Accelerated 3D multi-echo spin-echo sequence with a subspace constrained reconstruction for whole mouse brain T 2 mapping.

PURPOSE: To accelerate whole-brain quantitative T 2 $$ {\mathrm{T}}_2 $$ mapping in preclinical imaging setting. METHODS: A three-dimensional (3D) multi-echo spin echo sequence was highly undersampled with a variable density Poisson distribution to reduce the acquisition time. Advanced iterative reconstruction based on linear subspace constraints was employed to recover high-quality raw images. Different subspaces, generated using exponential or extended-phase graph (EPG) simulations or from low-resolution calibration images, were compared. The subspace dimension was investigated in terms of T 2 $$ {\mathrm{T}}_2 $$ precision. The method was validated on a phantom containing a wide range of T 2 $$ {\mathrm{T}}_2 $$ and was then applied to monitor metastasis growth in the mouse brain at 4.7T. Image quality and T 2 $$ {\mathrm{T}}_2 $$ estimation were assessed for 3 acceleration factors (6/8/10). RESULTS: The EPG-based dictionary gave robust estimations of a large range of T 2 $$ {\mathrm{T}}_2 $$ . A subspace dimension of 6 was the best compromise between T 2 $$ {\mathrm{T}}_2 $$ precision and image quality. Combining the subspace constrained reconstruction with a highly undersampled dataset enabled the acquisition of whole-brain T 2 $$ {\mathrm{T}}_2 $$ maps, the detection and the monitoring of metastasis growth of less than 500 µ m 3 $$ \mu {\mathrm{m}}^3 $$ . CONCLUSION: Subspace-based reconstruction is suitable for 3D T 2 $$ {\mathrm{T}}_2 $$ mapping. This method can be used to reach an acceleration factor up to 8, corresponding to an acquisition time of 25 min for an isotropic 3D acquisition of 156 µ $$ \mu $$ m on the mouse brain, used here for monitoring metastases growth.

New setup for multi-parametric MRI in young and old rat gastrocnemius at 4.7 and 7 T during muscle stimulation.

T1 and T2 relaxation times combined with 31 P spectroscopy have been proven efficient for muscular disease characterization as well as for pre- and post-muscle stimulation measurements. Even though 31 P spectroscopy can already be performed during muscle exercise, no method for T1 and T2 measurement enables this possibility. In this project, a complete setup and protocol for multi-parametrical MRI of the rat gastrocnemius before, during and after muscle stimulation at 4.7 and 7 T is presented. The setup is fully MRI compatible and is composed of a cradle, an electro-stimulator and an electronic card in order to synchronize MRI sequences with muscle stimulation. A 2D triggered radial-encoded Look-Locker sequence was developed, and enabled T1 measurements in less than 2 min on stimulated muscle. Also, a multi-slice multi-echo sequence was adapted and synchronized for T2 measurements as well as 31 P spectroscopy acquisitions in less than 4 min in both cases on stimulated muscle. Methods were validated on young rats using different stimulation paradigms. Then they were applied on older rats to compare quantification results, using the different stimulation paradigms, and allowed observation of metabolic changes related to aging with good reproducibility. The robustness of the whole setup shows wide application opportunities.

Three-dimensional ultrashort echo time (3D UTE) magnetic resonance imaging (MRI) of the normal and degenerative disco-vertebral complex at 4.7 T: a feasibility study with longitudinal evaluation.

OBJECTIVES: To assess feasibility of a three-dimensional ultrashort echo time (3D-UTE)-sequence to evaluate normal and pathological disco-vertebral complex (DVC), with assessment of its different portions in a rat model of degenerative disk disease (DDD) with histological correlation. To assess whether this sequence, in comparison with long echo time T2-weighted sequence, is able to monitor DDD with differentiation of early from chronic DVC changes in pathological mechanical conditions. METHODS: Five rats were induced with DDD model by percutaneous disk trituration of the tail with an 18-G needle under US-guidance and imaged at 4.7 T. MRI protocol included fat-saturated-T2 (RARE) and 3D-UTE-sequences performed at baseline (day 0. n = 5 animals /10 DVC) and each week (W) from W1 to W10 postoperatively. Visual analysis and signal intensity measurements of SNR and CNR of all DVC portions were performed on RARE and UTE images. Following killing (baseline, n = 1/2 DVC; W2, n = 2/4 DVC; W10, n = 2/4 DVC), histological analysis was performed and compared with MRI. RESULTS: In normal DVC, unlike conventional RARE-sequences, 3D-UTE allowed complete identification of DVC zonal anatomy including on visual analysis and CNR measurements. In pathological conditions, SNR and CNR measurements of the annulus fibrosus and nucleus pulposus on 3D-UTE distinguished early discitis at W1 from chronic discopathy (P < 0.001 for SNR and P < 0.001 for CNR). Neither the normal complete anatomy of the DVC nor its pathological patterns could be assessed on conventional sequences. CONCLUSIONS: Unlike conventional sequences, 3D-UTE enables visualization of the complete normal DVC anatomy and enables monitoring of DDD differentiating between early DVC changes from chronic ones. LEVEL OF EVIDENCE I: Diagnostic: individual cross-sectional studies with the consistently applied reference standard and blinding.

2D multislice MP2RAGE sequence for fast T1 mapping at 7 T: Application to mouse imaging and MR thermometry.

PURPOSE: To develop a 2D radial multislice MP2RAGE sequence for fast and reliable T1 mapping at 7 T in mice and for MR thermometry. METHODS: The 2D-MP2RAGE sequence was performed with the following parameters: TI1 -TI2 -MP2RAGETR = 1000-3000-9000 ms. The multiple dead times within the sequence were used for interleaved multislice acquisition, enabling one to acquire six slices in 9 seconds. The excitation pulse shape, inversion selectivity, and interslice gap were optimized. In vitro comparison with the inversion-recovery sequence was performed. The T1 variations with temperature were measured on tubes with T1 ranging from 800 ms to 2000 ms. The sequence was used to acquire T1 maps continuously during 30 minutes on the brain and abdomen of healthy mice. RESULTS: A three-lobe cardinal sine excitation pulse, combined with an inversion slice thickness and an interslice gap of respectively 150% and 50% of the imaging slice thickness, led to a SD and bias of the T1 measurements below 1% and 2%, respectively. A linear dependence of T1 with temperature was measured between 10°C and 60°C. In vivo, less than 1% variation was measured between successive T1 maps in the mouse brain. In the abdomen, no obvious in-plane motion artifacts were observed but respiratory motion in the slice dimension led to 6% T1 underestimation. CONCLUSION: The multislice MP2RAGE sequence could be used for fast whole-body T1 mapping and MR thermometry. Its reconstruction method would enable on-the-fly reconstruction.

Compressed-Sensing MP2RAGE sequence: Application to the detection of brain metastases in mice at 7T.

PURPOSE: To develop a Compressed Sensing (CS)-MP2RAGE sequence to drastically shorten acquisition duration and then detect and measure the T1 of brain metastases in mice at 7 T. METHODS: The encoding trajectory of the standard Cartesian MP2RAGE sequence has been modified (1) to obtain a variable density Poisson disk under-sampling distribution along the ky -kz plane, and (2) to sample the central part of the k-space exactly at TI1 and TI2 inversion times. In a prospective study, the accuracy of the T1 measurements was evaluated on phantoms containing increasing concentrations of gadolinium. The CS acceleration factors were increased to evaluate their influence on the contrast and T1 measurements of brain metastases in vivo. Finally, the 3D T1 maps were acquired with at 4-fold increased spatial resolution. The volumes and T1 values of the metastases were measured while using CS to reduce scan time. RESULTS: The implementation of the CS-encoding trajectory did not affect the T1 measurements in vitro. Accelerating the acquisition by a factor of 2 did not alter the contrast or the T1 values of the brain metastases. 3D T1 maps could be obtained in < 1 min using a CS factor of 6. Increasing the spatial resolution enabled more accurately measurement of the metastasis volumes while maintaining an acquisition duration below 5 min. CONCLUSION: The CS-MP2RAGE sequence could be of great interest in oncology to either rapidly obtain mouse brain 3D T1 maps or to increase the spatial resolution with no penalty on the scan duration.

Radial MP2RAGE sequence for rapid 3D T1 mapping of mouse abdomen: application to hepatic metastases.

OBJECTIVES: The T1 longitudinal recovery time is regarded as a biomarker of cancer treatment efficiency. In this scope, the Magnetization Prepared 2 RApid Gradient Echo (MP2RAGE) sequence relevantly complies with fast 3D T1 mapping. Nevertheless, with its Cartesian encoding scheme, it is very sensitive to respiratory motion. Consequently, a radial encoding scheme was implemented for the detection and T1 measurement of hepatic metastases in mice at 7T. METHODS: A 3D radial encoding scheme was developed using a golden angle distribution for the k-space trajectories. As in that case, each projection contributes to the image contrast, the signal equations had to be modified. Phantoms containing increasing gadoteridol concentrations were used to determine the accuracy of the sequence in vitro. Healthy mice were repetitively scanned to assess the reproducibility of the T1 values. The growth of hepatic metastases was monitored. Undersampling robustness was also evaluated. RESULTS: The accuracy of the T1 values obtained with the radial MP2RAGE sequence was > 90% compared to the Inversion-Recovery sequence. The motion robustness of this new sequence also enabled repeatable T1 measurements on abdominal organs. Hepatic metastases of less than 1-mm diameter were easily detected and T1 heterogeneities within the metastasis and between the metastases within the same animal were measured. With a twofold acceleration factor using undersampling, high-quality 3D T1 abdominal maps were achieved in 9 min. CONCLUSIONS: The radial MP2RAGE sequence could be used for fast 3D T1 mapping, to detect and characterize metastases in regions subjected to respiratory motion. KEY POINTS: • The Cartesian encoding of the MP2RAGE sequence was modified to a radial encoding. The modified sequence enabled accurate T 1 measurements on phantoms and on abdominal organs of mice. • Hepatic metastases were easily detected due to high contrast. Heterogeneity in T 1 was measured within the metastases and between each metastasis within the same animal. • As implementation of this sequence does not require specific hardware, we expect that it could be readily available for clinical practice in humans.

Fast 3D ultrashort echo-time spiral projection imaging using golden-angle: A flexible protocol for in vivo mouse imaging at high magnetic field.

PURPOSE: To develop a fast three-dimensional (3D) k-space encoding method based on spiral projection imaging (SPI) with an interleaved golden-angle approach and to validate this novel sequence on small animal models. METHODS: A disk-like trajectory, in which each disk contained spirals, was developed. The 3D encoding was performed by tilting the disks with a golden angle. The sharpness was first calculated at different T2* values. Then, the sharpness was measured on phantom using variable undersampling ratios. Finally, the sampling method was validated by whole brain time-of-flight angiography and ultrasmall superparamagnetic iron oxide (USPIO) enhanced free-breathing liver angiography on mouse. RESULTS: The in vitro results demonstrated the robustness of the method for short T2* and high undersampling ratios. In vivo experiments showed the ability to properly detect small vessels in the brain with an acquisition time shorter than 1 min. Free-breathing mice liver angiography showed the insensitivity of this protocol toward motions and flow artifacts, and enabled the visualization of liver motion during breathing. CONCLUSIONS: The method implemented here allowed fast 3D k-space sampling with a high undersampling ratio. Combining the advantages of center-out spirals with the flexibility of the golden angle approach could have major implications for real-time imaging. Magn Reson Med 77:1831-1840, 2017. © 2016 International Society for Magnetic Resonance in Medicine.

USPIO-enhanced 3D-cine self-gated cardiac MRI based on a stack-of-stars golden angle short echo time sequence: Application on mice with acute myocardial infarction.

PURPOSE: To develop and assess a 3D-cine self-gated method for cardiac imaging of murine models. MATERIALS AND METHODS: A 3D stack-of-stars (SOS) short echo time (STE) sequence with a navigator echo was performed at 7T on healthy mice (n = 4) and mice with acute myocardial infarction (MI) (n = 4) injected with ultrasmall superparamagnetic iron oxide (USPIO) nanoparticles. In all, 402 spokes were acquired per stack with the incremental or the golden angle method using an angle increment of (360/402)° or 222.48°, respectively. A cylindrical k-space was filled and repeated with a maximum number of repetitions (NR) of 10. 3D cine cardiac images at 156 µm resolution were reconstructed retrospectively and compared for the two methods in terms of contrast-to-noise ratio (CNR). The golden angle images were also reconstructed with NR = 10, 6, and 3, to assess cardiac functional parameters (ejection fraction, EF) on both animal models. RESULTS: The combination of 3D SOS-STE and USPIO injection allowed us to optimize the identification of cardiac peaks on navigator signal and generate high CNR between blood and myocardium (15.3 ± 1.0). The golden angle method resulted in a more homogeneous distribution of the spokes inside a stack (P < 0.05), enabling reducing the acquisition time to 15 minutes. EF was significantly different between healthy and MI mice (P < 0.05). CONCLUSION: The method proposed here showed that 3D-cine images could be obtained without electrocardiogram or respiratory gating in mice. It allows precise measurement of cardiac functional parameters even on MI mice. J. Magn. Reson. Imaging 2016;44:355-365.

Time-resolved TOF MR angiography in mice using a prospective 3D radial double golden angle approach.

PURPOSE: To develop an undersampled anatomical, three-dimensional (3-D) time-resolved magnetic resonance angiography (MRA) method for small animals based on time-of-flight (TOF) effect and radial sampling. METHODS: Mouse carotid arteries and Circle of Willis images were acquired on a 7T scanner with an electrocardiogram (ECG)-triggered sequence. Preliminary experiments were used to generate an approximately uniform distribution of radial projections with a first golden angle and to produce anatomical TOF images. A second golden angle ratio between consecutive projections of cine acquisitions was added to make it possible to use a temporal filter during reconstruction of time-resolved angiography. A decreasing number of projections were tested, and their impact on signal-to-noise ratio (SNR) and spatial resolution was assessed. RESULTS: In anatomical MRA, the undersampled radial approach efficiently allows fast acquisition of mouse angiogram in 3D (22 sec). It was also only slightly sensitive to motion and flow artifacts. The time-resolved sequence can be performed with only 2,500 projections per cine and a temporal resolution under 4 ms in a relatively short acquisition time (less than 5 min). CONCLUSION: This technique simultaneously provided high 3D isotropic spatial resolution and excellent temporal resolution with a good SNR level, allowing blood flow to be visualized in a restricted acquisition time.

Fast and robust 3D T1 mapping using spiral encoding and steady RF excitation at 7 T: application to cardiac manganese enhanced MRI (MEMRI) in mice.

Mapping longitudinal relaxation times in 3D is a promising quantitative and non-invasive imaging tool to assess cardiac remodeling. Few methods are proposed in the literature allowing us to perform 3D T1 mapping. These methods often require long scan times and use a low number of 3D images to calculate T1 . In this project, a fast 3D T1 mapping method using a stack-of-spirals sampling scheme and regular RF pulse excitation at 7 T is presented. This sequence, combined with a newly developed fitting procedure, allowed us to quantify T1 of the whole mouse heart with a high spatial resolution of 208 × 208 × 315 µm(3) in 10-12 min acquisition time. The sensitivity of this method for measuring T1 variations was demonstrated on mouse hearts after several injections of manganese chloride (doses from 25 to 150 µmol kg(-1) ). T1 values were measured in vivo in both pre- and post-contrast experiments. This protocol was also validated on ischemic mice to demonstrate its efficiency to visualize tissue damage induced by a myocardial infarction. This study showed that combining spiral gradient shape and steady RF excitation enabled fast and robust 3D T1 mapping of the entire heart with a high spatial resolution.

Self-gated bSSFP sequences to detect iron-labeled cancer cells and/or metastases in vivo in mouse liver at 7 Tesla.

BACKGROUND: To develop and evaluate three-dimensional (3D) self-gated balanced steady state free precession (bSSFP) imaging at high magnetic fields to track iron-labeled cells and metastases in murine abdomens. METHODS: Mice were injected intravenously with iron-labeled melanoma cells and imaged at 7 Tesla (T). Respiration peaks were identified using Free Induction Decay acquired immediately after the radiofrequency pulse. Respiration-corrupted k-space lines were deleted. Four images were acquired to reconstruct final images using the Sum-Of-Square technique. Image sharpness, metastasis contrast and iron-labeled cell detection with SG-bSSFP sequence (acquired with echo time [TE] = 3 ms or TE = 6 ms) were compared with standard methods (gradient echo (GRE) and RARE). RESULTS: After reconstruction, the 3D SG-bSSFP images were 75-80% sharper, free from banding (75% liver signal-to-noise ratio recovery) and respiratory motion (26-42% improvement in signal homogeneity) artifacts. Metastasis contrast was twice higher on SG-bSSFP with TE = 3 ms than on RARE images. Iron-labeled cells and metastases were simultaneously detected on SG-bSSFP images with TE = 6 ms, with similar void intensity and tumor contrast to GRE and RARE, respectively. Halving acquisition time preserved iron sensitivity and metastasis contrast, allowing for 3D abdomen imaging in 13 min (TE = 3 ms) or 26 min (TE = 6 ms). CONCLUSION: Combining a self-gating technique with bSSFP sequences at 7T provides high-resolution 3D artifact-free abdominal images of small animals.

Positive contrast high-resolution 3D-cine imaging of the cardiovascular system in small animals using a UTE sequence and iron nanoparticles at 4.7, 7 and 9.4 T.

BACKGROUND: To show that 3D sequences with ultra-short echo times (UTEs) can generate a positive contrast whatever the magnetic field (4.7, 7 or 9.4 T) and whatever Ultra Small Particles of Iron Oxide (USPIO) concentration injected and to use it for 3D time-resolved imaging of the murine cardiovascular system with high spatial and temporal resolutions. METHODS: Three different concentrations (50, 200 and 500 µmol Fe/kg) of USPIO were injected in mice and static images of the middle part of the animals were acquired at 4.7, 7 and 9.4 T pre and post-contrast with UTE (TE/TR = 0.05/4.5 ms) sequences. Signal-to-Noise Ratio (SNR) and Contrast-to-Noise Ratio (CNR) of blood and static tissus were evaluated before and after contrast agent injection. 3D-cine images (TE/TR = 0.05/3.5 ms, scan time < 12 min) at 156 µm isotropic resolution of the mouse cardiopulmonary system were acquired prospectively with the UTE sequence for the three magnetic fields and with an USPIO dose of 200 µmol Fe/kg. SNR, CNR and signal homogeneity of blood were measured. High spatial (104 µm) or temporal (3.5 ms) resolution 3D-cine imaging (scan time < 35 min) isotropic resolution were also performed at 7 T with a new sequence encoding scheme. RESULTS: UTE imaging generated positive contrast and higher SNR and CNR whatever the magnetic field and the USPIO concentration used compared to pre-contrast images. Time-resolved 3D acquisition enables high blood SNR (66.6 ± 4.5 at 7 T) and CNR (33.2 ± 4.2 at 7 T) without flow or motion artefact. Coronary arteries and aortic valve were visible on images acquired at 104 µm resolution. CONCLUSIONS: We have demonstrated that by combining the injection of iron nanoparticles with 3D-cine UTE sequences, it was possible to generate a strong positive contrast between blood and surrounding tissues. These properties were exploited to produce images of the cardiovascular system in small animals at high magnetic fields with a high spatial and temporal resolution. This approach might be useful to measure the functional cardiac parameters or to assess anatomical modifications to the blood vessels in cardio-vascular disease models.

Comprehensive phenotyping of salt-induced hypertensive heart disease in living mice using cardiac magnetic resonance.

OBJECTIVES: To characterise the effects of high-salt diet (HSD) on left ventricular (LV) mass, systolic function and coronary reserve in living mice using cardiac magnetic resonance imaging (MRI). METHODS: Thirty C57BL/6 1-month-old female mice were fed either a control (n = 15) or an HSD (n = 15). After 3 months, LV volumes, ejection fraction and mass were assessed using time-resolved three-dimensional (3D) black-blood manganese-enhanced MRI, and coronary flow velocity reserve (CFVR) was assessed using dynamic MR angiography at rest and during adenosine-induced hyperaemia. Hearts were excised to assess LV wet mass and micro-vascular remodelling at histology. RESULTS: Micro-vascular remodelling was found at histology in all investigated hearts from the HSD group and none from the control group. No difference between the HSD and control groups was found in terms of heart weight, LV volumes and ejection fraction. Heart to body weight ratio was higher in the HSD group (4.39 ± 0.24 vs 4.02 ± 0.16 mg/g, P < 0.001), because of lower body weight (22.3 ± 0.9 vs 24.0 ± 1.4 g, P < 0.001). CFVR was lower in the HSD group (1.73 ± 0.11 vs 1.94 ± 0.12, P < 0.001). CONCLUSIONS: Phenotyping of hypertensive heart disease is feasible in living mice using dynamic MR angiography and time-resolved 3D black-blood manganese-enhanced MRI. HSD is associated with early impairment of coronary reserve, before the onset of significant hypertrophy.

Acute and chronic effects of bupivacaine on muscle energetics during contraction in vivo: a modular metabolic control analysis.

Bupivacaine is a widely used anaesthetic injected locally in clinical practice for short-term neurotransmission blockade. However, persistent side effects on mitochondrial integrity have been demonstrated in muscle parts surrounding the injection site. We use the precise language of metabolic control analysis in the present study to describe in vivo consequences of bupivacaine injection on muscle energetics during contraction. We define a model system of muscle energy metabolism in rats with a sciatic nerve catheter that consists of two modules of reactions, ATP/PCr (phosphocreatine) supply and ATP/PCr demand, linked by the common intermediate PCr detected in vivo by (31)P-MRS (magnetic resonance spectroscopy). Measured system variables were [PCr] (intermediate) and contraction (flux). We first applied regulation analysis to quantify acute effects of bupivacaine. After bupivacaine injection, contraction decreased by 15.7% and, concomitantly, [PCr] increased by 11.2%. The regulation analysis quantified that demand was in fact directly inhibited by bupivacaine (-21.3%), causing an increase in PCr. This increase in PCr indirectly reduced mitochondrial activity (-22.4%). Globally, the decrease in contractions was almost fully explained by inhibition of demand (-17.0%) without significant effect through energy supply. Finally we applied elasticity analysis to quantify chronic effects of bupivacaine iterative injections. The absence of a difference in elasticities obtained in treated rats when compared with healthy control rats clearly shows the absence of dysfunction in energetic control of muscle contraction energetics. The present study constitutes the first and direct evidence that bupivacaine myotoxicity is compromised by other factors during contraction in vivo, and illustrates the interest of modular approaches to appreciate simple rules governing bioenergetic systems when affected by drugs.

A system for in vivo on-demand ultra-low field Overhauser-enhanced 3D-Magnetic resonance imaging.

Development of very-low field MRI is an active area of research. It aims at reducing operating costs and improve portability. However, the signal-to-noise issue becomes prominent at ultra-low field (<1 mT), especially for molecular imaging purposes that addresses specific biochemical events. In the context of preclinical molecular MRI of abnormal proteolysis the paper describes a MRI system able to produce Overhauser-enhanced MR images in living rats through in situ Dynamic Nuclear Polarization at 206 µT using stable and non-toxic nitroxides. In parallel conventional images are generated at 206 µT following pre-polarization at 20 mT. Results show that nitroxides are visualized in 3D within a few minutes in the lungs, kidneys and bladder post-administration. This system will be used for molecular imaging of inflammation using protease-specific nitroxide probes.

Hierarchical superparamagnetic metal-organic framework nanovectors as anti-inflammatory nanomedicines.

Among a plethora of drug nanocarriers, biocompatible nanoscale metal-organic frameworks (nanoMOFs) with a large surface area and an amphiphilic internal microenvironment have emerged as promising drug delivery platforms, mainly for cancer therapy. However, their application in biomedicine still suffers from shortcomings such as a limited chemical and/or colloidal stability and/or toxicity. Here, we report the design of a hierarchically porous nano-object (denoted as USPIO@MIL) combining a benchmark nanoMOF (that is, MIL-100(Fe)) and ultra-small superparamagnetic iron oxide (USPIO) nanoparticles (that is, maghemite) that is synthesized through a one-pot, cost-effective and environmentally friendly protocol. The synergistic coupling of the physico-chemical and functional properties of both nanoparticles confers to these nano-objects valuable features such as high colloidal stability, high biodegradability, low toxicity, high drug loading capacity as well as stimuli-responsive drug release and superparamagnetic properties. This bimodal MIL-100(Fe)/maghemite nanocarrier once loaded with anti-tumoral and anti-inflammatory drugs (doxorubicin and methotrexate) shows high anti-inflammatory and anti-tumoral activities. In addition, the USPIO@MIL nano-object exhibits excellent relaxometric properties and its applicability as an efficient contrast agent for magnetic resonance imaging is herein demonstrated. This highlights the high potential of the maghemite@MOF composite integrating the functions of imaging and therapy as a theranostic anti-inflammatory formulation.

A thermosensitive low molecular weight hydrogel as scaffold for tissue engineering.

Hydrogels that are non-toxic, easy to use, cytocompatible, injectable and degradable are valuable biomaterials for tissue engineering and tissue repair. However, few compounds currently fulfil these requirements. In this study, we describe the biological properties of a new type of thermosensitive hydrogel based on low-molecular weight glycosyl-nucleosyl-fluorinated (GNF) compound. This gel forms within 25 min by self-assembly of monomers as temperature decreases. It degrades slowly in vitro and in vivo. It induces moderate chronic inflammation and is progressively invaded by host cells and vessels, suggesting good integration to the host environment. Although human adult mesenchymal stem cells derived from adipose tissue (ASC) cannot adhere on the gel surface or within a 3D gel scaffold, cell aggregates grow and differentiate normally when entrapped in the GNF-based gel. Moreover, this hydrogel stimulates osteoblast differentiation of ASC in the absence of osteogenic factors. When implanted in mice, gel-entrapped cell aggregates survive for several weeks in contrast with gel-free spheroids. They are maintained in their original site of implantation where they interact with the host tissue and adhere on the extracellular matrix. They can differentiate in situ into alkaline phosphatase positive osteoblasts, which deposit a calcium phosphate-rich matrix. When injected into subcutaneous sites, gel-encapsulated cells show similar biological properties as implanted gel-cells complexes. These data point GNF-based gels as a novel class of hydrogels with original properties, in particular osteogenic potential, susceptible of providing new therapeutic solutions especially for bone tissue engineering applications.

The Compressed Sensing MP2RAGE as a Surrogate to the MPRAGE for Neuroimaging at 3 T.

OBJECTIVES: The magnetization-prepared 2 rapid acquisition gradient echo (MP2RAGE) sequence provides quantitative T1 maps in addition to high-contrast morphological images. Advanced acceleration techniques such as compressed sensing (CS) allow its acquisition time to be compatible with clinical applications. To consider its routine use in future neuroimaging protocols, the repeatability of the segmented brain structures was evaluated and compared with the standard morphological sequence (magnetization-prepared rapid gradient echo [MPRAGE]). The repeatability of the T1 measurements was also assessed. MATERIALS AND METHODS: Thirteen healthy volunteers were scanned either 3 or 4 times at several days of interval, on a 3 T clinical scanner, with the 2 sequences (CS-MP2RAGE and MPRAGE), set with the same spatial resolution (0.8-mm isotropic) and scan duration (6 minutes 21 seconds). The reconstruction time of the CS-MP2RAGE outputs (including the 2 echo images, the MP2RAGE image, and the T1 map) was 3 minutes 33 seconds, using an open-source in-house algorithm implemented in the Gadgetron framework.Both precision and variability of volume measurements obtained from CAT12 and VolBrain were assessed. The T1 accuracy and repeatability were measured on phantoms and on humans and were compared with literature.Volumes obtained from the CS-MP2RAGE and the MPRAGE images were compared using Student t tests (P < 0.05 was considered significant). RESULTS: The CS-MP2RAGE acquisition provided morphological images of the same quality and higher contrasts than the standard MPRAGE images. Similar intravolunteer variabilities were obtained with the CS-MP2RAGE and the MPRAGE segmentations. In addition, high-resolution T1 maps were obtained from the CS-MP2RAGE. T1 times of white and gray matters and several deep gray nuclei are consistent with the literature and show very low variability (<1%). CONCLUSIONS: The CS-MP2RAGE can be used in future protocols to rapidly obtain morphological images and quantitative T1 maps in 3-dimensions while maintaining high repeatability in volumetry and relaxation times.

Deep learning model for automatic segmentation of lungs and pulmonary metastasis in small animal MR images.

Lungs are the most frequent site of metastases growth. The amount and size of pulmonary metastases acquired from MRI imaging data are the important criteria to assess the efficacy of new drugs in preclinical models. While efficient solutions both for MR imaging and the downstream automatic segmentation have been proposed for human patients, both MRI lung imaging and segmentation in preclinical animal models remains challenging due to the physiological motion (respiratory and cardiac movements), to the low amount of protons in this organ and to the particular challenge of precise segmentation of metastases. As a consequence post-mortem analysis is currently required to obtain information on metastatic volume. In this work, we have developed a complete methodological pipeline for automated analysis of lungs and metastases in mice, consisting of an MR sequence for image acquisition and a deep learning method for automatic segmentation of both lungs and metastases. On one hand, we optimized an MR sequence for mouse lung imaging with high contrast for high detection sensitivity. On the other hand we developed DeepMeta, a multiclass U-Net 3+ deep learning model to automatically segment the images. To assess if the proposed deep learning pipeline is able to provide an accurate segmentation of both lungs and pulmonary metastases, we have longitudinally imaged mice with fast- and slow-growing metastasis. Fifty-five balb/c mice were injected with two different derivatives of renal carcinoma cells. Mice were imaged with a SG-bSSFP (self-gated balanced steady state free precession) sequence at different time points after the injection of cancer cells. Both lung and metastases segmentations were manually performed by experts. DeepMeta was trained to perform lung and metastases segmentation based on the resulting ground truth annotations. Volumes of lungs and of pulmonary metastases as well as the number of metastases per mouse were measured on a separate test dataset of MR images. Thanks to the SG method, the 3D bSSFP images of lungs were artifact-free, enabling the downstream detection and serial follow-up of metastases. Moreover, both lungs and metastases segmentation was accurately performed by DeepMeta as soon as they reached the volume of ∼ 0.02 m m 3 . Thus we were able to distinguish two groups of mice in terms of number and volume of pulmonary metastases as well as in terms of the slow versus fast patterns of growth of metastases. We have shown that our methodology combining SG-bSSFP with deep learning, enables processing of the whole animal lungs and is thus a viable alternative to histology alone.

Scribble Controls Social Motivation Behavior through the Regulation of the ERK/Mnk1 Pathway.

Social behavior is a basic domain affected by several neurodevelopmental disorders, including ASD and a heterogeneous set of neuropsychiatric disorders. The SCRIB gene that codes for the polarity protein SCRIBBLE has been identified as a risk gene for spina bifida, the most common type of neural tube defect, found at high frequencies in autistic patients, as well as other congenital anomalies. The deletions and mutations of the 8q24.3 region encompassing SCRIB are also associated with multisyndromic and rare disorders. Nonetheless, the potential link between SCRIB and relevant social phenotypes has not been fully investigated. Hence, we show that Scribcrc/+ mice, carrying a mutated version of Scrib, displayed reduced social motivation behavior and social habituation, while other behavioral domains were unaltered. Social deficits were associated with the upregulation of ERK phosphorylation, together with increased c-Fos activity. Importantly, the social alterations were rescued by both direct and indirect pERK inhibition. These results support a link between polarity genes, social behaviors and hippocampal functionality and suggest a role for SCRIB in the etiopathology of neurodevelopmental disorders. Furthermore, our data demonstrate the crucial role of the MAPK/ERK signaling pathway in underlying social motivation behavior, thus supporting its relevance as a therapeutic target.