Positive contrast imaging of iron oxide nanoparticles with susceptibility‐weighted imaging

Superparamagnetic iron oxide particles can be utilized to label cells for immune cell and stem cell therapy. The labeled cells cause significant field distortions induced in their vicinity, which can be detected with magnetic resonance imaging (MRI). In conventional imaging, the signal voids arising from the field distortions lead to negative contrast, which is not desirable, as detection of the cells can be masked by native low signal tissue. In this work, a new method for visualizing magnetically labeled cells with positive contrast is proposed and described. The technique presented is based on the susceptibility‐weighted imaging (SWI) post‐processing algorithm. Phase images from gradient‐echo sequences are evaluated pixel by pixel, and a mask is created with values ranging from 0 to 1, depending on the phase value of the pixel. The magnitude image is then multiplied by the mask. With an appropriate mask function, positive contrast in the vicinity of the labeled cells is created. The feasibility of this technique is proved using an agar phantom containing superparamagnetic iron oxide particles–labeled cells and an ex vivo bovine liver. The results show high potential for detecting even small labeled cell concentrations in structurally inhomogeneous tissue types. Magn Reson Med, 2010. © 2010 Wiley‐Liss, Inc.     

Quantification of superparamagnetic iron oxide (SPIO)-labeled cells using MRI

PURPOSE: To show the feasibility of using magnetic resonance imaging (MRI) to quantify superparamagnetic iron oxide (SPIO)-labeled cells. MATERIALS AND METHODS: Lymphocytes and 9L rat gliosarcoma cells were labeled with ferumoxides-protamine sulfate complex (FE-PRO). The cells were labeled efficiently (more than 95%) and the iron concentration inside each cell was measured by spectrophotometry (4.77-30.21 pg). Phantom tubes containing different numbers of labeled or unlabeled cells, as well as different concentrations of FE-PRO, were made. In addition, labeled and unlabeled cells were injected into fresh and fixed rat brains. RESULTS: Cellular viability and proliferation of labeled and unlabeled cells were shown to be similar. T2-weighted images were acquired using 7T and 3T MRI systems, and R2 maps of the tubes containing cells, free FE-PRO, and brains were made. There was a strong linear correlation between R2 values and labeled cell numbers, but the regression lines were different for the lymphocytes and gliosarcoma cells. Similarly, there was strong correlation between R2 values and free iron. However, free iron had higher R2 values than the labeled cells for the same concentration of iron. CONCLUSION: Our data indicate that in vivo quantification of labeled cells can be done by careful consideration of different factors and specific control groups.     

Positive contrast with alternating repetition time SSFP (PARTS): A fast imaging technique for SPIO‐labeled cells

There has been recent interest in positive‐contrast MRI methods for noninvasive tracking of cells labeled with superparamagnetic iron‐oxide nanoparticles. Low‐tip‐angle balanced steady‐state free precession sequences have been used for fast, high‐resolution, and flow‐insensitive positive‐contrast imaging; however, the contrast can be compromised by the limited suppression of the on‐resonant and fat signals. In this work, a new technique that produces positive contrast with alternating repetition time steady‐state free precession is proposed to achieve robust background suppression for a broad range of tissue parameters. In vitro and in vivo experiments demonstrate the reliability of the generated positive contrast. The results indicate that the proposed method can enhance the suppression level by up to 18 dB compared with conventional balanced steady‐state free precession. Magn Reson Med, 2010. © 2010 Wiley‐Liss, Inc.     

In vivo serial evaluation of superparamagnetic iron‐oxide labeled stem cells by off‐resonance positive contrast

MRI is emerging as a diagnostic modality to track iron‐oxide‐labeled stem cells. This study investigates whether an off‐resonance (OR) pulse sequence designed to generate positive contrast at 1.5T can assess the location, quantity, and viability of delivered stem cells in vivo. Using mouse embryonic stem cell transfected with luciferase reporter gene (luc‐mESC), multimodality validation of OR signal was conducted to determine whether engraftment parameters of superparamagnetic iron‐oxide labeled luc‐mESC (SPIO‐luc‐mESC) could be determined after cell transplantation into the mouse hindlimb. A significant increase in signal‐ and contrast‐to‐noise of the SPIO‐luc‐mESC was achieved with the OR technique when compared to a gradient recalled echo (GRE) sequence. A significant correlation between the quantity of SPIO‐luc‐mESC and OR signal was observed immediately after transplantation (R² = 0.74, P < 0.05). The assessment of transplanted cell viability by bioluminescence imaging (BLI) showed a significant increase of luciferase activities by day 16, while the MRI signal showed no difference. No significant correlation between BLI and MRI signals of cell viability was observed. In conclusion, using an OR sequence the precise localization and quantitation of SPIO‐labeled stem cells in both space and time were possible. However, the OR sequence did not allow evaluation of cell viability. Magn Reson Med 60:1269–1275, 2008. © 2008 Wiley‐Liss, Inc.     

Gradient echo acquisition for superparamagnetic particles with positive contrast (GRASP): sequence characterization in membrane and glass superparamagnetic iron oxide phantoms at 1.5T and 3T.

Iron oxides are used for cell trafficking and identification of macrophages in plaque using MRI. Due to the negative contrast, differentiation between signal loss caused by iron and native low signal in tissue may be problematic. It is, therefore, preferable to achieve positive contrast. The purpose of this study was to test the efficacy of a new MRI sequence GRASP (GRe Acquisition for Superparamagnetic Particles) to generate a positive signal in phantoms containing iron. Membrane phantoms were constructed containing Ferumoxide at 7 concentrations. Standard GRE sequences were modified with user controlled z-gradient rephasing (+/- 100%). CNR values were determined as a function of echo time (TE) and % rephasing at 1.5T and 3T. T(2)* values were determined using multiple double-echo GRE. The GRASP sequence generated positive signal enhancement in phantoms containing iron. For all rephasing values 相似文献   

Ultrashort T relaxometry for quantitation of highly concentrated superparamagnetic iron oxide (SPIO) nanoparticle labeled cells

A new method was developed to measure ultrashort T relaxation in tissues containing a focal area of superparamagnetic iron oxide (SPIO) nanoparticle‐labeled cells in which the T decay is too short to be accurately measured using regular gradient echo T mapping. The proposed method utilizes the relatively long T₂ relaxation of SPIO‐labeled cells and acquires a series of spin echo images with the readout echo shifted to sample the T decay curve. MRI experiments in phantoms and rats with SPIO‐labeled tumors demonstrated that it can detect ultrashort T down to 1 ms or less. The measured T values were about 10% higher than those from the ultrashort TE (UTE) technique. The shorter the TE, the less the measurements deviated from the UTE T mapping. Combined with the regular T mapping, this technique is expected to provide quantitation of highly concentrated iron‐labeled cells from direct cell transplantation. Magn Reson Med, 2009. © 2009 Wiley‐Liss, Inc.     

Effect of superparamagnetic iron oxide on tumor‐to‐liver contrast at T2*‐weighted gradient‐echo MRI: Comparison between 3.0T and 1.5T MR systems

Purpose

To compare 3.0T and 1.5T MR systems in terms of the effect of superparamagnetic iron oxide (SPIO) on tumor‐to‐liver contrast in T2*‐weighted gradient‐echo MRI.

Materials and Methods

SPIO‐enhanced gradient‐echo MR images of the liver with four different TEs (3, 5.3, 6.5, and 8.5 msec) were obtained by means of 1.5T and 3.0T systems. Quantitative analyses of relative signal intensities (SIs) and relative tumor contrast and qualitative analyses of image quality and lesion conspicuity of the liver were performed in 22 patients, 16 of whom had malignant liver tumors.

Results

With both 1.5T and 3.0T, at TE = 8.4 msec, the relative SI of liver and relative tumor contrast were significantly (P < 0.01) lower and higher, respectively, than that for any of the other TEs. There were no significant differences in the relative SI of the liver, relative tumor contrast, image quality, and tumor conspicuity for the same TE between the 1.5T and 3.0T systems.

Conclusion

Our results showed that the effect of SPIO on tumor‐to‐liver contrast at T2*‐weighted gradient‐echo imaging was similar for the 1.5T and 3.0T systems, and that the 8.4‐msec TE was optimal of the four TEs used in this study at 3.0T. J. Magn. Reson. Imaging 2009;29:595–600. © 2009 Wiley‐Liss, Inc.     

新型超顺磁性氧化铁标记SD大鼠脂肪干细胞的有效性及安全性研究

目的：采用新型超顺磁性氧化铁对 SD 大鼠来源的脂肪干细胞（ADSCs）进行标记,并与既往商用 SPIO 标记效果进行对比,探讨这种新型超顺磁性氧化铁标记的有效性及安全性。方法：分离、纯化、鉴定 SD 大鼠来源的 ADSCs,然后分不同浓度组（0、6、12、25、50和100μg／mL）和时间组（6、12、24和48 h）进行标记,通过普鲁士蓝染色测定铁标记率;在不影响细胞形态的前提下,对达到95％以上铁染色率的孵育浓度、时间进行标记安全性检测,包括活力、增殖力、细胞表面抗原表达;采用透射电子显微镜观察标记细胞的超微结构,采用 ICP-AES 对标记细胞内的铁含量进行测定,并与商用SPIO 标记效果进行对比。结果：在无细胞毒性的前提下,新型 SPIO 达到95％以上铁染色率的孵育浓度是12和25μg／mL,孵育时间是12 h;ICP-AES 检测显示具有表面正电荷的聚乙二醇（PEG）／聚乙烯亚胺（PEI）修饰的 SPIO 标记后细胞内的铁含量达到35．4 pg／cell（25μg／mL 中孵育12h 后）和20．16 pg／cell（12μg／mL 中孵育12h 后）,并随着孵育浓度的增加,细胞内的铁含量增加;而具有表面零电荷的 PEG／聚乙烯吡咯烷酮（PVP）修饰的 SPIO 标记后的铁含量仅为6．96 pg／cell（25μg／mL 中孵育12h 后）;透射电子显微镜显示标记后细胞器结构完整,内吸收的 SPIO 主要位于细胞质内的囊泡和溶酶体中。结论：新型 SPIO 在适当孵育浓度和时间下可以安全、快速标记 ADSCs;PEG／PEI 修饰的 SPIO 标记效果要远远比既往商用的 SPIO 快速有效,可作为一种优势的新型磁性标记物用于干细胞标记;而 PEG／PVP 修饰的SPIO 比起既往商用的 SPIO 并无明显优势,说明表面电荷在细胞标记中占有极其重要的角色。     

Absolute quantification of cerebral blood flow in neurologically normal volunteers: Dynamic‐susceptibility contrast MRI‐perfusion compared with computed tomography (CT)‐perfusion

To improve the reproducibility of arterial input function (AIF) registration and absolute cerebral blood flow (CBF) quantification in dynamic‐susceptibility MRI‐perfusion (MRP) at 1.5T, we rescaled the AIF by use of a venous output function (VOF). We compared CBF estimates of 20 healthy, elderly volunteers, obtained by computed tomography (CT)‐perfusion (CTP) and MRP on two consecutive days. MRP, calculated without the AIF correction, did not result in any significant correlation with CTP. The rescaled MRP showed fair to moderate correlation with CTP for the central gray matter (GM) and the whole brain. Our results indicate that the method used for correction of partial volume effects (PVEs) improves MRP experiments by reducing AIF‐introduced variance at 1.5T. Magn Reson Med, 2009. © 2009 Wiley‐Liss, Inc.     

Detection of hepatocellular carcinoma (HCC) using super paramagnetic iron oxide (SPIO)‐enhanced MRI: Added value of diffusion‐weighted imaging (DWI)

Purpose:

To evaluate whether diffusion‐weighted imaging (DWI) improves the detection of hepatocellular carcinoma (HCC) on super paramagnetic iron oxide (SPIO)‐enhanced MRI.

Materials and Methods:

This retrospective study group consisted of 30 patients with 50 HCC nodules who underwent MRI at 1.5 Tesla. Two combined MR sequence sets were compared for detecting HCC: SPIO‐enhanced MRI (axial T2‐weighted fast spin‐echo (FSE) and T1‐/T2*‐weighted fast field echo (FFE) scanned before and after administration of ferucarbotran) and SPIO‐enhanced MRI + DWI (SPIO‐enhanced MRI with axial DWI scanned before and after administration of ferucarbotran). Three blinded readers independently reviewed for the presence of HCC on a segment‐by‐segment basis using a four‐point confidence scale. The performance of the two combined MR sequence sets was evaluated using receiver operating characteristic (ROC) analysis.

Results:

The average area under the ROC curve (Az) of the three readers for the SPIO‐enhanced MRI + DWI set (0.870 ± 0.046) was significantly higher that that for the SPIO‐enhanced MRI set (0.820 ± 0.055) (P = .025). The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) for detection of HCC were 66.0%, 98.0%, 90.0%, and 91.4%, respectively, for the SPIO‐enhanced MRI set, and 70.0%, 98.6%, 92.9%, and 92.4%, respectively, for the SPIO‐enhanced MRI + DWI set.

Conclusion:

The SPIO‐enhanced MRI + DWI set outperformed the SPIO‐enhanced MRI set for depicting HCC. J. Magn. Reson. Imaging 2010; 31: 373–382. © 2010 Wiley‐Liss, Inc.     

Superparamagnetic iron oxide‐enhanced liver MRI with SHU 555 A (RESOVIST®): New protocol infusion to improve arterial phase evaluation—A prospective study

Purpose

To compare the arterial enhancement of hypervascular hepatic lesions by T1‐weighted 3D‐GRE (gradient‐recalled echo) fat‐sat sequence after slow (0.5 mL/sec) and fast (2 mL/sec) RESOVIST® infusion.

Materials and Methods

We prospectively enrolled 71 patients with hypervascular hepatic lesions to undergo dynamic magnetic resonance imaging (MRI) examination with RESOVIST®. A total of 92 benign and malignant lesions, 44 of which histologically confirmed, were examined. Three blinded and independent readers visually assessed the arterial enhancement using a score from 0 (none) to 3 (maximum), the latter score comparable to that achievable by MultiHance administration.

Results

Out of the 92 hypervascular lesions, 41, 31, and 20 nodules were examined using the slow, fast, and both protocols, respectively. Relevant enhancement (scores 2–3) was found in 42% vs. 14.5% of cases for slow and fast protocols, respectively. Intraindividual comparison evaluation confirmed the better results obtained by slow than fast protocol (25% vs. 10%), with statistically relevant difference in distribution of scores (P = 0.0004). The slow protocol showed values between 0 and 3 with an arithmetic mean of 1.1; the fast one, on the other hand, showed values between 0 and 2 with an arithmetic mean of 0.66.

Conclusion

Slow infusion improves arterial enhancement after RESOVIST® administration. J. Magn. Reson. Imaging 2009;29:607–616. © 2009 Wiley‐Liss, Inc.     

SWIFT‐CEST: A new MRI method to overcome T2 shortening caused by PARACEST contrast agents

The exchange of water molecules between the inner sphere of a paramagnetic chemical exchange saturation transfer (PARACEST) contrast agent and bulk water can shorten the bulk water T₂ through the T₂‐exchange (T_2ex) mechanism. The line‐broadening T_2ex effect is proportional to the agent concentration, the chemical shift of the exchanging water molecule, and is highly dependent on the water molecule exchange rate. A significant T_2ex contribution to the bulk water linewidth can make the regions of agent uptake appear dark when imaging with conventional sequences like gradient‐echo and fast spin‐echo. The minimum echo times for these sequences (1–10 ms) are not fast enough to capture signal from the regions of shortened T₂. This makes “Off” (saturation at ?Δω) minus “On” (saturation at +Δω) imaging of PARACEST agents difficult, because the regions of uptake are dark in both images. It is shown here that the loss of bulk water signal due to T_2ex can be reclaimed using the ultrashort echo times (<10 μs) achieved with the sweep imaging with Fourier transform pulse sequence. Modification of the sweep imaging with Fourier transform sequence for PARACEST imaging is first discussed, followed by parameter optimization using in vitro experiments. In vivo PARACEST studies comparing fast spin‐echo to sweep imaging with Fourier transform were performed using EuDOTA‐(gly) uptake in healthy mouse kidneys. The results show that the negative contrast caused by T_2ex can be overcome using the ultrashort echo time achieved with sweep imaging with Fourier transform, thereby enabling fast and sensitive in vivo PARACEST imaging. Magn Reson Med, 2011. © 2011 Wiley Periodicals, Inc.     

Use of ultrasmall superparamagnetic particles of iron oxide (USPIO)‐enhanced MRI to demonstrate diffuse inflammation in the normal‐appearing white matter (NAWM) of multiple sclerosis (MS) patients: An exploratory study

Purpose

To explore ultrasmall superparamagnetic particles of iron oxide (USPIO) as a marker for diffuse inflammation in multiple sclerosis (MS) normal‐appearing white matter (NAWM), using quantitative MRI. Disease activity in the NAWM of MS patients partly explains why MRI lesion burden correlates only moderately with disability. USPIO have been shown to visualize the cellular component of inflammation in focal MS lesions. In this study, we aimed to explore USPIO as a marker for the more diffuse inflammation in MS NAWM, using quantitative MRI.

Materials and Methods

In this prospective MRI study, 16 MS patients (eight relapsing‐remitting MS [RRMS] and eight primary‐progressive MS [PPMS] cases) and five healthy control (HC) subjects were included. Using a flip‐angle (FA) array, B1‐corrected T1 maps were generated before and 24 hours after USPIO (SHU555C) injection. White‐matter (WM) T1 histogram and region‐of‐interest (ROI) characteristics were compared between both time points using Wilcoxon signed‐rank test.

Results

Both NAWM ROI and histogram analyses showed T1 shortening after USPIO injection in MS patients (P < 0.01), but not in HCs (P = 0.68).

Conclusion

This exploratory study suggests that USPIO‐enhanced MRI may be a new potential marker for subtle inflammatory activity in MS NAWM. Further studies should focus on relating diffuse inflammation to clinical disease activity and treatment efficacy. J. Magn. Reson. Imaging 2009;29:774–779. © 2009 Wiley‐Liss, Inc.