Scott D. Swanson

Targeted gadolinium-loaded dendrimer nanoparticles for tumor-specific magnetic resonance contrast enhancement

A target-specific MRI contrast agent for tumor cells expressing high affinity folate receptor was synthesized using generation five (G5) of polyamidoamine (PAMAM) dendrimer. Surface modified dendrimer was functionalized for targeting with folic acid (FA) and the remaining terminal primary amines of the dendrimer were conjugated with the bifunctional NCS-DOTA chelator that forms stable complexes with gadolinium (Gd III). Dendrimer-DOTA conjugates were then complexed with GdCl3 followed by ICP-OES as well as MRI measurement of their longitudinal relaxivity (T1 s−1 mM−1) of water. In xenograft tumors established in immunodeficient (SCID) mice with KB human epithelial cancer cells expressing folate receptor (FAR), the 3D MRI results showed specific and statistically significant signal enhancement in tumors generated with targeted Gd(III)-DOTA-G5-FA compared with signal generated by non-targeted Gd(III)-DOTA-G5 contrast nanoparticle. The targeted dendrimer contrast nanoparticles infiltrated tumor and were retained in tumor cells up to 48 hours post-injection of targeted contrast nanoparticle. The presence of folic acid on the dendrimer resulted in specific delivery of the nanoparticle to tissues and xenograft tumor cells expressing folate receptor in vivo. We present the specificity of the dendrimer nanoparticles for targeted cancer imaging with the prolonged clearance time compared with the current clinically approved gadodiamide (Omniscan™) contrast agent. Potential application of this approach may include determination of the folate receptor status of tumors and monitoring of drug therapy.

Distribution and dynamics of laser-polarized 129Xe magnetization in vivo

The first magnetic resonance imaging studies of laser‐polarized 129Xe, dissolved in the blood and tissue of the lungs and the heart of Sprague‐Dawley rats, are described. 129Xe resonances at 0, 192, 199, and 210 ppm were observed and assigned to xenon in gas, fat, tissue, and blood, respectively. One‐dimensional chemical‐shift imaging (CSI) reveals xenon magnetization in the brain, kidney, and lungs. Coronal and axial two‐dimensional CSI show 129Xe dissolved in blood and tissue in the thorax. Images of the blood resonance show xenon in the lungs and the heart ventricle. Images of the tissue resonance reveal xenon in lung parenchyma and myocardium. The 129Xe spectrum from a voxel located in the heart ventricle shows a single blood resonance. Time‐resolved spectroscopy shows that the dynamics of the blood resonance match the dynamics of the gas resonance and demonstrates efficient diffusion of xenon gas to the lung parenchyma and then to pulmonary blood. These observations demonstrate the utility of laser‐polarized 129Xe to detect exchange across the gas‐blood barrier in the lungs and perfusion into myocardial tissue. Applications to measurement of lung function, kidney perfusion, myocardial perfusion, and regional cerebral blood flow are discussed. Magn Reson Med 42:1137–1145, 1999.

Magnetization Transfer Helps Detect Intestinal Fibrosis in an Animal Model of Crohn Disease

PURPOSE To determine the utility of magnetization transfer (MT) in the identification and quantification of intestinal fibrosis in a rat model of Crohn disease. MATERIALS AND METHODS The university committee on the use and care of animals approved this study (UCUCA 08592). Lewis rats injected subserosally with peptidoglycan-polysaccharide (PG-PS) develop bowel inflammation 1 day after laparotomy (early phase) and fibrosis starting 14 days after laparotomy (late phase). The authors performed 2.0-T magnetic resonance (MR) imaging in 25 rats injected with PG-PS and 13 injected with human serum albumin (HSA) (control animals). Imaging was performed before laparotomy and on a weekly basis thereafter for up to 28 days. The MT ratio in the bowel wall was calculated. Resected cecal tissue was scored for inflammation and fibrosis. Tissue fibrosis was determined with colorimetric analysis of trichrome-stained specimens. Collagen content was measured with Western blot analysis. Statistical analyses were performed with the Student t test for continuous bivariate comparisons, the Pearson correlation for continuous variables, and the Spearman correlation for ordinal variables. RESULTS All rats developed early inflammation, which subsided over time. Rats injected with PG-PS developed increased fibrosis in the late phase, whereas control rats did not. The mean MT ratio of rats injected with PG-PS with late-phase fibrosis was higher than that in rats with early phase inflammation (P = .017). In addition, the MT ratio of rats injected with PG-PS with late-phase fibrosis was higher than that of control animals that did not develop fibrosis in the late phase (P = .0001). The MT ratio of control animals remained unchanged over time as inflammation subsided. The MT ratio in rats injected with PG-PS showed correlation with tissue fibrosis (ρ = 0.63). The MT ratio showed correlation with tissue collagen (R = 0.74). The positive and negative predictive values of the MT ratio in the prediction of fibrosis were 92% (12 of 13 rats) and 83% (five of six rats), respectively. CONCLUSION These results indicate that MT is sensitive to bowel wall fibrosis as occurs in Crohn strictures.

Polarized 129Xe optical pumping/spin exchange and delivery system for magnetic resonance spectroscopy and imaging studies

We describe the design and construction of a laser-polarized 129Xe production and delivery system that is used in our in vitro and in vivo magnetic resonance imaging (MRI) experiments. The entire apparatus including lasers and optics, rapidly actuated valves, heating and cooling, and transport tubing lies in the high magnetic field environment of a 2 T MRI magnet. With approximately 7.5% 129Xe polarization, 157 cc atm of xenon gas is produced and stored as xenon ice every 5 min. Large quantities of polarized 129Xe can be obtained by cycling this process. The xenon is subsequently delivered in a controlled fashion to a sample or subject. With this device we have established the feasibility of using laser-polarized 129Xe as a magnetic tracer in MRI. This reliable, effective, and relatively simple production method for large volumes of 129Xe can be applied to other areas of research involving the use of laser-polarized noble gases.

Acoustic Droplet Vaporization for Enhancement of Thermal Ablation by High Intensity Focused Ultrasound

RATIONALE AND OBJECTIVES Acoustic droplet vaporization (ADV) shows promise for spatial control and acceleration of thermal lesion production. The investigators hypothesized that microbubbles generated by ADV could enhance high-intensity focused ultrasound (HIFU) thermal ablation by controlling and increasing local energy absorption. MATERIALS AND METHODS Thermal lesions were produced in tissue-mimicking phantoms using focused ultrasound (1.44 MHz) with a focal intensity of 4000 W · cm(-2) in degassed water at 37°C. The average lesion volume was measured by visible change in optical opacity and by T2-weighted magnetic resonance imaging. In addition, in vivo HIFU lesions were generated in a canine liver before and after an intravenous injection of droplets with a similar acoustic setup. RESULTS Thermal lesions were sevenfold larger in phantoms containing droplets (3 × 10(5) droplets/mL) compared to phantoms without droplets. The mean lesion volume with a 2-second HIFU exposure in droplet-containing phantoms was comparable to that made by a 5-second exposure in phantoms without droplets. In the in vivo study, the average lesion volumes without and with droplets were 0.017 ± 0.006 cm(3) (n = 4; 5-second exposure) and 0.265 ± 0.005 cm(3) (n = 3; 5-second exposure), respectively, a factor of 15 difference. The shape of ADV bubbles imaged with B-mode ultrasound was very similar to the actual lesion shape as measured optically and by magnetic resonance imaging. CONCLUSION ADV bubbles may facilitate clinical HIFU ablation by reducing treatment time or requisite in situ total acoustic power and provide ultrasonic imaging feedback of the thermal therapy.

Transient decay of longitudinal magnetization in heterogeneous spin systems under selective saturation

The transient behavior of the longitudinal magnetization of the mobile protons in aqueous heterogeneous materials is investigated both theoretically and experimentally when selective saturation is applied by off-resonance, RF irradiation to the homogeneously broadened, immobile protons which are coupled to the mobile protons through cross relaxation. Analytical solution of this problem is obtained by a generalization of H. C. Torrey’s solution to the Bloch equations. Progressive (but indirect) saturation of the magnetization of the mobile protons under this RF irradiation is dynamically monitored using very-small-tipangle sampling pulses. The apparent relaxation rate of heat-denatured egg albumin was measured as a function of frequency offset of the saturating RF with different amplitudes using a new dispersion method modified from a broadband technique recently invented for the rapid

Tissue-Compliant Neural Implants from Microfabricated Carbon Nanotube Multilayer Composite

Current neural prosthetic devices (NPDs) induce chronic inflammation due to complex mechanical and biological reactions related, in part, to staggering discrepancies of mechanical properties with neural tissue. Relatively large size of the implants and traumas to blood-brain barrier contribute to inflammation reactions, as well. Mitigation of these problems and the realization of long-term brain interface require a new generation of NPDs fabricated from flexible materials compliant with the brain tissue. However, such materials will need to display hard-to-combine mechanical and electrical properties which are not available in the toolbox of classical neurotechnology. Moreover, these new materials will concomitantly demand different methods of (a) device micromanufacturing and (b) surgical implantation in brains because currently used processes take advantage of high stiffness of the devices. Carbon nanotubes (CNTs) serve as a promising foundation for such materials because of their record mechanical and electrical properties, but CNT-based tissue-compliant devices have not been realized yet. In this study, we formalize the mechanical requirements to tissue-compliant implants based on critical rupture strength of brain tissue and demonstrate that miniature CNT-based devices can satisfy these requirements. We fabricated them using MEMS-like technology and miniaturized them so that at least two dimensions of the electrodes would be comparable to brain tissue cells. The nanocomposite-based flexible neural electrodes were implanted into the rat motor cortex using a surgical procedure specifically designed for soft tissue-compliant implants. The post-surgery implant localization in the motor cortex was successfully visualized with magnetic resonance and photoacoustic imaging. In vivo functionality was demonstrated by successful registration of the low-frequency neural recording in the live brain of anesthetized rats. Investigation of inflammation processes around these electrodes will be required to establish their prospects as long-term neural electrodes.

Comparison of noncontrast MRI magnetization transfer and T2 -Weighted signal intensity ratios for detection of bowel wall fibrosis in a Crohn's disease animal model.

To compare the abilities of magnetization transfer magnetic resonance imaging (MT‐MRI) and T2‐weighted signal intensity (T2WSI) ratios to detect intestinal fibrosis in a Crohns disease animal model.

Broadband excitation and detection of cross-relaxation NMR spectra

Nuclear magnetic resonance cross-relaxation spectroscopy maps the proton solidstate NMR spectrum onto the proton water NMR signal of aqueous heterogeneous materials ( Z-3). Application of a relatively long, low-intensity RF pulse, off resonance from the water Larmor frequency but within the linewidth of the solid, partially saturates the nuclear magnetism of the solid protons. Magnetic cross relaxation between the immobile and mobile protons transfers the saturation of the solid protons to the water protons, decreasing the magnitude of the water NMR signal. A cross-relaxation spectrum is obtained by saturating the immobile protons at many discrete frequencies and plotting the ratio of the water signal with and without RF saturation as a function of the saturation frequency. The intensity and the width ofthe cross-relaxation spectrum are a function of the longitudinal, transverse, and cross-relaxation rates of the liquid and solid components, the mole fraction of liquid to solid protons, and the magnitude and duration of the saturating RF pulse. This Communication describes a method for obtaining the entire cross-relaxation spectrum of a spatially homogeneous material with two acquisitions: RF saturation on and RF saturation off. The pulse sequence is demomtrated schematically in Fig. I. A magnetic field gradient and RF pulse are applied to the sample concurrently. The gradient creates a continuum of frequencies across the !;ample and establishes at once all conditions of off-resonance saturation for the RF pulse. The decrease in water magnetization by cross relaxation as a function of off-resonance frequency is stored in the sample as a function of the position in the sample and detected by recording a onedimensional image with the readout gradient applied along the same axis as the frequency-dispersal gradient. The cross-relaxation spectrum is created by dividing the image obtained with RF saturation turned on by one obtained with RF saturation turned off. The pulse sequence shown in Fig. 1 represents the simplest implementation of broadband cross-relaxation spectroscopy. The sequence may be modified to include slice selection, spin-echo detection, and imaging by phase encoding in either or both of the two spatial dimensions which are not needed to record the cross-relaxation spectrum. In addition the magnitude of the readout gradient may be decreased to lower the bandwidths of the receiver and increase the signal-to-noise of the crossrelaxation spectrum.

Association Between Impaired Cardiovascular Autonomic Function and Hypoglycemia in Patients With Type 1 Diabetes

OBJECTIVE We studied the association between glycemic variability (GV) reflecting hypoglycemic stress and cardiovascular autonomic function in subjects with type 1 diabetes. RESEARCH DESIGN AND METHODS Forty-four type 1 diabetic patients (mean age 34 ± 13 years, 40% male, 86% Caucasian, mean diabetes duration 13 ± 6 years, mean hemoglobin A1c [HbA1c] 8.0 ± 1.2% [64 ± 5 mmol/mol]) without cardiovascular disease, dyslipidemia, or hypertension participated in this pilot study. Indices of GV reflective of hypoglycemic stress (low blood glucose index [LBGI] and area under the curve [AUC] for hypoglycemia) were computed using data obtained during 5-day continuous glucose monitoring. Cardiovascular autonomic neuropathy (CAN) was assessed using standardized cardiovascular reflex testing and measures of heart rate variability (HRV), which were analyzed as time and frequency domain measures. RESULTS Both LBGI and AUC hypoglycemia had a significant negative association with the low-frequency power of HRV (r = −0.47, P = 0.002; r = −0.43, P = 0.005, respectively) and with the high-frequency power of HRV (r = −0.37, P = 0.018; r = −0.38, P = 0.015, respectively). These inverse associations persisted after adjusting for HbA1c, although they were attenuated in multivariable analysis after adjustment for age, diabetes duration, and several other covariates. CONCLUSIONS Increased GV promoting hypoglycemic stress was associated with reduced HRV independent of glycemic control as assessed by HbA1c. These pilot data suggest that glucose variability may contribute to cardiovascular autonomic dysfunction among adults with type 1 diabetes.