Stelios Angeli

Stress-mediated progression of solid tumors: effect of mechanical stress on tissue oxygenation, cancer cell proliferation, and drug delivery.

Oxygen supply plays a central role in cancer cell proliferation. While vascular density increases at the early stages of carcinogenesis, mechanical solid stresses developed during growth compress tumor blood vessels and, thus, drastically reduce not only the supply of oxygen, but also the delivery of drugs at inner tumor regions. Among other effects, hypoxia and reduced drug delivery compromise the efficacy of radiation and chemo/nanotherapy, respectively. In the present study, we developed a mathematical model of tumor growth to investigate the interconnections among tumor oxygenation that supports cancer cell proliferation, the heterogeneous accumulation of mechanical stresses owing to tumor growth, the non-uniform compression of intratumoral blood vessels due to the mechanical stresses, and the insufficient delivery of oxygen and therapeutic agents because of vessel compression. We found that the high vascular density and increased cancer cell proliferation often observed in the periphery compared to the interior of a tumor can be attributed to heterogeneous solid stress accumulation. Highly vascularized peripheral regions are also associated with greater oxygenation compared with the compressed, less vascularized inner regions. We also modeled the delivery of drugs of two distinct sizes, namely chemotherapy and nanomedicine. Model predictions suggest that drug delivery is affected negatively by vessel compression independently of the size of the therapeutic agent. Finally, we demonstrated the applicability of our model to actual geometries, employing a breast tumor model derived from MR images.

A high-resolution cardiovascular magnetic resonance diffusion tensor map from ex-vivo C57BL/6 murine hearts

BackgroundThe complex cardiac fiber structural organization and spatial arrangement of cardiomyocytes in laminar sheetlets contributes greatly to cardiac functional and contractile ejection patterns. This study presents the first comprehensive, ultra-high resolution, fully quantitative statistical tensor map of the fixed murine heart at isotropic resolution of 43 μm using diffusion tensor (DT) cardiovascular magnetic resonance (CMR).MethodsImaging was completed in approximately 12 hours using a six-directional encoding scheme, in five ex vivo healthy C57BL/6 mouse hearts. The tensor map constructed from this data provides an average description of the murine fiber architecture visualized with fiber tractography, and its population variability, using the latest advances in image tensor analysis and statistics.ResultsResults show that non-normalized cardiac tensor maps are associated with mean fractional anisotropy of 0.25 ± 0.07 and mean diffusivity of 8.9 ± 1.6 × 10−4 mm2/s. Moreover, average mid-ventricular helical angle distributions ranged between –41 ± 3° and +52 ± 5° and were highly correlated with transmural depth, in agreement with prior published results in humans and canines. Calculated variabilities of local myocyte orientations were 2.0° and 1.4°. Laminar sheet orientation variability was found to be less stable at 2.6°. Despite such variations, the murine heart seems to be highly structured, particularly when compared to canines and humans.ConclusionsThis tensor map has the potential to yield an accurate mean representation and identification of common or unique features of the cardiac myocyte architecture, to establish a baseline standard reference of DTI indices, and to improve detection of biomarkers, especially in pathological states or post-transgenetic modifications.

Biphasic modeling of brain tumor biomechanics and response to radiation treatment

Biomechanical forces are central in tumor progression and response to treatment. This becomes more important in brain cancers where tumors are surrounded by tissues with different mechanical properties. Existing mathematical models ignore direct mechanical interactions of the tumor with the normal brain. Here, we developed a clinically relevant model, which predicts tumor growth accounting directly for mechanical interactions. A three-dimensional model of the gray and white matter and the cerebrospinal fluid was constructed from magnetic resonance images of a normal brain. Subsequently, a biphasic tissue growth theory for an initial tumor seed was employed, incorporating the effects of radiotherapy. Additionally, three different sets of brain tissue properties taken from the literature were used to investigate their effect on tumor growth. Results show the evolution of solid stress and interstitial fluid pressure within the tumor and the normal brain. Heterogeneous distribution of the solid stress exerted on the tumor resulted in a 35% spatial variation in cancer cell proliferation. Interestingly, the model predicted that distant from the tumor, normal tissues still undergo significant deformations while it was found that intratumoral fluid pressure is elevated. Our predictions relate to clinical symptoms of brain cancers and present useful tools for therapy planning.

Murine Cardiac Catheterizations and Hemodynamics: On the issue of Parallel Conductance

Catheter-based measurements are extensively used nowadays in animal models to quantify global left ventricular (LV) cardiac function and hemodynamics. Conductance catheter measurements yield estimates of LV volumes. Such estimates, however, are confounded by the catheters nonhomogeneous emission field and the contribution to the total conductance of surrounding tissue or blood conductance values (other than LV blood), a term often known as parallel conductance. In practice, in most studies, volume estimates are based on the assumptions that the catheters electric field is homogeneous and that parallel conductance is constant, despite prior results showing that these assumptions are incorrect. This study challenges the assumption for spatial homogeneity of electric field excitation of miniature catheters and investigated the electric field distribution of miniature catheters in the murine heart, based on cardiac model-driven (geometric, lump component) simulations and noninvasive imaging, at both systolic and diastolic cardiac phases. Results confirm the nonuniform catheter emission field, confined spatially within the LV cavity and myocardium, falling to 10% of its peak value at the ring electrode surface, within 1.1-2.0 mm, given a relative tissue permittivity of 33 615. Additionally, <;1% of power leaks were observed into surrounding cavities or organs at end-diastole. Temporally varying parallel conductance effects are also confirmed, becoming more prominent at end-systole.

Elimination of mutual inductance in NMR phased arrays: the paddle design revisited.

This study proposes a method to empirically minimize mutual inductance, using passive end-ring circular paddles, with neighboring coil loops placed in a non-overlapped configuration. The proposed concepts are validated through B(1)-field simulations for resonant coils at f(o)=300.5 MHz, having various sizes (3-10 cm), and for paddles with sizes ranging from 16 to 30 mm, and bench tests on constructed 4×4cm(2) two- (1×2) and four-coil loop (2×2) planar arrays. Simulation results yield total mean percentage B(1)-field differences of only 7.03% between the two non-overlapping coil array configurations (paddles vs. no-paddles). Pair-wise comparisons of elicited mean B(1)-field differences from the use of different circular and rectangular paddle sizes, yield values <5.3%. Theoretical calculation of the normalized mutual coupling coefficient in the non-overlapped coil configuration reduces to almost zero with optimally sized-paddles having a radius of approximately 28% the coils largest dimension. In the absence of paddles, differences in the split of resonance peaks of 9.9 MHz were observed for the two coils in the 1×2 array, which vanished with paddle placement. Single coil responses (unloaded/loaded) without paddles, and responses from array coils with use of optimally-sized paddles yielded quality factor ratios that ranged between 1.1-1.86 and 1.0-1.5, respectively. Phantom and mouse loaded reflection coefficients S(11)/S(22) were -16.7/-16.2dB and -28.2/-16.1 dB, for the two array loops, respectively. Under unloaded conditions and in the absence of paddles, split resonances were observed for the 1×2 array, yielding transmission coefficients of -5.5 to -8.1 dB, reversing to single resonance responses upon paddle placements, with transmission coefficients of -14.4 to -15.6 dB.

Towards patient-specific modeling of brain tumor growth and formation of secondary nodes guided by DTI-MRI

Previous studies to simulate brain tumor progression, often investigate either temporal changes in cancer cell density or the overall tissue-level growth of the tumor mass. Here, we developed a computational model to bridge these two approaches. The model incorporates the tumor biomechanical response at the tissue level and accounts for cellular events by modeling cancer cell proliferation, infiltration to surrounding tissues, and invasion to distant locations. Moreover, acquisition of high resolution human data from anatomical magnetic resonance imaging, diffusion tensor imaging and perfusion imaging was employed within the simulations towards a realistic and patient specific model. The model predicted the intratumoral mechanical stresses to range from 20 to 34 kPa, which caused an up to 4.5 mm displacement to the adjacent healthy tissue. Furthermore, the model predicted plausible cancer cell invasion patterns within the brain along the white matter fiber tracts. Finally, by varying the tumor vascular density and its invasive outer ring thickness, our model showed the potential of these parameters for guiding the timing (83–90 days) of cancer cell distant invasion as well as the number (0–2 sites) and location (temportal and/or parietal lobe) of the invasion sites.

Experimental measurements and mathematical modeling towards quantification of brain swelling stress

Traumatic brain injury results in brain tissue swelling which can be a life threatening condition due to skull confinement. While previous efforts successfully measured the exhibited volume change in brain tissue swelling, no data exist to provide information about the exhibited stresses. In this study, confined compression mechanical testing was employed to measure swelling stress in murine brain tissue samples by varying the ionic concentration of the bathing solutions. Subsequently, computer simulations of the experimental protocol were employed to confirm a triphasic mathematical model describing the effect and provide insights into the experimental data. We measured the swelling stress to be in the range of 1.2-6.7kPa (9.0-50.2mmHg) depending on the ionic strength of the bathing solution, while a good correspondence was demonstrated among the experimentally measured and simulated responses. Furthermore, the mathematical model featured the osmotic pressure as the primary contributor to the swelling stress, while a parametric analysis showed that the densities of the intracellular fixed charges and of the non-permeable solutes significantly affect the swelling stress.

Mechanical Stress Regulates Tissue Oxygenation, Cancer Cell Proliferation and Drug Delivery During Progression of Solid Tumors

Oxygen supply plays a central role in cancer cell proliferation. While vascular density increases at the early stages of carcinogenesis, mechanical solid stresses developed during growth compress tumor blood vessels and, thus, drastically reduce the supply of oxygen, but also the delivery of drugs at inner tumor regions. Among other effects, hypoxia and reduced drug delivery compromise the efficacy of radiation and chemo/nano therapy, respectively. In the present study, we developed a mathematical model of tumor growth to investigate the interconnections among tumor oxygenation that supports cancer cell proliferation, the heterogeneous accumulation of mechanical stresses owing to tumor growth, the non-uniform compression of intratumoral blood vessels due to the mechanical stresses, and the insufficient delivery of oxygen and therapeutic agents because of vessel compression. We found that the high vascular density and increased cancer cell proliferation often observed in the periphery compared to the interior of a tumor can be attributed to heterogeneous solid stress accumulation. Highly vascularized peripheral regions are also associated with greater oxygenation compared with the compressed, less vascularized inner regions. We also modeled the delivery of drugs of two distinct sizes, namely chemotherapy and nanomedicine. Model predictions suggest that drug delivery is negatively affected by vessel compression independently of the size of the therapeutic agent. Finally, we demonstrated the applicability of our model to actual geometries, employing a breast tumor model derived from MR images.