EMSL: Kevin R Minard's Publications

Corley RA, KR Minard, S Kabilan, DR Einstein, AP Kuprat, JR harkema, J Kimbell, ML Gargas, and JH Kinzell. 2009. "Magnetic resonance imaging and computational fluid dynamics (CFD) simulations of rabbit nasal airflows for the development of hybrid CFD/PBPK models ." Inhalation Toxicology 21(5-7):512-518. Abstract The percentages of total airἀows over the nasal respiratory and olfactory epithelium of female rabbits were cal-culated from computational ἀuid dynamics (CFD) simulations of steady-state inhalation. These airἀow calcula-tions, along with nasal airway geometry determinations, are critical parameters for hybrid CFD/physiologically based pharmacokinetic models that describe the nasal dosimetry of water-soluble or reactive gases and vapors in rabbits. CFD simulations were based upon three-dimensional computational meshes derived from magnetic resonance images of three adult female New Zealand White (NZW) rabbits. In the anterior portion of the nose, the maxillary turbinates of rabbits are considerably more complex than comparable regions in rats, mice, mon-keys, or humans. This leads to a greater surface area to volume ratio in this region and thus the potential for increased extraction of water soluble or reactive gases and vapors in the anterior portion of the nose compared to many other species. Although there was considerable interanimal variability in the Ḁne structures of the nasal turbinates and airἀows in the anterior portions of the nose, there was remarkable consistency between rabbits in the percentage of total inspired airἀows that reached the ethmoid turbinate region (~50%) that is presumably lined with olfactory epithelium. These latter results (airἀows reaching the ethmoid turbinate region) were higher than previous published estimates for the male F344 rat (19%) and human (7%). These diᴀerences in regional airἀows can have signiḀcant implications in interspecies extrapolations of nasal dosimetry.

Ferguson MR, KR Minard, and KM Krishnan. 2009. "Optimization of nanoparticle core size for magnetic particle imaging." Journal of Magnetism and Magnetic Materials 321(10):1548-1551. Abstract Magnetic Particle Imaging (MPI) is a powerful new diagnostic visualization platform designed for measuring the amount and location of superparamagnetic nanoscale molecular probes (NMPs) in biological tissues. Promising initial results indicate that MPI can be extremely sensitive and fast, with good spatial resolution for imaging human patients or live animals. Here, we present modeling results that show how MPI sensitivity and spatial resolution both depend on NMP-core physical properties, and how MPI performance can be effectively optimized through rational core design. Monodisperse magnetite cores are attractive since they are readily produced with a biocompatible coating and controllable size that facilitates quantitative imaging.

Einstein DR, B Neradilak, N Pollisar, KR Minard, C Wallis, M Fanucchi, JP Carson, AP Kuprat, S Kabilan, R Jacob, and R Corley. 2008. "An Automated Self-similarity Analysis of the Pulmonary Tree of the Sprague-Dawley Rat." The Anatomical Record 291(12):1628-1648. doi:10.1002/ar.20771 Abstract Abstract In this study, we present an automated method for tabulating geometric information of biological trees, based on magnetic resonance imaging data of silicone casts of the pulmonary airway trees of Sprague Dawley rats. From a segmentation of the airway tree, we construct a scale-invariant triangulated surface that is subsequently distilled into a connected graph, representing the airway centerline. Segment statistics are derived from this graph. To validate the method, these statistics are compared to manual measurements of a single lung cast. Subsequently, we analyze the morphometry of the airway tree by assembling individual airway segments into structures that span multiple generations, which we call branches. We show that branches not segments are the fundamental repeating unit in the rat lung and develop a parameterization of these structures for the entire lung. Our analysis shows that airway diameters and lengths have both a deterministic and stochastic character and can be described by a simple set of equations.

Hu JZ, DN Rommereim, KR Minard, A Woodstock, BJ Harrer, RA Wind, RP Phipps, and PJ Sime. 2008. "Metabolomics in Lung Inflammation: A High Resolution ¹H NMR Study of Mice Exposed to Silica Dust ." Toxicology Mechanisms and Methods 18(5):385-398. doi:10.1080/15376510701611032 Abstract First ¹H NMR metabolomics studies on excised lungs and bronchoalveolar lavage fluids (BALF) from mice exposed to crystalline silica are reported. High resolution ¹H NMR metabolic profiling on intact excised lungs is carried out using slow magic angle sample spinning (slow-MAS) ¹H PASS (phase altered spinning sidebands) at a sample spinning rate of 80 Hz while metabolic profiling on BALF is carried out using fast magic angle spinning at 2kHz. Major findings are that the relative concentrations of choline, phosphocholine (PC) and glycerophosphocholine(GPC) are significantly increased in silica exposed mice versus sham controls, indicating an altered membrane choline phospholipids metabolism (MCPM) during lung inflammation. The relative concentrations of glycogen/glucose, lactate and creatine are also increased in mice exposed to silica dusts, suggesting that the cellular energy pathways are affected by silica dust exposure. Elevated levels of Glycine, lysine, glutamate and proline are also fund increased in exposed mice suggesting the activation of a collagen pathway. Overall, metabolic profiles in the lungs of mice exposed to silica dusts are found to be spatially heterogeneous consistent with regional inflammation revealed by in vivo magnetic resonance imaging (MRI).

Jacob RE, KR Minard, GJ Laicher, and C Timchalk. 2008. "3D He-3 diffusion MRI as a local in vivo morphometric tool to evaluate emphysematous rat lungs." Journal of Applied Physiology 105:1291-1300. doi:10.1152/japplphysiol.90375.2008 Abstract In this work, we validate 3He magnetic resonance imaging as a non-invasive morphometric tool to assess emphysematous disease state on a local level. Emphysema was induced intratracheally in rats with 25U/100g body weight of porcine pancreatic elastase dissolved in 200 μL saline. Rats were then paired with saline-dosed controls. Nine three-dimensional 3He diffusion-weighted images were acquired at one-, two-, or three-weeks post-dose, after which the lungs were harvested and prepared for histological analysis. Recently introduced indices sensitive to the heterogeneity of the airspace size distribution were calculated. These indices, D1 and D2, were derived from the moments of the mean equivalent airway diameters. Averaged over the entire lung, it is shown that the 3He diffusivity (Dave) and anisotropy (Dan) both correlate with histology (R = 0.85, p < 0.0001 and R = 0.88, p < 0.0001, respectively). By matching small (0.046 cm2) regions in 3He images with corresponding regions in histological slices, Dave and Dan each correlate significantly with both D1 and D2 (R = 0.93, p < 0.0001). It is concluded that 3He MRI is a viable non-invasive morphometric tool for localized in vivo emphysema assessment.

Minard KR, RE Jacob, G Laicher, DR Einstein, AP Kuprat, and RA Corley. 2008. "MR Imaging of Apparent 3He Gas Transport in Narrow Pipes and Rodent Airways ." Journal of Magnetic Resonance 194(2):182-191. doi:10.1016/j.jmr.2008.07.006 Abstract High sensitivity makes hyperpolarized 3He an attractive signal source for visualizing gas flow with magnetic resonance (MR) imaging. Its rapid Brownian motion, however, can blur observed flow lamina and alter measured diffusion rates when excited nuclei traverse shear-induced velocity gradients during data acquisition. Here, both effects are described analytically, and predicted values for measured transport during laminar flow through a straight, 3.2-mm-diameter pipe are validated using two-dimensional (2D) constant-time images of different binary gas mixtures. Results show explicitly how measured transport in narrow conduits is characterized by apparent values that depend on underlying gas dynamics and imaging time. In ventilated rats, this is found to obscure acquired airflow images. Flow splitting at airway branches is still evident, however, and use of 3D vector flow mapping is shown to provide a quantitative view of pulmonary gas supply that highlights the correlation of airflow dynamics with lung structure.

Carey SA, KR Minard, LL Trease, JG Wagner, GM Garcia, CA Ballinger, J Kimbell, CG Plopper, RA Corley, E Postlewait, and JR Harkema. 2007. "Three-Dimensional Mapping of Ozone-Induced Injury in the Nasal Airways of Monkeys Using Magnetic Resonance Imaging and Morphometric Techniques." Toxicologic Pathology 35(1):27-40. Abstract ABSTRACT Age-related changes in gross and microscopic structure of the nasal cavity can alter local tissue susceptibility as well as the dose of inhaled toxicant delivered to susceptible sites. This article describes a novel method for the use of magnetic resonance imaging, 3-dimensional airway modeling, and morphometric techniques to characterize the distribution and magnitude of ozone-induced nasal injury in infant monkeys. Using this method, we are able to generate age-specific, 3-dimensional, epithelial maps of the nasal airways of infant Rhesus macaques. The principal nasal lesions observed in this primate model of ozone-induced nasal toxicology were neutrophilic rhinitis, along with necrosis and exfoliation of the epithelium lining the anterior maxilloturbinate. These lesions, induced by acute or cyclic (episodic) exposures, were examined by light microscopy, quantified by morphometric techniques, and mapped on 3-dimensional models of the nasal airways. Here, we describe the histopathologic, imaging, and computational biology methods developed to efficiently characterize, localize, quantify, and map these nasal lesions. By combining these techniques, the location and severity of the nasal epithelial injury were correlated with epithelial type, nasal airway geometry, and local biochemical and molecular changes on an individual animal basis. These correlations are critical for accurate predictive modeling of exposure-dose-response relationships in the nasal airways, and subsequent extrapolation of nasal findings in animals to humans for developing risk assessment.

Jacob RE, G Laicher, and KR Minard. 2007. "3D MRI of Non-Gaussian ³He Gas Diffusion in the Rat Lung." Journal of Magnetic Resonance 188(2):357-366. doi:10.1016/j.jmr.2007.08.014 Abstract In ³He magnetic resonance images of pulmonary air spaces, the confining architecture of the parenchymal tissue results in a non-Gaussian distribution of signal phase that non-exponentially attenuates image intensity as diffusion weighting is increased. Here, two approaches previously used for the analysis of non-Gaussian effects in the lung are compared and related using diffusion-weighted ³He MR images of mechanically ventilated rats. Total lung coverage is achieved using a hybrid 3D pulse sequence that combines conventional phase encoding with sparse radial sampling for efficient gas usage. This enables the acquisition of nine 3D images using a total of only ~ 1 L of hyperpolarized ³He gas. Diffusion weighting ranges from 0 s/cm² to 40 s/cm². Results show that the non-Gaussian effects of ³He gas diffusion in healthy rat lungs are directly attributed to the anisotropic geometry of lung microstructure, and that quantitative analysis over the entire lung can be reliably repeated in time-course studies of the same animal.

Minard KR, DR Einstein, RE Jacob, S Kabilan, AP Kuprat, C Timchalk, LL Trease, and RA Corley. 2006. "Application of Magnetic Resonance (MR) Imaging for the Development and Validation of Computational Fluid Dynamic (CFD) Models of the Rat Respiratory System." Inhalation Toxicology 18(10):787-794. doi: 10.1080/08958370600748729 Abstract Computational fluid dynamic (CFD) models of the respiratory system provide a quantitative, biological basis for extrapolating the localized dosimetry of inhaled materials and improving human health risk assessments based upon inhalation studies conducted in animals. Nevertheless, model development and validation have historically been tedious and time-consuming tasks that have traditionally limited CFD’s wider utilization for inhalation research. In recognition of this we previously reported on the use of proton (1H) Magnetic Resonance (MR) imaging for visualizing nasal-sinus passages in the rat, and on the use of three-dimensional (3D) image data for speeding computational mesh generation. Here, detailed 3D 1H MR imaging of pulmonary casts is reported, mesh generation is described in more detail, simulated gas-flows in nasal-sinus airways are presented, and the feasibility of validating CFD predictions with MR is tested by imaging the dynamics of hyperpolarized 3He at physiological flow rates in a straight pipe with a diameter comparable to the rat trachea. Results show that measured laminar flow structure is significantly blurred by rapid 3He diffusion but that the degree of blurring is generally predictable from the diffusion equation. Findings therefore support the notion that MR imaging is not only useful for defining airway architecture but also rapid CFD validation, and in this context, progress towards applications involving live animals and airway models is described.

Minard KR, VV Vishwanathan, PD Majors, LQ Wang, and PC Rieke. 2006. "Magnetic Resonance Imaging (MRI) of PEM Dehydration and Gas Manifold Flooding During Continuous Fuel Cell Operation." Journal of Power Sources 161(2):856-863. Abstract The methods, apparatus, and results are reported for in-situ, near real time, magnetic resonance imaging (MRI) of MEA dehydration and gas manifold flooding in an operating PEM fuel cell. To acquire high-resolution, artifact-free images for visualizing water distribution, acquisition parameters for a standard, two-dimensional (2D), spin-echo sequence were first optimized for the measured magnetic field heterogeneity induced by fuel cell components. 2D images of water inside the fuel cell were then acquired every 128 seconds during 11.4 hours of continuous operation under constant load. Collected images revealed that MEA dehydration proceeded non-uniformly across its plane, starting from gas inlets and ending at gas outlets, and that upon completion of this dehydration process manifold flooding began. To understand these observations, acquired images were correlated to the current output and operating characteristics of the fuel cell. Results demonstrate the power of MRI for in-situ, near real-time imaging of water distribution and non-uniformity in operating PEM fuel cells, and highlight its utility for understanding PEM fuel cell operation, the causes of cell failure, and for developing new strategies of water management.