Heterogeneous Tissue Models Research Articles

Computer-aided multiple-head 3D printing system for printing of heterogeneous organ/tissue constructs.

Recently, much attention has focused on replacement or/and enhancement of biological tissues via the use of cell-laden hydrogel scaffolds with an architecture that mimics the tissue matrix, and with the desired three-dimensional (3D) external geometry. However, mimicking the heterogeneous tissues that most organs and tissues are formed of is challenging. Although multiple-head 3D printing systems have been proposed for fabricating heterogeneous cell-laden hydrogel scaffolds, to date only the simple exterior form has been realized. Here we describe a computer-aided design and manufacturing (CAD/CAM) system for this application. We aim to develop an algorithm to enable easy, intuitive design and fabrication of a heterogeneous cell-laden hydrogel scaffolds with a free-form 3D geometry. The printing paths of the scaffold are automatically generated from the 3D CAD model, and the scaffold is then printed by dispensing four materials; i.e., a frame, two kinds of cell-laden hydrogel and a support. We demonstrated printing of heterogeneous tissue models formed of hydrogel scaffolds using this approach, including the outer ear, kidney and tooth tissue. These results indicate that this approach is particularly promising for tissue engineering and 3D printing applications to regenerate heterogeneous organs and tissues with tailored geometries to treat specific defects or injuries.

Acoustic and thermal simulations of tcMRgFUS in patient specific models: validation with experiments

In tcMRgFUS, acoustic and spatial heterogeneities of the skull cause reflection, attenuation, and phase aberrations of the acoustic beams, which may cause patient-specific thermal responses to the same transducer power. In this work, we use acoustic and thermal simulations based on patient-specific 3D heterogeneous tissue models to predict heating at the center of the brain. We validate the model through comparison of the simulated temperature rises to experimentally derived energies for five patients treated using tcMRgFUS. Further, we separate the components of energy loss in the acoustic simulations into reflection-only, attenuation-only, phase aberration-only, and reflection and attenuation both to understand the cause of potential inter-patient variability in these treatments.

Other applications of medical microwaves – Breast tumour classification

This talk addresses the development of imaging techniques for the early detection of breast cancer, based on Ultra Wideband (UWB) radar, a promising emerging technology that exploits the dielectric contrast between normal and tumour tissues at microwave frequencies. Of particular interest in this work are issues related to techniques for classification of potential breast tumours into benign and malignant. This is particularly important given the results from recent studies of the dielectric properties of breast and tumour tissue, which have found that strong similarities exist between the dielectric properties of malignant, benign and normal fibroglandular breast tissue. This creates a more challenging imaging scenario and motivates the development of enhanced signal processing techniques for UWB imaging systems.Tumour growth and development patterns are modelled using Gaussian Random Spheres, using four discrete sizes and four different shapes. Feature extraction methods including Principal Component Analysis (PCA), Independent Component Analysis (ICA) and Discrete Wavelet Transform (DWT), are used to extract the most relevant features from the detailed Radar Target Signatures of the tumours, which are then classified with a number of different classification techniques: Linear Discriminant Analysis (LDA), Quadratic Discriminant Analysis (QDA) and Support Vector Machines (SVM). In addition to these techniques, a number of different multi-stage classification architectures are considered. The feature extraction and classification algorithms are evaluated for both homogeneous and heterogeneous breast tissue models, for a range of different tumour sizes and shapes.Also, the first experimental results using a pre-clinical UWB prototype imaging system for tumour classification based on the shape of tumours. A database of benign and malignant tumour phantoms was created using dielectrically–representative tissue-mimicking material. Classification of benign and malignant tumour models of the experimental data was completed with Linear Discriminant Analysis, Quadratic Discriminant Analysis and Support Vector Machines classifiers.

A μm-resolution heterogeneous tissue model for the magnetic stimulation of multifascicular sciatic nerve.

Efficacy of magnetic stimulation of the central or peripheral nervous system depends on the spatial and temporal distribution of the induced electric field generated by the magnetic coil. Therefore, accurate estimation of the induced electric field is crucial to the design and optimization of magnetic coils, particularly as the coil dimensions are reduced. In this work, we developed a numerical model of a multifascicular sciatic nerve to study the effect of tissue heterogeneity on the induced electric field. Using a multi-resolution electric field solver, we can resolve feature sizes as small as 1μm, allowing inclusion of the nerve membrane and the myelination layer. Preliminary results indicate that fascicle distribution and axons' proximity to each other significantly affect the magnitude and distribution of the induced electric field as compared to traditional homogeneous tissue models for field simulation.

Optimization of electromagnetic wave focusing in heterogeneous biological tissue model

The paper presents some optimization approaches to the electromagnetic wave focusing in heterogeneous biological tissue model. The model of human arm was used for investigation. The possibility of focusing of electromagnetic wave optimisation is strongly connected with investigation of electromagnetic wave propagation through complicated heterogeneous biological structure. Firstly we concentrated on the influence of particular structures thickness on scattering parameters value which gives us information about transmission and reflection of electromagnetic wave on interfaces of structures which differ by dielectric parameters. The next simulation showed the influence of water bolus placed on the arm model surface on values of SAR and consequently the possibility to avoid the overheating of upper region of arm model in the process of microwave hyperthermia. The next step connected with possible optimisation of electromagnetic wave focusing showed the influence of metamaterial structure placed in the front of microwave patch antenna used in role of microwave hyperthermia applicator on the electromagnetic wave focusing. The simulations were done for various numbers of metamaterial structures and various distances from arm model. Finally we simulated the focusing accuracy in the case when the combination of water bolus with metamaterial structure was used.

High-resolution simulations of the thermophysiological effects of human exposure to 100 MHz RF energy

Human exposure to radio frequency (RF) electromagnetic energy is known to result in tissue heating and can raise temperatures substantially in some situations. Standards for safe exposure to RF do not reflect bio-heat transfer considerations however. Thermoregulatory function (vasodilation, sweating) may mitigate RF heating effects in some environments and exposure scenarios. Conversely, a combination of an extreme environment (high temperature, high humidity), high activity levels and thermally insulating garments may exacerbate RF exposure and pose a risk of unsafe temperature elevation, even for power densities which might be acceptable in a normothermic environment. A high-resolution thermophysiological model, incorporating a heterogeneous tissue model of a seated adult has been developed and used to replicate a series of whole-body exposures at a frequency (100 MHz) which approximates that of human whole-body resonance. Exposures were simulated at three power densities (4, 6 and 8 mW cm−2) plus a sham exposure and at three different ambient temperatures (24, 28 and 31 °C). The maximum hypothalamic temperature increase over the course of a 45 min exposure was 0.28 °C and occurred in the most extreme conditions (Tamb = 31 °C, PD = 8 mW cm−2). Skin temperature increases attributable to RF exposure were modest, with the exception of a ‘hot spot’ in the vicinity of the ankle where skin temperatures exceeded 39 °C. Temperature increases in internal organs and tissues were small, except for connective tissue and bone in the lower leg and foot. Temperature elevation also was noted in the spinal cord, consistent with a hot spot previously identified in the literature.

Stress relaxation of heterogeneous myocardial tissue. Numerical experiments with 3D model

We present here a simple block model of heterogeneous system describing the processes of stress relaxation in spatial and mechanically heterogeneous myocardial tissue. In numerical experiments with this model it is established that in order to obtain the same level of tension as in the case with a uniform model the less stiff and less viscous heterogeneous blocks are required. It is shown that in the model of heterogeneous myocardial tissue not only stress relaxation but also strain relaxation -- creep is observed. Notably step-by-step adjustment of the neighbor structural blocks in response to the whole model deformation takes place. Furthermore stationary deformation properties of separated blocks become nonlinear.

Synchronization of Early Afterdepolarizations and Arrhythmogenesis in Heterogeneous Cardiac Tissue Models

Early afterdepolarizations (EADs) are linked to both triggered arrhythmias and reentrant arrhythmias by causing premature ventricular complexes (PVCs), focal excitations, or heterogeneous tissue substrates for reentry formation. However, a critical number of cells that synchronously exhibit EADs are needed to result in arrhythmia triggers and substrates in tissue. In this study, we use mathematical modeling and computer simulations to investigate EAD synchronization and arrhythmia induction in tissue models with random cell-to-cell variations. Our major observations are as follows. Random cell-to-cell variations in action potential duration without EAD presence do not cause large dispersion of refractoriness in well-coupled tissue. In the presence of phase-2 EADs, the cells may synchronously exhibit the same number of EADs or no EADs with a very small dispersion of refractoriness, or synchronize regionally to result in large dispersion of refractoriness. In the presence of phase-3 EADs, regional synchronization leads to propagating EADs, forming PVCs in tissue. Interestingly, even though the uncoupled cells exhibit either no EAD or only a single EAD, when these cells are coupled to form a tissue, more than one PVC can occur. When the PVCs occur at different locations and time, multifocal arrhythmias are triggered, with the foci shifting in space and time in an irregular manner. The focal arrhythmias either spontaneously terminate or degenerate into reentrant arrhythmias due to heterogeneities and spatiotemporal chaotic dynamics of the foci.

Is optical imaging spectroscopy a viable measurement technique for the investigation of the negative BOLD phenomenon? A concurrent optical imaging spectroscopy and fMRI study at high field (7T)

Traditionally functional magnetic resonance imaging (fMRI) has been used to map activity in the human brain by measuring increases in the Blood Oxygenation Level Dependent (BOLD) signal. Often accompanying positive BOLD fMRI signal changes are sustained negative signal changes. Previous studies investigating the neurovascular coupling mechanisms of the negative BOLD phenomenon have used concurrent 2D-optical imaging spectroscopy (2D-OIS) and electrophysiology (Boorman et al., 2010). These experiments suggested that the negative BOLD signal in response to whisker stimulation was a result of an increase in deoxy-haemoglobin and reduced multi-unit activity in the deep cortical layers. However, Boorman et al. (2010) did not measure the BOLD and haemodynamic response concurrently and so could not quantitatively compare either the spatial maps or the 2D-OIS and fMRI time series directly. Furthermore their study utilised a homogeneous tissue model in which is predominantly sensitive to haemodynamic changes in more superficial layers.Here we test whether the 2D-OIS technique is appropriate for studies of negative BOLD. We used concurrent fMRI with 2D-OIS techniques for the investigation of the haemodynamics underlying the negative BOLD at 7 Tesla. We investigated whether optical methods could be used to accurately map and measure the negative BOLD phenomenon by using 2D-OIS haemodynamic data to derive predictions from a biophysical model of BOLD signal changes. We showed that despite the deep cortical origin of the negative BOLD response, if an appropriate heterogeneous tissue model is used in the spectroscopic analysis then 2D-OIS can be used to investigate the negative BOLD phenomenon.

Proarrhythmia in KCNJ2-linked short QT syndrome: insights from modelling

One form of the short QT syndrome (SQT3) has been linked to the D172N gain-in-function mutation to Kir2.1, which preferentially increases outward current through channels responsible for inward rectifier K(+) current (I(K1)). This study investigated mechanisms by which the Kir2.1 D172N mutation facilitates and perpetuates ventricular arrhythmias. The ten Tusscher et al. model for human ventricular action potentials (APs) was modified to incorporate changes to I(K1) based on experimentally observed changes to Kir2.1 function: both heterozygous (WT-D172N) and homozygous (D172N) mutant scenarios were studied. Cell models were incorporated into heterogeneous one-dimensional (1D), 2D tissue, and 3D models to compute the restitution curves of AP duration (APD-R), effective refractory period (ERP-R), and conduction velocity (CV). Temporal and spatial vulnerability of ventricular tissue to re-entry was measured and dynamic behaviour of re-entrant excitation waves (lifespan and dominant frequency) in 2D and 3D models of the human ventricle was characterized. D172N 'mutant' I(K1) led to abbreviated APD and ERP, as well as steeper APD-R and ERP-R curves. It reduced tissue excitability at low excitation rates but increased it at high rates. It increased tissue temporal vulnerability for initiating re-entry, but reduced the minimal substrate size necessary to sustain re-entry. SQT3 'mutant' I(K1) also stabilized and accelerated re-entrant excitation waves, leading to sustained rapid re-entry. Increased I(K1) due to the Kir2.1 D172N mutation increases arrhythmia risk due to increased tissue vulnerability, shortened ERP, and altered excitability, which in combination facilitate initiation and maintenance of re-entrant circuits.

Surgical Retraction of Non-Uniform Deformable Layers of Tissue: 2D Robot Grasping and Path Planning.

Robotic surgical assistants (RSAs) have the potential to facilitate surgeries and reduce human fatigue. In this paper we focus on surgical retraction, the common surgical primitive of grasping and lifting a thin layer of tissue to expose an underlying area. Given a 2D cross-sectional model of heterogeneous tissue with embedded structures (such as veins) and a desired underlying exposure region, we present an algorithm that computes a set of stable and secure grasp-and-retract trajectories, and runs a 3D finite element (FEM) simulation to certify the quality of each trajectory. To choose secure candidate grasp locations, we introduce the continuous spring method and combine it with the Deformation Space (D-Space) approach to grasping deformable objects with a linearized potential energy model based on the locations of embedded bodies. Experiments show that this method produces many of the same grasps as an exhaustive computation with an FEM mesh, but is orders of magnitude cheaper: our method runs in O(υ log υ) time, when υ is the number of veins, while the FEM computation takes O(pn 3) time, where n is the number of nodes in the FEM mesh and p is the number of nodes on its perimeter. Furthermore, we present a constant tissue curvature (CTC) retraction trajectory that distributes strain uniformly around the medial axis of the tissue, by moving the gripper such that the tissue follows a constant-curvature, constant-length arc. 3D FEM simulations show that the CTC achieves retractions with lower tissue strain than circular and linear trajectories. Overall, our algorithm computes and certifies a high-quality retraction in about one minute on a PC.

Effects of fibroblast-myocyte coupling on cardiac conduction and vulnerability to reentry: A computational study

Recent experimental studies have documented that functional gap junctions form between fibroblasts and myocytes, raising the possibility that fibroblasts play roles in cardiac electrophysiology that extend beyond acting as passive electrical insulators. The purpose of this study was to use computational models to investigate how fibroblasts may affect cardiac conduction and vulnerability to reentry under different fibroblast-myocyte coupling conditions and tissue structures. Computational models of two-dimensional tissue with fibroblast-myocyte coupling were developed and numerically simulated. Myocytes were modeled by the phase I of the Luo-Rudy model, and fibroblasts were modeled by a passive model. Besides slowing conduction by cardiomyocyte decoupling and electrotonic loading, fibroblast coupling to myocytes elevates myocyte resting membrane potential, causing conduction velocity to first increase and then decrease as fibroblast content increases, until conduction failure occurs. Fibroblast-myocyte coupling can also enhance conduction by connecting uncoupled myocytes. These competing effects of fibroblasts on conduction give rise to different conduction patterns under different fibroblast-myocyte coupling conditions and tissue structures. Elevation of myocyte resting potential due to fibroblast-myocyte coupling slows sodium channel recovery, which extends postrepolarization refractoriness. Owing to this prolongation of the myocyte refractory period, reentry was more readily induced by a premature stimulation in heterogeneous tissue models when fibroblasts were electrotonically coupled to myocytes compared with uncoupled fibroblasts acting as pure passive electrical insulators. Fibroblasts affect cardiac conduction by acting as obstacles or by creating electrotonic loading and elevating myocyte resting potential. Functional fibroblast-myocyte coupling prolongs the myocyte refractory period, which may facilitate induction of reentry in cardiac tissue with fibrosis.

Refinement of optical imaging spectroscopy algorithms using concurrent BOLD and CBV fMRI

We describe the use of the three dimensional characteristics of the functional magnetic resonance imaging (fMRI) blood oxygenation level dependent (BOLD) and cerebral blood volume (CBV) MRI signal changes to refine a two dimensional optical imaging spectroscopy (OIS) algorithm. The cortical depth profiles of the BOLD and CBV changes following neural activation were used to parameterise a 5-layer heterogeneous tissue model used in the Monte Carlo simulations (MCS) of light transport through tissue in the OIS analysis algorithm. To transform the fMRI BOLD and CBV measurements into deoxy-haemoglobin (Hbr) profiles we inverted an MCS of extra-vascular MR signal attenuation under the assumption that the extra-/intravascular ratio is 2:1 at a magnetic field strength of 3 T. The significant improvement in the quantitative accuracy of haemodynamic measurements using the new heterogeneous tissue model over the original homogeneous tissue model OIS algorithm was demonstrated on new concurrent OIS and fMRI data covering a range of stimulus durations.

In Vivo Measurement and Modeling of Multispectral Reflectance Images for Melanoma Diagnosis

Noninvasive detection of malignant melanoma in early stages is critical to improve patients’ prognosis. We acquired in vivo reflectance images of dysplastic lesions from 12 patients at 31 wavelengths from 500 to 950 nm. Based on these image data, we developed a parallel Monte Carlo code to simulate reflectance images from a heterogeneous skin tissue model. With this tool, we have investigated the dependence of the lesion contrast in the reflectance image on the heterogeneous distribution of tissue optical parameters. The Monte Carlo model is currently used to generate multispectral reflectance imaging data for multivariate analysis of the in vivo imaging data. DOI: 10.2529/PIERS061020122702 It has been estimated that Caucasians may develop up to 50 clinically benign nevi by age 40. Patients with more than 100 nevi were estimated to have a 3-fold to 10-fold increased risk of developing malignant melanomas and pigmented basal cell carcinomas in comparison to the general population [1]. Diagnosis of MM is currently established by histopathology of biopsied tissues from the suspicious-appearing nevi or pigmented lesions. These patients often present a difficult dilemma to primary-care physicians and dermatologists. A physician has to either prescribe painful and costly excision biopsy with likely cosmetic disfigurement with limited information on the lesion or leave untouched with the risk of MM developing in the patients. Therefore, cost-effective pre-biopsy methods of examination could greatly improve patient care and reduce medical cost with better specificity and sensitivity than what are available now. In this report, we present multispectral reflectance image data acquired from 12 patients with dysplastic lesions at 31 wavelengths from 500 to 950 nm and results of numerical studies of reflectance imaging method by a Monte Carlo (MC) code. A multispectral imaging system employing a thermoelectrically cooled CCD camera has been constructed to acquire polarimetric images [2]. Fig. 1 presents a schematic of the imaging system. We used a xenon fiber optic light source and a collimating lens to produce a parallel light beam of

Calculation of energy absorption in a human body model in a homogeneous pulsed high-frequency field

The purpose of this work was to estimate whether a considerable thermal absorption appears in the human body during standardized 1.5 T magnetic resonance imaging (MRI) system procedures applied in medical diagnostics. Therefore, based on magnetic resonance (MR) scans of a male volunteer, a human body heterogeneous tissue model has been simulated by a finite element method using isoparametric formulation, verified before with measurements. Numerical calculation has been performed for two radiofrequency (RF) exposure systems: saddle-shaped coils and bird-cage coil. Energy deposition in terms of specific absorption, specific absorption rate (SAR) and temperature elevation in the model has been calculated for the `worst-case' imaging sequence, i.e., multislice turbo spin echo sequence. Comparison to existing recommendations shows that there is no thermal hazard at 64 MHz, corresponding to 1.5 T MRI systems. However, new simulations should be performed for MR systems operating at higher frequencies.

Comparison of homogeneous and heterogeneous tissue models for coil optimization in neural stimulation

In stimulation of peripheral nerves by strong pulsed magnetic fields, it is desirable to produce a well‐focused activating function. Previous analyses and an experiment have indicated that quadruple coils provide many advantages. An analytical solution has been obtained for a homogeneous cylindrical volume conductor, and a finite difference numerical solution for a realistic heterogeneous model of a human forearm. In both models it has been assumed that nerves are straight and long, and therefore the activating function is an induced field derivative in the neuron direction. The magnitudes of the activating function for various coil geometries are compared for the two models.

Oxygen supply by perfusion and diffusion in heterogeneous tissue models.

Ample evidence for tissue perfusion inhomogeneity has been provided in resting and stimulated skeletal muscle preparations by microsphere embolization (Cerretelli et al., 1984; Iversen and Nicolaysen, 1989, 1990; Iversen et al., 1989; Marconi et al., 1988; Pendergast et al., 1985; Piiper et al., 1985), by inert gas washout (Grønlund et al., 1989; Piiper and Meyer, 1984), by local radioactive xenon clearance (Cerretelli et al., 1984), by observation of the variance of transit times, of the local tissue Po 2 heterogeneity and by other methods (cf. Piiper, 1985; Piiper, 1990). There is also morphometrical evidence for the irregularity of the capillary array in the myocardium (Turek and Rakusan, 1981; Hoofd et al., 1985; Rakusan et al., 1984) and in skeletal muscle (Egginton et al., 1988).KeywordsHomogeneous ModelRequirement RatioBlood Flow DistributionMammalian Skeletal MusclePerfusion HeterogeneityThese keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Diffusion limitation of oxygen in heterogeneous lung and tissue models.

In the analysis of gas exchange in lungs models have been developed to distinguish diffusion limitation from other mechanisms producing gas exchange inefficiency such as ventilation/perfusion (VA/Q) inhomogeneity and shunt. It will be attempted to apply similar models to describe and explain gas exchange in tissues, in particular to establish the role played by diffusion limitation in O2 supply to exercising muscle.KeywordsDiffusion LimitationUnequal DistributionLung ModelMammalian Skeletal MuscleDiffusion ConductanceThese keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

A heterogeneous tissue model for measurement of regional blood perfusion in the myocardium using inert gas isotopes

Inert gas isotopes are finding increasing application in the measurement of blood perfusion in the capillary beds of muscle, especially the myocardium. When measuring blood perfusion of the myocardium, washout curves are first produced by precordial monitoring of isotope activity following intracoronary artery injection of an inert gas isotope dissolved in saline. The washout curve data are then applied to a mathematical model to yield blood perfusion rate. Present models for this purpose either ignore any diffusive effects of gas movement (Kety-Schmidt model), or diffusive effects are accounted for by weighting the calculated perfusion value (Zierler's height-over-area technique). A new model is described here for convective and diffusive movement of an inert, nonpolar gas in myocardial tissue. A digital computer simulation of the model equations is used both to simply the model and to show agreement between the model response and experimental 133Xe washout curves from normal and infracted canine hearts. The model assumes that the tail of the washout curves (portion after roughly 1.5 minutes) is caused by a heterogeneous, diffusion-limited tissue structure. The model provides two parameters which can be adjusted to washout curve data using model-matching techniques. These are perfusion rate, and a parameter which is an index of the diffusive nature of the particular myocardial area under study.

Heterogeneous models of oxygen transport in tissue slices.

Recent development of the oxygen microelectrode (Whalen,1967) has made possible more accurate measurements of tissue oxygen transport. Such measurements could greatly benefit and indeed demand the development of more sophisticated mathematical models. Since tissue is heterogeneous both in structure and in transport properties, heterogeneous tissue models appear to be in order.