T Hu

Porous-wall hollow glass microspheres as novel potential nanocarriers for biomedical applications

UNLABELLED Porous-wall hollow glass microspheres (PW-HGMs) are a novel form of glass material consisting of a 10- to 100-microm-diameter hollow central cavity surrounded by a 1-microm-thick silica shell. A tortuous network of nanometer-scale channels completely penetrates the shell. We show here that these channels promote size-dependent uptake and controlled release of biological molecules in the 3- to 8-nm range, including antibodies and a modified single-chain antibody variable fragment. In addition, a 6-nm (70-kDa) dextran can be used to gate the porous walls, facilitating controlled release of an internalized short interfering RNA. PW-HGMs remained in place after mouse intratumoral injection, suggesting a possible application for the delivery of anticancer drugs. The combination of a hollow central cavity that can carry soluble therapeutic agents with mesoporous walls for controlled release is a unique characteristic that distinguishes PW-HGMs from other glass materials for biomedical applications. FROM THE CLINICAL EDITOR Porous-wall hollow glass microspheres (PW-HGMs) are a novel form of glass microparticles with a tortuous network of nanometer-scale channels. These channels allow size-dependent uptake and controlled release of biological molecules including antibodies and single-chain antibody fragments. PW-HGMs remained in place after mouse intratumoral injection, suggesting a possible application for the delivery of anti-cancer drugs.

Relationship between blood and myocardium manganese levels during manganese-enhanced MRI (MEMRI) with T1 mapping in rats.

Manganese ions (Mn2+) enter viable myocardial cells via voltage‐gated calcium channels. Because of its shortening of T1 and its relatively long half‐life in cells, Mn2+ can serve as an intracellular molecular contrast agent to study indirect calcium influx into the myocardium. One major concern in using Mn2+ is its sensitivity over a limited range of concentrations employing T1‐weighted images for visualization, which limits its potential in quantitative techniques. Therefore, this study assessed the implementation of a T1 mapping method for cardiac manganese‐enhanced MRI to enable a quantitative estimate of the influx of Mn2+ over a wide range of concentrations in male Sprague‐Dawley rats. This MRI method was used to compare the relationship between T1 changes in the heart as a function of myocardium and blood Mn2+ levels. Results showed a biphasic relationship between ΔR1 and the total Mn2+ infusion dose. Nonlinear relationships were observed between the total Mn2+ infusion dose versus blood levels and left ventricular free wall ΔR1. At low blood levels of Mn2+, there was proportionally less cardiac enhancement seen than at higher levels of blood Mn2+. We hypothesize that Mn2+ blood levels increase as a result of rate‐limiting excretion by the liver and kidneys at these higher Mn2+ doses. Copyright

Manganese-Enhanced Magnetic Resonance Imaging: Applications to Preclinical Research

Ionic manganese in divalent form (Mn2+) is a particularly useful contrast agent known for its sensitivity as well as its function as a calcium (Ca2+) analog in magnetic resonance imaging. Consequently, the use of Mn2+ in imaging studies has increased dramatically as molecular medicine incorporates clinical imaging techniques. Both the physical and chemical characteristics of Mn2+ are reviewed in Chapter XXXXX.

The use of novel gradient directions with DTI to synthesize data with complicated diffusion behavior

This study demonstrates a new technique for synthesizing diffusion tensor imaging (DTI) data sets that exhibit complex diffusion characteristics by performing operations on acquired DTI data of simple structures with anisotropic diffusive properties. The motivation behind this technique is to characterize the behavior of noise in complicated data using a phantom. Compared to simulations, an advantage to this approach is that the acquired data contain noise characteristic of the scanner and protocol. Using this technique, a simple capillary phantom is employed to infer the quality of data for more clinically realistic tissue structures (e.g., crossing fiber tracts). A water-filled phantom containing capillary arrays was constructed to demonstrate this technique, which uses a DTI protocol with typical clinical parameters. Eigenvalues and fractional anisotropy were calculated for the initial prolate data. Data were adjusted to synthesize different apparent diffusion coefficient (ADC) spatial distributions, which were compared to theoretical and analytical models. RMS differences and volumetric overlap between expected and measured ADC distributions were quantified for all synthesized distributions. Differences between synthesized and actual distributions were discussed.

SU‐FF‐J‐150: Experimental Demonstration of Dose Enhancement Due to Gold Nanoparticles and Kilovoltage X‐Rays Using Radio‐Sensitive Polymer Gel Dosimeter

Purpose: To demonstrate the dose enhancement due to goldnanoparticles and kilovoltage x‐rays by experimental measurements using radio‐sensitive gel dosimeters. Method and Materials: The dose enhancement due to goldnanoparticles and kilovoltage x‐rays has been well demonstrated through in‐vitro, in‐vivo, and computational work. However, it has not been clearly shown by any physical measurements over a volume loaded with goldnanoparticles. This study attempted to demonstrate the dose enhancement across the phantom made of radio‐sensitive gel, known as MAGIC gel, uniformly mixed with goldnanoparticles at a concentration of 1 % by weight. Specifically, formaldehyde‐containing MAGIC gel, reportedly more radio‐sensitive than the conventional MAGIC gel, was poured into 2 mL cylindrical plastic containers serving as the phantoms for x‐ray irradiation. Seven of them had MAGIC gel only, while the remaining two were filled with MAGIC gel and goldnanoparticles. Each gel phantom was irradiated using 110 kVp x‐rays entered into the phantom from six different directions separated by 60°. The total dose delivered to the phantom ranged from 0 to 30 Gy. One phantom in each group was unirradiated and taken as the control. All phantoms were read using a 7T small animal MR scanner. The inverse T2 relaxation time (i.e., R2 value) for each phantom was plotted against the delivered dose to obtain the calibration curve. Results: Preliminary results suggest addition of goldnanoparticles to MAGIC gel did not significantly change the R2 value, at least at the currently tested gold concentration level. They also show there was more than 100% dose enhancement across the volume of the phantom. Conclusion: The current investigation provides, probably for the first time, a solid physical evidence for the dose enhancement under the given conditions. It also provides a strong support for the previous estimation of dose enhancement by the Monte Carlo method.

SU‐GG‐BRC‐01: Modeling Myocardial Mn2+ Efflux Rates Using Manganese‐Enhanced MRI T1 Mapping in a Murine Myocardial Infarction Model

Purpose: Alterations in myocyte Ca 2+ handling appear to be centrally involved in the dysfunctional characteristics of the failing heart. This study uses quantitative manganese‐enhanced MRI techniques to detect changes in the Mn 2+ efflux relative to Ca 2+ fluctuations in mice following inhibition of the sodiumcalcium exchanger (NCX) with SEA0400. Furthermore, the technique was applied to a mouse myocardial infarction (MI) model. Segmentation and modeling analyses were used to examine regional changes in Mn 2+ efflux rates, allowing for a study of the dynamics in the peri‐infarction zone. Methods and Materials: MnCl 2 was infused via the tail vein into C57Bl/6 mice (n=88). T1‐maps were obtained both pre‐ and post‐infusion at multiple time points. Time dependent changes in the relaxation rate (ΔR1) were calculated in the myocardium. For the MI mice various affected zones within the myocardium were identified and analyzed using segmentation software. The results from control and SEA0400 treated mice were applied to a pharmacokinetic model in order to estimate the Mn 2+ transfer rates. Results: The ΔR1 efflux half‐life was doubled following treatment with 50 mg/kg SEA0400, with the two compartment model predicting a reduction in the myocardial efflux rate by more than a factor of two. In the MI group constant ΔR1 values for viable and infarcted tissue were fit with radial analysis. A significant difference was observed between the efflux rates of the infarcted region to that of the viable region, with a continuous range of efflux rates in the peri‐infarcted region. Conclusions: Quantitative MEMRI with T1‐mapping has demonstrated the sensitivity to observe changes in Mn 2+ efflux with the ability to model the relative efflux rates. The technique also provides enough sensitivity for identifying the potentially salvageable adjacent zone as well as examining regional alterations in Mn 2+ fluxes leading to relative Ca 2+ information, potentially applicable to monitoring disease progression.

TU‐D‐352‐02: Magnetic Resonance Imaging to Track Mesenchymal Stem Cells (MSCs) in a Murine Myocardial Infarction Model

Purpose: To track the migration and engraftment of the mesenchymal stem cells (MSCs) with micrometer‐sized particles of iron oxide (MPIO) labeling into myocardial infarcted site using MRI in mice. Method and Materials: MSCs with GFP fluorescence were labeled with MPIO. Mice were irradiated with a dose of 8 Gy and received rescuing bone marrow transplantation 24 hrs later. The labeled MSCs (∼3–7×105cells) were then transplanted into the tibial modullary space of mice. The mice were randomly divided into two groups. At 14 days post‐MSCs transplantation, one group underwent myocardial infarction (MI; n=4; open chest with ligation of the left anterior descending coronary artery (LAD)) and the other group underwent sham‐operated surgery (Sham; n=2; open chest without ligating the LAD). MRI was performed at baseline, 3 days (D3), 7 days (D7) and 14 days (D14) post‐surgery. Short‐axis cardiac images were acquired using T2*‐weighted imaging and T2 mapping technique. The results were confirmed by fluorescent microscopy. The contrast‐to‐noise ratio (CNR) at the MI zone was calculated. For the Sham group, a CNR at a region of interest (ROI) designated in the left ventricular anterior wall was also calculated and compared with the MI group. Results: Pronounced signal intensity attenuation at the MI zone was observed by MRI at D7 and D14, potentially due to the accumulation of MPIO labeled stem cells. Both accumulation of stem cells with GFP signal and MPIO deposition in the heart were detected in the fluorescent microscopic images. The CNR were significantly different between the MI and Sham groups at D7 and D14 (p<0.05). Conclusion: Hypointense signal was observed at the MI zone in MRI, suggesting the infiltration of labeled MSCs. Current study may support a potential approach in cell therapy to noninvasive monitor migration of labeled cells post myocardial injury.

TU‐D‐332‐05: The Benefits of Non‐Uniform Gradient Direction Specification in DTI: Simulations and Phantom Data

Purpose: The goal of this project was to optimize angular precision in determining the principle diffusioneigenvector of prolate tensors in a diffusiontensorimaging (DTI) series, using prior knowledge of principle eigenvector direction and non‐uniform specification of gradient directions. Additionally, the effect of non‐uniform gradient distributions on fractional anisotropy (FA) was characterized. Method and Materials: Simulations were conducted, representing diffusive behavior in tissue as manifest in a DTI image series. Diffusion‐encoding gradient directions were constrained in elevation, for a prolate tensor oriented along the z‐axis. Noise was added to generate multiple measurements as per a DTI ROI analysis.Tensors were calculated as well as FA. Angular precision was quantified as the dispersion in the angle between the principle eigenvector of the prolate and the z‐axis. To confirm simulations, a phantom containing glass capillary arrays (FA=0.68) was imaged with DTI using a 3.0T GE HDx scanner. Gradient directions were specified to match simulation results. Eigenvalues,eigenvectors, and FA were calculated within an ROI. Results: Simulations identify the range of elevation angles θ=30°–40° as being most sensitive to the determination of principle eigenvector direction. This result is fairly consistent within the range of FA=0.2–0.8. Prescription of gradients within a band of elevation angles having a width of Δθ ∼40°–60° and centered at θ ∼30° can improve angular precision by 30–40%, given an uncertainty in prior eigenvector direction of <30°. FA precision using this scheme is similar to uniform gradient prescriptions, and accuracy is improved at low SNR values. Data from phantom measurements generally agree with simulation results. Conclusion: This work suggests that prior knowledge of principle eigenvector direction can improve its final determination, using gradients prescribed non‐uniformly. This technique may be useful for increasing sensitivity in these conditions (e.g., spinal lesions, determining tumor infiltration of white matter tracts).

SU‐FF‐I‐93: Use of Novel Gradient Directions to Synthesize Complex Diffusion Geometries: When A Hot Dog Is a Pancake

Purpose: The goal of this project is to demonstrate that usage of different gradient directions during the acquisition and reconstruction phases of a DTI scan can produce images exhibiting complex diffusioncharacteristics. In this manner, a simple anisotropic phantom (e.g., “hot dog” geometry) could be employed to infer the quality of data for more clinically‐realistic tissue structures (e.g., oblate, or “pancake” structures, and two prolate structures that intersect). Method and Materials: A water‐filled phantom containing glass capillary arrays was constructed. Three DTI series of images from a 3.0T GE HDx scanner were acquired by specifying sets of acquisition directions to produce synthetic oblate diffusion distributions and two diffusion distributions where prolate distributions intersect, using standard gradient directions for reconstruction. Acquisition directions were calculated so that diffusion was most restricted in the y‐direction. The three desired diffusion distributions were first simulated using MATLAB, and acquisition directions appropriate for each were computed. Eigenvalues,eigenvectors, and fractional anisotropy of the oblate tensor were calculated within an ROI. RMS differences between generated and measured ADCs were determined. Results: The simulated oblate data produced a tensor with reasonable symmetry in the x‐z plane, restricted in the y direction. Eigenvalue magnitudes were consistent with those measured for the capillary array, albeit with the values associated with different eigenvectors. ADC distributions for intersecting prolate distributions qualitatively resemble the simulated distributions, and quantitatively match the simulated distributions more closely than a spherical distribution. Conclusion: This work suggests that one could use simple phantoms to monitor scanner performance for measuring diffusion distributions with more similarity to tissue. Gradient duty cycle is similar to an ordinary diffusion protocol; the effect of noise, originating from sources other than the gradients, on complicated diffusion distributions could be characterized empirically.

TH‐C‐L100J‐06: Monitoring Myocardial Infarction Induced Calcium Homeostasis Alteration by MRI in a Small Murine Model

Purpose: Alterations in myocyte calcium regulation for both the mechanical dysfunction and the arrhythmogenesis associated with congestive heart failure. In spite of the established importance calcium regulation in the heart both prior to, and following, myocardial injury, monitoring strategies to assess calcium homeostasis in affected cardiactissues are extremely limited. We propose to characterize the dynamic and temporal features of calcium responses due to myocardial injury in a small murine model using Mn 2+ as a contrast agent. Method and Materials: There are 3 groups of mice (6–10 weeks) namely control, sham‐operated, and myocardial infarction (MI). In the MI studies, permanent myocardial infarcts were produced by ligating the left anterior descending coronary artery.Images were acquired on a horizontal 7.0 T Bruker BioSpec MRI spectrometer equipped with a micro imaging gradient. A series of short‐axis T1‐weighted cardiacimages were acquired as well as pre‐ Mn 2+ and post‐ Mn 2+ infusion T1 maps using an ECG‐gated, flow‐compensated Lock‐Locker MRI pulse sequence. Results: ECG gated cardiacMRI provided high quality images for left‐ventricle, and the infusion of Mn 2+ clearly showed a large change in T1 values. The left‐ventricular post‐ Mn 2+ relaxivity, ΔR1 (=1/ΔT1), thus far for control, sham‐operated, and MI groups are 3.54±0.94, 2.63±1.37, and 1.91 sec−1, respectively. The post‐MI group showed potentially lower ΔR1 values. Increased sample size for each animal group is warranted. Further investigation is necessary to determine if Mn 2+ could provide insights into the temporal myocardial remodeling process where Ca 2+ influx might be altered. Conclusion: One motivation for this study is that myocardial injury causes physiological remodeling leading to potential Ca 2+ handling alteration. This process can be potentially monitored with a cardiac manganese‐enhanced T1 mapping technique. Furthermore, changes in ΔR1 could potentially be calibrated to the absolute manganese content for left‐ventricular myocardium.