Evaluation of Coronary Stents in the Animal Model: A Review

Metallic vascular endoprotheses (stents) have been introduced clinically to help to retain or to restore a patent vascular lumen after balloon angioplasty and to improve long-term patency of vessels. Despite the widespread use of intracoronary stents, instent restenosis remains a major clinical problem. During the last years considerable research effort had been spent on the understanding of the pathophysiology of restenosis and developing strategies to prevent this major shortcoming of PTCA and stent implantation. The current review focuses in its first part on basic pathophysiological mechanisms, which are involved in the formation of restenosis after ballon angioplasty and stent implantation. In the second part different animal models are presented, which serve as experimental models for examining these processes and testing strategies for the prevention of restenosis. Advantages and disadvantages of each model will be discussed, which are important when transferring results from animal models to clinical practice.     

冠脉血管支架介入耦合系统力学行为数值模拟研究

针对冠脉支架植入术后引起的血管内再狭窄问题,开展了冠脉支架介入耦合系统力学行为的数值模拟研究。基于Ogden非线性弹性理论,构建了冠脉血管和动脉粥样硬化斑块的超弹性本构模型。通过非线性有限元法,建立了冠脉支架与狭窄血管的耦合作用模型,研究了冠脉支架在经历压握收缩、压握卸载、球囊扩张与球囊收缩等介入过程后的体内扩张性能,分析了冠脉支架的介入对狭窄血管损伤及再狭窄的力学影响因素。对比分析了S型支架和N型支架介入后狭窄冠脉血管的生物力学响应,数值计算结果表明:狭窄冠脉血管在支架支撑体波峰处存在较高的应力梯度,而且由于2种支架联接筋结构的类似性,血管内膜与斑块的应力分布规律一致。但是,N型支架的径向回弹率与轴向短缩率均小于S型支架,导致了更高的狭窄血管壁面峰值应力和应力梯度,更易于引起冠脉血管损伤造成血管内再狭窄。综上,该文提出的冠脉支架介入耦合系统力学模型,对于优化支架结构、抑制冠脉血管再狭窄问题,提供了重要的理论依据和临床参考。     

球囊扩张式血管支架介入对弯曲血管的生物力学损伤研究

构建了球囊扩张式血管支架介入系统的非线性有限元模型,考虑了血管斑块类型对其本构模型的影响,分析了A型与B型血管支架在血管狭窄率-24%、40%、50%,曲率半径-6 mm、10 mm、20 mm,狭窄血管的壁面应力分布规律,研究了血管支架构型、狭窄血管几何参数和血管生物力学损伤的关系。数值分析结果表明,血管壁面应力随着狭窄率的增加而显著升高,随着血管曲率半径的增加而下降相对平缓;但是,扩张加载阶段的血管壁面应力显著高于卸载阶段,易于引起血管斑块的脆性断裂引起血管生物力学损伤。由于A型血管支架相对于B型血管支架具有纵向柔顺性更优的联接筋构型,导致A型血管支架引起的血管壁面应力低于B型支架,因而降低了A型血管支架对于血管的生物力学损伤。     

Nearby boundaries create eddies near microscopic filter feeders

We show through calculations, simulations and experiments that the eddies often observed near sessile filter feeders are frequently due to the presence of nearby boundaries. We model the common filter feeder Vorticella, which is approximately 50 µm across and which feeds by removing bacteria from ocean or pond water that it draws towards itself. We use both an analytical stokeslet model and a Brinkman flow approximation that exploits the narrow-gap geometry to predict the size of the eddy caused by two parallel no-slip boundaries that represent the slides between which experimental observations are often made. We also use three-dimensional finite-element simulations to fully solve for the flow around a model Vorticella and analyse the influence of multiple nearby boundaries. Additionally, we track particles around live feeding Vorticella in order to determine the experimental flow field. Our models are in good agreement both with each other and with experiments. We also provide approximate equations to predict the experimental eddy sizes owing to boundaries both for the case of a filter feeder between two slides and for the case of a filter feeder attached to a perpendicular surface between two slides.     

Transient dynamic phenotypes as criteria for model discrimination: fold-change detection in Rhodobacter sphaeroides chemotaxis

The chemotaxis pathway of the bacterium Rhodobacter sphaeroides shares many similarities with that of Escherichia coli. It exhibits robust adaptation and has several homologues of the latter''s chemotaxis proteins. Recent theoretical results have correctly predicted that the E. coli output behaviour is unchanged under scaling of its ligand input signal; this property is known as fold-change detection (FCD). In the light of recent experimental results suggesting that R. sphaeroides may also show FCD, we present theoretical assumptions on the R. sphaeroides chemosensory dynamics that can be shown to yield FCD behaviour. Furthermore, it is shown that these assumptions make FCD a property of this system that is robust to structural and parametric variations in the chemotaxis pathway, in agreement with experimental results. We construct and examine models of the full chemotaxis pathway that satisfy these assumptions and reproduce experimental time-series data from earlier studies. We then propose experiments in which models satisfying our theoretical assumptions predict robust FCD behaviour where earlier models do not. In this way, we illustrate how transient dynamic phenotypes such as FCD can be used for the purposes of discriminating between models that reproduce the same experimental time-series data.     

Nanoscale heterogeneity promotes energy dissipation in bone

Nanomechanical heterogeneity is expected to influence elasticity, damage, fracture and remodelling of bone. Here, the spatial distribution of nanomechanical properties of bone is quantified at the length scale of individual collagen fibrils. Our results show elaborate patterns of stiffness ranging from approximately 2 to 30 GPa, which do not correlate directly with topographical features and hence are attributed to underlying local structural and compositional variations. We propose a new energy-dissipation mechanism arising from nanomechanical heterogeneity, which offers a means for ductility enhancement, damage evolution and toughening. This hypothesis is supported by computational simulations that incorporate the nanoscale experimental results. These simulations predict that non-uniform inelastic deformation over larger areas and increased energy dissipation arising from nanoscale heterogeneity lead to markedly different biomechanical properties compared with a uniform material. The fundamental concepts discovered here are applicable to a broad class of biological materials and may serve as a design consideration for biologically inspired materials technologies.     

A new hyper-elastic model for predicting multi-axial behaviour of rubber-like materials: formulation and computational aspects

We propose a new hyper-elastic model that is based on the standard invariants of Green–Cauchy. Experimental data reported by Treloar (Trans. Faraday Soc. 40:59, 1944) are used to identify the model parameters. To this end, the data of uni-axial tension and equi-bi-axial tension are used simultaneously. The new model has four material parameters, their identification leads to linear optimisation problem and it is able to predict multi-axial behaviour of rubber-like materials. We show that the response quality of the new model is equivalent to that of the well-known Ogden six parameters model. Thereafter, the new model is implemented in FE code. Then, we investigate the inflation of a rubber balloon with the new model and Ogden models. We compare both the analytic and numerical solutions derived from these models.     

Dynamic compositional modeling of pedestrian crash counts on urban roads in Connecticut

Uncovering the temporal trend in crash counts provides a good understanding of the context for pedestrian safety. With a rareness of pedestrian crashes it is impossible to investigate monthly temporal effects with an individual segment/intersection level data, thus the time dependence should be derived from the aggregated level data. Most previous studies have used annual data to investigate the differences in pedestrian crashes between different regions or countries in a given year, and/or to look at time trends of fatal pedestrian injuries annually. Use of annual data unfortunately does not provide sufficient information on patterns in time trends or seasonal effects. This paper describes statistical methods uncovering patterns in monthly pedestrian crashes aggregated on urban roads in Connecticut from January 1995 to December 2009. We investigate the temporal behavior of injury severity levels, including fatal (K), severe injury (A), evident minor injury (B), and non-evident possible injury and property damage only (C and O), as proportions of all pedestrian crashes in each month, taking into consideration effects of time trend, seasonal variations and VMT (vehicle miles traveled). This type of dependent multivariate data is characterized by positive components which sum to one, and occurs in several applications in science and engineering. We describe a dynamic framework with vector autoregressions (VAR) for modeling and predicting compositional time series. Combining these predictions with predictions from a univariate statistical model for total crash counts will then enable us to predict pedestrian crash counts with the different injury severity levels. We compare these predictions with those obtained from fitting separate univariate models to time series of crash counts at each injury severity level. We also show that the dynamic models perform better than the corresponding static models. We implement the Integrated Nested Laplace Approximation (INLA) approach to enable fast Bayesian posterior computation.     

Photon-noise-limited operation of intensified CCD cameras

Intensified CCD cameras are increasingly being used in quantitative applications, which requires not only a greater understanding of their operation but also more detailed modeling to predict their performance more accurately. We have developed a model based on photon-noise-limited operation that incorporates the effects of the point spread function of the intensifier on signal-to-noise ratio. These effects are absent in other models, which renders them inadequate to model the camera performance properly. Calculations of noise-equivalent irradiance with our model are shown to be in good agreement with experimental results presented for two Xybion intensified cameras, Models GEN-III IMC and NIR DCIC intensified cameras.     

Excessive adventitial stress drives inflammation-mediated fibrosis in hypertensive aortic remodelling in mice

Hypertension induces significant aortic remodelling, often adaptive but sometimes not. To identify immuno-mechanical mechanisms responsible for differential remodelling, we studied thoracic aortas from 129S6/SvEvTac and C57BL/6 J mice before and after continuous 14-day angiotensin II infusion, which elevated blood pressure similarly in both strains. Histological and biomechanical assessments of excised vessels were similar at baseline, suggesting a common homeostatic set-point for mean wall stress. Histology further revealed near mechano-adaptive remodelling of the hypertensive 129S6/SvEvTac aortas, but a grossly maladaptive remodelling of C57BL/6 J aortas. Bulk RNA sequencing suggested that increased smooth muscle contractile processes promoted mechano-adaptation of 129S6/SvEvTac aortas while immune processes prevented adaptation of C57BL/6 J aortas. Functional studies confirmed an increased vasoconstrictive capacity of the former while immunohistochemistry demonstrated marked increases in inflammatory cells in the latter. We then used multiple computational biomechanical models to test the hypothesis that excessive adventitial wall stress correlates with inflammatory cell infiltration. These models consistently predicted that increased vasoconstriction against an increased pressure coupled with modest deposition of new matrix thickens the wall appropriately, restoring wall stress towards homeostatic consistent with adaptive remodelling. By contrast, insufficient vasoconstriction permits high wall stresses and exuberant inflammation-driven matrix deposition, especially in the adventitia, reflecting compromised homeostasis and gross maladaptation.     

Bone tissue remodelling analysis considering a radial point interpolator meshless method

In this work the natural neighbour radial point interpolation method (NNRPIM), an improved meshless method, is extended to the bone remodelling analysis. A biomechanical model for predicting the bone density distribution was developed. The proposed gradient remodelling algorithm considers an anisotropic material law for the mechanical behaviour of the bone tissue, based on experimental data available in the literature, allowing to gradually correlate the bone density with the obtained level of stress. The viability and efficiency of the model were successfully tested on the classical femur bone example and a novel calcaneus bone example under multiple loading conditions.     

Mathematical and computational models of drug transport in tumours

The ability to predict how far a drug will penetrate into the tumour microenvironment within its pharmacokinetic (PK) lifespan would provide valuable information about therapeutic response. As the PK profile is directly related to the route and schedule of drug administration, an in silico tool that can predict the drug administration schedule that results in optimal drug delivery to tumours would streamline clinical trial design. This paper investigates the application of mathematical and computational modelling techniques to help improve our understanding of the fundamental mechanisms underlying drug delivery, and compares the performance of a simple model with more complex approaches. Three models of drug transport are developed, all based on the same drug binding model and parametrized by bespoke in vitro experiments. Their predictions, compared for a ‘tumour cord’ geometry, are qualitatively and quantitatively similar. We assess the effect of varying the PK profile of the supplied drug, and the binding affinity of the drug to tumour cells, on the concentration of drug reaching cells and the accumulated exposure of cells to drug at arbitrary distances from a supplying blood vessel. This is a contribution towards developing a useful drug transport modelling tool for informing strategies for the treatment of tumour cells which are ‘pharmacokinetically resistant’ to chemotherapeutic strategies.     

A simulation-based heuristic solution procedure for analyzing human postural balance

Human postural movements can be simulated by a biomechanical model. Biomechanical models, however, involve differential equations and do not admit conventional optimization techniques for solution. Introducing the notion of dynamic grid-sizing, this paper presents an easy-to-implement simulation-based heuristic procedure for solving biomechanical models. We adopt the four-segment sagittal model for human postural analysis from [Iqbal K, Pai YC (2000) Predicted region of stability for balance recovery: motion at the knee joint can improve termination of forward movement. J Biomech 33:1,619–1,627] for illustration and solve it to predict a region of stability for the model. The size and the feasibility of the stability region predicted by the proposed scheme in comparison with results reported in (Iqbal K, Pai YC (2000) Predicted region of stability for balance recovery: motion at the knee joint can improve termination of forward movement. J Biomech 33:1,619–1,627) demonstrate that the proposed scheme is fairly efficient and effective and further suggest its practical usage in analyzing human postural balance.     

Time and dose-dependent risk of pneumococcal pneumonia following influenza: a model for within-host interaction between influenza and Streptococcus pneumoniae

A significant fraction of seasonal and in particular pandemic influenza deaths are attributed to secondary bacterial infections. In animal models, influenza virus predisposes hosts to severe infection with both Streptococcus pneumoniae and Staphylococcus aureus. Despite its importance, the mechanistic nature of the interaction between influenza and pneumococci, its dependence on the timing and sequence of infections as well as the clinical and epidemiological consequences remain unclear. We explore an immune-mediated model of the viral–bacterial interaction that quantifies the timing and the intensity of the interaction. Taking advantage of the wealth of knowledge gained from animal models, and the quantitative understanding of the kinetics of pathogen-specific immunological dynamics, we formulate a mathematical model for immune-mediated interaction between influenza virus and S. pneumoniae in the lungs. We use the model to examine the pathogenic effect of inoculum size and timing of pneumococcal invasion relative to influenza infection, as well as the efficacy of antivirals in preventing severe pneumococcal disease. We find that our model is able to capture the key features of the interaction observed in animal experiments. The model predicts that introduction of pneumococcal bacteria during a 4–6 day window following influenza infection results in invasive pneumonia at significantly lower inoculum size than in hosts not infected with influenza. Furthermore, we find that antiviral treatment administered later than 4 days after influenza infection was not able to prevent invasive pneumococcal disease. This work provides a quantitative framework to study interactions between influenza and pneumococci and has the potential to accurately quantify the interactions. Such quantitative understanding can form a basis for effective clinical care, public health policies and pandemic preparedness.     

Logic programming to predict cell fate patterns and retrodict genotypes in organogenesis

Caenorhabditis elegans vulval development is a paradigm system for understanding cell differentiation in the process of organogenesis. Through temporal and spatial controls, the fate pattern of six cells is determined by the competition of the LET-23 and the Notch signalling pathways. Modelling cell fate determination in vulval development using state-based models, coupled with formal analysis techniques, has been established as a powerful approach in predicting the outcome of combinations of mutations. However, computing the outcomes of complex and highly concurrent models can become prohibitive. Here, we show how logic programs derived from state machines describing the differentiation of C. elegans vulval precursor cells can increase the speed of prediction by four orders of magnitude relative to previous approaches. Moreover, this increase in speed allows us to infer, or ‘retrodict’, compatible genomes from cell fate patterns. We exploit this technique to predict highly variable cell fate patterns resulting from dig-1 reduced-function mutations and let-23 mosaics. In addition to the new insights offered, we propose our technique as a platform for aiding the design and analysis of experimental data.     

Corneal asphericity after refractive surgery when the Munnerlyn formula is applied

We deduce a mathematical equation for corneal asphericity after refractive surgery when the Munnerlyn formula is used. For this, an analytical least-squares procedure is used. The equation explains the discrepancies found by different authors when the Munnerlyn formula or its paraxial approximation is used. Equations for corneal asphericity deduced here may be of clinical relevance, for example, in studying quantitatively the role of different factors (decentration, type of laser, optical role of the flap, wound healing, biomechanical effects, technical procedures) during corneal ablation.     

Biomechanics of oral mucosa

The prevalence of prosthodontic treatment has been well recognized, and the need is continuously increasing with the ageing population. While the oral mucosa plays a critical role in the treatment outcome, the associated biomechanics is not yet fully understood. Using the literature available, this paper provides a critical review on four aspects of mucosal biomechanics, including static, dynamic, volumetric and interactive responses, which are interpreted by its elasticity, viscosity/permeability, apparent Poisson''s ratio and friction coefficient, respectively. Both empirical studies and numerical models are analysed and compared to gain anatomical and physiological insights. Furthermore, the clinical applications of such biomechanical knowledge on the mucosa are explored to address some critical concerns, including stimuli for tissue remodelling (interstitial hydrostatic pressure), pressure–pain thresholds, tissue displaceability and residual bone resorption. Through this review, the state of the art in mucosal biomechanics and their clinical implications are discussed for future research interests, including clinical applications, computational modelling, design optimization and prosthetic fabrication.     

Compliance of the fish outflow tract is altered by thermal acclimation through connective tissue remodelling

To protect the gill capillaries from high systolic pulse pressure, the fish heart contains a compliant non-contractile chamber called the bulbus arteriosus which is part of the outflow tract (OFT) which extends from the ventricle to the ventral aorta. Thermal acclimation alters the form and function of the fish atria and ventricle to ensure appropriate cardiac output at different temperatures, but its impact on the OFT is unknown. Here we used ex vivo pressure–volume curves to demonstrate remodelling of passive stiffness in the rainbow trout (Oncorhynchus mykiss) bulbus arteriosus following more than eight weeks of thermal acclimation to 5, 10 and 18°C. We then combined novel, non-biased Fourier transform infrared spectroscopy with classic histological staining to show that changes in compliance were achieved by changes in tissue collagen-to-elastin ratio. In situ gelatin zymography and SDS-PAGE zymography revealed that collagen remodelling was underpinned, at least in part, by changes in activity and abundance of collagen degrading matrix metalloproteinases. Collectively, we provide the first indication of bulbus arteriosus thermal remodelling in a fish and suggest this remodelling ensures optimal blood flow and blood pressure in the OFT during temperature change.     

Application of Different Turbulence Models in Unsteady Flow Simulations of a Radial Diffuser Pump

In this paper, the unsteady flow in a radial pump has been investigated numerically by utilizing different turbulence models at both design and off-design conditions. The numerical results are analyzed and compared on the pressure, relative velocity, and turbulence fields with experimental results from LDV and PIV. The analysis of the results shows that the turbulence model does not show significant influences on the pressure field. At the design condition (Q _des), k-ε predicts generally the best result on the relative velocity magnitude, slightly better than k-ω. However, k-ω has an overwhelming predominance on predicting the velocity vector directions and also on the turbulence kinetic energy. Furthermore, CFD can provide much better agreement to the measurements in the radial gap region than in the impeller region for all examined turbulence models. At off-design condition (0.5Q _des), DES and SST turbulence models predict successfully a “two-channel” stall phenomenon in the impeller detected by the measurements, and other turbulence models failed to predict it.