Design optimization of vena cava filters: an application to dual filtration devices

Pulmonary embolism (PE) is a significant medical problem that results in over 300,000 fatalities per year. A common preventative treatment for PE is the insertion of a metallic filter into the inferior vena cava that traps thrombi before they reach the lungs. The goal of this work is to use methods of mathematical modeling and design optimization to determine the configuration of trapped thrombi that minimizes the hemodynamic disruption. The resulting configuration has implications for constructing an optimally designed vena cava filter. Computational fluid dynamics is coupled with a nonlinear optimization algorithm to determine the optimal configuration of a trapped model thrombus in the inferior vena cava. The location and shape of the thrombus are parametrized, and an objective function, based on wall shear stresses, determines the worthiness of a given configuration. The methods are fully automated and demonstrate the capabilities of a design optimization framework that is broadly applicable. Changes to thrombus location and shape alter the velocity contours and wall shear stress profiles significantly. For vena cava filters that trap two thrombi simultaneously, the undesirable flow dynamics past one thrombus can be mitigated by leveraging the flow past the other thrombus. Streamlining the shape of the thrombus trapped along the cava wall reduces the disruption to the flow but increases the area exposed to low wall shear stress. Computer-based design optimization is a useful tool for developing vena cava filters. Characterizing and parametrizing the design requirements and constraints is essential for constructing devices that address clinical complications. In addition, formulating a well-defined objective function that quantifies clinical risks and benefits is needed for designing devices that are clinically viable.     

The influence of out-of-plane geometry on pulsatile flow within a distal end-to-side anastomosis

We present an experimental and computational investigation of time-varying flow in an idealized fully occluded 45 degrees distal end-to-side anastomosis. Two geometric configurations are assessed, one where the centerlines of host and bypass vessels lie within a plane, and one where the bypass vessel is deformed out of the plane of symmetry, respectively, termed planar and non-planar. Flow experiments were conducted by magnetic resonance imaging in rigid wall models and computations were performed using a high order spectral/hp algorithm. Results indicate a significant change in the spatial distribution of wall shear stress and a reduction of the time-averaged peak wall shear stress magnitude by 10% in the non-planar model as compared to the planar configuration. In the planar geometry the stagnation point follows a straight-line path along the host artery bed with a path length of 0.8 diameters. By contrast in the non-planar case the stagnation point oscillates about a center that is located off the symmetry plane intersection with the host artery bed wall, and follows a parabolic path with a 0.7 diameter longitudinal and 0.5 diameter transverse excursion. A definition of the oscillatory shear index (OSI) is introduced that varies between 0 and 0.5 and that accounts for a continuous range of wall shear stress vector angles. In both models, regions of elevated oscillatory shear were spatially associated with regions of separated or oscillating stagnation point flow. The mean oscillatory shear magnitude (considering sites where OSI>0.1) in the non-planar geometry was reduced by 22% as compared to the planar configuration. These changes in the dynamic behavior of the stagnation point and the oscillatory shear distribution introduced by out-of-plane graft curvature may influence the localization of vessel wall sites exposed to physiologically unfavorable flow conditions.     

Use of DIL-type cava filters for the prevention of thromboembolism of the pulmonary artery]

New type cava filters were employed to prevent pulmonary artery thromboembolism in 12 cases. DIL cava filter was used, that represents a string made of a special alloy that can 'memorize' its shape. The design of this filter is in principle different from all the known filters, for it functions as an intraluminal filter and at the same time stretches the vena cava inferior, enlarging its diameter in the frontal plane. The DIL cava filter proved to be effective in the majority of cases, but if the walls of vena cava inferior were too rigid, for example, if a tumor grew into them, it was difficult to place the filter properly. On the whole this filter is characterized by a number of advantages: it can be easily implanted via 7 F catheter without injuring the vena cava inferior walls. No cases of dislocation of cava filters in relation to bone markers were noted in 9 patients over 60 +/- 17 days.     

A resolved two-way coupled CFD/6-DOF approach for predicting embolus transport and the embolus-trapping efficiency of IVC filters

Inferior vena cava (IVC) filters are medical devices designed to provide a mechanical barrier to the passage of emboli from the deep veins of the legs to the heart and lungs. Despite decades of development and clinical use, IVC filters still fail to prevent the passage of all hazardous emboli. The objective of this study is to (1) develop a resolved two-way computational model of embolus transport, (2) provide verification and validation evidence for the model, and (3) demonstrate the ability of the model to predict the embolus-trapping efficiency of an IVC filter. Our model couples computational fluid dynamics simulations of blood flow to six-degree-of-freedom simulations of embolus transport and resolves the interactions between rigid, spherical emboli and the blood flow using an immersed boundary method. Following model development and numerical verification and validation of the computational approach against benchmark data from the literature, embolus transport simulations are performed in an idealized IVC geometry. Centered and tilted filter orientations are considered using a nonlinear finite element-based virtual filter placement procedure. A total of 2048 coupled CFD/6-DOF simulations are performed to predict the embolus-trapping statistics of the filter. The simulations predict that the embolus-trapping efficiency of the IVC filter increases with increasing embolus diameter and increasing embolus-to-blood density ratio. Tilted filter placement is found to decrease the embolus-trapping efficiency compared with centered filter placement. Multiple embolus-trapping locations are predicted for the IVC filter, and the trapping locations are predicted to shift upstream and toward the vessel wall with increasing embolus diameter. Simulations of the injection of successive emboli into the IVC are also performed and reveal that the embolus-trapping efficiency decreases with increasing thrombus load in the IVC filter. In future work, the computational tool could be used to investigate IVC filter design improvements, the effect of patient anatomy on embolus transport and IVC filter embolus-trapping efficiency, and, with further development and validation, optimal filter selection and placement on a patient-specific basis.     

Neutrophil retention in model capillaries: deformability, geometry, and hydrodynamic forces

The initial retention of neutrophils within the pulmonary microvascular bed occurs in both physiological and pathological states, yet the factors responsible for this retention are poorly understood. Because the diameter of the neutrophil is approximately 7.03 micron and the mean pulmonary capillary diameter is 5.5 micron, we postulated that geometric constraints imposed by the microvascular bed, the deformability of the neutrophil, and the hydrodynamic characteristics of blood were important determinants of neutrophil retention. We used a filtration system wherein 111In-labeled human neutrophils (111In-N) suspended in a serum-containing buffer were passed through Nuclepore filters of known pore size. Compared with 99mTc-labeled erythrocytes (99mTc-RBC), the passage of 111In-N was delayed and a higher percentage was retained within the filter. Because the neutrophil and RBC are approximately equal in diameter, the deformability of the neutrophil must be less than that of RBC. As the flow rate increased, retention in the filters decreased logarithmically from 72 +/- 5% (flow rate 0.5 ml/min) to 15 +/- 4% (10.0 ml/min). As the number of RBC in the buffer increased, neutrophil retention in 5-micron filters decreased in a linear fashion from 65 +/- 6% at hematocrit of 0 to 33 +/- 2% at hematocrit of 10. The perfusion pressure and shear stress were of critical importance, and there was a logarithmic relationship between retention and perfusion pressure or shear stress (tau), whether the increase in pressure or tau was generated by increasing flow or by increasing the hematocrit of the perfusate. As the pore size of the filter increased, the retention of neutrophils decreased in a logarithmic fashion: from 75 +/- 5% in the 3-micron filter to 4 +/- 1.3% in the 12-micron filter.(ABSTRACT TRUNCATED AT 250 WORDS)     

Microfluidic and computational study of structural properties and resistance to flow of blood clots under arterial shear

The ability of a blood clot to modulate blood flow is determined by the clot’s resistance, which depends on its structural features. For a flow with arterial shear, we investigated the characteristic patterns relating to clot shape, size, and composition on the one hand, and its viscous resistance, intraclot axial flow velocity, and shear distributions on the other. We used microfluidic technology to measure the kinetics of platelet, thrombin, and fibrin accumulation at a thrombogenic surface coated with collagen and tissue factor (TF), the key clot-formation trigger. We subsequently utilized the obtained data to perform additional calibration and validation of a detailed computational fluid dynamics model of spatial clot growth under flow. We then ran model simulations to gain insights into the resistance of clots formed under our experimental conditions. We found that increased thrombogenic surface length and TF surface density enhanced the bulk thrombin and fibrin generation in a nonadditive, synergistic way. The height of the platelet deposition domain—and, therefore, clot occlusivity—was rather robust to thrombogenic surface length and TF density variations, but consistently increased with time. Clot viscous resistance was non-uniform and tended to be higher in the fibrin-rich, inner “core” region of the clot. Interestingly, despite intraclot structure and viscous resistance variations, intraclot flow velocity variations were minor compared to the abrupt decrease in flow velocity around the platelet deposition region. Our results shed new light on the connection between the structure of clots under arterial shear and spatiotemporal variations in their resistance to flow.

     

Computation in the rabbit aorta of a new metric – the transverse wall shear stress – to quantify the multidirectional character of disturbed blood flow

Spatial variation of the haemodynamic stresses acting on the arterial wall is commonly assumed to explain the focal development of atherosclerosis. Disturbed flow in particular is thought to play a key role. However, widely-used metrics developed to quantify its extent are unable to distinguish between uniaxial and multidirectional flows. We analysed pulsatile flow fields obtained in idealised and anatomically-realistic arterial geometries using computational fluid dynamics techniques, and in particular investigated the multidirectionality of the flow fields, capturing this aspect of near-wall blood flow with a new metric – the transverse wall shear stress (transWSS) – calculated as the time-average of wall shear stress components perpendicular to the mean flow direction. In the idealised branching geometry, multidirectional flow was observed downstream of the branch ostium, a region of flow stagnation, and to the sides of the ostium. The distribution of the transWSS was different from the pattern of traditional haemodynamic metrics and more dependent on the velocity waveform imposed at the branch outlet. In rabbit aortas, transWSS patterns were again different from patterns of traditional metrics. The near-branch pattern varied between intercostal ostia, as is the case for lesion distribution; for some branches there were striking resemblances to the age-dependent patterns of disease seen in rabbit and human aortas. The new metric may lead to improved understanding of atherogenesis.     

Calcium-dependent calcium occlusion in the sarcoplasmic reticulum Ca2+-ATPase. Its enhancement by phosphorylation of the enzyme

45Ca2+-40Ca2+ exchangeability of 45Ca bound to the calcium transport sites of unphosphorylated sarcoplasmic reticulum Ca2+-ATPase at equilibrium has been found to be heterogeneous: Half of the bound calcium is [Ca2+]-dependent in a slowly exchangeable (k less than 0.3 s-1), "occluded" state in the Ca2+-ATPase, and the other calcium is [Ca2+]-independent in a rapidly exchangeable (k approximately 0.3 s-1), "unoccluded" state (Nakamura, J. (1986) Biochim. Biophys. Acta 870, 495-501). In this paper, the two different forms of exchangeable calcium were studied after phosphorylation of the enzyme by ATP without added Mg2+ at pH 7.0 and 0 degree C. By the phosphorylation, the degree of the occlusion became higher (k less than 0.03 s-1). The unoccluded calcium was, however, not significantly affected. The more highly occluded calcium exchanged at the same rate as the decay rate of the phosphoenzyme (EP) in the steady state at a ratio of about 1:1. The occluded calcium was relieved by dephosphorylation of EP by ADP. These results suggest that 1 mol of ADP-sensitive EP more highly occluded 1 mol of calcium, already occluded before phosphorylation. After transformation of ADP-sensitive EP to its ADP-insensitive form by the addition of 20 mM Mg2+ at pH 8.8, the unoccluded calcium was rapidly (k = 0.1-0.3 s-1) released from the transformed EP. However, the occluded calcium was maintained in an occluded state in which the calcium was slowly (k approximately 0.01 s-1) released from the EP without exchange. The results suggest that calcium occlusion in the ADP-sensitive EP is not relieved by the loss of ADP sensitivity of the EP itself.     

Spike-Triggered Covariance Analysis Reveals Phenomenological Diversity of Contrast Adaptation in the Retina

When visual contrast changes, retinal ganglion cells adapt by adjusting their sensitivity as well as their temporal filtering characteristics. The latter has classically been described by contrast-induced gain changes that depend on temporal frequency. Here, we explored a new perspective on contrast-induced changes in temporal filtering by using spike-triggered covariance analysis to extract multiple parallel temporal filters for individual ganglion cells. Based on multielectrode-array recordings from ganglion cells in the isolated salamander retina, we found that contrast adaptation of temporal filtering can largely be captured by contrast-invariant sets of filters with contrast-dependent weights. Moreover, differences among the ganglion cells in the filter sets and their contrast-dependent contributions allowed us to phenomenologically distinguish three types of filter changes. The first type is characterized by newly emerging features at higher contrast, which can be reproduced by computational models that contain response-triggered gain-control mechanisms. The second type follows from stronger adaptation in the Off pathway as compared to the On pathway in On-Off-type ganglion cells. Finally, we found that, in a subset of neurons, contrast-induced filter changes are governed by particularly strong spike-timing dynamics, in particular by pronounced stimulus-dependent latency shifts that can be observed in these cells. Together, our results show that the contrast dependence of temporal filtering in retinal ganglion cells has a multifaceted phenomenology and that a multi-filter analysis can provide a useful basis for capturing the underlying signal-processing dynamics.     

The influence of out-of-plane geometry on the flow within a distal end-to-side anastomosis

This paper describes a computational and experimental investigation of flow in a proto-type model geometry of a fully occluded 45 deg distal end-to-side anastomosis. Previous investigations have considered a similar configuration where the centerlines of the bypass and host vessels lie within a plane, thereby producing a plane of symmetry within the flow. We have extended these investigations by deforming the bypass vessel out of the plane of symmetry, thereby breaking the symmetry of the flow and producing a nonplanar geometry. Experimental data were obtained using magnetic resonance imaging of flow within perspex models and computational data were obtained from simulations using a high-order spectral/hp element method. We found that the nonplanar three-dimensional flow notably alters the distribution of wall shear stress at the bed of the anastomosis, reducing the peak wall shear stress peak by approximately 10 percent when compared with the planar model. Furthermore, an increase in the absolute flux of velocity into the occluded region, proximal to the anastomosis, of 80 percent was observed in the nonplanar geometry when compared with the planar geometry.     

Impact of Tissue Factor Localization on Blood Clot Structure and Resistance under Venous Shear

The structure and growth of a blood clot depend on the localization of tissue factor (TF), which can trigger clotting during the hemostatic process or promote thrombosis when exposed to blood under pathological conditions. We sought to understand how the growth, structure, and mechanical properties of clots under flow are shaped by the simultaneously varying TF surface density and its exposure area. We used an eight-channel microfluidic device equipped with a 20- or 100-μm-long collagen surface patterned with lipidated TF of surface densities ～0.1 and ～2 molecules/μm². Human whole blood was perfused at venous shear, and clot growth was continually measured. Using our recently developed computational model of clot formation, we performed simulations to gain insights into the clot’s structure and its resistance to blood flow. An increase in TF exposure area resulted not only in accelerated bulk platelet, thrombin, and fibrin accumulation, but also in increased height of the platelet mass and increased clot resistance to flow. Moreover, increasing the TF surface density or exposure area enhanced platelet deposition by approximately twofold, and thrombin and fibrin generation by greater than threefold, thereby increasing both clot size and its viscous resistance. Finally, TF effects on blood flow occlusion were more pronounced for the longer thrombogenic surface than for the shorter one. Our results suggest that TF surface density and its exposure area can independently enhance both the clot’s occlusivity and its resistance to blood flow. These findings provide, to our knowledge, new insights into how TF affects thrombus growth in time and space under flow.     

Compound Ex Vivo and In Silico Method for Hemodynamic Analysis of Stented Arteries

Hemodynamic factors such as low wall shear stress have been shown to influence endothelial healing and atherogenesis in stent-free vessels. However, in stented vessels, a reliable quantitative analysis of such relations has not been possible due to the lack of a suitable method for the accurate acquisition of blood flow. The objective of this work was to develop a method for the precise reconstruction of hemodynamics and quantification of wall shear stress in stented vessels. We have developed such a method that can be applied to vessels stented in or ex vivo and processed ex vivo. Here we stented the coronary arteries of ex vivo porcine hearts, performed vascular corrosion casting, acquired the vessel geometry using micro-computed tomography and reconstructed blood flow and shear stress using computational fluid dynamics. The method yields accurate local flow information through anatomic fidelity, capturing in detail the stent geometry, arterial tissue prolapse, radial and axial arterial deformation as well as strut malapposition. This novel compound method may serve as a unique tool for spatially resolved analysis of the relationship between hemodynamic factors and vascular biology. It can further be employed to optimize stent design and stenting strategies.     

Microvascular dilation in response to occlusion: a coordinating role for conducted vasomotor responses

In rat cremasteric microcirculation, mechanical occlusion of one branch of an arteriolar bifurcation causes an increase in flow and vasodilation of the unoccluded daughter branch. This dilation has been attributed to the operation of a shear stress-dependent mechanism in the microcirculation. Instead of or in addition to this, we hypothesized that the dilation observed during occlusion is the result of a conducted signal originating distal to the occlusion. To test this hypothesis, we blocked the ascending spread of conducted vasomotor responses by damaging the smooth muscle and endothelial cells in a 200-microm segment of second- or third-order arterioles. We found that a conduction blockade eliminated or diminished the occlusion-associated increase in flow through the unoccluded branch and abolished or strongly attenuated the vasodilatory response in both vessels at the branch. We also noted that vasodilations induced by ACh (10(-4) M, 0.6 s) spread to, but not beyond, the area of damage. Taken together, these data provide strong evidence that conducted vasomotor responses have an important role in coordinating blood flow in response to an arteriolar occlusion.     

Control of the shape of a thrombus-neointima-like structure by blood shear stress

Fluid mechanical factors are thought to influence vascular morphogenesis. Here we show how blood shear stress regulates the shape of a thrombus-neointima-like tissue on a polymer micro-cylinder implanted in the center of the rat vena cava with the micro-cylinder perpendicular to blood flow. In this model, the micro-cylinder is exposed to a laminarflow with a known shear stress field in the leading region and a vortexflow in the trailing region. At 1, 5, 10, 20, and 30 days after implantation, it was found that the micro-cylinder was encapsulated by a thrombus-neointima-like tissue with a streamlined body profile. The highest growth rate of the thrombus-neointima-like tissue was found along the trailing and leading stagnation edges of the micro-cylinder. Blood shear stress in the laminar flow region was inversely correlated with the rate of thrombus formation and cell proliferation, and the percentage of smooth muscle a actin-positive cells. These biological changes were also found in the trailing vortex flow region, which was associated with lowered shear stress. These results suggest that blood shear stress regulates the rate of thrombus and neointimal formation and, thus, influences the shape of the thrombus-neointima-like structure in the present model.     

Recurrent fracture of a recovery inferior vena cava filter with pulmonary migration

Inferior vena cava (IVC) filters are indicated in patients with venous thromboembolic disease in whom standard anticoagulation therapy is contraindicated or ineffective. A 32-year-old female presented to our hospital with chest pain 5 years after IVC filter placement. Imaging revealed sequential fracturing and embolization of two of the IVC filter arms to the pulmonary arteries. IVC filter fracture and subsequent migration to the lung is a rare complication. Systematic long-term follow-up in patients with IVC filters and, if possible, filter removal should be considered to prevent possible complications.     

Analysis of Flow Phenomena in Gastric Contents Induced by Human Gastric Peristalsis Using CFD

This paper uses computational fluid dynamics to simulate and analyze intragastric fluid motions induced by human peristalsis. We created a two-dimensional computational domain of the distal stomach where peristalsis occurs. The motion of the gastric walls induced by an antral contraction wave (ACW) on the wall of the computational domain was well simulated using a function defined in this study. Retropulsive flow caused by ACW was observed near the occluded region, reaching its highest velocity of approximately 12 mm/s in the narrowest region. The viscosity of the model gastric contents applied in this study hardly affected the highest velocity, but greatly affected the velocity profile in the computational domain. The shear rate due to gastric fluid motion was calculated using the numerical output data. The shear rate reached relatively high values of approximately 20 s⁻¹ in the most occluded region. The shear rate profile was almost independent of the fluid viscosity. We also simulated mass transfer of a gastric digestive enzyme (pepsin) in model gastric content when peristalsis occurs on the gastric walls. The visualized simulation results suggest that gastric peristalsis is capable of efficiently mixing pepsin secreted from the gastric walls with an intragastric fluid.     

Resistance of Bacillus subtilis var. niger Spores Occluded in Water-insoluble Crystals to Three Sterilization Agents

The resistance to destruction of spores of Bacillus subtilis var. niger occluded in crystals of calcium carbonate and exposed to ethylene oxide and moist and dry heat was determined and compared with the destruction of unoccluded spores. Occluded spores could not be inactivated with ethylene oxide. Resistance to inactivation was approximately 900 and 9 times higher for occluded than for unoccluded spores subjected to moist and dry heat, respectively, at 121 C. The protective effect may be due either to the unavailability of oxygen for destruction by oxidation or to inhibition of the loss of essential cell constituents by vaporization. Evidence also implicates the crystal structure as a thermal conductivity barrier. Occluded spores retained viability over a 3-year period compared with unoccluded spores which decreased over 90% during this period. Occluded spores in insoluble materials are seldom encountered in the technology of sterilization, but could be the most critical factor in the sterilization of interplanetary vehicles. Entrapped spores in insoluble materials are usually difficult to detect, and are very stable as well as extremely resistant to destruction by heat and ethylene oxide.     

Dose effect of pentobarbital sodium on control of breathing in cats

The dose effect of pentobarbital sodium on integrated ("moving time average") phrenic activity (EPHR), transdiaphragmatic pressure (Pdi), gastric pressure (Pga), changes in lung volume (V), and mechanical properties of the respiratory system was studied in six cats breathing room air. Increased pentobarbital dose from an initial value of 35 mg/kg ip, had no substantial effect on the relationship between EPHR and Pdi during both unoccluded and occluded inspirations, indicating that the diaphragmatic excitation-contraction coupling was not affected. Similarly, increased anesthetic dose had no effect on the relationship between EPHR and delta Pga during both occluded and unoccluded breaths, suggesting that the contribution of the diaphragm to the breathing movements did not change with increasing depth of anesthesia. Although the time course of phrenic activity showed substantial interanimal differences, the shape of the phrenic neurogram did not change substantially with increased pentobarbital dose in any of the cats studied. Increased anesthetic dose depressed, in the same proportion, the rate of rise of EPHR, Pdi, and V, but the mechanical properties of the respiratory system remained unchanged. The depression of ventilation with increased anesthetic dose was not proportional to the drop in central inspiratory activity, as quantified in terms of rate of rise of EPHR.     

Theory of filtration of mixed blood suspensions

A theory is developed for the flow of suspensions of blood cells through filters in which the properties of the cells are defined by statistical distributions. It is shown that conditions are generally transient, and computational procedures are developed to compute the pressure drop and the fraction of the pores of the filter containing cells of various types as a function of time. The computations show a large influence of very small concentrations of stiff cells which gradually collect in the filter and effectively plug the filter during the time of a typical test. It is also shown that the mean value of the resistance offered by a cell population with a limited distribution of resistances is more important than dispersion of resistances about the mean in determining the observable pressure curve. Experimental data are presented demonstrating that the drug pentoxifylline reduces the stiffness of leukocytes.     

犬不同血管搭桥方法及搭桥血管内流场的计算机数值模拟

目的血管搭桥术后的内膜增生往往导致手术失败,而内膜增生与搭桥血管内的流场密切相关,为改善搭桥血管中的流场结构,作者设计了偏心搭桥手术方法,利用计算机数值模拟技术,探索偏心搭桥和传统搭桥血管中流场的变化,为血管搭桥方法提供优化设计方案。方法16只犬随机分为偏心搭桥组和传统搭桥组进行血管搭桥,测定搭桥前后血管几何数据,搭桥后近心端及远心端吻合口血流量和血压。按测定的血管几何数据,FLUENT 6.2模拟搭桥血管内的流场。结果偏心搭桥近心端和远心端吻合口不在同一平面。传统搭桥中,主体动脉远心端吻合口对应面处存在一个较低壁面剪切应力（WSS）区域及流体停滞点,离脚跟较近的一部分流体会形成涡漩,血流进入主体动脉后,还会表现出迪恩涡二次流;偏心搭桥中,主体动脉吻合口对应面上的低WSS区域和流体停滞点消失,血流接触到吻合口底面后,以切向旋转的方式改变其流动方向,不会形成涡漩,且当血流进入主体动脉后,立即发生螺旋流态且能持续很长一段。结论偏心搭桥能够产生血液旋动流,显著增加远心端血流量、提高WSS。