Heterogeneous Tissue Models Research Articles

Discrete anisotropy model of heterogeneous cardiac tissue predicting the occurrence of symmetry breaking of reentrant activity

Discrete anisotropy model of heterogeneous cardiac tissue predicting the occurrence of symmetry breaking of reentrant activity

Discrete Anisotropy Model of Heterogeneous Cardiac Tissue Predicting the Occurrence of Symmetry Breaking of Reentrant Activity

Cardiac arrhythmias are a major cause of cardiovascular mortality worldwide. Functional heterogeneity of cardiac tissue is an inevitable arrhythmogenic condition that may create nonlinear wave turbulence or reentry with subsequent arrhythmia initiation. The relation between propagation heterogeneity and the onset of reentry is of great theoretical and practical importance. Here, we present a conceptual representation of heterogeneous tissue expressed through alternating local and global tissue anisotropy with discreteness of membrane conductance. To contrast the influence of distributed heterogeneity, we investigated the interaction of a high-frequency wavetrain at a sharp anisotropy-symmetric obstacle. The revealed tendency of a heterogeneous system to form reentry was formalized into the single concept of a vulnerable frequency corridor that can be estimated experimentally. Using the joint in vitro–in silico approach, we defined an anomalous stable growth of a unidirectional block in the vicinity of an obstacle, depending on the direction of the anisotropy vector. This effect explains the limited applicability of homogeneous models to predicting the occurrence of primary reentry. Furthermore, computer simulations showed the special role played by other possible mechanisms of excitation, as ephaptic intercellular coupling, in the formation of a unidirectional block of conduction and reentry onset, which could not be predicted by conduction velocity measurements.

Computational methods for the estimation of ideal current patterns in realistic human models.

To introduce a method for the estimation of the ideal current patterns (ICP) that yield optimal signal-to-noise ratio (SNR) for realistic heterogeneous tissue models in MRI. The ICP were calculated for different surfaces that resembled typical radiofrequency (RF) coil formers. We constructed numerical electromagnetic (EM) bases to accurately represent EM fields generated by RF current sources located on the current-bearing surfaces. Using these fields as excitations, we solved the volume integral equation and computed the EM fields in the sample. The fields were appropriately weighted to calculate the optimal SNR and the corresponding ICP. We demonstrated how to qualitatively use ICP to guide the design of a coil array to maximize SNR inside a head model. In agreement with previous analytic work, ICP formed large distributed loops for voxels in the middle of the sample and alternated between a single loop and a figure-eight shape for a voxel 3-cm deep in the sample's cortex. For the latter voxel, a surface quadrature loop array inspired by the shape of the ICP reached of the optimal SNR at 3T, whereas a single loop placed above the voxel reached only of the optimal SNR. At 7T, the performance of the two designs decreased to and , respectively, suggesting that loops could be suboptimal at ultra-high field MRI. ICP can be calculated for human tissue models, potentially guiding the design of application-specific RF coil arrays.

Highly accurate and reliable ultrasonic focusing capability in heterogeneous media using a spherical cavity transducer

Introduction: Focused ultrasound ablation surgery (FUAS) has been emerging to treat a wide range of conditions non-invasively and effectively with promising therapeutic outcomes. The focusing capability of an ultrasound transducer (i.e., focus shift, beam distortion, and acoustic pressure at the focus) determines the ablation effects. However, the focus shift and focal beam distortion after ultrasound propagating through multi-layered heterogeneous viscoelastic biological tissues become significant and are found to deteriorate the performance of FUAS in clinics.Methods: To achieve an accurate and reliable focal field among patients with large variations in the anatomical structures and properties, a spherical cavity transducer with open ends and sub-wavelength focal size (Li et al., APL, 2013,102:204102) was applied here. Both experimental measurements and numerical simulations were performed to characterize the acoustic fields of the spherical cavity transducer in water, the multi-layered concentric cylindrical phantom, and the heterogeneous tissue model (an adult male pelvis enclosed by porcine skin, fat, and muscle) and then compared with those of a conventional concave transducer at the same electrical power output.Results: It is found that standing-wave focusing using the spherical cavity transducer results in much less focus shift (0.25λ vs. 1.67λ) along the transducer axis and focal beam distortion (−6 dB beam area of 0.71 mm2vs. 4.72 mm2 in water and 2.55 mm2vs. 17.30 mm2 in tissue) in the focal plane but higher pressure focusing gain (40.05 dB vs. 33.61 dB in tissue).Discussion: Such a highly accurate and reliable focal field is due to the excitation at an appropriate eigen-frequency of the spherical cavity with the varied media inside rather than the reverberation from the concave surface. Together with its sub-wavelength focal size, the spherical cavity transducer is technically advantageous in comparison to the concave one. The improved focusing capability would benefit ultrasound exposure for not only safer and more effective FUAS in clinics, but also broad acoustic applications.

Synchronization of pacemaker cell firing underlies autonomic modulation of beating intervals and their variability in a numerical model of heterogeneous SA node tissue.

The normal heart beats regularly but not metronomically. It is initiated by pacemaker cells within the sinoatrial node (SAN), an extremely heterogeneous cellular network. The functional role of SAN cell heterogeneity remains unknown. Here we investigated the problem in a SAN tissue model comprised of 2025 single cell models. Each cell model features a coupled operation of the Ca and membrane clocks. We modeled tissue heterogeneity by varying the ICaL conductance (gCaL) and SR Ca pumping (Pup). In our simulations heterogeneous cells interacted in tissue and acquired new properties: while cells in isolation had all rhythmic or no firing, cells firing irregular APs emerged in local cell communities with similar properties. The heart rate is naturally increased via β-adrenergic receptors (βAR) and decreased via cholinergic receptors (ChR) in the SAN. βAR stimulation increased the rate and synchronization of AP firing of individual cell models within the SAN tissue, whereas ChR stimulation decreased the rate and synchronization of AP firing. The number of firing cells increased in βAR stimulation to 99% from 80%, and the average cycle length of the SAN decreased by ∼20%. Meanwhile the standard deviation of the cycle length decreased by a multiple of 25, reflecting a much higher level of synchronization. During ChR stimulation, the number of firing cells remained almost unchanged, but the average AP cycle length increased by almost 20%. The standard deviation also increased by a multiple of 2, demonstrating the higher level of desynchronization. The number of cells with emergent irregular APs firing was substantially greater under ChR stimulation than BAR stimulation, indicating importance of these cells as an intrinsic source of heart rate variability at various conditions.

A Mucin-Deficient Ocular Surface Mimetic Platform for Interrogating Drug Effects on Biolubrication, Antiadhesion Properties, and Barrier Functionality.

Dry eye disease (DED) affects more than 100 million people worldwide, causing significant patient discomfort and imposing a multi-billion-dollar burden on global health care systems. In DED patients, the natural biolubrication process that facilitates pain-free blinking goes awry due to an imbalance of lipids, aqueous medium, and mucins in the tear film, resulting in ocular surface damage. Identifying strategies to reduce adhesion and shear stresses between the ocular surface and the conjunctival cells lining the inside of the eyelid during blink cycles is a promising approach to improve the signs and symptoms of DED. However, current preclinical models for screening ocular lubricants rely on scarce, heterogeneous tissue samples or model substrates that do not capture the complex biochemical and biophysical cues present at the ocular surface. To recapitulate the hierarchical architecture and phenotype of the ocular interface for preclinical drug screening, we developed an in vitro mucin-deficient DED model platform that mimics the complexity of the ocular interface and investigated its utility in biolubrication, antiadhesion, and barrier protection studies using recombinant human lubricin, a promising investigational therapy for DED. The biomimetic platform recapitulated the pathological changes in biolubrication, adhesion, and barrier functionality often observed in mucin-deficient DED patients and demonstrated that recombinant human lubricin can reverse the damage induced by mucin loss in a dose- and conformation-dependent manner. Taken together, these results highlight the potential of the platform—and recombinant human lubricin—in advancing the standard of care for mucin-deficient DED patients.

Artificial Taste Buds: Bioorthogonally Ligated Gustatory-Neuronal Multicellular Hybrids Enabling Intercellular Taste Signal Transmission.

Heterogeneous tissue models require the assembly and co-culture of multiple types of cells. Our recent work demonstrated taste signal transmission from gustatory cells to neurons by grafting single-stranded DNA into the cell membrane to construct multicellular assemblies. However, the weak DNA linkage and low grafting density allowed the formation of large gustatory cell self-aggregates that cannot communicate with neurons efficiently. This article presents the construction of artificial taste buds exhibiting active intercellular taste signal transmission through the hybridization of gustatory-neuronal multicellular interfaces using bioorthogonal click chemistry. Hybrid cell clusters were formed by the self-assembly of neonatal gustatory cells displaying tetrazine with a precultured embryonic hippocampal neuronal network displaying trans-cyclooctene. A bitter taste signal transduction was provoked in gustatory cells using denatonium benzoate and transmitted to neurons as monitored by intracellular calcium ion sensing. In the multicellular hybrids, the average number of signal transmissions was five to six peaks per cell, and the signal transmission lasted for ∼5 min with a signal-to-signal gap time of 10-40 s. The frequent and extended intercellular signal transmission suggests that the cell surface modification by the bioorthogonal click chemistry is a promising approach to fabricating functional multicellular hybrid clusters potentially useful for cell-based biosensors, toxicity assays, and tissue regeneration.

3D bioprinting of high cell-density heterogeneous tissue models through spheroid fusion within self-healing hydrogels

Cellular models are needed to study human development and disease in vitro, and to screen drugs for toxicity and efficacy. Current approaches are limited in the engineering of functional tissue models with requisite cell densities and heterogeneity to appropriately model cell and tissue behaviors. Here, we develop a bioprinting approach to transfer spheroids into self-healing support hydrogels at high resolution, which enables their patterning and fusion into high-cell density microtissues of prescribed spatial organization. As an example application, we bioprint induced pluripotent stem cell-derived cardiac microtissue models with spatially controlled cardiomyocyte and fibroblast cell ratios to replicate the structural and functional features of scarred cardiac tissue that arise following myocardial infarction, including reduced contractility and irregular electrical activity. The bioprinted in vitro model is combined with functional readouts to probe how various pro-regenerative microRNA treatment regimes influence tissue regeneration and recovery of function as a result of cardiomyocyte proliferation. This method is useful for a range of biomedical applications, including the development of precision models to mimic diseases and the screening of drugs, particularly where high cell densities and heterogeneity are important.

In Silico Prediction of Drug-Induced Ventricular Arrhythmia using Heterogeneous Tissue Models of the Purkinje-Ventricular System

In Silico Prediction of Drug-Induced Ventricular Arrhythmia using Heterogeneous Tissue Models of the Purkinje-Ventricular System

Lattice Boltzmann method for simulation of diffusion magnetic resonance imaging physics in multiphase tissue models.

We report an implementation of the lattice Boltzmann method (LBM) to integrate the Bloch-Torrey equation, which describes the evolution of the transverse magnetization vector and the fate of the signal of diffusion magnetic resonance imaging (dMRI). Motivated by the need to interpret dMRI experiments in biological tissues, and to offset the small time-step limitation of classical LBM, a hybrid LBM scheme is introduced and implemented to solve the Bloch-Torrey equation. A membrane boundary condition is presented which is able to accurately represent the effects of thin curvilinear membranes typically found in biological tissues. As implemented, the hybrid LBM scheme accommodates piece-wise uniform transport, dMRI parameters, periodic and mirroring outer boundary conditions, and finite membrane permeabilities on non-boundary-conforming inner boundaries. By comparing with analytical solutions of limiting cases, we demonstrate that the hybrid LBM scheme is more accurate than the classical LBM scheme. The proposed explicit LBM scheme maintains second-order spatial accuracy, stability, and first-order temporal accuracy for a wide range of parameters. The parallel implementation of the hybrid LBM code in a multi-CPU computer system, as well as on GPUs, is straightforward and efficient. Along with offering certain advantages over finite element or Monte Carlo schemes, the proposed hybrid LBM constitutes a flexible scheme that can by easily adapted to model more complex interfacial conditions and physics in heterogeneous multiphase tissue models and to accommodate sophisticated dMRI sequences.

Steering the Volume of Tissue Activated With a Directional Deep Brain Stimulation Lead in the Globus Pallidus Pars Interna: A Modeling Study With Heterogeneous Tissue Properties

Objective: To study the effect of directional deep brain stimulation (DBS) electrode configuration and vertical electrode spacing on the volume of tissue activated (VTA) in the globus pallidus, pars interna (GPi).Background: Directional DBS leads may allow clinicians to precisely direct current fields to different functional networks within traditionally targeted brain areas. Modeling the shape and size of the VTA for various monopolar or bipolar configurations can inform clinical programming strategies for GPi DBS. However, many computational models of VTA are limited by assuming tissue homogeneity.Methods: We generated a multimodal image-based detailed anatomical (MIDA) computational model with a directional DBS lead (1.5 mm or 0.5 mm vertical electrode spacing) placed with segmented contact 2 at the ventral posterolateral “sensorimotor” region of the GPi. The effect of tissue heterogeneity was examined by replacing the MIDA tissues with a homogeneous tissue of conductance 0.3 S/m. DBS pulses (amplitude: 1 mA, pulse width: 60 μs, frequency: 130 Hz) were used to produce VTAs. The following DBS contact configurations were tested: single-segment monopole (2B-/Case+), two-segment monopole (2A-/2B-/Case+ and 2B-/3B-/Case+), ring monopole (2A-/2B-/2C-/Case+), one-cathode three-anode bipole (2B-/3A+/3B+/3C+), three-cathode three-anode bipole (2A-/2B-/2C-/3A+/3B+/3C+). Additionally, certain vertical configurations were repeated with 2 mA current amplitude.Results: Using a heterogeneous tissue model affected both the size and shape of the VTA in GPi. Electrodes with both 0.5 mm and 1.5 mm vertical spacing (1 mA) modeling showed that the single segment monopolar VTA was entirely contained within the GPi when the active electrode is placed at the posterolateral “sensorimotor” GPi. Two segments in a same ring and ring settings, however, produced VTAs outside of the GPi border that spread into adjacent white matter pathways, e.g., optic tract and internal capsule. Both stacked monopolar settings and vertical bipolar settings allowed activation of structures dorsal to the GPi in addition to the GPi. Modeling of the stacked monopolar settings with the DBS lead with 0.5 mm vertical electrode spacing further restricted VTAs within the GPi, but the VTA volumes were smaller compared to the equivalent settings of 1.5 mm spacing.

Variability in electrophysiological properties and conducting obstacles controls re-entry risk in heterogeneous ischaemic tissue.

Ischaemia, in which inadequate blood supply compromises and eventually kills regions of cardiac tissue, can cause many types of arrhythmia, some life-threatening. A significant component of this is the effects of the resulting hypoxia, and concomitant hyperklaemia and acidosis, on the electrophysiological properties of myocytes. Clinical and experimental data have also shown that regions of structural heterogeneity (fibrosis, necrosis, fibro-fatty infiltration) can act as triggers for arrhythmias under acute ischaemic conditions. Mechanistic models have successfully captured these effects in silico. However, the relative significance of these separate facets of the condition, and how sensitive arrhythmic risk is to the extents of each, is far less explored. In this work, we use partitioned Gaussian process emulation and new metrics for source-sink mismatch that rely on simulations of bifurcating cardiac fibres to interrogate a model of heterogeneous ischaemic tissue. Re-entries were most sensitive to the level of hypoxia and the fraction of non-excitable tissue. In addition, our results reveal both protective and pro-arrhythmic effects of hyperklaemia, and present the levels of hyperklaemia, hypoxia and percentage of non-excitable tissue that pose the highest arrhythmic risks. This article is part of the theme issue 'Uncertainty quantification in cardiac and cardiovascular modelling and simulation'.

An integrated cell printing system for the construction of heterogeneous tissue models

A new three-dimensional (3D) cell printing system was developed and investigated to organize multiple cells/biomaterials with a control precision within 100 μm. This system can be used for the in vitro construction of heterogeneous tissue models. The proposed printing system was achieved by the integration of extrusion printing and alternating viscous and inertial force jetting (AVIFJ) techniques using dual-nozzle switching. In this technique, hydrogels containing high cell densities were extruded using extrusion printing, while droplets containing single cells were precisely manipulated using AVIFJ. The droplets that contained single cells were at the scale of pico-liters and could be accurately positioned at the micron scale. Stable hydrogel structures with adjustable diameters were also printed, with cell viabilities exceeding 90% after printing. A heterogeneous tumor model that contained spheroids and human umbilical vein endothelial cells (HUVECs) was then constructed using the established integrated cell printing system in a stepwise or simultaneous fashion. HUVEC-loaded droplets were observed to locate around the preformed tumor spheroids as designed. Cells and spheroids in the model maintained high cell viability and sustained growth throughout the culture period. The ELISA results of albumin production also proved that the spheroids maintained increased cellular function during the culture. These results demonstrated the feasibility of this integrated 3D printing system for the engineering of in vitro heterogeneous tissue models for future biological and pathological studies. Statement of SignificanceAddressing the challenge of multi-scale printing in the construction of heterogeneous tissue models, a new 3D cell printing system was developed to organize cells/biomaterials of a control precision within 100 μm. AVIFJ was integrated with extrusion printing, thereby achieving the construction of cell interactions between single cells and spheroids, the manipulation of single cells in a 3D microenvironment with high accuracy, and the real-time on-demand printing. The printed heterogeneous tumor model maintained cell viability, sustained cell growth, and increased cell function during 7 days of culture. We believed that this work would benefit the production of functional artificial tissues, enabling the construction of more biomimetic cell arrangements and microenvironment to support cell functions.

Analysis of heterogeneous cardiac pacemaker tissue models and traveling wave dynamics

The sinoatrial-node (SAN) is a complex heterogeneous tissue that generates a stable rhythm in healthy hearts, yet a general mechanistic explanation for when and how this tissue remains stable is lacking. Although computational and theoretical analyses could elucidate these phenomena, such methods have rarely been used in realistic (large-dimensional) gap-junction coupled heterogeneous pacemaker tissue models. In this study, we adapt a recent model of pacemaker cells (Severi et al., 2012), incorporating biophysical representations of ion channel and intracellular calcium dynamics, to capture physiological features of a heterogeneous population of pacemaker cells, in particular “center” and “peripheral” cells with distinct intrinsic frequencies and action potential morphology. Large-scale simulations of the SAN tissue, represented by a heterogeneous tissue structure of pacemaker cells, exhibit a rich repertoire of behaviors, including complete synchrony, traveling waves of activity originating from periphery to center, and transient traveling waves originating from the center. We use phase reduction methods that do not require fully simulating the large-scale model to capture these observations. Moreover, the phase reduced models accurately predict key properties of the tissue electrical dynamics, including wave frequencies when synchronization occurs, and wave propagation direction in a variety of tissue models. With the reduced phase models, we analyze the relationship between cell distributions and coupling strengths and the resulting transient dynamics. Further, the reduced phase model predicts parameter regimes of irregular electrical dynamics. Thus, we demonstrate that phase reduced oscillator models applied to realistic pacemaker tissue is a useful tool for investigating the spatial-temporal dynamics of cardiac pacemaker activity.

A heterogeneous tissue model for treatment planning for magnetic resonance-guided laser interstitial thermal therapy

We evaluated a physics-based model for planning for magnetic resonance-guided laser interstitial thermal therapy for focal brain lesions. Linear superposition of analytical point source solutions to the steady-state Pennes bioheat transfer equation simulates laser-induced heating in brain tissue. The line integral of the photon attenuation from the laser source enables computation of the laser interaction with heterogeneous tissue. Magnetic resonance thermometry data sets (n = 31) were used to calibrate and retrospectively validate the model’s thermal ablation prediction accuracy, which was quantified by the Dice similarity coefficient (DSC) between model-predicted and measured ablation regions (T > 57 °C). A Gaussian mixture model was used to identify independent tissue labels on pre-treatment anatomical magnetic resonance images. The tissue-dependent optical attenuation coefficients within these labels were calibrated using an interior point method that maximises DSC agreement with thermometry. The distribution of calibrated tissue properties formed a population model for our patient cohort. Model prediction accuracy was cross-validated using the population mean of the calibrated tissue properties. A homogeneous tissue model was used as a reference control. The median DSC values in cross-validation were 0.829 for the homogeneous model and 0.840 for the heterogeneous model. In cross-validation, the heterogeneous model produced a DSC higher than that produced by the homogeneous model in 23 of the 31 brain lesion ablations. Results of a paired, two-tailed Wilcoxon signed-rank test indicated that the performance improvement of the heterogeneous model over that of the homogeneous model was statistically significant (p < 0.01).

Atrial arrhythmogenicity of KCNJ2 mutations in short QT syndrome: Insights from virtual human atria.

Gain-of-function mutations in KCNJ2-encoded Kir2.1 channels underlie variant 3 (SQT3) of the short QT syndrome, which is associated with atrial fibrillation (AF). Using biophysically-detailed human atria computer models, this study investigated the mechanistic link between SQT3 mutations and atrial arrhythmogenesis, and potential ion channel targets for treatment of SQT3. A contemporary model of the human atrial action potential (AP) was modified to recapitulate functional changes in IK1 due to heterozygous and homozygous forms of the D172N and E299V Kir2.1 mutations. Wild-type (WT) and mutant formulations were incorporated into multi-scale homogeneous and heterogeneous tissue models. Effects of mutations on AP duration (APD), conduction velocity (CV), effective refractory period (ERP), tissue excitation threshold and their rate-dependence, as well as the wavelength of re-entry (WL) were quantified. The D172N and E299V Kir2.1 mutations produced distinct effects on IK1 and APD shortening. Both mutations decreased WL for re-entry through a reduction in ERP and CV. Stability of re-entrant excitation waves in 2D and 3D tissue models was mediated by changes to tissue excitability and dispersion of APD in mutation conditions. Combined block of IK1 and IKr was effective in terminating re-entry associated with heterozygous D172N conditions, whereas IKr block alone may be a safer alternative for the E299V mutation. Combined inhibition of IKr and IKur produced a synergistic anti-arrhythmic effect in both forms of SQT3. In conclusion, this study provides mechanistic insights into atrial proarrhythmia with SQT3 Kir2.1 mutations and highlights possible pharmacological strategies for management of SQT3-linked AF.

Construction of a biomechanical head and neck motion model as a guide to evaluation of deformable image registration

The use of deformable image registration methods in the context of adaptive radiotherapy leads to uncertainties in the simulation of the administered dose distributions during the treatment course. Evaluation of these methods is a prerequisite to decide if a plan adaptation will improve the individual treatment. Current approaches using manual references limit the validity of evaluation, especially for low-contrast regions. In particular, for the head and neck region, the highly flexible anatomy and low soft tissue contrast in control images pose a challenge to image registration and its evaluation. Biomechanical models promise to overcome this issue by providing anthropomorphic motion modelling of the patient. We introduce a novel biomechanical motion model for the generation and sampling of different postures of the head and neck anatomy. Motion propagation behaviour of the individual bones is defined by an underlying kinematic model. This model interconnects the bones by joints and thus is capable of providing a wide range of motion. Triggered by the motion of the individual bones, soft tissue deformation is described by an extended heterogeneous tissue model based on the chainmail approach. This extension, for the first time, allows the propagation of decaying rotations within soft tissue without the necessity for explicit tissue segmentation. Overall motion simulation and sampling of deformed CT scans including a basic noise model is achieved within 30 s. The proposed biomechanical motion model for the head and neck site generates displacement vector fields on a voxel basis, approximating arbitrary anthropomorphic postures of the patient. It was developed with the intention of providing input data for the evaluation of deformable image registration.

Photon fluencies for diffuse optical tomography systems

In this work, photon fluencies have been used to explore the depth of buried layers for diffuse optical tomography (DOT) systems. Back-reflected diffuse reflectance data were generated by Monte Carlo Modelling of Light Transport (MCMLT) simulations. Heterogeneous layers which have 1mm thickness were buried from 1mm to 8mm for 8 different simulations, consecutively. DOT systems are categorized based on the physical appearence as transmission through or back reflection geometry. Transmission through systems are more successful than back-reflected geometrical models from the view of the accuracy of the locations of the reconstructed images. On the other hand in the real world, back-reflection geometry is necessary for diagnostics and treatment purposes in the medical units and hospitals. DOT imaging systems basically use photon transport diffusion equation inside the turbid media. In literature, researchers and companies are using the linearized model of non-linear diffusion equation which is the first Taylor term of Rytov or Born approximation of radiative transport equation (RTE). The unknowns of the linearized equation system are differences of absorption coefficients over homogeneous background. After modeling of the linearized equation system, the next step is to solve the linearized equation system. Finally, researchers and company workers are using the forward model in different mathematical inverse problem solution algorithms which can be grouped as iterative, subspace, and regularization methods. Regularization methods are used very frequently hence the measurement system usually has noises and artifacts and the forward model transfer functions matrix is also not square. In this work a new method is presented for DOT imaging modalities without using any mathematical inverse problem solution algorithms. This new philosophy is using comparison of photon fluencies for different depth layers between homogeneous and heterogeneous tissue models. The new philosophical approach is being presented to explore the depth of the buried layers for DOT systems.

Effects of cellular electromechanical coupling on functional heterogeneity in a one-dimensional tissue model of the myocardium

Based on the experimental evidence, we developed a one-dimensional (1D) model of heterogeneous myocardial tissue consisting of in-series connected cardiomyocytes from distant transmural regions using mathematical models of subendocardial and subepicardial cells. The regional deformation patterns produced by our 1D model are consistent with the transmural regional strain patterns obtained experimentally in the normal heart in vivo. The modelling results suggest that the mechanical load may essentially affect the transmural gradients in the electrical and mechanical properties of interacting myocytes within a tissue, thereby regulating global myocardial output.

Large-scale Retrospective Monte Carlo Dosimetric Study for Permanent Implant Prostate Brachytherapy

To retrospectively compare water-based and full tissue model Monte Carlo dose calculations in a large cohort of patients undergoing 125I permanent implant prostate brachytherapy. For 613 patients, EGSnrc BrachyDose dose calculations were performed in 2 virtual patient models: TG43sim (simulated American Association of Physicists in Medicine Task Group Report 43 conditions) and MCref (computed tomography-derived heterogeneous tissue model with interseed effects). A sensitivity analysis was performed in a patient subset (25 with and 25 without prostatic calcifications) to explore dose calculation dependence on organ-at-risk (OAR) and calcification tissue elemental compositions and modelling approach. In the target volume, the minimum radiation dose delivered to 90% of prostate (D90) (volume of prostate receiving at least 100% of prescription dose [V100]) was lower with MCref than with TG43sim by 5.9%±1.6% (2.6%±1.7%), on average. Patients with prostatic calcifications can have substantial underdosed volumes due to calcification shielding, lowering the D90 by ≤25%. In the urethra, the average D5 (D30) was lower with MCref than with TG43sim by 4.4%±1.8% (4.7%±1.9%). In the rectum (bladder), the minimum dose to the hottest 0.1 cm3 (D_0.1cm3) of the contoured organ was lower (higher) with MCref than with TG43sim by 5.2%±1.8% (1.3%±1.8%). Doses to the target and OARs can increase or decrease by several percentages, depending on the assumed tissue elemental composition. In patients with calcifications, differences between approaches to model calcifications can change the target and OAR dose metrics by upward of 10%. TG43sim typically overestimates the target and OAR doses by several percentages, on average, compared with MCref. The considerable variation in the relative TG43sim and MCref doses between patients, and the larger dose differences for patients with calcification, suggests that clinical adoption of Monte Carlo dose calculations for permanent implant prostate brachytherapy should be pursued. The substantial sensitivity of the Monte Carlo dose calculations to the patient modelling approach supports the adoption of a consensus modelling scheme, such as MCref described in the present study, to ensure consistency of practice.