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Myocardial infarction (MI) results in cardiac myocyte death and the formation of a fibrotic scar in the left ventricular free wall (LVFW). Following an acute MI, LVFW remodeling takes place consisting of several alterations in the structure and properties of cellular and extracellular components with a heterogeneous pattern across the LVFW. The normal function of the heart is strongly influenced by the passive and active biomechanical behavior of the LVFW, and progressive myocardial structural remodeling can have a detrimental effect on both diastolic and systolic functions of the LV leading to heart failure. Despite important advances in understanding LVFW passive remodeling in the setting of MI, heterogeneous remodeling in the LVFW active properties and its relationship to organ-level LV function remain understudied. To address these gaps, we developed high-fidelity finite-element (FE) rodent computational cardiac models (RCCMs) of MI using extensive datasets from MI rat hearts representing the heart remodeling from one-week (1-wk) to four-week (4-wk) post-MI timepoints. The rat-specific models (n = 2 for each timepoint) integrate detailed imaging data of the heart geometry, myocardial fiber architecture, and infarct zone determined using late gadolinium enhancement prior to terminal measurements. The computational models predicted a significantly higher level of active tension in remote myocardium in early post-MI hearts (1-wk post-MI) followed by a return to near the control level in late-stage MI (3- and 4-wk post-MI). The late-stage MI rats showed smaller myofiber ranges in the remote region and in-silico experiments using RCCMs suggested that the smaller fiber helicity is consistent with lower contractile forces needed to meet the measured ejection fractions in late-stage MI. In contrast, in-silico experiments predicted that collagen fiber transmural orientation in the infarct region has little influence on organ-level function. In addition, our MI RCCMs indicated that reduced and potentially positive circumferential strains in the infarct region at end-systole can be used to infer information about the time-varying properties of the infarct region. The detailed description of regional passive and active remodeling patterns can complement and enhance the traditional measures of LV anatomy and function that often lead to a gross and limited assessment of cardiac performance. The translation and implementation of our model in patient-specific organ-level simulations offer to advance the investigation of individualized prognosis and intervention for MI.

Errors in development occur in all vertebrates. When severe, these anomalies are lethal and frequently escape attention. In rare cases, animals with profound malformations are born and can provide a glimpse into structures and their respective function that would otherwise go unnoticed. A rare abnormality in a hatchling Alligator mississippiensis is described in which duplication of the skull, face, and brain was incomplete. The rostral skull, face, and associated forebrain, including the olfactory apparatus, were duplicated. However, the caudal skull and brainstem were not. These observations were made with advanced imaging using both computed tomography and magnetic resonance coupled with gross brain dissections. These abnormal features emphasize the complex and intertwined relationship between the development of the brain, face, and skull which are influenced by certain signaling molecules, possible gene mutation(s), and potential environmental factors.

Mouse models of atherosclerosis have become effective resources to study atherogenesis, including the relationship between hemodynamics and lesion development. Computational methods aid the prediction of the in vivo hemodynamic environment in the mouse vasculature, but careful selection of inflow and outflow boundary conditions (BCs) is warranted to promote model accuracy. Herein, we investigated the impact of animal-specific versus reduced/idealized flow boundary conditions on predicted blood flow patterns in the mouse thoracic aorta. Blood velocities were measured in the aortic root, arch branch vessel, and descending aorta in ApoE−/− mice using phase-contrast MRI. Computational geometries were derived from micro-CT imaging and combinations of high-fidelity or reduced/idealized MR-derived BCs were applied to predict the bulk flow field and hemodynamic metrics (e.g., wall shear stress, WSS; cross-flow index, CFI). Results demonstrate that pressure-free outlet BCs significantly overestimate outlet flow rates as compared to measured values. When compared to models that incorporate 3-component inlet velocity data [ $$\mathop{v}\limits^{\rightharpoonup} \left( {v_{r} ,v_{\theta } ,v_{z} } \right)$$ ] and time-varying outlet mass flow splits [ $$Q\left( t \right)$$ ] (i.e., high-fidelity model), neglecting in-plane inlet velocity components (i.e., $$\mathop{v}\limits^{\rightharpoonup} (v_{z}$$ )) leads to errors in WSS and CFI values ranging from 10 to 30% across the model domain whereas the application of a steady outlet mass flow splits results in negligible differences in these hemodynamics metrics. This investigation highlights that 3-component inlet velocity data and at least steady mass flow splits are required for accurate predictions of flow patterns in the mouse thoracic aorta.

This study aims to examine phenotypic variations in pigeon feather growth patterns by rendering computed tomography (CT) scans as point clouds, and developing machine learning based, feature extraction techniques to isolate the feathers, and map the growth patterns on the skin.

Expansion of myocardium after myocardial infarction (MI) has long been identified as the primary mechanism that drives adverse left ventricular (LV) remodeling towards heart failure and death. Direct injection of hydrogels into the myocardium to mechanically constrain the infarct has demonstrated promise in limiting its remodeling and expansion. Despite early successes, there remain open questions in the determination of optimal hydrogel therapies, key application characteristics for which include injected polymer volume, stiffness, and spatial placement. Addressing these questions is complicated by the substantial variations in infarct type and extent, as well as limited understanding of the underlying mechanisms. Herein, we present an investigation on how hydrogel inclusions affect the effective tissue-level stiffness and strain fields in myocardium using full three-dimensional (3D) finite element simulations at early and late post-MI time points. We calibrated our simulations to triaxial mechanical and structural measurements of cuboidal LV myocardial specimens of post-infarcted myocardium, 0 and 4 weeks post-MI, injected with a dual-crosslinking hyaluronic acid-based hydrogel. Simulations included multiple deformation modes that spanned the anticipated physiological range in order to assess the effects of variations in inclusion size, location, and modulus on tissue-level myocardial mechanics. We observed significant local stiffening in the hydrogel-injected specimens that was highly dependent on the volume and mechanical properties of the injected hydrogel. Simulations revealed that the primary effect of the injections under physiological loading was a reduction in myocardial strain. This result suggests that hydrogel injections reduce infarct expansion by limiting the peak strains over the cardiac cycle. Overall, our study indicated that modulation of local effective tissue stiffness and corresponding strain reduction are governed by the volume and stiffness of the hydrogel, but relatively insensitive to its transmural placement. These findings provide important insights into mechanisms for ameliorating post-MI remodeling, as well as guidance for the future design of post-MI therapies.

Mouse models of atherosclerosis have become effective resources to study atherogenesis, including the relationship between hemodynamics and lesion development. Computational methods aid the prediction of the in vivo hemodynamic environment in the mouse vasculature, but careful selection of inflow and outflow boundary conditions (BCs) is warranted to promote model accuracy. Herein, we investigated the impact of animal-specific versus reduced/idealized flow boundary conditions on predicted blood flow patterns in the mouse thoracic aorta. Blood velocities were measured in the aortic root, arch branch vessel, and descending aorta in ApoE

Vanishing White Matter disease (VWM) is a severe leukodystrophy of the central nervous system caused by mutations in subunits of the eukaryotic initiation factor 2B complex (eIF2B). Current models only partially recapitulate key disease features, and pathophysiology is poorly understood. Through development and validation of zebrafish (Danio rerio) models of VWM, we demonstrate that zebrafisheif2bmutants phenocopy VWM, including impaired somatic growth, early lethality, impaired myelination, loss of oligodendrocyte precursor cells, increased apoptosis in the CNS, and impaired motor swimming behavior. Expression of humanEIF2B2in the zebrafisheif2b2mutant rescues lethality and CNS apoptosis, demonstrating conservation of function between zebrafish and human. In the mutants, intron 12 retention leads to expression of a truncatedeif2b5transcript. Expression of the truncatedeif2b5in wild-type larva impairs motor behavior and activates the ISR, suggesting that a feed-forward mechanism in VWM is a significant component of disease pathophysiology.

Peripheral nerve injury is a significant public health challenge, and perfusion in the nerve is a potential biomarker for assessing the injury severity and prognostic outlook. Here, we applied a novel formalism that combined intravoxel incoherent motion (IVIM) and diffusion tensor imaging (DTI) to simultaneously characterize anisotropic microcirculation and microstructure in the rat sciatic nerve. Comparison to postmortem measurements revealed that the in vivo IVIM-DTI signal contained a fast compartment (2.32 ± 0.04 × 10−3 mm2/s mean diffusivity, mean ± sem, n = 6, paired t test p < 0.01) that could be attributed to microcirculation in addition to a slower compartment that had similar mean diffusivity as the postmortem nerve (1.04 ± 0.01 vs. 0.96 ± 0.05 × 10−3 mm2/s, p > 0.05). Although further investigation and technical improvement are warranted, this preliminary study demonstrates both the feasibility and potential for applying the IVIM-DTI methodology to peripheral nerves for quantifying perfusion in the presence of anisotropic tissue microstructure.

Myocardium possesses a hierarchical structure that results in complex three-dimensional (3D) mechanical behavior, forming a critical component of ventricular function in health and disease. A wide range of constitutive model forms have been proposed for myocardium since the first planar biaxial studies were performed by Demer and Yin (J. Physiol. 339 (1), 1983). While there have been extensive studies since, none have been based on full 3D kinematic data, nor have they utilized optimal experimental design to estimate constitutive parameters, which may limit their predictive capability. Herein we have applied our novel 3D numerical-experimental methodology (Avazmohammadi et al., Biomechanics Model. Mechanobiol., 2018) to explore the applicability of an orthotropic constitutive model for passive ventricular myocardium (Holzapfel and Ogden, Philos. Trans. R. Soc. Lond.: Math. Phys. Eng. Sci. 367, 2009) by integrating 3D optimal loading paths, spatially varying material structure, and inverse modeling techniques. Our findings indicated that the initial model form was not successful in reproducing all optimal loading paths, due to previously unreported coupling behaviors via shearing of myofibers and extracellular collagen fibers in the myocardium. This observation necessitated extension of the constitutive model by adding two additional terms based on the I(8)(C) pseudo-invariant in the fiber-normal and sheet-normal directions. The modified model accurately reproduced all optimal loading paths and exhibited improved predictive capabilities. These unique results suggest that more complete constitutive models are required to fully capture the full 3D biomechanical response of left ventricular myocardium. The present approach is thus crucial for improved understanding and performance in cardiac modeling in healthy, diseased, and treatment scenarios.

Diffusion tensor imaging (DTI) has emerged as a promising method for noninvasive quantification of myocardial microstructure. However, the origin and behavior of DTI measurements during myocardial normal development and remodeling remain poorly understood. In this work, conventional and bicompartmental DTI in addition to three-dimensional histological correlation were performed in a sheep model of myocardial development from third trimester to postnatal 5 months of age. Comparing the earliest time points in the third trimester with the postnatal 5 month group, the scalar transverse diffusivities preferentially increased in both left ventricle (LV) and right ventricle (RV): secondary eigenvalues D2 increased by 54% (LV) and 36% (RV), whereas tertiary eigenvalues D3 increased by 85% (LV) and 67% (RV). The longitudinal diffusivity D1 changes were small, which led to a decrease in fractional anisotropy by 41% (LV) and 33% (RV) in 5 month versus fetal hearts. Histological analysis suggested that myocardial development is associated with hyperplasia in the early stages of the third trimester followed by myocyte growth in the later stages up to 5 months of age (increased average myocyte width by 198%, myocyte length by 128%, and decreased nucleus density by 70% between preterm and postnatal 5 month hearts.) In a few histological samples (N = 6), correlations were observed between DTI longitudinal diffusivity and myocyte length (r = 0.86, P

Knowledge of brain circuitry is critical for understanding the organization, function, and evolution of central nervous systems. Most commonly, brain connections have been elucidated using histological and experimental methods that require animal sacrifice. On the other hand, magnetic resonance diffusion tensor imaging and associated tractography have emerged as a preferred method to noninvasively visualize brain white matter tracts. However, existing studies have primarily examined large, heavily myelinated fiber tracts. Whether tractography can visualize fiber bundles that contain thin and poorly myelinated axons is uncertain. To address this question, the midbrain auditory pathway to the thalamus was investigated in Alligator. This species was chosen because of its evolutionary importance as it is the reptilian group most closely related to birds and because its brain contains many thin and poorly myelinated tracts. Furthermore, this auditory pathway is well documented in other reptiles, including a related crocodilian. Histological observations and experimental determination of anterograde connections confirmed this path in Alligator. Tractography identified these tracts in Alligator and provided a 3-dimensional picture that accurately identified the neural elements of this circuit. In addition, tractography identified one possible unrecognized pathway. These results demonstrate that tractography can visualize circuits containing thin, poorly myelinated fibers. These findings open the door for future studies to examine these types of pathways in other vertebrates.

Purpose The main objective of this study is to develop a 2D single-shot radial-DWI (2D ss-rDWI) technique to reduce motion artifacts and geometric distortion in DW images. Method A diffusion-preparation module is developed and applied prior to the data acquisition. Because the diffusion-prepared longitudinal magnetization is measured over multiple RF excitations in each shot, 2D ss-rDWI is subject to low signal-to-noise ratio (SNR). We used variable-flip angle (VFA), random view ordering (RVO), and sliding spokes, and compared the performances to constant flip angle (CFA), smooth view ordering (SVO), and identical spoke averaging, respectively. For each technique, we performed numerical simulation and MRI experiments on a fluid phantom as well as in-vivo human brain studies with a 3 T MRI system. Results Using VFA, optimal SNR was acquired for 2D ss-rDWI. Using SVO, the high signal is clustered at specific quadrant in 2D k-space: the first quadrant using high initial flip angle or the last quadrant using the low flip angle. This clustered signal in k-space led to geometric distortion in image space. 2D ss-rDWI using RVO spreads the high signaled spokes over all angular directions and removes the view-order-related distortion. The in-vivo images using 2D ss-rDWI with VFA and RVO show no geometric distortion at the skull base brain, but greatly reduced SNR compared with those using 2D ss-DWEPI. Conclusion 2D ss-rDWI is optimized by using VFA with RVO. The resultant DWI using 2D ss-rDWI is insensitive to motion-induced artifacts and geometric distortion. Even with low SNR, it may be useful for DWI of organs limited by severe susceptibility-induced geometric distortion.

Pulmonary arterial hypertension (PAH) imposes pressure overload on the right ventricle (RV), leading to RV enlargement via the growth of cardiac myocytes and remodeling of the collagen fiber architecture. The effects of these alterations on the functional behavior of the right ventricular free wall (RVFW) and organ-level cardiac function remain largely unexplored. Computational heart models in the rat (RHMs) of the normal and hypertensive states can be quite valuable in simulating the effects of PAH on cardiac function to gain insights into the pathophysiology of underlying myocardium remodeling. We thus developed high-fidelity biventricular finite-element RHMs for the normal and post-PAH hypertensive states using extensive experimental data collected from rat hearts. We then applied the RHM to investigate the transmural nature of RVFW remodeling and its connection to wall stress elevation under PAH. We found a strong correlation between the longitudinally-dominated fiber-level adaptation of the RVFW and the transmural alterations of relevant wall stress components. We further conducted several numerical experiments to gain new insights on how the RV responds both normally and in the post-PAH state. We found that the effect of pressure overload alone on the increased contractility of the RV is secondary to the effects of changes in the RV geometry and stiffness. Furthermore, our RHMs provided fresh perspectives on long-standing questions of the functional role of the interventricular septum in RV function. Specifically, we demonstrated that an inaccurate identification of the mechanical adaptation of the septum can lead to a significant underestimation of RVFW contractility in the post-PAH state. These findings showed that how integrated experimental-computational models can facilitate a more comprehensive understanding of the cardiac remodeling events during PAH.

Purpose To seek a better understanding of the effect of organized capillary flow on the MR diffusion-weighted signal. Methods A theoretical framework was proposed to describe the diffusion-weighted MR signal, which was then validated both numerically using a realistic model of capillary network and experimentally in an animal model of isolated perfused heart preparation with myocardial blood flow verified by means of direct arterial spin labeling measurements. Results Microcirculation in organized tissues gave rise to an MR signal that could be described as a combination of the bi-exponential behavior of conventional intravoxel incoherent motion (IVIM) theory and diffusion tensor imaging (DTI) -like anisotropy of the vascular signal, with the flow-related pseudo diffusivity represented as the linear algebraic product between the encoding directional unit vector and an appropriate tensor entity. Very good agreement between theoretical predictions and both numerical and experimental observations were found. Conclusion These findings suggest that the DTI formalism of anisotropic spin motion can be incorporated into the classical IVIM theory to describe the MR signal arising from diffusion and microcirculation in organized tissues. Magn Reson Med 76:1252-1262, 2016. © 2015 Wiley Periodicals, Inc.

Diffusion tensor imaging and high angular resolution diffusion imaging are often used to analyze the fiber complexity of tissues. In these imaging techniques, the most commonly calculated metric is anisotropy, such as fractional anisotropy (FA), generalized anisotropy (GA), and generalized fractional anisotropy (GFA). The basic idea underlying these metrics is to compute the deviation from free or spherical diffusion. However, in many cases, the question is not really to know whether it concerns spherical diffusion. Instead, the main concern is to describe and quantify fiber complexity such as fiber crossing in a voxel. In this context, it would be more direct and effective to compute the deviation from a single fiber bundle instead of a sphere. We propose a new metric, called PEAM (PEAnut Metric), which is based on computing the deviation of orientation diffusion functions (ODFs) from a single fiber bundle ODF represented by a peanut. As an example, the proposed PEAM metric is used to classify intravoxel fiber configurations. The results on simulated data, physical phantom data and real brain data consistently showed that the proposed PEAM provides greater accuracy than FA, GA and GFA and enables parallel and complex fibers to be better distinguished.

Background Heart failure is a leading cause of death but very little is known about right ventricular (RV) failure (RVF) and right ventricular recovery (RVR). A robust animal model of reversible, RVF does not exist, which currently limits research opportunities and clinical progress. We sought to develop an animal model of reversible, pressure-overload RVF to study RVF and RVR. Materials and methods Fifteen New Zealand rabbits underwent implantation of a fully implantable, adjustable, pulmonary artery band. Animals were assigned to the control, RVF, and RVR groups (n = 5 for each). For the RVF and RVR groups, the pulmonary artery bands were serially tightened to create RVF and released for RVR. Echocardiographic, cardiac magnetic resonance imaging, and histologic analysis were performed. Results RV chamber size and wall thickness increased during RVF and regressed during RVR. RV volumes were 1023 μL ± 123 for control, 2381 μL ± 637 for RVF, and 635 μL ± 549 for RVR, and RV wall thicknesses were 0.98 mm ± 0.12 for controls (P = 0.05), 1.72 mm ± 0.60 for RVF, and 1.16 mm ± 0.03 for RVR animals (P = 0.04), respectively. Similarly, heart weight, liver weight, cardiomyocyte size, and the degree of cardiac and hepatic fibrosis increased with RVF and decreased during RVR. Conclusions We report an animal model of chronic, reversible, pressure-overload RVF to study RVF and RVR. This model will be used for preclinical studies that improve our understanding of the mechanisms of RVF and that develop and test RV protective and RVR strategies to be studied later in humans.

Non-invasive imaging techniques are highly desirable as an alternative to conventional biopsy for the characterization of the remodeling of tissues associated with disease progression, including end-stage heart failure. Cardiac diffusion tensor imaging (DTI) has become an established method for the characterization of myocardial microstructure. However, the relationships between diffuse myocardial fibrosis, which is a key biomarker for staging and treatment planning of the failing heart, and measured DTI parameters have yet to be investigated systematically. In this study, DTI was performed on left ventricular specimens collected from patients with chronic end-stage heart failure as a result of idiopathic dilated cardiomyopathy (n = 14) and from normal donors (n = 5). Scalar DTI parameters, including fractional anisotropy (FA) and mean (MD), primary (D1 ), secondary (D2 ) and tertiary (D3 ) diffusivities, were correlated with collagen content measured by digital microscopy. Compared with hearts from normal subjects, the FA in failing hearts decreased by 22%, whereas the MD, D2 and D3 increased by 12%, 14% and 24%, respectively (P < 0.01). No significant change was detected for D1 between the two groups. Furthermore, significant correlation was observed between the DTI scalar indices and quantitative histological measurements of collagen (i.e. fibrosis). Pearson's correlation coefficients (r) between collagen content and FA, MD, D2 and D3 were -0.51, 0.59, 0.56 and 0.62 (P < 0.05), respectively. The correlation between D1 and collagen content was not significant (r = 0.46, P = 0.05). Computational modeling analysis indicated that the behaviors of the DTI parameters as a function of the degree of fibrosis were well explained by compartmental exchange between myocardial and collagenous tissues. Combined, these findings suggest that scalar DTI parameters can be used as metrics for the non-invasive assessment of diffuse fibrosis in failing hearts.

The development of cell- and gene-based strategies for regenerative medicine offers a therapeutic option for the repair and potential regeneration of damaged cardiac tissue post-myocardial infarction (MI). Human umbilical cord subepithelial cell-derived stem cells (hUC-SECs), human bone marrow-derived mesenchymal stem cells (hBM-MSCs), and human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), all derived from human tissue, have been shown to have in vitro and in vivo therapeutic potential. Additionally, S100a1, VEGF165, and stromal-derived factor-1α (SDF-1α) genes all have the potential to improve cardiac function and/or effect adverse remodeling. In this study, we compared the therapeutic potential of hBM-MSCs, hUC-SECs, and hiPSC-CMs along with plasmid-based genes to evaluate the in vivo potential of intramyocardially injected biologics to enhance cardiac function in a mouse MI model. Human cells derived from various tissue types were expanded under hypoxic conditions and injected intramyocardially into mice that had undergone left anterior descending (LAD) artery ligation. Similarly, plasmids were also injected into three groups of mice after LAD ligation. Seven experimental groups were studied in total: ( 1 ) control (saline), ( 2 ) hBM-MSCs, ( 3 ) hiPSC-CMs, ( 4 ) hUC-SECs, ( 5 ) S100a1 plasmid, ( 6 ) VEGF165 plasmid, and ( 7 ) SDF-1α plasmid. We evaluated echocardiography, hemodynamic catheterization measurements, and histology at 4 and 12 weeks post-biologic injection. Significant improvement was observed in cardiac function and contractility in hiPSC-CM and S100a1 groups and a significant reduction in left ventricle scar within the hUC-SEC group and a slight improvement in the SDF-1α and VEGF165 groups compared to the control group. These results demonstrate the potential for new biologic therapies to reduce scar burden and improve contractile function.

Background Ventricular non-compaction is characterized by a thin layer of compact ventricular myocardium and it is an important abnormality in the mouse heart. It is reminiscent of left ventricular non-compaction, a fairly common human congenital cardiomyopathy. Non-compaction in transgenic mice has been classically evaluated by measuring the thickness of the compact myocardium through histological techniques involving image analysis of 2-dimensional (D) sections. Given the 3D nature of the heart, the aim of this study was to determine whether a technique for the non-destructive, 3D assessment of the mouse embryonic compact myocardium could be developed. Methods and results Micro-computed tomography (micro-CT), in combination with iodine staining, enabled the differentiation of the trabecular from the compact myocardium in wild-type mice. The 3D and digital nature of the micro-CT data allowed computation anatomical techniques to be readily applied, which were demonstrated via construction of group atlases and atlas-based descriptive statistics. Finally, micro-CT was used to identify the presence of non-compaction in mice with a deletion of the cell cycle inhibitor protein, p27(Kip1). Conclusions Iodine staining-enhanced micro-CT with computational anatomical analysis represents a valid addition to classical histology for the delineation of compact myocardial wall thickness in the mouse embryo. Given the quantitative 3D resolution of micro-CT, these approaches might provide helpful information for the analysis of non-compaction. (Circ J 2016; 80: 1795-1803).

The practical utility of diffusion tensor imaging (DTI), especially for 3D high resolution spin warp experiments of ex vivo specimens, has been hampered by long acquisition times. To accelerate the acquisition, a compressed sensing framework that employs a model-based formulation to reconstruct diffusion tensor fields from undersampled k-space data was presented and evaluated. Accuracies in brain specimen white matter fiber orientation, fractional anisotropy (FA) and mean diffusivity (MD) mapping were compared to alternative methods achievable using the same scan time via reduced image resolution, fewer diffusion encoding directions, standard compressed sensing or asymmetrical sampling reconstruction. The efficiency of the proposed approach was also compared to fully-sampled cases across a range of the number of diffusion encoding directions. In general, the proposed approach was found to reduce the image blurring and noise, and provide more accurate fiber orientation, FA and MD measurements compared to the alternative methods. Moreover, depending on the degree of undersampling used and the DTI parameter examined, the measurement accuracy of the proposed scheme was equivalent to fully sampled DTI datasets that consist of 33% to 67% more encoding directions and require proportionally longer scan times. The findings show model-based compressed sensing to be promising for improving the resolution, accuracy or scan time of DTI.

A new, biocompatible hyaluronic acid (HA)–silk hydrogel composite was fabricated and tested for use as a securable drug delivery vehicle. The composite consisted of a hydrogel formed by cross-linking thiol–modified HA with poly(ethylene glycol)-diacrylate, within which was embedded a reinforcing mat composed of electrospun silk fibroin protein. Both HA and silk are biocompatible, selectively degradable biomaterials with independently controllable material properties. Mechanical characterization showed the composite tensile strength as fabricated to be 4.43 ± 2.87 kPa, two orders of magnitude above estimated tensions found around potential target organs. In the presence of hyaluronidase (HAse) in vitro, the rate of gel degradation increased with enzyme concentration although the reinforcing silk mesh was not digested. Composite gels demonstrated the ability to store and sustainably deliver therapeutic agents. Time constants for in vitro release of selected representative antibacterial and anti-inflammatory drugs varied from 46.7 min for cortisone to 418 min for hydrocortisone. This biocomposite showed promising mechanical characteristics for direct fastening to tissue and organs, as well as controllable degradation properties suitable for storage and release of therapeutically relevant drugs.

The deleterious effects of hydrocephalus, a disorder that primarily affects children, include reactive astrocytosis, microgliosis and inflammatory responses; however, the roles that these mechanisms play in the pathophysiology of hydrocephalus are still not clear in terms of cytopathology and gene expression. Therefore we have examined neuroinflammation at both the cellular and the molecular levels in an experimental model of neonatal obstructive hydrocephalus. On post-natal day 1, rats received an intracisternal injection of kaolin to induce hydrocephalus; control animals received saline injections. Prior to sacrifice on post-natal day 22, animals underwent magnetic resonance imaging to quantify ventricular enlargement, and the parietal cortex was harvested for analysis. Immunohistochemistry and light microscopy were performed on 5 hydrocephalic and 5 control animals; another set of 5 hydrocephalic and 5 control animals underwent molecular testing with Western blots and a gene microarray. Scoring of immunoreactivity on a 4-point ranking scale for GFAP and Iba-1 demonstrated an increase in reactive astrocytes and reactive microglia respectively in the hydrocephalic animals compared to controls (2.90±0.11 vs. 0.28±0.26; 2.91±0.11 vs. 0.58±0.23, respectively). Western blots confirmed these results. Microarray analysis identified significant (1.5-fold) changes in 1729 of 33,951 genes, including 26 genes out of 185 genes (26/185) in the cytokine-cytokine receptor interaction pathway, antigen processing and presentation pathways (15/66), and the apoptosis pathway (10/69). Collectively, these results demonstrate alterations in normal physiology and an up-regulation of the inflammatory response. These findings lead to a better understanding of neonatal hydrocephalus and begin to form a baseline for future treatments that may reverse these effects.

The purpose is to address the problem in magnetic resonance imaging (MRI) of contrast agent dilution.In situ magnetic labeling of cells and MRI were used to assess distribution and growth of human hepatic stem cells (hHpSCs) transplanted into severe combined immunodeficiency (SCID)/non-obese diabetic (NOD) mice. It was done with commercially available magnetic microbeads coupled to an antibody to a surface antigen, epithelial cell adhesion molecule (EpCAM), uniquely expressed in the liver by hepatic progenitors.We validated the microbead connection to cells and related MRI data to optical microscopy observations in order to develop a means to quantitatively estimate cell numbers in the aggregates detected. Cell counts of hHpSCs at different times post-transplantation revealed quantifiable evidence of cell engraftment and expansion.This magnetic labeling methodology can be used with any antibody coupled to a magnetic particle to target any surface antigen that distinguishes transplanted cells from host cells, thus facilitating studies that define methods and strategies for clinical cell therapy programs.

The objective of this study was to evaluate an injectable, in situ crosslinkable elastin-like polypeptide (ELP) gel for application to cartilage matrix repair in critically sized defects in goat kn...

Orientation distribution functions (ODFs) are widely used to resolve fiber crossing problems in high angular resolution diffusion imaging (HARDI). The characteristics of the ODFs are often assessed using a visual criterion, although the use of objective criteria is also reported, which are directly borrowed from classic signal and image processing theory because they are intuitive and simple to compute. However, they are not always pertinent for the characterization of ODFs. We propose a more general paradigm for assessing the characteristics of ODFs. The idea consists in regarding an ODF as a three-dimensional (3D) point cloud, projecting the 3D point cloud onto an angle-distance map, constructing an angle-distance matrix, and calculating metrics such as length ratio, separability, and uncertainty. The results from both simulated and real data show that the proposed metrics allow for the assessment of the characteristics of ODFs in a quantitative and relatively complete manner.

Adipose-derived stem cells are an alternative stem cell source for CNS therapies. The goals of the current study were to label adipose-derived stem cells with superparamagnetic iron oxide (SPIO) particles, to use MRI to guide the transplantation of adipose-derived stem cells in middle cerebral artery occlusion (MCAO)-injured mice, and to localize donor adipose-derived stem cells in the injured brain using MRI. We hypothesized that we would successfully label adipose-derived stem cells and image them with MRI.Adipose-derived stem cells harvested from mice inbred for green fluorescent protein were labeled with SPIO ferumoxide particles through the use of poly-L-lysine. Adipose-derived stem cell viability, iron staining, and proliferation were measured after SPIO labeling, and the sensitivity of MRI in the detection of SPIO-labeled adipose-derived stem cells was assessed ex vivo. Adult mice (n = 12) were subjected to unilateral MCAO. Two weeks later, in vivo 7-T MRI was performed to guide stereotactic transplantation of SPIO-labeled adipose-derived stem cells into brain tissue adjacent to the infarct. After 24 hours, the mice were sacrificed for high-resolution ex vivo 7-T or 9.4-T MRI and histologic study.Adipose-derived stem cells were efficiently labeled with SPIO particles without loss of cell viability or proliferation. Using MRI, we guided precise transplantation of adipose-derived stem cells. MR images of mice given injections of SPIO-labeled adipose-derived stem cells had hypointense regions that correlated with the histologic findings in donor cells.MRI proved useful in transplantation of adipose-derived stem cells in vivo. This imaging technique may be useful for studies of CNS stem cell therapies.

Diffusion tensor imaging (DTI) has emerged as a promising method for noninvasive quantification of myocardial microstructure. However, the origin and behavior of DTI measurements during myocardial normal development and remodeling remain poorly understood. In this work, conventional and bicompartmental DTI in addition to three-dimensional histological correlation were performed in a sheep model of myocardial development from third trimester to postnatal 5 months of age. Comparing the earliest time points in the third trimester with the postnatal 5 month group, the scalar transverse diffusivities preferentially increased in both left ventricle (LV) and right ventricle (RV): secondary eigenvalues D2 increased by 54% (LV) and 36% (RV), whereas tertiary eigenvalues D3 increased by 85% (LV) and 67% (RV). The longitudinal diffusivity D1 changes were small, which led to a decrease in fractional anisotropy by 41% (LV) and 33% (RV) in 5 month versus fetal hearts. Histological analysis suggested that myocardial development is associated with hyperplasia in the early stages of the third trimester followed by myocyte growth in the later stages up to 5 months of age (increased average myocyte width by 198%, myocyte length by 128%, and decreased nucleus density by 70% between preterm and postnatal 5 month hearts.) In a few histological samples (N = 6), correlations were observed between DTI longitudinal diffusivity and myocyte length (r = 0.86, P 0.05), and transverse diffusivity and myocyte width (r = 0.96, P 0.01). Linear regression analysis showed that transverse diffusivities are more affected by changes in myocyte size and nucleus density changes than longitudinal diffusivities, which is consistent with predictions of classical models of diffusion in porous media. Furthermore, primary and secondary DTI eigenvectors during development changed significantly. Collectively, the findings demonstrate a role for DTI to monitor and quantify myocardial development, and potentially cardiac disease. Copyright © 2016 John WileySons, Ltd.

Introduction: The magnetic resonance (MR) signal in the presence of a magnetic field gradient is highly sensitive to the aggregate translational molecular motion of water. In highly vascularized tissues, diffusion-like contrast induced by microcirculation has been used to characterize blood flow in heart. The effect in tissues with random capillary orientations has been modeled as intravoxel incoherent motion (IVIM), but is not completely understood in organized tissues. Hypothesis: We hypothesize that blood flow in organized tissues will manifest as speed- and orientation- dependent “pseudo” diffusion coefficient D*. Methods: For Gaussian-distributed flow with mean speed vm in parallel capillaries as a function of the relative encoding angle θ, it can be shown that D* is proportional to the square power of both vm and cos(θ), which is then incorporated into a generalized formulation of anisotropic tissue diffusion and flow with a tensor entity D* to characterize the flow pseudo diffusivity in 3D space using the familiar diffusion tensor imaging (DTI) notation. Validation experiments were conducted on isolated, perfused, guinea pig hearts (n=7) in a Langendorff setup and imaged with Bruker (7T) MRI scanner under normal and low flow conditions. Statistical analyses were conducted via 1-way ANOVA with Bonferroni post-hoc multiple-comparison correction (P Results: Figure 1A-C show representative diffusion-weighted MR images encoded at perpendicular directions, and Fig 1D shows the flow-speed and angular dependence (or anisotropy) of the fitted D* component at high flow and low flow. D* significantly decreased by 63% only in the parallel direction to myocytes (or capillaries) (P Conclusions: These findings suggest that the DTI formalism of anisotropic spin motion can be incorporated into the classical IVIM theory to describe the MR signal arising from diffusion and microcirculation in organized tissues.

Magnetic resonance diffusion tensor imaging (DTI) has greatly facilitated detailed quantifications of myocardial structures. However, structural patterns, such as the distinctive transmural rotation of the fibers, remain incompletely described. To investigate the validity and practicality of pattern-based analysis, 3D DTI was performed on 13 fixed mouse hearts and fiber angles in the left ventricle were transformed and fitted to parametric expressions constructed from elementary functions of the prolate spheroidal spatial variables. It was found that, on average, the myocardial fiber helix angle could be represented to 6.5° accuracy by the equivalence of a product of 10th-order polynomials of the radial and longitudinal variables, and 17th-order Fourier series of the circumferential variable. Similarly, the fiber imbrication angle could be described by 10th-order polynomials and 24th-order Fourier series, to 5.6° accuracy. The representations, while relatively concise, did not adversely affect the information commonly derived from DTI datasets including the whole-ventricle mean fiber helix angle transmural span and atlases constructed for the group. The unique ability of parametric models for predicting the 3D myocardial fiber structure from finite number of 2D slices was also demonstrated. These findings strongly support the principle of parametric modeling for characterizing myocardial structures in the mouse and beyond.

To seek a better understanding of the effect of organized capillary flow on the MR diffusion-weighted signal.A theoretical framework was proposed to describe the diffusion-weighted MR signal, which was then validated both numerically using a realistic model of capillary network and experimentally in an animal model of isolated perfused heart preparation with myocardial blood flow verified by means of direct arterial spin labeling measurements.Microcirculation in organized tissues gave rise to an MR signal that could be described as a combination of the bi-exponential behavior of conventional intravoxel incoherent motion (IVIM) theory and diffusion tensor imaging (DTI) -like anisotropy of the vascular signal, with the flow-related pseudo diffusivity represented as the linear algebraic product between the encoding directional unit vector and an appropriate tensor entity. Very good agreement between theoretical predictions and both numerical and experimental observations were found.These findings suggest that the DTI formalism of anisotropic spin motion can be incorporated into the classical IVIM theory to describe the MR signal arising from diffusion and microcirculation in organized tissues. Magn Reson Med 76:1252-1262, 2016. © 2015 Wiley Periodicals, Inc.

Myocardial microstructures are responsible for key aspects of cardiac mechanical function. Natural myocardial deformation across the cardiac cycle induces measurable structural alteration, which varies across disease states. Diffusion tensor magnetic resonance imaging (DT-MRI) has become the tool of choice for myocardial structural analysis. Yet, obtaining the comprehensive structural information of the whole organ, in 3D and time, for subject-specific examination is fundamentally limited by scan time. Therefore, subject-specific finite-element (FE) analysis of a group of rat hearts was implemented for extrapolating a set of initial DT-MRI to the rest of the cardiac cycle. The effect of material symmetry (isotropy, transverse isotropy, and orthotropy), structural input, and warping approach was observed by comparing simulated predictions against in vivo MRI displacement measurements and DT-MRI of an isolated heart preparation at relaxed, inflated, and contracture states. Overall, the results indicate that, while ventricular volume and circumferential strain are largely independent of the simulation strategy, structural alteration predictions are generally improved with the sophistication of the material model, which also enhances torsion and radial strain predictions. Moreover, whereas subject-specific transversely isotropic models produced the most accurate descriptions of fiber structural alterations, the orthotropic models best captured changes in sheet structure. These findings underscore the need for subject-specific input data, including structure, to extrapolate DT-MRI measurements across the cardiac cycle.

Magnetic resonance diffusion tensor imaging (DTI) can be complicated by distortions that contribute to errors in tissue characterization and loss of fine structures. This work presents a correction scheme based on retrospective registration via mutual information (MI), using Fourier transform (FT)-based deformations to enhance the reliability of the entropy-based image registration. The registration methodology is applied to correcting distortions in 3D high-resolution DTI datasets, incorporating a complete set of affine deformations. Results demonstrate that the proposed methodology can consistently and significantly reduce the number of mis-registered pixels, leading to marked improvement in the visualization of internal brain white matter structure via DTI. Post-registration analysis reveals that eddy current effects cannot fully account for the observed image distortions. Combined, these findings are supportive of the non-model-based, post-processing approach for correcting the distortions, and demonstrate the advantages of combining FT-based deformations and MI registration in enhancing the practical utility of DTI.