pO2 reporter composite hydrogel macroencapsulation devices for magnetic resonance imaging oxygen quantification.

Hydrogel cell encapsulation devices are a common approach to reduce the need for chronic systemic immunosuppression in allogeneic cell product transplantation. Macroencapsulation approaches are an appealing strategy, as they maximize graft retrievability and cell dosage within a single device; however, macroencapsulation devices face oxygen transport challenges as geometries increase from preclinical to clinical scales. Device design guided by computational approaches can facilitate graft oxygen availability to encapsulated cells in vivo but is limited without accurate measurement of oxygen levels within the transplant site and graft. In this study, we engineer pO2 reporter composite hydrogels (PORCH) to enable spatiotemporal measurement of oxygen tension within macroencapsulation devices using the proton Imaging of siloxanes to map tissue oxygenation levels (PISTOL) magnetic resonance imaging approach. We engineer two methods of incorporating siloxane oximetry reporters within hydrogel devices, an emulsion and microbead-based approach, and evaluate PORCH cytotoxicity on co-encapsulated cells and accuracy in quantifying oxygen tension in vitro. We find that both emulsion and microbead PORCH approaches enable accurate in situ oxygen quantification using PISTOL magnetic resonance oximetry, and that the emulsion-based PORCH approach results in higher spatial resolution.

Development and Characterization of Isogenic Cardiac Organoids from Human-Induced Pluripotent Stem Cells Under Supplement Starvation Regimen.

The prevalence of cardiovascular risk factors is expected to increase the occurrence of cardiovascular diseases (CVDs) worldwide. Cardiac organoids are promising candidates for bridging the gap between in vitro experimentation and translational applications in drug development and cardiac repair due to their attractive features. Here we present the fabrication and characterization of isogenic scaffold-free cardiac organoids derived from human induced pluripotent stem cells (hiPSCs) formed under a supplement-deprivation regimen that allows for metabolic synchronization and maturation of hiPSC-derived cardiac cells. We propose the formation of coculture cardiac organoids that include hiPSC-derived cardiomyocytes and hiPSC-derived cardiac fibroblasts (hiPSC-CMs and hiPSC-CFs, respectively). The cardiac organoids were characterized through extensive morphological assessment, evaluation of cellular ultrastructures, and analysis of transcriptomic and electrophysiological profiles. The morphology and transcriptomic profile of the organoids were improved by coculture of hiPSC-CMs with hiPSC-CFs. Specifically, upregulation of Ca2+ handling-related genes, such as RYR2 and SERCA, and structure-related genes, such as TNNT2 and MYH6, was observed. Additionally, the electrophysiological characterization of the organoids under supplement deprivation shows a trend for reduced conduction velocity for coculture organoids. These studies help us gain a better understanding of the role of other isogenic cells such as hiPSC-CFs in the formation of mature cardiac organoids, along with the introduction of exogenous chemical cues, such as supplement starvation.

Methods for improving colorectal cancer annotation efficiency for artificial intelligence-observer training.

BACKGROUND: Missing occult cancer lesions accounts for the most diagnostic errors in retrospective radiology reviews as early cancer can be small or subtle, making the lesions difficult to detect. Second-observer is the most effective technique for reducing these events and can be economically implemented with the advent of artificial intelligence (AI). AIM: To achieve appropriate AI model training, a large annotated dataset is necessary to train the AI models. Our goal in this research is to compare two methods for decreasing the annotation time to establish ground truth: Skip-slice annotation and AI-initiated annotation. METHODS: We developed a 2D U-Net as an AI second observer for detecting colorectal cancer (CRC) and an ensemble of 5 differently initiated 2D U-Net for ensemble technique. Each model was trained with 51 cases of annotated CRC computed tomography of the abdomen and pelvis, tested with 7 cases, and validated with 20 cases from The Cancer Imaging Archive cases. The sensitivity, false positives per case, and estimated Dice coefficient were obtained for each method of training. We compared the two methods of annotations and the time reduction associated with the technique. The time differences were tested using Friedman's two-way analysis of variance. RESULTS: Sparse annotation significantly reduces the time for annotation particularly skipping 2 slices at a time (P < 0.001). Reduction of up to 2/3 of the annotation does not reduce AI model sensitivity or false positives per case. Although initializing human annotation with AI reduces the annotation time, the reduction is minimal, even when using an ensemble AI to decrease false positives. CONCLUSION: Our data support the sparse annotation technique as an efficient technique for reducing the time needed to establish the ground truth.

Cardiac ischemia on-a-chip to investigate cellular and molecular response of myocardial tissue under hypoxia.

Tissue engineering has enabled the development of advanced and physiologically relevant models of cardiovascular diseases, with advantages over conventional 2D in vitro assays. We have previously demonstrated development of a heart on-a-chip microfluidic model with mature 3D anisotropic tissue formation that incorporates both stem cell-derived cardiomyocytes and cardiac fibroblasts within a collagen-based hydrogel. Using this platform, we herein present a model of myocardial ischemia on-a-chip, that recapitulates ischemic insult through exposure of mature 3D cardiac tissues to hypoxic environments. We report extensive validation and molecular-level analyses of the model in its ability to recapitulate myocardial ischemia in response to hypoxia, demonstrating the 1) induction of tissue fibrosis through upregulation of contractile fibers, 2) dysregulation in tissue contraction through functional assessment, 3) upregulation of hypoxia-response genes and downregulation of contractile-specific genes through targeted qPCR, and 4) transcriptomic pathway regulation of hypoxic tissues. Further, we investigated the complex response of ischemic myocardial tissues to reperfusion, identifying 5) cell toxicity, 6) sustained contractile irregularities, as well as 7) re-establishment of lactate levels and 8) gene expression, in hypoxic tissues in response to ischemia reperfusion injury.

GdDO3NI Enhanced Magnetic Resonance Imaging Allows Imaging of Hypoxia After Brain Injury.

BACKGROUND: Brain tissue hypoxia is a common consequence of traumatic brain injury (TBI) due to the rupture of blood vessels during impact and it correlates with poor outcome. The current magnetic resonance imaging (MRI) techniques are unable to provide a direct map of tissue hypoxia. PURPOSE: To investigate whether GdDO3NI, a nitroimidazole-based T1 MRI contrast agent allows imaging hypoxia in the injured brain after experimental TBI. STUDY TYPE: Prospective. ANIMAL MODEL: TBI-induced mice (controlled cortical impact model) were intravenously injected with either conventional T1 agent (gadoteridol) or GdDO3NI at 0.3 mmol/kg dose (n = 5 for each cohort) along with pimonidazole (60 mg/kg) at 1 hour postinjury and imaged for 3 hours following which they were euthanized. FIELD STRENGTH/SEQUENCE: 7 T/T2 -weighted spin echo and T1 -weighted gradient echo. ASSESSMENT: Injured animals were imaged with T2 -weighted spin-echo sequence to estimate the extent of the injury. The mice were then imaged precontrast and postcontrast using a T1 -weighted gradient-echo sequence for 3 hours postcontrast. Regions of interests were drawn on the brain injury region, the contralateral brain as well as on the cheek muscle region for comparison of contrast kinetics. Brains were harvested immediately post-imaging for immunohistochemical analysis. STATISTICAL TESTS: One-way analysis of variance and two-sample t-tests were performed with a P < 0.05 was considered statistically significant. RESULTS: GdDO3NI retention in the injury region at 2.5-3 hours post-injection was significantly higher compared to gadoteridol (mean retention fraction 63.95% ± 27.43% vs. 20.68% ± 7.43% for gadoteridol at 3 hours) while it rapidly cleared out of the muscle region. Pimonidazole staining confirmed the presence of hypoxia in both gadoteridol and GdDO3NI cohorts, and the later cohort showed good agreement with MRI contrast enhancement. DATA CONCLUSION: GdDO3NI was successfully shown to visualize hypoxia in the brain post-TBI using T1 -weighted MRI at 2.5-3 hours postcontrast. EVIDENCE LEVEL: 1 TECHNICAL EFFICACY: Stage 1.

In Situ Generated Novel 1H MRI Reporter for ß-Galactosidase Activity Detection and Visualization in Living Tumor Cells.

For wide applications of the lacZ gene in cellular/molecular biology, small animal investigations, and clinical assessments, the improvement of noninvasive imaging approaches to precisely assay gene expression has garnered much attention. In this study, we investigate a novel molecular platform in which alizarin 2-O-ß-d-galactopyranoside AZ-1 acts as a lacZ gene/ß-gal responsive 1H-MRI probe to induce significant 1H-MRI contrast changes in relaxation times T 1 and T 2 in situ as a concerted effect for the discovery of ß-gal activity with the exposure of Fe3+. We also demonstrate the capability of this strategy for detecting ß-gal activity with lacZ-transfected human MCF7 breast and PC3 prostate cancer cells by reaction-enhanced 1H-MRI T 1 and T 2 relaxation mapping.

Correlation of Tumor Hypoxia Metrics Derived from 18F-Fluoromisonidazole Positron Emission Tomography and Pimonidazole Fluorescence Images of Optically Cleared Brain Tissue.

18F-fluoromisonidazole (FMISO) positron emission tomography (PET) is a widely used noninvasive imaging modality for assessing hypoxia. We describe the first spatial comparison of FMISO PET with an ex vivo reference standard for hypoxia across whole tumor volumes. Eighteen rats were orthotopically implanted with C6 or 9L brain tumors and made to undergo FMISO PET scanning. Whole brains were excised, sliced into 1-mm-thick sections, optically cleared, and fluorescently imaged for pimonidazole using an in vivo imaging system. FMISO maximum tumor uptake, maximum tumor-to-cerebellar uptake (TCmax), and hypoxic fraction (extracted 110 minutes after FMISO injection) were correlated with analogous metrics derived from pimonidazole fluorescence images. FMISO SUVmax was not significantly different between C6 and 9L brain tumors (P = .70), whereas FMISO TCmax and hypoxic fraction were significantly greater for C6 tumors (P < .01). FMISO TCmax was significantly correlated with the maximum tumor pimonidazole intensity (ρ = 0.76, P < .01), whereas FMISO SUVmax was not. FMISO tumor hypoxic fraction was significantly correlated with the pimonidazole-derived hypoxic fraction (ρ = 0.78, P < .01). Given that FMISO TCmax and tumor hypoxic fraction had strong correlations with the pimonidazole reference standard, these metrics may offer more reliable measures of tumor hypoxia than conventional PET uptake metrics (SUVmax). The voxel-wise correlation between FMISO uptake and pimonidazole intensity for a given tumor was strongly dependent on the tumor's TCmax (ρ = 0.81, P < .01) and hypoxic fraction (ρ = 0.85, P < .01), indicating PET measurements within individual voxels showed greater correlation with pimonidazole reference standard in tumors with greater hypoxia.

A practical method for multimodal registration and assessment of whole-brain disease burden using PET, MRI, and optical imaging.

Many neurological diseases present with substantial genetic and phenotypic heterogeneity, making assessment of these diseases challenging. This has led to ineffective treatments, significant morbidity, and high mortality rates for patients with neurological diseases, including brain cancers and neurodegenerative disorders. Improved understanding of this heterogeneity is necessary if more effective treatments are to be developed. We describe a new method to measure phenotypic heterogeneity across the whole rodent brain at multiple spatial scales. The method involves co-registration and localized comparison of in vivo radiologic images (e.g. MRI, PET) with ex vivo optical reporter images (e.g. labeled cells, molecular targets, microvasculature) of optically cleared tissue slices. Ex vivo fluorescent images of optically cleared pathology slices are acquired with a preclinical in vivo optical imaging system across the entire rodent brain in under five minutes, making this methodology practical and feasible for most preclinical imaging labs. The methodology is applied in various examples demonstrating how it might be used to cross-validate and compare in vivo radiologic imaging with ex vivo optical imaging techniques for assessing hypoxia, microvasculature, and tumor growth.

Sex-Dependent Macromolecule and Nanoparticle Delivery in Experimental Brain Injury.

The development of effective therapeutics for brain disorders is challenging, in particular, the blood-brain barrier (BBB) severely limits access of the therapeutics into the brain parenchyma. Traumatic brain injury (TBI) may lead to transient BBB permeability that affords a unique opportunity for therapeutic delivery via intravenous administration ranging from macromolecules to nanoparticles (NPs) for developing precision therapeutics. In this regard, we address critical gaps in understanding the range/size of therapeutics, delivery window(s), and moreover, the potential impact of biological factors for optimal delivery parameters. Here we show, for the first time, to the best of our knowledge, that 24-h postfocal TBI female mice exhibit a heightened macromolecular tracer and NP accumulation compared with male mice, indicating sex-dependent differences in BBB permeability. Furthermore, we report for the first time the potential to deliver NP-based therapeutics within 3 days after focal injury in both female and male mice. The delineation of injury-induced BBB permeability with respect to sex and temporal profile is essential to more accurately tailor time-dependent precision and personalized nanotherapeutics. Impact statement In this study, we identified a sex-dependent temporal profile of blood/brain barrier disruption in a preclinical mouse model of traumatic brain injury (TBI) that contributes to starkly different macromolecule and nanoparticle delivery profiles post-TBI. The implications and potential impact of this work are profound and far reaching as it indicates that a demand of true personalized medicine for TBI is necessary to deliver the right therapeutic at the right time for the right patient.

More bullets for PISTOL: linear and cyclic siloxane reporter probes for quantitative 1H MR oximetry.

Tissue oximetry can assist in diagnosis and prognosis of many diseases and enable personalized therapy. Previously, we reported the ability of hexamethyldisiloxane (HMDSO) for accurate measurements of tissue oxygen tension (pO2) using Proton Imaging of Siloxanes to map Tissue Oxygenation Levels (PISTOL) magnetic resonance imaging. Here we report the feasibility of several commercially available linear and cyclic siloxanes (molecular weight 162-410 g/mol) as PISTOL-based oxygen reporters by characterizing their calibration constants. Further, field and temperature dependence of pO2 calibration curves of HMDSO, octamethyltrisiloxane (OMTSO) and polydimethylsiloxane (PDMSO) were also studied. The spin-lattice relaxation rate R1 of all siloxanes studied here exhibited a linear relationship with oxygenation (R1 = A' + B'*pO2) at all temperatures and field strengths evaluated here. The sensitivity index η( = B'/A') decreased with increasing molecular weight with values ranged from 4.7 × 10-3-11.6 × 10-3 torr-1 at 4.7 T. No substantial change in the anoxic relaxation rate and a slight decrease in pO2 sensitivity was observed at higher magnetic fields of 7 T and 9.4 T for HMDSO and OMTSO. Temperature dependence of calibration curves for HMDSO, OMTSO and PDMSO was small and simulated errors in pO2 measurement were 1-2 torr/°C. In summary, we have demonstrated the feasibility of various linear and cyclic siloxanes as pO2-reporters for PISTOL-based oximetry.

2-D magnetic resonance spectroscopic imaging of the pediatric brain using compressed sensing.

BACKGROUND: Magnetic resonance spectroscopic imaging helps to determine abnormal brain tissue conditions by evaluating metabolite concentrations. Although a powerful technique, it is underutilized in routine clinical studies because of its long scan times. OBJECTIVE: In this study, we evaluated the feasibility of scan time reduction in metabolic imaging using compressed-sensing-based MR spectroscopic imaging in pediatric patients undergoing routine brain exams. MATERIALS AND METHODS: We retrospectively evaluated compressed-sensing reconstructions in MR spectroscopic imaging datasets from 20 pediatric patients (11 males, 9 females; average age: 5.4±4.5 years; age range: 3 days to 16 years). We performed retrospective under-sampling of the MR spectroscopic imaging datasets to simulate accelerations of 2-, 3-, 4-, 5-, 7- and 10-fold, with subsequent reconstructions in MATLAB. Metabolite maps of N-acetylaspartate, creatine, choline and lactate (where applicable) were quantitatively evaluated in terms of the root-mean-square error (RMSE), peak amplitudes and total scan time. We used the two-tailed paired t-test along with linear regression analysis to statistically compare the compressed-sensing reconstructions at each acceleration with the fully sampled reference dataset. RESULTS: High fidelity was maintained in the compressed-sensing MR spectroscopic imaging reconstructions from 50% to 80% under-sampling, with the RMSE not exceeding 3% in any dataset. Metabolite intensities and ratios evaluated on a voxel-by-voxel basis showed no statistically significant differences and mean metabolite intensities showed high correlation compared to the fully sampled reference dataset up to an acceleration factor of 5. CONCLUSION: Compressed-sensing MR spectroscopic imaging has the potential to reduce MR spectroscopic imaging scan times for pediatric patients, with negligible information loss.

A faster PISTOL for 1 H MR-based quantitative tissue oximetry.

Quantitative mapping of oxygen tension (pO2 ), noninvasively, could potentially be beneficial in cancer and stroke therapy for monitoring therapy and predicting response to certain therapies. Intracellular pO2 measurements may also prove useful in tracking the health of labeled cells and understanding the dynamics of cell therapy in vivo. Proton Imaging of Siloxanes to map Tissue Oxygenation Levels (PISTOL) is a relatively new oximetry technique that measures the T1 of administered siloxanes such as hexamethyldisiloxane (HMDSO), to map the tissue pO2 at various locations with a temporal resolution of 3.5 minutes. We have now developed a siloxane-selective Look-Locker imaging sequence equipped with an echo planar imaging (EPI) readout to accelerate PISTOL acquisitions. The new tissue oximetry sequence, referred to as PISTOL-LL, enables the mapping of HMDSO T1 , and hence tissue pO2 in under one minute. PISTOL-LL was tested and compared with PISTOL in vitro and in vivo. Both sequences were used to record dynamic changes in pO2 of the rat thigh muscle (healthy Fischer rats, n = 6), and showed similar results (P > 0.05) as the other, with each sequence reporting a significant increase in pO2 (P < 0.05) under hyperoxia compared with steady state normoxia. This study demonstrates the ability of the new sequence in rapidly and accurately mapping the pO2 changes and accelerating quantitative 1 H MR tissue oximetry by approximately 4-fold. The faster PISTOL-LL technique could enable dynamic 1 H oximetry with higher temporal resolution for assesing tissue oxygentation and tracking the health of transplanted cells labeled with siloxane-based probes. With minor modifications, this sequence can be useful for 19 F applications as well.

Fast data acquisition techniques in magnetic resonance spectroscopic imaging.

Magnetic resonance spectroscopic imaging (MRSI) is an important technique for assessing the spatial variation of metabolites in vivo. The long scan times in MRSI limit clinical applicability due to patient discomfort, increased costs, motion artifacts, and limited protocol flexibility. Faster acquisition strategies can address these limitations and could potentially facilitate increased adoption of MRSI into routine clinical protocols with minimal addition to the current anatomical and functional acquisition protocols in terms of imaging time. Not surprisingly, a lot of effort has been devoted to the development of faster MRSI techniques that aim to capture the same underlying metabolic information (relative metabolite peak areas and spatial distribution) as obtained by conventional MRSI, in greatly reduced time. The gain in imaging time results, in some cases, in a loss of signal-to-noise ratio and/or in spatial and spectral blurring. This review examines the current techniques and advances in fast MRSI in two and three spatial dimensions and their applications. This review categorizes the acceleration techniques according to their strategy for acquisition of the k-space. Techniques such as fast/turbo-spin echo MRSI, echo-planar spectroscopic imaging, and non-Cartesian MRSI effectively cover the full k-space in a more efficient manner per TR . On the other hand, techniques such as parallel imaging and compressed sensing acquire fewer k-space points and employ advanced reconstruction algorithms to recreate the spatial-spectral information, which maintains statistical fidelity in test conditions (ie no statistically significant differences on voxel-wise comparisions) with the fully sampled data. The advantages and limitations of each state-of-the-art technique are reviewed in detail, concluding with a note on future directions and challenges in the field of fast spectroscopic imaging.

Blood-brainbarrier disruption dictates nanoparticle accumulation following experimental brain injury.

Clinically, traumatic brain injury (TBI) results in complex heterogeneous pathology that cannot be recapitulated in single pre-clinical animal model. Therefore, we focused on evaluating utility of nanoparticle (NP)-based therapeutics following three diffuse-TBI models: mildclosed-head injury (mCHI), repetitive-mCHI and midline-fluid percussion injury (FPI). We hypothesized that NP accumulation after diffuse TBI correlates directly with blood-brainbarrier permeability. Mice received PEGylated-NP cocktail (20-500 nm) (intravenously) after single- or repetitive-(1 impact/day, 5 consecutive days) CHI (immediately) and midline-FPI (1 h, 3 h and 6 h). NPs circulated for 1 h before perfusion/brain extraction. NP accumulation was analyzed using fluorescent microscopy in brain regions vulnerable to neuropathology. Minimal/no NP accumulation after mCHI/RmCHI was observed. In contrast, midlineFPI resulted in significant peak accumulation of up to 500 nm NP at 3 h post-injury compared to sham, 1 h, and 6 h groups in the cortex. Therefore, our study provides the groundwork for feasibility of NP-delivery based on NPinjection time and NPsize after mCHI/RmCHI and midline-FPI.

Nanoparticle-Based Therapeutics for Brain Injury.

Brain injuries affect a large patient population with major physical and emotional suffering for patients and their relatives; at a significant cost to the society. Effective diagnostic and therapeutic options available for brain injuries are limited by the complex brain injury pathology involving blood-brain barrier (BBB). Brain injuries, including ischemic stroke and brain trauma, initiate BBB opening for a short period of time, which is followed by a second reopening for an extended time. The leaky BBB and/or the alterations in the receptor expression on BBB may provide opportunities for therapeutic delivery via nanoparticles (NPs). The approaches for therapeutic interventions via NP delivery are aimed at salvaging the pericontusional/penumbra area for possible neuroprotection and neurovascular unit preservation. The focus of this progress report is to provide a survey of NP strategies employed in cerebral ischemia and brain trauma and finally provide insights for improved NP-based diagnostic/treatment approaches.

Multishot echo-planar MREIT for fast imaging of conductivity, current density, and electric field distributions.

PURPOSE: Magnetic resonance electrical impedance tomography (MREIT) sequences typically use conventional spin or gradient echo-based acquisition methods for reconstruction of conductivity and current density maps. Use of MREIT in functional and electroporation studies requires higher temporal resolution and faster sequences. Here, single and multishot echo planar imaging (EPI) based MREIT sequences were evaluated to see whether high-quality MREIT phase data could be obtained for rapid reconstruction of current density, conductivity, and electric fields. METHODS: A gel phantom with an insulating inclusion was used as a test object. Ghost artifact, geometric distortion, and MREIT correction algorithms were applied to the data. The EPI-MREIT-derived phase-projected current density and conductivity images were compared with simulations and spin-echo images as a function of EPI shot number. RESULTS: Good agreement among measures in simulated, spin echo, and EPI data was achieved. Current density errors were stable and below 9% as the shot number decreased from 64 to 2, but increased for single-shot images. Conductivity reconstruction relative contrast ratios were stable as the shot number decreased. The derived electric fields also agreed with the simulated data. CONCLUSIONS: The EPI methods can be combined successfully with MREIT reconstruction algorithms to achieve fast imaging of current density, conductivity, and electric field. Magn Reson Med 79:71-82, 2018. © 2017 International Society for Magnetic Resonance in Medicine.

Multifunctional PHPMA-Derived Polymer for Ratiometric pH Sensing, Fluorescence Imaging, and Magnetic Resonance Imaging.

In this paper, we report synthesis and characterization of a novel multimodality (MRI/fluorescence) probe for pH sensing and imaging. A multifunctional polymer was derived from poly(N-(2-hydroxypropyl)methacrylamide) (PHPMA) and integrated with a naphthalimide-based-ratiometric fluorescence probe and a gadolinium-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid complex (Gd-DOTA complex). The polymer was characterized using UV-vis absorption spectrophotometry, fluorescence spectrofluorophotometry, magnetic resonance imaging (MRI), and confocal microscopy for optical and MRI-based pH sensing and cellular imaging. In vitro labeling of macrophage J774 and esophageal CP-A cell lines shows the polymer's ability to be internalized in the cells. The transverse relaxation time (T2) of the polymer was observed to be pH-dependent, whereas the spin-lattice relaxation time (T1) was not. The pH probe in the polymer shows a strong fluorescence-based ratiometric pH response with emission window changes, exhibiting blue emission under acidic conditions and green emission under basic conditions, respectively. This study provides new materials with multimodalities for pH sensing and imaging.

Mathematical Analysis of Glioma Growth in a Murine Model.

Five immunocompetent C57BL/6-cBrd/cBrd/Cr (albino C57BL/6) mice were injected with GL261-luc2 cells, a cell line sharing characteristics of human glioblastoma multiforme (GBM). The mice were imaged using magnetic resonance (MR) at five separate time points to characterize growth and development of the tumor. After 25 days, the final tumor volumes of the mice varied from 12 mm3 to 62 mm3, even though mice were inoculated from the same tumor cell line under carefully controlled conditions. We generated hypotheses to explore large variances in final tumor size and tested them with our simple reaction-diffusion model in both a 3-dimensional (3D) finite difference method and a 2-dimensional (2D) level set method. The parameters obtained from a best-fit procedure, designed to yield simulated tumors as close as possible to the observed ones, vary by an order of magnitude between the three mice analyzed in detail. These differences may reflect morphological and biological variability in tumor growth, as well as errors in the mathematical model, perhaps from an oversimplification of the tumor dynamics or nonidentifiability of parameters. Our results generate parameters that match other experimental in vitro and in vivo measurements. Additionally, we calculate wave speed, which matches with other rat and human measurements.

Temporal assessment of nanoparticle accumulation after experimental brain injury: Effect of particle size.

Nanoparticle (NP) based therapeutic and theranostic agents have been developed for various diseases, yet application to neural disease/injury is restricted by the blood-brain-barrier (BBB). Traumatic brain injury (TBI) results in a host of pathological alterations, including transient breakdown of the BBB, thus opening a window for NP delivery to the injured brain tissue. This study focused on investigating the spatiotemporal accumulation of different sized NPs after TBI. Specifically, animal cohorts sustaining a controlled cortical impact injury received an intravenous injection of PEGylated NP cocktail (20, 40, 100, and 500 nm, each with a unique fluorophore) immediately (0 h), 2 h, 5 h, 12 h, or 23 h after injury. NPs were allowed to circulate for 1 h before perfusion and brain harvest. Confocal microscopy demonstrated peak NP accumulation within the injury penumbra 1 h post-injury. An inverse relationship was found between NP size and their continued accumulation within the penumbra. NP accumulation preferentially occurred in the primary motor and somatosensory areas of the injury penumbra as compared to the parietal association and visual area. Thus, we characterized the accumulation of particles up to 500 nm at different times acutely after injury, indicating the potential of NP-based TBI theranostics in the acute period after injury.

A role for dynamic contrast-enhanced magnetic resonance imaging in predicting tumour radiation response.

BACKGROUND: Dynamic contrast-enhanced (DCE) MRI may provide prognostic insights into tumour radiation response. This study examined quantitative DCE MRI parameters in rat tumours, as potential biomarkers of tumour growth delay following single high-dose irradiation. METHODS: Dunning R3327-AT1 prostate tumours were evaluated by DCE MRI following intravenous injection of Gd-DTPA. The next day tumours were irradiated (single dose of 30 Gy), while animals breathed air (n=4) or oxygen (n=4); two animals were non-irradiated controls. Growth was followed and tumour volume-quadrupling time (T4) was compared with pre-irradiation DCE assessments. RESULTS: Irradiation caused significant tumour growth delay (T4 ranged from 28 to 48 days for air-breathing rats, and 40 to 75 days for oxygen-breathing rats) compared with the controls (T4=7 to 9 days). A strong correlation was observed between T4 and extravascular-extracellular volume fraction (ve) irrespective of the gas inhaled during irradiation. There was also a correlation between T4 and volume transfer constant (K(trans)) for the air-breathing group alone. CONCLUSIONS: The data provide rationale for expanded studies of other tumour sites, types and progressively patients, and are potentially significant, as many patients undergo contrast-enhanced MRI as part of treatment planning.