Quantification of the regional bioarchitecture in the human aorta.

Regional variance in human aortic bioarchitecture responsible for the elasticity of the vessel is poorly understood. The current study quantifies the elements responsible for aortic compliance, namely, elastin, collagen and smooth muscle cells, using histological and stereological techniques on human tissue with a focus on regional heterogeneity. Using donated cadaveric tissue, a series of samples were excised between the proximal ascending aorta and the distal abdominal aorta, for five cadavers, each of which underwent various staining procedures to enhance specific constituents of the wall. Using polarised light microscopy techniques, the orientation of collagen fibres was studied for each location and each tunical layer of the aorta. Significant transmural and longitudinal heterogeneity in collagen fibre orientations were uncovered throughout the vessel. It is shown that a von Mises mixture model is required accurately to fit the complex collagen fibre distributions that exist along the aorta. Additionally, collagen and smooth muscle cell density was observed to increase with increasing distance from the heart, whereas elastin density decreased. Evidence clearly demonstrates that the aorta is a highly heterogeneous vessel which cannot be simplistically represented by a single compliance value. The quantification and fitting of the regional aortic bioarchitectural data, although not without its limitations, including mean cohort age of 77.6 years, facilitates the development of next-generation finite element models that can potentially simulate the influence of regional aortic composition and microstructure on vessel biomechanics.

A Dual-VENC Four-Dimensional Flow MRI Framework for Analysis of Subject-Specific Heterogeneous Nonlinear Vessel Deformation.

Advancement of subject-specific in silico medicine requires new imaging protocols tailored to specific anatomical features, paired with new constitutive model development based on structure/function relationships. In this study, we develop a new dual-velocity encoding coefficient (VENC) 4D flow MRI protocol that provides unprecedented spatial and temporal resolution of in vivo aortic deformation. All previous dual-VENC 4D flow MRI studies in the literature focus on an isolated segment of the aorta, which fail to capture the full spectrum of aortic heterogeneity that exists along the vessel length. The imaging protocol developed provides high sensitivity to all blood flow velocities throughout the entire cardiac cycle, overcoming the challenge of accurately measuring the highly unsteady nonuniform flow field in the aorta. Cross-sectional area change, volumetric flow rate, and compliance are observed to decrease with distance from the heart, while pulse wave velocity (PWV) is observed to increase. A nonlinear aortic lumen pressure-area relationship is observed throughout the aorta such that a high vessel compliance occurs during diastole, and a low vessel compliance occurs during systole. This suggests that a single value of compliance may not accurately represent vessel behavior during a cardiac cycle in vivo. This high-resolution MRI data provide key information on the spatial variation in nonlinear aortic compliance, which can significantly advance the state-of-the-art of in-silico diagnostic techniques for the human aorta.

Improving the finite element model accuracy of tissue engineering scaffolds produced by selective laser sintering.

In bone tissue engineering, both geometrical and mechanical properties of a scaffold play a major part in the success of the treatment. The mechanical stresses and strains that act on cells on a scaffold in a physiological environment are a determining factor on the subsequent tissue formation. Computational models are often used to simulate the effect of changes of internal architectures and external loads applied to the scaffold in order to optimise the scaffold geometry for the prospective implantation site. Finite element analysis (FEA) based on computer models of the scaffold is a common technique, but would not take into account actual inaccuracies due to the manufacturing process. Image based FEA using CT scans of fabricated scaffolds can provide a more accurate analysis of the scaffold, and was used in this work in order to accurately simulate and predict the mechanical performance of bone tissue engineering scaffolds, fabricated using selective laser sintering (SLS), with a view to generating a methodology that could be used to optimise scaffold design. The present work revealed that an approach that assumes isotropic properties of SLS fabricated scaffolds will lead to inaccurate predictions of the FE model. However, a dependency of the grey value of the CT scans and the mechanical properties was discovered, which may ultimately lead to accurate FE models without the need of experimental validation.

Osteogenic differentiation of mesenchymal stem cells is regulated by osteocyte and osteoblast cells in a simplified bone niche.

Mesenchymal stem cells (MSCs) within their native environment of the stem cell niche in bone receive biochemical stimuli from surrounding cells. These stimuli likely influence how MSCs differentiate to become bone precursors. The ability of MSCs to undergo osteogenic differentiation is well established in vitro;however, the role of the natural cues from bone's regulatory cells, osteocytes and osteoblasts in regulating the osteogenic differentiation of MSCs in vivo are unclear. In this study we delineate the role of biochemical signalling from osteocytes and osteoblasts, using conditioned media and co-culture experiments, to understand how they direct osteogenic differentiation of MSCs. Furthermore, the synergistic relationship between osteocytes and osteoblasts is examined by transwell co-culturing of MSCs with both simultaneously. Osteogenic differentiation of MSCs was quantified by monitoring alkaline phosphatase (ALP) activity, calcium deposition and cell number. Intracellular ALP was found to peak earlier and there was greater calcium deposition when MSCs were co-cultured with osteocytes rather than osteoblasts, suggesting that osteocytes are more influential than osteoblasts in stimulating osteogenesis in MSCs. Osteoblasts initially stimulated an increase in the number of MSCs, but ultimately regulated MSC differentiation down the same pathway. Our novel co-culture system confirmed a synergistic relationship between osteocytes and osteoblasts in producing biochemical signals to stimulate the osteogenic differentiation of MSCs. This study provides important insights into the mechanisms at work within the native stem cell niche to stimulate osteogenic differentiation and outlines a possible role for the use of co-culture or conditioned media methodologies for tissue engineering applications.

Finite element predictions compared to experimental results for the effective modulus of bone tissue engineering scaffolds fabricated by selective laser sintering.

A current challenge in bone tissue engineering is to create scaffolds with suitable mechanical properties, high porosity, full interconnectivity and suitable pore size. In this paper, polyamide and polycaprolactone scaffolds were fabricated using a solid free form technique known as selective laser sintering. These scaffolds had fully interconnected pores, minimized strut thickness, and a porosity of approximately 55%. Tensile and compression tests as well as finite element analysis were carried out on these scaffolds. It was found that the values predicted for the effective modulus by the FE model were much higher than the actual values obtained from experimental results. One possible explanation for this discrepancy, viz. the surface roughness of the scaffold and the presence of micropores in the scaffold struts, was investigated with a view to making recommendations on improving FE model configurations for accurate effective property predictions.

Effects of intervertebral disk degeneration on the flexibility of the human thoracolumbar spine.

The objective of this study was to investigate the effects of intervertebral disk degeneration on the flexibility of the thoracolumbar spine in flexion and extension, both experimentally and computationally. A seven-level biomechanically tested human cadaveric spine (T11-L5) and a 3D finite element model of the same thoracolumbar spine were used for this purpose. The anatomically accurate computer model was generated from detailed computed tomography images and included the vertebral shell, the trabecular centrum, cartilage endplates, intervertebral disks, seven spinal ligament groups, and the facet joints. The cadaveric spinal segment and the specimen-specific finite element model were subjected to various compressive loads ranging from 75 to 975 N using the follower load principle and an oscillating bending moment of +/-5 Nm applied in the sagittal plane. The biomechanical behavior of the finite element model of the spine was validated with the experimental mechanical test data for the corresponding physical thoracolumbar spine specimen. In addition, the effect of intervertebral disk material property variation within the thoracolumbar spinal column on the spinal flexibility was extensively studied. The results of this study provided significant insight into how mechanical properties of the intervertebral disk influence spinal flexibility along the thoracolumbar spinal column. It was found that in order to get comparable results between experimental and computed data, the material properties of the intervertebral disks had to vary along the spinal column. However, these effects are diminished with increasing axial compressive load. Because of the trend between disk properties and spinal level, we further concluded that there might be a mechanism at play that links endplate size, body weight fraction, and segmental flexibility. More studies are needed to further investigate that relationship.

Mathematical models of cell motility.

Cell motility is an essential biological action in the creation, operation and maintenance of our bodies. Developing mathematical models elucidating cell motility will greatly advance our understanding of this fundamental biological process. With accurate models it is possible to explore many permutations of the same event and concisely investigate their outcome. While great advancements have been made in experimental studies of cell motility, it now has somewhat fallen on mathematical models to taking a leading role in future developments. The obvious reason for this is the complexity of cell motility. Employing the processing power of today's computers will give researches the ability to run complex biophysical and biochemical scenarios, without the inherent difficulty and time associated with in vitro investigations. Before any great advancement can be made, the basics of cell motility will have to be well-defined. Without this, complicated mathematical models will be hindered by their inherent conjecture. This review will look at current mathematical investigations of cell motility, explore the reasoning behind such work and conclude with how best to advance this interesting and challenging research area.

Measurement of the microstructural fracture toughness of cortical bone using indentation fracture.

The purpose of this work is to investigate the use of indentation fracture as a method of measuring toughness at the microscale in cortical bone. Indentation fracture employs sharp indenters to initiate cracks, whose length can be used to calculate the toughness of the material. Only a cube corner indenter tip is found to initiate cracks at a suitable size scale for microstructural measurement. Cracks from 7 to 56 microm in length are produced using loads from 0.05 to 3N. Preliminary data predicts rising toughness with increasing crack length (rising R-curve behaviour) at the microscale. This technique provides a new insight into fracture in cortical bone since it allows the investigator to observe mechanisms and measure toughness at a size scale at which in vivo damage is known to exist.

Endothelial cell response to biomechanical forces under simulated vascular loading conditions.

In vivo, endothelial cells (EC) are constantly exposed to the haemodynamic forces (HF) of pressure, wall shear stress and hoop stress. The main aim of this study was to design, create and validate a novel perfusion bioreactor capable of delivering shear stress and intravascular pressure to EC in vitro and to characterise their morphology, orientation and gene expression. Here we report the creation and validation of such a simulator and the dual application of pressure (120/60 mmHg) and low shear stress (5 dyn/cm(2)) to a monolayer of EC established on a non-compliant silicone tube. Under these conditions, EC elongated and realigned obliquely to the direction of applied shear stress in a time-dependent manner. Furthermore, randomly distributed F-actin microfilaments reorganised into long, dense stress fibres crossing the cells in a direction perpendicular to that of flow. Finally, combinatorial biomechanical conditioning of EC induced the expression of the inflammatory-associated E-selectin gene.

Finite element comparison of performance related characteristics of balloon expandable stents.

Cardiovascular stents are commonly made from 316L stainless steel and are deployed within stenosed arterial lesions using balloon expansion. Deployment involves inflating the balloon and plastically deforming the stent until the required diameter is obtained. This plastic deformation induces static stresses in the stent, which will remain for the lifetime of the device. In order to determine these stresses, finite element models of the unit cells of geometrically different, commercially available balloon expandable stents have been created, and deployment and elastic recoil have been simulated. In this work the residual stresses associated with deployment and recoil are compared for the various stent geometries, with a view to establishing appropriate initial stress states for fatigue loading for the stents. The maximum, minimum, and mean stresses induced in the stent due to systolic/diastolic pressure are evaluated, as are performance measures such as radial and longitudinal recoil.

Micromechanical modelling of cortical bone.

Cortical bone is a heterogeneous material with a complex hierarchical microstructure. In this work, unit cell finite element models were developed to investigate the effect of microstructural morphology on the macroscopic properties of cortical bone. The effect of lacunar and vascular porosities, percentage of osteonal bone and orientation of the Haversian system on the macroscopic elastic moduli and Poisson's ratios was investigated. The results presented provide relationships for applying more locally accurate material properties to larger scale and whole bone models of varying porosity. Analysis of the effect of the orientation of the Haversian system showed that its effects should not be neglected in larger scale models. This study also provides insight into how microstructural features effect local distributions and cause a strain magnification effect. Limitations in applying the unit cell methodology approach to bone are also discussed.

Numerical Simulation of Stent Angioplasty with Predilation: An Investigation into Lesion Constitutive Representation and Calcification Influence.

It is acceptable clinical practice to predilate a severely occluded vessel to allow better positioning of endovascular stents, and while the impact of this intervention has been examined for aggregate response in animals there has been no means to examine whether there are specific vessels that might benefit. Finite element methods offer the singular ability to explore the mechanical response of arteries with specific pathologic alterations in mechanics to stenting and predilation. We examined varying representations of atherosclerotic tissue including homogeneous and heterogeneous dispersion of calcified particles, and elastic, pseudo-elastic, and elastic-plastic constitutive representations of bulk atherosclerotic tissue. The constitutive representations of the bulk atherosclerotic tissue were derived from experimental test data and highlight the importance of accounting for testing mode of loading. The impact of arterial predilation is presented and, in particular, its effect on intimal predicted damage, atherosclerotic tissue von Mises and maximum principal stresses, and luminal deformation was dependent on the type of constitutive representation of diseased tissue, particularly in the presence of calcifications.

Review of Mechanical Testing and Modelling of Thrombus Material for Vascular Implant and Device Design.

A thrombus or blood clot is a solid mass, made up of a network of fibrin, platelets and other blood components. Blood clots can form through various pathways, for example as a result of exposed tissue factor from vascular injury, as a result of low flow/stasis, or in very high shear flow conditions. Embolization of cardiac or vascular originating blood clots, causing an occlusion of the neurovasculature, is the major cause of stroke and accounts for 85% of all stroke. With mechanical thrombectomy emerging as the new standard of care in the treatment of acute ischemic stroke (AIS), the need to generate a better understanding of the biomechanical properties and material behaviour of thrombus material has never been greater, as it could have many potential benefits for the analysis and performance of these treatment devices. Defining the material properties of a thrombus has obvious implications for the development of these treatment devices. However, to-date this definition has not been adequately established. While some experimentation has been performed, model development has been extremely limited. This paper reviews the previous literature on mechanical testing of thrombus material. It also explores the use of various constitutive and computational models to model thrombus formation and material behaviour.

An Experimental and Computational Investigation of Bone Formation in Mechanically Loaded Trabecular Bone Explants.

Understanding how bone marrow multipotent stromal cells (MSCs) contribute to new bone formation and remodeling in vivo is of principal importance for informing the development of effective bone tissue engineering strategies in vitro. However, the precise in situ stimuli that MSCs experience have not been fully established. The shear stress generated within the bone marrow of physiologically loaded samples has never been determined, but could be playing an important role in the generation of sufficient stimulus for MSCs to undergo osteogenic differentiation. In this study fluid structure interaction (FSI) computational models were used in conjunction with a bioreactor which physiologically compresses explanted trabecular bone samples to determine whether MSCs can be directly stimulated by mechanical cues within the bone marrow. Experimentally loaded samples were found to have greater osteogenic activity, as verified by bone histomorphometry, compared to control static samples. FSI models demonstrated a linear relationship between increasing shear stress and decreasing bone volume. The FSI models demonstrated that bone strain, not marrow shear stress, was likely the overall driving mechanical signal for new bone formation during compression. However, the shear stress generated in the models is within the range of values which has been shown previously to generate an osteogenic response in MSCs.

Webbing and Delamination of Drug Eluting Stent Coatings.

The advancement of the drug-eluting stent technology raises the significant challenge of safe mechanical design of polymer coated stent systems. Experimental images of stent coatings undergoing significant damage during deployment have been reported; such coating damage and delamination can lead to complications such as restenosis and increased thrombogenicity. In the current study a cohesive zone modeling framework is developed to predict coating delamination and buckling due to hinge deformation during stent deployment. Models are then extended to analyze, for the first time, stent-coating damage due to webbing defects. Webbing defects occur when a bond forms between coating layers on adjacent struts, resulting in extensive delamination of the coating from the strut surfaces. The analyzes presented in this paper uncover the mechanical factors that govern webbing induced coating damage. Finally, an experimental fracture test of a commercially available stent coating material is performed and results demonstrate that the high cohesive strength of the coating material will prevent web fracture, resulting in significant coating delamination during stent deployment.

Evaluation of cover effects on bare stent mechanical response.

Covered tracheobronchial stents are used to prevent tumour growth from reoccluding the airways. In the present work a combination of experimental and computational methods are used to present the mechanical effects that adhered covers can have on stent performance. A prototype tracheobronchial stent is characterised in bare and covered configurations using radial force, flat plate and a novel non-uniform radial force test, while computational modelling is performed in parallel to extensively inform the physical testing. Results of the study show that cover configuration can have a significant structural effect on stent performance, and that stent response (bare or covered) is especially loading specific, highlighting that the loading configuration that a stent is about to be subjected to should be considered before stent implantation.

Thermo-electrical equivalents for simulating the electro-mechanical behavior of biological tissue.

Equivalence is one of most popular techniques to simulate the behavior of systems governed by the same type of differential equation. In this case, a thermo-electrical equivalence is considered as a method for modelling the inter-dependence of electrical and mechanical phenomena in biological tissue. We seek to assess this approach for multi-scale models (from micro-structure to tissue scale) of biological media, such as nerve cells and cardiac tissue, in which the electrical charge distribution is modelled as a heat distribution in an equivalent thermal system. This procedure allows for the reduction in problem complexity and it facilitates the coupling of electrical and mechanical phenomena in an efficient and practical way. Although the findings of this analysis are mainly addressed towards the electro-mechanics of tissue within the biomedical domain, the same approach could be used in other studies in which a coupled finite element analysis is required.

Micro-scale testing and micromechanical modelling for high cycle fatigue of CoCr stent material.

This paper presents a framework of experimental testing and crystal plasticity micromechanics for high cycle fatigue (HCF) of micro-scale L605 CoCr stent material. Micro-scale specimens, representative of stent struts, are manufactured via laser micro-machining and electro-polishing from biomedical grade CoCr alloy foil. Crystal plasticity models of the micro-specimens are developed using a length scale-dependent, strain-gradient constitutive model and a phenomenological (power-law) constitutive model, calibrated from monotonic and cyclic plasticity test data. Experimental microstructural characterisation of the grain morphology and precipitate distributions is used as input for the polycrystalline finite element (FE) morphologies. Two microstructure-sensitive fatigue indicator parameters are applied, using local and non-local (grain-averaged) implementations, for the phenomenological and length scale-dependent models, respectively, to predict fatigue crack initiation (FCI) in the HCF experiments.

Computational Bench Testing to Evaluate the Short-Term Mechanical Performance of a Polymeric Stent.

Over the last decade, there has been a significant volume of research focussed on the utilization of biodegradable polymers such as poly-L-lactide-acid (PLLA) for applications associated with cardiovascular disease. More specifically, there has been an emphasis on upgrading current clinical shortfalls experienced with conventional bare metal stents and drug eluting stents. One such approach, the adaption of fully formed polymeric stents has led to a small number of products being commercialized. Unfortunately, these products are still in their market infancy, meaning there is a clear non-occurrence of long term data which can support their mechanical performance in vivo. Moreover, the load carry capacity and other mechanical properties essential to a fully optimized polymeric stent are difficult, timely and costly to establish. With the aim of compiling rapid and representative performance data for specific stent geometries, materials and designs, in addition to reducing experimental timeframes, Computational bench testing via finite element analysis (FEA) offers itself as a very powerful tool. On this basis, the research presented in this paper is concentrated on the finite element simulation of the mechanical performance of PLLA, which is a fully biodegradable polymer, in the stent application, using a non-linear viscous material model. Three physical stent geometries, typically used for fully polymeric stents, are selected, and a comparative study is performed in relation to their short-term mechanical performance, with the aid of experimental data. From the simulated output results, an informed understanding can be established in relation to radial strength, flexibility and longitudinal resistance, that can be compared with conventional permanent metal stent functionality, and the results show that it is indeed possible to generate a PLLA stent with comparable and sufficient mechanical performance. The paper also demonstrates the attractiveness of FEA as a tool for establishing fundamental mechanical characteristics of polymeric stent performance.

Mechanical stimulation of bone marrow in situ induces bone formation in trabecular explants.

Low magnitude high frequency (LMHF) loading has been shown to have an anabolic effect on trabecular bone in vivo. However, the precise mechanical signal imposed on the bone marrow cells by LMHF loading, which induces a cellular response, remains unclear. This study investigates the influence of LMHF loading, applied using a custom designed bioreactor, on bone adaptation in an explanted trabecular bone model, which isolated the bone and marrow. Bone adaptation was investigated by performing micro CT scans pre and post experimental LMHF loading, using image registration techniques. Computational fluids dynamic models were generated using the pre-experiment scans to characterise the mechanical stimuli imposed by the loading regime prior to adaptation. Results here demonstrate a significant increase in bone formation in the LMHF loaded group compared to static controls and media flow groups. The calculated shear stress in the marrow was between 0.575 and 0.7 Pa, which is within the range of stimuli known to induce osteogenesis by bone marrow mesenchymal stem cells in vitro. Interestingly, a correlation was found between the bone formation balance (bone formation/resorption), trabecular number, trabecular spacing, mineral resorption rate, bone resorption rate and mean shear stresses. The results of this study suggest that the magnitude of the shear stresses generated due to LMHF loading in the explanted bone cores has a contributory role in the formation of trabecular bone and improvement in bone architecture parameters.