Positive Contrast Imaging Research Articles

Engineering Protein-Nanoparticle Hybrids as Targeted Contrast Agents.

Iron oxide nanoparticles (IONPs) have shown great promise in biomedical applications, particularly as MRI contrast agents due to their magnetic properties and biocompatibility. Although several IONPs have been approved by regulatory agencies as MRI contrast agents, their primary application as negative contrast agents limits their usage. Additionally, there is an emerging need for the development of molecular contrast agents that can specifically target biomarkers, enabling more accurate and sensitive diagnostics. To address these challenges, we exploited the engineerability of proteins to stabilize IONPs with tailored magnetic properties, creating protein-stabilized iron oxide nanoparticles (Prot-IONPs) and leveraged the chemical diversity of proteins to functionalize Prot-IONPs with targeting moieties. As a proof-of-concept, we used alendronate (Ald) to target atherosclerotic plaques in the aorta. Simple protein functionalization allowed targeting while maintaining the stability and relaxation properties of the Prot-IONPs. Prot-IONPs-Ald successfully enabled positive contrast imaging of atherosclerotic plaques in vivo in an atherosclerotic mouse model (ApoE-/- mice on a high-fat diet). This study demonstrates the potential of engineering protein-nanoparticle hybrids as versatile platforms for developing targeted in vivo MRI contrast agents.

ClO– Induced Dual-Excitation Fluorescent Probes Responding to Diverse Testing Modes with Ratio Methodology

Single-excitation ratio fluorescent probes have enabled the output signal with high signal-to-noise ratio, but are still plagued with technique challenges, including signal distortion and limited application scenario. Herein, a dual-excitation near-infrared (NIR) fluorescent probe P1 of coumarin derivatives is constructed, showing high signal output ability in the visible region and high tissue penetration depth ability in the NIR region. As NIR probe P1 selectively recognizes ClO-, the emission signal in the visible region (480 nm) of P1 is enhanced during the recognition process. Meanwhile, the NIR emission (830 nm) of the conjugated system is weakened, finally realizing that ClO- triggered the dual-excitation (720/400 nm) ratio fluorescence signal detection and monitoring. The signal of detection in vitro has high responsiveness. Meanwhile, in the process of NIR monitoring in vivo, positive contrast imaging of fluorescence is constructed, which can accurately monitor ClO- changes over time. The current dual-excitation fluorescence-based data calibration and/or comparison method improves the application of the traditional single-excitation ratio fluorescence strategy and provide innovative detection tools for accurate measurement of fluorescence detection, with detection/monitoring modes suitable for different physiological environments.

PO24 Presentation Time: 7:40 AM: Impact of Intra-Operative MRI-Guidance on Dose Escalation to the HR-CTV Using Advanced Gynecological Applicators

<h3>Purpose</h3> To quantify the impact of intraoperative MRI-guidance on implant quality for patients receiving brachytherapy (BT) for cervical cancer by calculating dose to the HR-CTV and OARs at three stages of the implant procedure. <h3>Materials and Methods</h3> Three patients enrolled on an IRB-approved prospective clinical trial were treated with EBRT followed by two fractions of pulsed-dose rate (PDR) brachytherapy. For each patient, one of the two PDR implants was performed in a dedicated MRI-Operating Room (MRI-OR) using 3.0 T MRI-guidance (Discovery MR750w, GE Healthcare, Waukesha, WI). An Advanced Gynecological Applicator (AGA) was used for each of the implants. Straight or straight and oblique needle trajectories were used. 3D T2-weighted MRI scans were acquired at three time points during the procedure: (1) following placement of the intracavitary components of the hybrid applicator (initial); (2) following initial needle selection and advancement (intermediate); and (3) following final modifications of implant position (final). The first scan was used to inform needle selection and estimate the appropriate advancement depth for each needle. The second scan was used to determine if modifications to the implant were necessary, including advancement of additional needles, removal of previously advanced needles, or modification of advancement depth. The final scan was used to generate a clinical plan for patient treatment. The titanium obturators used to advance the needles were replaced with C4 positive-contrast imaging markers (C4 Imaging, Houston, TX) prior to each scan to facilitate needle digitization during treatment planning. Retrospective plans were generated on the initial and intermediate scans for each of the three patients and compared to the final plans used for treatment. AGA solid applicator models were registered to the initial and intermediate MRI scans. Needles present at the time of scanning were manually digitized in the Oncentra Treatment Planning System (Elekta, Stockholm, Sweden). Clinical treatment plans were optimized to meet EMBRACE dose constraints. For a given patient, the initial and intermediate plans were optimized to escalate dose to the HR-CTV without exceeding the clinical doses delivered to the OARs. The dose-limiting structure varied based on the patient's anatomy and implant geometry. For each patient, the HR-CTV D90 and bladder, rectum, and sigmoid D2cc doses were compared between the initial, intermediate, and final plans. <h3>Results</h3> One needle was advanced during the first patient's implant. Activity was loaded into the tandem, ovoids, needle, and vaginal caps. The dose to the HR-CTV increased by 4.6 Gy between the initial and intermediate plans and 3.0 Gy between the intermediate and final plan used for treatment. The final dose to the HR-CTV was 10.2% greater than the initial HR-CTV dose. Five needles were advanced for the second patient. The dose to the HR-CTV increased by 3.8 Gy between the initial and intermediate implants and 0.96 Gy between the intermediate and final plan used for treatment. The final dose to the HR-CTV was 5.8% greater than the initial HR-CTV dose. Eight needles were advanced for the third patient. Dose to the HR-CTV increased by 8.3 Gy between the initial and intermediate implants and 5.7 Gy between the intermediate and final plans. The final dose to the HR-CTV was 19.7% greater than the initial HR-CTV dose. None of the OAR doses in the initial or intermediate plans exceeded the OAR doses delivered clinically. <h3>Conclusions</h3> Performing interstitial implants using an AGA under MRI-guidance improves implant quality, defined by dose escalation to the HR-CTV and maintenance of OAR doses.

Rapid variable flip angle positive susceptibility contrast imaging for clinical metal seeds

Positive susceptibility contrast imaging (PSCI) based on susceptibility mapping exhibits excellent efficacy for visualizing magnetic resonance (MR)-compatible metallic devices because of their high magnetic susceptibility compared to that of human tissues. However, the long-acquisition time required by the two-dimensional fast spin echo (2D FSE)-based PSCI approach, impedes its practical applications in 3D imaging. In this study, a three-dimensional (3D) susceptibility-based variable flip angle (vFA) FSE sequence was proposed to accelerate data acquisition in the clinical radiotherapy applications of ex vivo and in vivo rapid 3D PSCI for the imaging of metal seeds. Here, the proposed scheme applied a 3D modulated vFA technique for refocused imaging with an extended echo-train sequence for sampling data. The scheme integrated the projection-onto-dipole fields (PDF) to remove the background field and accelerate PSCI by using a compressive sensing framework with a variable-densitysampling mask. The experiments involved some gelatin phantoms, porcine tissues and patients with scapular tumors and brachytherapy seeds. All of the experimental results showed that the proposed scheme could accelerate data acquisition of 3D PSCI at the reduction factors of 2 ∼ 5 while accurately localizing the actual positions of the brachytherapy seeds in the ex vivo and in vivo applications. The results were compared with those of the existing methods, including susceptibility gradient mapping using the original resolution (SUMO) and gradient echo acquisition for superparamagnetic particle (GRASP).

Tracking of Labelled Stem Cells Using Molecular MR Imaging in a Mouse Burn Model in Vivo as an Approach to Regenerative Medicine.

Therapies based on stem cell transplants offer significant potential in the field of regenerative medicine. Monitoring the fate of the transplanted stem cells in a timely manner is considered one of the main limitations for long-standing success of stem cell transplants. Imaging methods that visualize and track stem cells in vivo non-invasively in real time are helpful towards the development of successful cell transplantation techniques. Novel molecular imaging methods which are non-invasive particularly such as MRI have been of great recent interest. Hence, mouse models which are of clinical relevance have been studied by injecting contrast agents used for labelling cells such as super-paramagnetic iron-oxide (SPIO) nanoparticles for cellular imaging. The MR techniques which can be used to generate positive contrast images have been of much relevance recently for tracking of the labelled cells. Particularly when the off-resonance region in the vicinity of the labeled cells is selectively excited while suppressing the signals from the non-labeled regions by the method of spectral dephasing. Thus, tracking of magnetically labelled cells employing positive contrast in vivo MR imaging methods in a burn mouse model in a non-invasive way has been the scope of this study. The consequences have direct implications for monitoring labeled stem cells at some stage in wound healing. We suggest that our approach can be used in clinical trials in molecular and regenerative medicine.

Positive Contrast Susceptibility MR Imaging Using GPU-based Primal-Dual Algorithm.

The susceptibility-based positive contrast MR technique was applied to estimate arbitrary magnetic susceptibility distributions of the metallic devices using a kernel deconvolution algorithm with a regularized L-1 minimization. Previously, the first-order primal-dual (PD) algorithm could provide a faster reconstruction time to solve the L-1 minimization, compared with other methods. Here, we propose to accelerate the PD algorithm of the positive contrast image using the multi-core multi-thread feature of graphics processor units (GPUs). The some experimental results showed that the GPU-based PD algorithm could achieve comparable accuracy of the metallic interventional devices in positive contrast imaging with less computational time. And the GPU-based PD approach was 4~15 times faster than the previous CPU-based scheme.Clinical Relevance-This can estimate arbitrary magnetic susceptibility distributions of the metallic devices with the processing efficacy of 4~15 times faster than before.

Positive‐contrast susceptibility imaging based on first‐order primal‐dual optimization

To achieve faster reconstruction and better imaging quality of positive-contrast MRI based on the susceptibility mapping by incorporating a primal-dual (PD) formulation. The susceptibility-based positive contrast MR technique was applied to estimate arbitrary magnetic susceptibility distributions of the metallic devices using a kernel deconvolution algorithm with a regularized minimization. The regularized positive-contrast inversion problem and its PD formulation were derived. The visualization of the positive contrast and convergence behavior of the PD algorithm were compared with those of the nonlinear conjugate gradient algorithm, fast iterative soft-thresholding algorithm, and alternating direction method of multipliers. These methods were tested and validated on computer simulations and phantom experiments. The PD approach could provide a faster reconstruction time compared with other methods. Experimental results showed that the PD algorithm could achieve comparable or even better visualization and accuracy of the metallic interventional devices in positive-contrast imaging with different SNRs and orientations to the B0 field. A susceptibility-based positive-contrast imaging technique by PD algorithm was proposed. The PD approach has more superior performance than other algorithms in terms of reconstruction time and accuracy for imaging the metallic interventional devices.

Accelerated positive contrast MRI of interventional devices using parallel compressed sensing imaging

Susceptibility-based magnetic resonance imaging (MRI) method can image small MR-compatible devices with positive contrast. However, the relatively long data acquisition time required by the method hinders its practical applications. This study presents a parallel compressive sensing technique with a modified fast spin echo to accelerate data acquisition for the susceptibility-based positive contrast MRI. The method integrates the generalized autocalibrating partially parallel acquisitions and the compressive sensing techniques in the reconstruction algorithm. MR imaging data acquired from several phantoms containing interventional devices such as biopsy needles, stent, and brachytherapy seeds, used for validating the proposed technique. The results show that it can speed up data acquisition by a factor of about five while preserving the quality of the positive contrast images.

Normalized averaged range (nAR), a robust quantification method for MPIO-content.

Micron-sized paramagnetic iron oxide particles (MPIO) are commonly used as contrast agents in magnetic resonance imaging (MRI) that produce negative contrast enhancement, i.e. darkening, on T2*-weighted images. However, estimation and quantification of MPIO in vivo is still challenging. This limitation mainly arises from smearing and displacement of the negative contrast of the MPIO, so-called blooming, potentially leading to false-positive detection. Further, the bias field induced by the MR coils also hinders visualization and quantification of the MPIO. To mitigate these drawbacks, a positive contrast image can be generated, for example by using a frequency offset technique, which can significantly improve the accuracy of quantification methods. In this research, we introduce the normalized average range (nAR) as a new way to quantify the relative MPIO content within a study. The method compares the average value of test ROIs to that of a control ROI in range filtered images. The nAR can be used on both positive and negative contrast images. The nAR was tested on agar phantoms containing various MPIO concentrations, and on a rostral migration model for MPIO labeled stem cells in mice. The amount of MPIO was quantified for biased and unbiased data, and both for positive and negative contrast images. In addition, the presence of MPIOs in the olfactory bulb was verified by histology. The results show the nAR can indicate the presence and relative content of MPIO for both negative and positive images. However, the nAR showed slightly higher sensitivity in optimized positive contrast images compared to negative contrast images. In all cases, the bias field played a minor role in the quantification, making debiasing less of a concern. The dependency of the nAR values on the MPIO content in the ROI was further validated histologically. Thus, the nAR provides a robust and reliable tool for quantification of MPIO in mice.

Dual T1/ T2 Nanoscale Coordination Polymers as Novel Contrast Agents for MRI: A Preclinical Study for Brain Tumor.

In the last years, extensive attention has been paid on designing and developing functional imaging contrast agents for providing accurate noninvasive evaluation of pathology in vivo. However, the issue of false-positives or ambiguous imaging and the lack of a robust strategy for simultaneous dual-mode imaging remain to be fully addressed. One effective strategy for improving it is to rationally design magnetic resonance imaging (MRI) contrast agents (CAs) with intrinsic T1/ T2 dual-mode imaging features. In this work, the development and characterization of one-pot synthesized nanostructured coordination polymers (NCPs) which exhibit dual mode T1/ T2 MRI contrast behavior is described. The resulting material comprises the combination of different paramagnetic ions (Fe3+, Gd3+, Mn2+) with selected organic ligands able to induce the polymerization process and nanostructure stabilization. Among them, the Fe-based NCPs showed the best features in terms of colloidal stability, low toxicity, and dual T1/ T2 MRI contrast performance overcoming the main drawbacks of reported CAs. The dual-mode CA capability was evaluated by different means: in vitro phantoms, ex vivo and in vivo MRI, using a preclinical model of murine glioblastoma. Interestingly, the in vivo MRI of Fe-NCPs show T1 and T2 high contrast potential, allowing simultaneous recording of positive and negative contrast images in a very short period of time while being safer for the mouse. Moreover, the biodistribution assays reveals the persistence of the nanoparticles in the tumor and subsequent gradual clearance denoting their biodegradability. After a comparative study with commercial CAs, the results suggest these nanoplatforms as promising candidates for the development of dual-mode MRI CAs with clear advantages.

Positive chemical exchange contrast in MRI using Refocused Acquisition of Chemical Exchange Transferred Excitations (RACETE)

PurposeA new chemical exchange MRI method is proposed which allows for direct detection of exchanging solute protons with concurrent water background suppression. MethodsThe proposed method, RACETE (Refocused Acquisition of Chemical Exchange Transferred Excitations), is based on a stimulated-echo-technique, where the first two excitation pulses are replaced by a train of N solute-selective excitation-transfer modules. This excitation cycle is then followed by a stimulated echo acquisition via selective refocusing of exchanged solute protons now present in the solvent pool. ResultsThe obtained magnitude and phase phantom images demonstrate that with only one RACETE-imaging experiment two different chemical exchange active substances with mMol-concentrations can be detected and distinguished simultaneously. ConclusionThe proposed RACETE-approach allows for true positive chemical exchange contrast imaging with the proven ability to exploit magnitude as well as phase image data.

Accelerated susceptibility-based positive contrast imaging of MR compatible metallic devices based on modified fast spin echo sequences

This study aims to develop an accelerated susceptibility-based positive contrast MR imaging method for visualizing MR compatible metallic devices. A modified fast spin echo sequence is used to accelerate data acquisition. Each readout gradient in the modified fast spin echo is slightly shifted by a short distance Tshift. Phase changes accumulated within Tshift are then used to calculate the susceptibility map by using a kernel deconvolution algorithm with a regularized ℓ1 minimization. To evaluate the proposed fast spin echo method, three phantom experiments were conducted and compared to a spin echo based technique and the gold standard CT for visualizing biopsy needles and brachytherapy seeds. Compared to the spin echo based technique, the data sampling speed of the proposed method was faster by 2–4 times while still being able to accurately visualize and identify the location of the biopsy needle and brachytherapy seeds. These results were confirmed by CT images of the same devices. Results also demonstrated that the proposed fast spin echo method can achieve good visualization of the brachytherapy seeds in positive contrast and in different orientations. It is also capable of correctly differentiating brachytherapy seeds from other similar structures on conventional magnitude images.

Abstract B22: Quantitative tumor imaging using magnetic nanoparticles

Abstract Introduction: We have developed a new method of Quantitative MRI named QUTE-CE MRI that yields images of the vasculature with unparalleled clarity and definition and is quantitative. QUTE-CE MRI can produce contrast enhanced magnetic resonance angiograms (CE-MRA) using super paramagnetic iron-oxide nanoparticle (SPION), including the FDA approved ferumoxytol, with high contrast in cardiovascular, cerebral, and tumor imaging. Based upon principles of magnetic nanoparticle interactions with neighboring water molecules, the method achieves robust, reproducible results by utilizing rapid signal acquisition at ultra-short time-to-echo (UTE) to produce positive-contrast images with pure T1 weighting and little T2* decay. The spoiled gradient echo equation (SPGR) is used to transform UTE intensities directly into concentration using experimentally determined relaxivity constants and image acquisition parameters. Methods: All animal experiments were conducted in accordance with the Northeastern University Division of Laboratory Animal Medicine and Institutional Animal Care and Use Committee. MRI images were obtained at ambient temperature (∼25°C) using a Bruker Biospec 7.0T/20-cm USR horizontal magnet (Bruker, Billerica, Massachusetts, USA) equipped with a 20-G/cm magnetic field gradient insert (ID =12 cm, Bruker) and the same quadrature 300 MHz, 30 mm Mouse MRI coil was used for all in vivo work as previously utilized for mouse experiments in Section 3.8 (Animal Imaging Research, LLC, Holden, Massachusetts, USA). PC 3 cells were injected into the right flank of immunocompromised FoxNu1 mice (n=5, Charles River Laboratories). After tumors reached about 0.5-1.0cm3, animals underwent three separate imaging sessions: Session 1 - pre-contrast T1, T2 and QUTE-CE measurements, Session 2 - immediate post-contrast QUTE-CE measurement and Session 3 - 24h post-contrast T1, T2 and QUTE-CE measurements. For contrast, 100μl of ferumoxytol diluted to 6mg/ml was injected i.v. to render a blood concentration of ~200μg/ml Fe (2x clinical dose). Results: Contrary to more standard MRI techniques, QUTE-CE pre-contrast images render a nearly homogenous signal with a Gaussian distribution in the tumor. The immediate post-contrast images render the vasculature clearly and skew the distribution of voxels within the whole tumor to the left, however also increases the overall mean of the signal intensity because the movement of voxels within the tumor is to the right, leaving a long bright tail with the brightest voxels represented by those containing 100% blood. 24h after the initial administration of ferumoxytol the vasculature is no longer visible, but the locations within the tumor that have passively accumulated SPIONs resulting from the EPR effect becomes apparent. While the distribution of voxels within the tumor becomes less skewed, the overall shape is still slightly skewed to the left and the mean of the distribution has moved to the right. Nanoparticle accumulation in the post-contrast image is heterogeneous and unambiguous. Angiography and TBV in tumors Assuming a partial 2-volume model of blood and tissue, we determine the tumor blood volume (TBV) across the entire tumor volume. The resultant TBV heatmaps show a clear range of TBV values are apparent, delineating areas of the tissue with high contrast in regard to overall vascular health, including apparently necrotic tissue. Nanoparticle accumulation Next, a unique feature of the methodology to produce high-contrast images of purely T1-weighted signal is employed to unambiguously delineate nanoparticle accumulation in a PC3 subcutaneous tumor model with ferumoxytol accumulation 24 hours after just one dose. From this, contrast efficiency was produced compared to standard techniques with the additional benefit that pre-contrast images are not necessitated. A major advantage of delineating SPION accumulation using QUTE-CE, compared to ΔT2 or ΔT1 imaging, is that the post-contrast image contains sufficient information for nanoparticle localization, eliminating the need for pre-contrast images. Conclusion: QUTE-CE MRI exploits physical principles of magnetic relaxation modulated by SPIONs to achieve quantitative MRI yielding exceptional vascular images. This ability to longitudinally quantify blood pool CA concentration is unique to the QUTE-CE method, and makes QUTE-CE MRI competitive with nuclear imaging. Quantitative tumor blood volume distributions are obtained at short times, while nanoparticle accumulation maps are obtained at long times. QUTE-CE MRI is a new method that can be used to study tumor properties longitudinally. The technique is immediately translatable to the clinic using the FDA approved contrast agent ferumoxytol and is expected to have a major impact on clinical tumor imaging. Work supported by NSF-DGE- 0965843. Citation Format: Gharagouzloo Codi, Ju Qiao, Liam Timms, Anne van de Ven, Srinivas Sridhar. Quantitative tumor imaging using magnetic nanoparticles. [abstract]. In: Proceedings of the AACR Special Conference on Engineering and Physical Sciences in Oncology; 2016 Jun 25-28; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2017;77(2 Suppl):Abstract nr B22.

Positive contrast spiral imaging for visualization of commercial nitinol guidewires with reduced heating.

BackgroundCMR-guidance has the potential to improve tissue visualization during cardiovascular catheterization procedures and to reduce ionizing radiation exposure, but a lack of commercially available CMR guidewires limits widespread adoption. Standard metallic guidewires are considered to be unsafe in CMR due to risks of RF-induced heating. Here, we propose the use of RF-efficient gradient echo (GRE) spiral imaging for reduced guidewire heating (low flip angle, long readout), in combination with positive contrast for guidewire visualization.MethodsA GRE spiral sequence with 8 interleaves was used for imaging. Positive contrast was achieved using through-slice dephasing such that the guidewire appeared bright and the background signal suppressed. Positive contrast images were interleaved with anatomical images, and real-time image processing was used to produce a color overlay of the guidewire on the anatomy. Temperature was measured with a fiber-optic probe attached to the guidewire in an acrylic gel phantom and in vivo.ResultsLeft heart catheterization was performed on swine using the real-time color overlay for procedural guidance with a frame rate of 6.25 frames/second. Using our standard Cartesian real-time imaging (flip angle 60°), temperature increases up to 50 °C (phantom) and 4 °C (in vivo) were observed. In comparison, spiral GRE images (8 interleaves, flip angle 10°) generated negligible heating measuring 0.37 °C (phantom) and 0.06 °C (in vivo).ConclusionsThe ability to use commercial metallic guidewires safely during CMR-guided catheterization could potentially expedite clinical translation of these methods.Electronic supplementary materialThe online version of this article (doi:10.1186/s12968-015-0219-9) contains supplementary material, which is available to authorized users.

Selective magnetic resonance imaging of magnetic nanoparticles by acoustically induced rotary saturation.

The goal of this study was to introduce a new method to selectively detect iron oxide contrast agents using an acoustic wave to perturb the spin-locked water signal in the vicinity of the magnetic particles. The acoustic drive can be modulated externally to turn the effect on and off, allowing sensitive and quantitative statistical comparison and removal of confounding image background variations. We demonstrated the effect in spin-locking experiments using piezoelectric actuators to generate vibrational displacements of iron oxide samples. We observed a resonant behavior of the signal changes with respect to the acoustic frequency where iron oxide is present. We characterized the effect as a function of actuator displacement and contrast agent concentration. The resonant effect allowed us to generate block-design "modulation response maps" indicating the contrast agent's location, as well as positive contrast images with suppressed background signal. We found that the acoustically induced rotary saturation (AIRS) effect stayed approximately constant across acoustic frequency and behaved monotonically over actuator displacement and contrast agent concentration. AIRS is a promising method capable of using acoustic vibrations to modulate the contrast from iron oxide nanoparticles and thus perform selective detection of the contrast agents, potentially enabling more accurate visualization of contrast agents in clinical and research settings.

Positive contrast of SPIO-labeled cells by off-resonant reconstruction of 3D radial half-echo bSSFP.

This article describes a new acquisition and reconstruction concept for positive contrast imaging of cells labeled with superparamagnetic iron oxides (SPIOs). Overcoming the limitations of a negative contrast representation as gained with gradient echo and fully balanced steady state (bSSFP), the proposed method delivers a spatially localized contrast with high cellular sensitivity not accomplished by other positive contrast methods. Employing a 3D radial bSSFP pulse sequence with half-echo sampling, positive cellular contrast is gained by adding artificial global frequency offsets to each half-echo before image reconstruction. The new contrast regime is highlighted with numerical intravoxel simulations including the point-spread function for 3D half-echo acquisitions. Furthermore, the new method is validated on the basis of in vitro cell phantom measurements on a clinical MRI platform, where the measured contrast-to-noise ratio (CNR) of the new approach exceeds even the negative contrast of bSSFP. Finally, an in vivo proof of principle study based on a mouse model with a clear depiction of labeled cells within a subcutaneous cell islet containing a cell density as low as 7 cells/mm(3) is presented. The resultant isotropic images show robustness to motion and a high CNR, in addition to an enhanced specificity due to the positive contrast of SPIO-labeled cells.

Susceptibility-based positive contrast MRI of brachytherapy seeds.

To provide visualization of the brachytherapy seeds and differentiation with natural structures in MRI by taking advantage of their high magnetic susceptibility to generate positive-contrast images. The method is based on mapping the susceptibility using an equivalent short-TE sequence and a kernel deconvolution algorithm with a regularized L1 minimization. An appealing aspect of the method is that signals from the surrounding areas where signal to noise ratio (SNR) is sufficiently high are used to derive the susceptibility of the seeds, even though the SNR in the immediate vicinity of the seeds can be extremely low due to rapid signal decay. The method is tested using computer simulations and experimental data. Comparing to conventional methods, the proposed method improves seed definition by a factor of >70% in the experiments. It produces the enhanced contrast at the exact seed location, whereas methods based on susceptibility gradient mapping produce highlighted regions surrounding the seeds. The proposed method is capable to perform the function for a wide range of resolutions and SNRs. The results show that the proposed method provides positive contrast for the seeds and correctly differentiates them from other structures that appear similar to the seeds on conventional magnitude images.

Quantitative contrast-enhanced MRI with superparamagnetic nanoparticles using ultrashort time-to-echo pulse sequences.

Conventional MRI using contrast agents is semiquantitative because it is inherently sensitive to extravoxular susceptibility artifacts, field inhomogeneity, partial voluming, perivascular effects, and motion/flow artifacts. Herein we demonstrate a quantitative contrast-enhanced MRI technique using ultrashort time-to-echo pulse sequences for measuring clinically relevant concentrations of ferumoxytol, a superparamagnetic iron oxide nanoparticle contrast agent with high sensitivity and precision in vitro and in vivo. The method achieves robust, reproducible results by using rapid signal acquisition at ultrashort time-to-echo (UTE) to produce positive contrast images with pure T1 weighting and little T2* decay. The spoiled gradient echo equation is used to transform UTE intensities directly into concentration using experimentally determined relaxivity constants and image acquisition parameters. A multiparametric optimization of acquisition parameters revealed an optimal zone capable of producing high-fidelity measurements. Clinically relevant intravascular concentrations of ferumoxytol were measured longitudinally in mice with high sensitivity and precision (∼7.1% error). MRI measurements were independently validated by elemental iron analysis of sequential blood draws. Automated segmentation of ferumoxytol concentration yielded high quality three-dimensional images for visualization of perfusion. This ability to longitudinally quantify blood pool CA concentration is unique to quantitative UTE contrast-enhanced (QUTE-CE) MRI and makes QUTE-CE MRI competitive with nuclear imaging.

Negative contrast Cerenkov luminescence imaging of blood vessels in a tumor mouse model using [68Ga]gallium chloride

BackgroundCerenkov luminescence imaging (CLI) is an emerging imaging technique where visible light emitted from injected beta-emitting radionuclides is detected with an optical imaging device. CLI research has mostly been focused on positive contrast imaging for ascertaining the distribution of the radiotracer in a way similar to other nuclear medicine techniques. Rather than using the conventional technique of measuring radiotracer distribution, we present a new approach of negative contrast imaging, where blood vessel attenuation of Cerenkov light emitted by [68Ga]GaCl3 is used to image vasculature.MethodsBALB/c nude mice were injected subcutaneously in the right flank with HT-1080 fibrosarcoma cells 14 to 21 days prior to imaging. On the imaging day, [68Ga]GaCl3 was injected and the mice were imaged from 45 to 90 min after injection using an IVIS Spectrum in vivo imaging system. The mice were imaged one at a time, and manual focus was used to bring the skin into focus. The smallest view with pixel size around 83 μm was used to achieve a sufficiently high image resolution for blood vessel imaging.ResultsThe blood vessels in the tumor were clearly visible, attenuating 7% to 18% of the light. Non-tumor side blood vessels had significantly reduced attenuation of 2% to 4%. The difference between the attenuation of light of tumor vessels (10% ± 4%) and the non-tumor vessels (3% ± 1%) was significant. Moreover, a necrotic core confirmed by histology was clearly visible in one of the tumors with a 21% reduction in radiance.ConclusionsThe negative contrast CLI technique is capable of imaging vasculature using [68Ga]GaCl3. Since blood vessels smaller than 50 μm in diameter could be imaged, CLI is able to image structures that conventional nuclear medicine techniques cannot. Thus, the negative contrast imaging technique shows the feasibility of using CLI to perform angiography on superficial blood vessels, demonstrating an advantage over conventional nuclear medicine techniques.

In vivo visualization of cells labeled with superparamagnetic iron oxides by a sub-millisecond gradient echo sequence

In vivo magnetic resonance imaging (MRI) of iron-labeled pancreatic islets (PIs) transplanted into the liver is still challenging in humans. The aim of this study was to develop and evaluate a double contrast method for the detection of PIs labeled with superparamagnetic iron oxide (SPIO) nanoparticles. A double-echo three-dimensional (3D) spoiled gradient echo sequence was adapted to yield a sub-millisecond first echo time using variable echo times and highly asymmetric Cartesian readout. Positive contrast was achieved by conventional and relative image subtraction. Experiments for cell detection efficiency were performed in vitro on gelatin phantoms, in vivo on a Lewis rat and on a patient 6months after PI transplantation. It was demonstrated that the proposed method can be used for the detection of transplanted PIs with positive contrast in vitro and in vivo. For all experiments, relative subtraction yielded comparable and in some cases better contrast than conventional subtraction. For the first time, positive contrast imaging of transplanted human PIs was performed in vivo in patients. The proposed method allows 3D data acquisition within a single breath-hold and yields enhanced contrast-to-noise ratios of transplanted SPIO labeled pancreatic islets relative to negative contrast images, therefore providing improved identification.