe micro-computed tomography for longitudinal evaluation of murine disease models

10.1101/847434 ◽

2019 ◽

Author(s):

Nathalie Berghen ◽

Kaat Dekoster ◽

Eyra Marien ◽

Jérémie Dabin ◽

Amy Hillen ◽

...

Keyword(s):

Computed Tomography ◽

High Resolution ◽

Blood Cell ◽

Lung Disease ◽

Blood Platelets ◽

Whole Body ◽

Disease Models ◽

Micro Computed Tomography ◽

Cell Counts

AbstractImplementation of in vivo high-resolution micro-computed tomography (μCT), a powerful tool for longitudinal analysis of murine lung disease models, is hampered by the lack of data on cumulative low-dose radiation effects on the investigated disease models. We aimed to measure radiation doses and effects of repeated μCT scans, to establish cumulative radiation levels and scan protocols without relevant toxicity.Lung metastasis, inflammation and fibrosis models and healthy mice were weekly scanned over one-month with μCT using high-resolution respiratory-gated 4D and expiration-weighted 3D protocols, comparing 5-times weekly scanned animals with controls. Radiation dose was measured by ionization chamber, optical fiberradioluminescence probe and thermoluminescent detectors in a mouse phantom. Dose effects were evaluated by in vivo μCT and bioluminescence imaging read-outs, gold standard endpoint evaluation and blood cell counts.Weekly exposure to 4D μCT, dose of 540-699 mGy/scan, did not alter lung metastatic load nor affected healthy mice. We found a disease-independent decrease in circulating blood platelets and lymphocytes after repeated 4D μCT. This effect was eliminated by optimizing a 3D protocol, reducing dose to 180-233 mGy/scan while maintaining equally high-quality images.We established μCT safety limits and protocols for weekly repeated whole-body acquisitions with proven safety for the overall health status, lung, disease process and host responses under investigation, including the radiosensitive blood cell compartment.

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Radiosafe micro-computed tomography for longitudinal evaluation of murine disease models

Scientific Reports ◽

10.1038/s41598-019-53876-x ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 5

Author(s):

Nathalie Berghen ◽

Kaat Dekoster ◽

Eyra Marien ◽

Jérémie Dabin ◽

Amy Hillen ◽

...

Keyword(s):

Computed Tomography ◽

High Resolution ◽

Blood Cell ◽

Lung Disease ◽

Blood Platelets ◽

Whole Body ◽

Disease Models ◽

Micro Computed Tomography ◽

Cell Counts

AbstractImplementation of in vivo high-resolution micro-computed tomography (µCT), a powerful tool for longitudinal analysis of murine lung disease models, is hampered by the lack of data on cumulative low-dose radiation effects on the investigated disease models. We aimed to measure radiation doses and effects of repeated µCT scans, to establish cumulative radiation levels and scan protocols without relevant toxicity. Lung metastasis, inflammation and fibrosis models and healthy mice were weekly scanned over one-month with µCT using high-resolution respiratory-gated 4D and expiration-weighted 3D protocols, comparing 5-times weekly scanned animals with controls. Radiation dose was measured by ionization chamber, optical fiberradioluminescence probe and thermoluminescent detectors in a mouse phantom. Dose effects were evaluated by in vivo µCT and bioluminescence imaging read-outs, gold standard endpoint evaluation and blood cell counts. Weekly exposure to 4D µCT, dose of 540–699 mGy/scan, did not alter lung metastatic load nor affected healthy mice. We found a disease-independent decrease in circulating blood platelets and lymphocytes after repeated 4D µCT. This effect was eliminated by optimizing a 3D protocol, reducing dose to 180–233 mGy/scan while maintaining equally high-quality images. We established µCT safety limits and protocols for weekly repeated whole-body acquisitions with proven safety for the overall health status, lung, disease process and host responses under investigation, including the radiosensitive blood cell compartment.

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Mild Whole-Body Hyperthermia-Induced Interstitial Fluid Pressure Reduction and Enhanced Nanoparticle Delivery to PC3 Tumors: In Vivo Studies and Micro-Computed Tomography Analyses

Journal of Thermal Science and Engineering Applications ◽

10.1115/1.4046520 ◽

2020 ◽

Vol 12 (6) ◽

Author(s):

Qimei Gu ◽

Shuaishuai Liu ◽

Arunendra Saha Ray ◽

Stelios Florinas ◽

Ronald James Christie ◽

...

Keyword(s):

Computed Tomography ◽

Interstitial Fluid ◽

Fluid Pressure ◽

Whole Body ◽

Control Group ◽

Micro Computed Tomography ◽

Nanoparticle Delivery ◽

Whole Body Hyperthermia ◽

Experimental Group

Abstract In this study, we performed in vivo experiments on mice to evaluate whether whole-body hyperthermia enhances nanoparticle delivery to PC3 (prostatic cancer) tumors. PC3 xenograft tumors in immunodeficient mice were used in this study. The mice in the experimental group were subjected to whole-body hyperthermia by maintaining their body temperatures at 39–40 °C for 1 h. Interstitial fluid pressures (IFPs) in tumors were measured before heating, immediately after, and at 2 and 24 h postheating in both the experimental group and in a control group (without heating). A total of 0.2 ml of a newly developed nanofluid containing gold nanoparticles (AuNPs) was delivered via the tail vein in both groups. The micro-computed tomography (microCT) scanned images of the resected tumors were analyzed to visualize the nanoparticle distribution in the tumors and to quantify the total amount of nanoparticles delivered to the tumors. Statistically significant IFP reductions of 45% right after heating, 47% 2 h after heating, and 52% 24 h after heating were observed in the experimental group. Analyses of microCT scans of the resected tumors illustrated that nanoparticles were more concentrated near the tumor periphery rather than at the tumor center. The 1-h whole-body hyperthermia treatment resulted in more nanoparticles present in the tumor central region than that in the control group. The mass index calculated from the microCT scans suggested overall 42% more nanoparticle delivery in the experimental group than that in the control group. We conclude that 1-h mild whole-body hyperthermia leads to sustained reduction in tumoral IFPs and significantly increases the total amount of targeted gold nanoparticle deposition in PC3 tumors. The present study suggests that mild whole-body hyperthermia is a promising approach for enhancing targeted drug delivery to tumors.

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Mixing Matrix-corrected Whole-body Pharmacokinetic Modeling Using Longitudinal Micro-computed Tomography and Fluorescence-mediated Tomography

Molecular Imaging and Biology ◽

10.1007/s11307-021-01623-y ◽

2021 ◽

Author(s):

Simin Zuo ◽

Wa’el Al Rawashdeh ◽

Stefanie Rosenhain ◽

Zuzanna Magnuska ◽

Yamoah Grace Gyamfuah ◽

...

Keyword(s):

Computed Tomography ◽

Kinetic Model ◽

Kinetic Parameters ◽

Pharmacokinetic Modeling ◽

Retention Rates ◽

Whole Body ◽

Labeled Compounds ◽

Micro Computed Tomography ◽

Mixing Matrix

Abstract Purpose Pharmacokinetic modeling can be applied to quantify the kinetics of fluorescently labeled compounds using longitudinal micro-computed tomography and fluorescence-mediated tomography (μCT-FMT). However, fluorescence blurring from neighboring organs or tissues and the vasculature within tissues impede the accuracy in the estimation of kinetic parameters. Contributions of elimination and retention activities of fluorescent probes inside the kidneys and liver can be hard to distinguish by a kinetic model. This study proposes a deconvolution approach using a mixing matrix to model fluorescence contributions to improve whole-body pharmacokinetic modeling. Procedures In the kinetic model, a mixing matrix was applied to unmix the fluorescence blurring from neighboring tissues and blood vessels and unmix the fluorescence contributions of elimination and retention in the kidney and liver compartments. Accordingly, the kinetic parameters of the hepatobiliary and renal elimination routes and five major retention sites (the kidneys, liver, bone, spleen, and lung) were investigated in simulations and in an in vivo study. In the latter, the pharmacokinetics of four fluorescently labeled compounds (indocyanine green (ICG), HITC-iodide-microbubbles (MB), Cy7-nanogels (NG), and OsteoSense 750 EX (OS)) were evaluated in BALB/c nude mice. Results In the simulations, the corrected modeling resulted in lower relative errors and stronger linear relationships (slopes close to 1) between the estimated and simulated parameters, compared to the uncorrected modeling. For the in vivo study, MB and NG showed significantly higher hepatic retention rates (P<0.05 and P<0.05, respectively), while OS had smaller renal and hepatic retention rates (P<0.01 and P<0.01, respectively). Additionally, the bone retention rate of OS was significantly higher (P<0.01). Conclusions The mixing matrix correction improves pharmacokinetic modeling and thus enables a more accurate assessment of the biodistribution of fluorescently labeled pharmaceuticals by μCT-FMT.

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Application of standards and models in body composition analysis

Proceedings of The Nutrition Society ◽

10.1017/s0029665115004206 ◽

2015 ◽

Vol 75 (2) ◽

pp. 181-187 ◽

Cited By ~ 28

Author(s):

Manfred J. Müller ◽

Wiebke Braun ◽

Maryam Pourhassan ◽

Corinna Geisler ◽

Anja Bosy-Westphal

Keyword(s):

Body Composition ◽

Clinical Decision Making ◽

Compartment Model ◽

Clinical Decision ◽

Whole Body ◽

Composition Analysis ◽

Body Composition Analysis ◽

Physical Functions ◽

Body Components

The aim of this review is to extend present concepts of body composition and to integrate it into physiology. In vivo body composition analysis (BCA) has a sound theoretical and methodological basis. Present methods used for BCA are reliable and valid. Individual data on body components, organs and tissues are included into different models, e.g. a 2-, 3-, 4- or multi-component model. Today the so-called 4-compartment model as well as whole body MRI (or computed tomography) scans are considered as gold standards of BCA. In practice the use of the appropriate method depends on the question of interest and the accuracy needed to address it. Body composition data are descriptive and used for normative analyses (e.g. generating normal values, centiles and cut offs). Advanced models of BCA go beyond description and normative approaches. The concept of functional body composition (FBC) takes into account the relationships between individual body components, organs and tissues and related metabolic and physical functions. FBC can be further extended to the model of healthy body composition (HBC) based on horizontal (i.e. structural) and vertical (e.g. metabolism and its neuroendocrine control) relationships between individual components as well as between component and body functions using mathematical modelling with a hierarchical multi-level multi-scale approach at the software level. HBC integrates into whole body systems of cardiovascular, respiratory, hepatic and renal functions. To conclude BCA is a prerequisite for detailed phenotyping of individuals providing a sound basis for in depth biomedical research and clinical decision making.

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Follow-up of GK rats during prediabetes highlights increased insulin action and fat deposition despite low insulin secretion

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00501.2007 ◽

2008 ◽

Vol 294 (1) ◽

pp. E168-E175 ◽

Cited By ~ 32

Author(s):

Jamileh Movassat ◽

Danièle Bailbé ◽

Cécile Lubrano-Berthelier ◽

Françoise Picarel-Blanchot ◽

Eric Bertin ◽

...

Keyword(s):

Body Composition ◽

Insulin Secretion ◽

Insulin Sensitivity ◽

Cell Function ◽

Cell Mass ◽

The Body ◽

Whole Body ◽

Β Cell ◽

Gk Rats

The adult Goto-Kakizaki (GK) rat is characterized by impaired glucose-induced insulin secretion in vivo and in vitro, decreased β-cell mass, decreased insulin sensitivity in the liver, and moderate insulin resistance in muscles and adipose tissue. GK rats do not exhibit basal hyperglycemia during the first 3 wk after birth and therefore could be considered prediabetic during this period. Our aim was to identify the initial pathophysiological changes occurring during the prediabetes period in this model of type 2 diabetes (T2DM). To address this, we investigated β-cell function, insulin sensitivity, and body composition in normoglycemic prediabetic GK rats. Our results revealed that the in vivo secretory response of GK β-cells to glucose is markedly reduced and the whole body insulin sensitivity is increased in the prediabetic GK rats in vivo. Moreover, the body composition of suckling GK rats is altered compared with age-matched Wistar rats, with an increase of the number of adipocytes before weaning despite a decreased body weight and lean mass in the GK rats. None of these changes appeared to be due to the postnatal nutritional environment of GK pups as demonstrated by cross-fostering GK pups with nondiabetic Wistar dams. In conclusion, in the GK model of T2DM, β-cell dysfunction associated with increased insulin sensitivity and the alteration of body composition are proximal events that might contribute to the establishment of overt diabetes in adult GK rats.

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In vivo micro–computed tomography evaluation of BoneCeramic grafted alveolar defects during orthodontic tooth movement

The Angle Orthodontist ◽

10.2319/112315-797.1 ◽

2016 ◽

Cited By ~ 1

Author(s):

Nan Ru ◽

Sean Shih-Yao Liu ◽

Yuxing Bai ◽

Song Li ◽

Yunfeng Liu ◽

...

Keyword(s):

Computed Tomography ◽

Tooth Movement ◽

Orthodontic Tooth Movement ◽

Micro Computed Tomography

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Demineralized bone matrix-based microcarrier scaffold favors vascularized large bone regeneration in vivo in a rat model

Journal of Biomaterials Applications ◽

10.1177/0885328218784370 ◽

2018 ◽

Vol 33 (2) ◽

pp. 182-195 ◽

Cited By ~ 4

Author(s):

Qiannan Li ◽

Wenjie Zhang ◽

Guangdong Zhou ◽

Yilin Cao ◽

Wei Liu ◽

...

Keyword(s):

Computed Tomography ◽

Stem Cells ◽

Bone Marrow ◽

Bone Regeneration ◽

Demineralized Bone Matrix ◽

Bone Matrix ◽

Matrix Group ◽

Micro Computed Tomography ◽

Demineralized Bone

Insufficient neo-vascularization of in vivo implanted cell-seeded scaffold remains a major bottleneck for clinical translation of engineered bone formation. Demineralized bone matrix is an ideal bone scaffold for bone engineering due to its structural and biochemical components similar to those of native bone. We hypothesized that the microcarrier form of demineralized bone matrix favors ingrowth of vessels and bone regeneration upon in vivo implantation. In this study, a rat model of femoral vessel pedicle-based bone engineering was employed by filling the demineralized bone matrix scaffolds inside a silicone chamber that surrounded the vessel pedicles, and to compare the efficiency of vascularized bone regeneration between microcarrier demineralized bone matrix and block demineralized bone matrix. The results showed that bone marrow stem cells better adhered to microcarrier demineralized bone matrix and produced more extracellular matrices during in vitro culture. After in vivo implantation, microcarrier demineralized bone matrix seeded with bone marrow stem cells formed relatively more bone tissue than block demineralized bone matrix counterpart at three months upon histological examination. Furthermore, micro-computed tomography three-dimensional reconstruction showed that microcarrier demineralized bone matrix group regenerate significantly better and more bone tissues than block demineralized bone matrix both qualitatively and quantitatively (p < 0.05). Moreover, micro-computed tomography reconstructed angiographic images also demonstrated significantly enhanced tissue vascularization in microcarrier demineralized bone matrix group than in block demineralized bone matrix group both qualitatively and quantitatively (p < 0.05). Anti-CD31 immunohistochemical staining of (micro-) vessels and semi-quantitative analysis also evidenced enhanced vascularization of regenerated bone in microcarrier demineralized bone matrix group than in block demineralized bone matrix group (p < 0.05). In conclusion, the microcarrier form of demineralized bone matrix is an ideal bone regenerative scaffold due to its advantages of osteoinductivity and vascular induction, two essentials for in vivo bone regeneration.

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Intraosteal Behavior of Porous Scaffolds: The mCT Raw-Data Analysis as a Tool for Better Understanding

Symmetry ◽

10.3390/sym11040532 ◽

2019 ◽

Vol 11 (4) ◽

pp. 532 ◽

Cited By ~ 1

Author(s):

Parrilla-Almansa ◽

González-Bermúdez ◽

Sánchez-Sánchez ◽

Meseguer-Olmo ◽

Martínez-Cáceres ◽

...

Keyword(s):

Computed Tomography ◽

Mathematical Analysis ◽

Demineralized Bone Matrix ◽

Bone Matrix ◽

Hounsfield Unit ◽

In Vivo Studies ◽

Porous Scaffolds ◽

Micro Computed Tomography ◽

Radiological Analysis

The aim of the study is to determine the existing correlation between high-resolution 3D imaging technique obtained through Micro Computed Tomography (mCT) and histological-histomorphometric images to determine in vivo bone osteogenic behavior of bioceramic scaffolds. A Ca-Si-P scaffold ceramic doped and non-doped (control) with a natural demineralized bone matrix (DBM) were implanted in rabbit tibias for 1, 3, and 5 months. A progressive disorganization and disintegration of scaffolds and bone neoformation occurs, from the periphery to the center of the implants, without any differences between histomorphometric and radiological analysis. However, significant differences (p < 0.05) between DMB-doped and non-doped materials where only detected through mathematical analysis of mCT. In this way, average attenuation coefficient for DMB-doped decreased from 0.99 ± 0.23 Hounsfield Unit (HU) (3 months) to 0.86 ± 0.32 HU (5 months). Average values for non-doped decreased from 0.86 ± 0.25 HU (3 months) to 0.66 ± 0.33 HU. Combination of radiological analysis and mathematical mCT seems to provide an adequate in vivo analysis of bone-implanted biomaterials after surgery, obtaining similar results to the one provided by histomorphometric analysis. Mathematical analysis of Computed Tomography (CT) would allow the conducting of long-term duration in vivo studies, without the need for animal sacrifice, and the subsequent reduction in variability.

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