Effects of diffusion coefficients and struts apposition using numerical simulations for drug eluting coronary stents

In the context of drug eluting stent, we present two-dimensional numerical models of mass transport of the drug in the wall and in the lumen to study the effect of the drug diffusion coefficients in the three principal media (blood, vascular wall, and polymer coating treated as a three-compartment problem) and the impact of different strut apposition configurations (fully embedded, half embedded, and not embedded). The different conditions were analyzed in terms of their consequence on the drug concentration distribution in the arterial wall. We apply the concept of the therapeutic window to the targeted vascular wall region and derive simple metrics to assess the efficiency of the various stent configurations. Although most of the drug is dispersed in the lumen, variations in the blood flow rate within the physiological range of coronary blood flow and the diffusivity of the drug molecule in the blood were shown to have a negligible effect on the amount of drug in the wall. Our results reveal that the amount of drug cumulated in the wall depends essentially on the relative values of the diffusion coefficients in the polymer coating and in the wall. Concerning the strut apposition, it is shown that the fully embedded strut configuration would provide a better concentration distribution.     

Numerical simulation of iontophoresis in the drug delivery system

The architecture and composition of stratum corneum act as barriers and limit the diffusion of most drug molecules and ions. Much effort has been made to overcome this barrier and it can be seen that iontophoresis has shown a good effect. Iontophoresis represents the application of low electrical potential to increase the transport of drugs into and across the skin or tissue. Iontophoresis is a noninvasive drug delivery system, and therefore, it is a useful alternative to drug transportation by injection. In this study, we present a numerical model and effects of electrical potential on the drug diffusion in the buccal tissue and the stratum corneum. The initial numerical results are in good comparison with experimental observation. We demonstrate that the application of an applied voltage can greatly improve the efficacy of localized drug delivery as compared to diffusion alone.     

不同海拔地区同级别医院鲍曼不动杆菌的分布与 耐药性的连续对比性分析

目的连续对比分析不同海拔地区同级别医院非鲍曼不动杆菌的耐药性,寻找不同海拔对鲍曼不动杆菌的耐药性的影响并指导合理应用抗生素。方法回顾分析2011-2013年两家不同海拔地区同级别医院临床分离的鲍曼不动杆菌药敏结果。结果 2011年至2013年,低海拔地区医院鲍曼不动杆菌检出率为12.66%、17.01%、15.33%。高海拔的地区院鲍曼不动杆菌检出率为0.24%、1.50%、1.44%。低海拔地区医院鲍曼不动杆菌仅对美满环素仍保持较高的敏感率;除头孢哌酮/舒巴坦外,对多数常用药物耐药率均高于70%。而且保持稳定。高海拔的地区院鲍曼不动杆菌对常用抗生素的耐药率逐年下降,庆大霉素、左旋氧氟沙星、亚胺培南、头孢哌酮、头孢他啶的敏感率近两年均在60%以上。结论低海拔地区医院鲍曼不动杆菌检出率高,常用抗生素耐药率高。高海拔的地区院鲍曼不动杆菌检出率低,常用抗生素敏感率高。环境因素对微生态具有重要的影响作用。     

Observations on the effects of distribution and numbers of slug pellets on the catch of slugs

Thirty comparisons were made of the catch of different numbers of slug pellets and the effect of meteorological factors on them. Ten pellets/2 1/2 ft (0.75 m) gave the greatest catch although, economically, the best treatment was from two to five pellets for Agriolimax reticulatus ; for Arion hortensis and Milax budapestensis the return per pellet was low. Throughout the year only 16.6% of the catch variance was removed by meteorological factors.     

Numerical simulation of the flow and concentration fields for oxygen delivery systems

The flow and concentration fields for various medical oxygen delivery devices are numerically investigated. Simulations are performed for a classical Venturi mask and two new OxyArm portable devices. The velocity and oxygen concentration fields are investigated for: (i) a constant (steady-state) inhalation and (ii) a complete respiratory cycle (unsteady). The numerical results are qualitatively compared with clinical trials. It is found that the optimal functioning of these medical devices implies a balance between oxygen delivery by advection and the mixing process that allows for reliable CO2 monitoring (capnographic capability). Also, at the typical scales associated with these devices the flow is found to be Reynolds number dependent.     

Experiments on steady and oscillatory flows at moderate Reynolds numbers in a quasi-two-dimensional channel with a throat.

The study of steady and unsteady oscillatory static fluid pressures acting on the internal wall of a collapsible tube is essential for investigation of the complicated behavior observed when a flow is conveyed inside a tube. To examine the validity of two one-dimensional nonsteady theoretical flow models, this paper presents basic experimental observations of flow separation and reattachment and measured data on the static pressure distributions of the flow in a quasi-two-dimensional channel with a throat, together with information on the corresponding shape of the wall deflection and motion. For combinations of moderate Reynolds numbers and angles of the divergent segment of the channel, a smooth flow is separated from the wall downstream of the minimum cross section and reattached to the wall farther downstream. The measured data are compared with numerical results calculated by the two flow models.     

Functional state of the liver during simulation of the hemodynamic effects of microgravity on the human body

Radioisotope studies of the choleresis function of the liver, ultrasonic studies of the liver and contractile function of the gallbladder and gastroduodenoscopy were carried out in eight subjects after a 24-h stay in a 12° antiorthostatic position (AOP) simulating the hemodynamic changes in the abdominal cavity caused by microgravity. The dynamically hindered venous blood outflow from the liver induced in the AOP model caused activation of choleresis on an empty stomach. This activation manifested itself as an increase in the central perfusion zone of the liver parenchyma, dilation of the biliary ductules, and contraction of the gall-bladder, as well as choleresis into the duodenum. Activation of choleresis in the liver took place against the background of a reduction of the area of radioactive marker distribution in the liver and a decrease in the hepatocyte metabolic activity and the concentration function of the biliary excretion system. The functional characteristics of the liver in the AOP model reflected the reaction caused by changes in its blood content due to the changes in the body position negative to the gravity vector. The mechanism of the changes includes the occurrence of a dynamic venous plethora in the liver; centralization of hepatic blood flow, and activation of choleresis activity against the background of peripheral blood flow depletion, as well as the reduction of metabolic activity of hepatocytes and the concentration function of the biliary excretion system.     

Disaggregating effects of ethanol at low concentration on beta-poly-L-lysines

Protein aggregation is involved in a number of disorders, such as Alzheimer's disease, cystic fibrosis, and prion diseases. Such aggregates are formed by peptides in beta-conformation. The study of the processes of aggregation or its inhibition makes it necessary for the peptide to remain in a monomeric state at the beginning of aggregation assays. Using three poly-L-lysine as a model of beta-peptide, we measured the spectral changes occurring in the visible spectrum of Congo Red (CR), a diazo dye, in two solvent media, namely, an aqueous solution of ethanol 10% (v/v), and an aqueous solution of dimethyl sulfoxide (DMSO) 5% (v/v). Aggregation constants show that the presence of ethanol at low concentration produces a disaggregating effect, regardless of the degree of polymerisation of the peptide. This effect is considered to be due to the direct binding of ethanol molecules to the peptide. This binding undergoes an enhancement of the electrostatic repulsion among charged lysine chains.     

Modelling intravascular delivery from drug-eluting stents with biodurable coating: investigation of anisotropic vascular drug diffusivity and arterial drug distribution

In-stent restenosis occurs in coronary arteries after implantation of drug-eluting stents with non-uniform restenosis thickness distribution in the artery cross section. Knowledge of the spatio-temporal drug uptake in the arterial wall is useful for investigating restenosis growth but may often be very expensive/difficult to acquire experimentally. In this study, local delivery of a hydrophobic drug from a drug-eluting stent implanted in a coronary artery is mathematically modelled to investigate the drug release and spatio-temporal drug distribution in the arterial wall. The model integrates drug diffusion in the coating and drug diffusion with reversible binding in the arterial wall. The model is solved by the finite volume method for both high and low drug loadings relative to its solubility in the stent coating with varied isotropic–anisotropic vascular drug diffusivities. Drug release profiles in the coating are observed to depend not only on the coating drug diffusivity but also on the properties of the surrounding arterial wall. Time dependencies of the spatially averaged free- and bound-drug levels in the arterial wall on the coating and vascular drug diffusivities are discussed. Anisotropic vascular drug diffusivities result in slightly different average drug levels in the arterial wall but with very different spatial distributions. Higher circumferential vascular diffusivity results in more uniform drug loading in the upper layers and is potentially beneficial in reducing in-stent restenosis. An analytical expression is derived which can be used to determine regions in the arterial with higher free-drug concentration than bound-drug concentration.     

Numerical simulation of convective and diffusive transport effects on a high-pressure-induced inactivation process

High-pressure-induced conversions, such as the inactivation of enzymes or of microorganisms, are dependent on the applied pressure and the temperature of the process. The former can be considered to be a spatially homogeneous quantity, while the latter, being a transport quantity, varies over space and time. Here we question whether the uniformity of a high-pressure conversion can be disturbed by convective and conductive heat and mass transport conditions. Enzyme inactivation is taken as a model process for a high-pressure conversion. To cover a broad range of parameters and to consider scale-up effects, the investigation is based on mathematical modeling and numerical simulation for different sizes of the pressure chamber and different solvent viscosities. Apart from viscosity, the physical properties of the enzyme solutions are assumed to be identical in all cases. Therefore, matrix effects other than that of viscosity are excluded. Moreover, the authors postulate that viscosity solely acts on the continuum mechanical scale of momentum exchange but not on the molecular scale on the inactivation kinetics. It has been found that nonuniform thermal conditions can strongly influence the result of a high-pressure process. A variation of the activity retention between 28% and 48% can be observed after 20 minutes for a 0.8-L high-pressure chamber and a matrix fluid with a viscosity comparable to that of edible oils. The same process carried out in a 6.3-L device leads to an activity retention that varies between 16% and 40%. From the analysis of the time scales for the inactivation and for hydrodynamic and thermal compensation, it can be deduced that a nonuniform activity retention has to be expected if the inactivation time scale is larger than the hydrodynamic time scale and smaller than the thermal compensation time scale.     

Modeling the transport of drugs eluted from stents: physical phenomena driving drug distribution in the arterial wall

Despite recent data that suggest that the overall performance of drug-eluting stents (DES) is superior to that of bare-metal stents, the long-term safety and efficacy of DES remain controversial. The risk of late stent thrombosis associated with the use of DES has also motivated the development of a new and promising treatment option in recent years, namely drug-coated balloons (DCB). Contrary to DES where the drug of choice is typically sirolimus and its derivatives, DCB use paclitaxel since the use of sirolimus does not appear to lead to satisfactory results. Since both sirolimus and paclitaxel are highly lipophilic drugs with similar transport properties, the reason for the success of paclitaxel but not sirolimus in DCB remains unclear. Computational models of the transport of drugs eluted from DES or DCB within the arterial wall promise to enhance our understanding of the performance of these devices. The present study develops a computational model of the transport of the two drugs paclitaxel and sirolimus eluted from DES in the arterial wall. The model takes into account the multilayered structure of the arterial wall and incorporates a reversible binding model to describe drug interactions with the constituents of the arterial wall. The present results demonstrate that the transport of paclitaxel in the arterial wall is dominated by convection while the transport of sirolimus is dominated by the binding process. These marked differences suggest that drug release kinetics of DES should be tailored to the type of drug used.     

Impact of transport and drug properties on the local pharmacology of drug-eluting stents

Drugs released from stents are driven by physiological transport forces, principally solvent-driven flow (convection) and random molecular agitation (diffusion). The relative strength of these two forces determines drug penetration and distribution in the arterial wall. Drug physicochemical factors can induce critical modulations to the primary distribution, both transiently and at steady state. Hydrophobic interactions and nonspecific binding, for example, can both result in tissue drug concentrations severalfold above administered concentration. Drug interaction with native proteins may also interfere with drug transfer at the stent-artery interface. These transport forces and tissue interactions can induce local drug concentrations even at steady state to vary by one or more orders of magnitude over the span of a few cells. To account for significant local variations in drug concentrations following stent-based delivery, rational design of vascular delivery systems requires consideration of drug distribution and tissue interactions on a local, continuum basis. Continuum analysis adapts traditional pharmacokinetics to the local environment by supplementing discrete global parameters of drug content with continuous local values of concentration, transport and binding. The interplay of these parameters with local flux conditions and drug and tissue properties defines the local drug distribution in space and over time. This type of analysis may well become increasingly relevant given the trend toward stent-based drug therapy in cardiovascular care.     

Modelling drug elution from stents: effects of reversible binding in the vascular wall and degradable polymeric matrix

Today the most popular approach for the prevention of the restenosis consists in the use of the drug eluting stents. The stent acts as a source of drug, from a coating or from a reservoir, which is transported into and through the artery wall. In this study, the behaviour of a model of a hydrophilic drug (heparin) released from a coronary stent into the arterial wall is investigated. The presence of the specific binding site action is modelled using a reversible chemical reaction that explains the prolonged presence of drug in the vascular tissue. An axi-symmetric model of a single stent strut is considered. First an advection–diffusion problem is solved using the finite element method. Then a simplified model with diffusion only in the arterial wall is compared with: (i) a model including the presence of reversible binding sites in the vascular wall and (ii) a model featuring a drug reservoir made of a degradable polymeric matrix. The results show that the inclusion of a reversible binding for the drug leads to delayed release curves and that the polymer erosion affects the drug release showing a quicker elution of the drug from the stent.     

冬小麦生育期农田尺度下土壤硝态氮淋失动态的数值模拟

在北京通州区永乐店田间试验的基础上 ,假设土壤由一系列不发生相互作用的一维土柱组成 ,根据实测的土壤有机质含量 ,假定土壤有机氮的矿化作用速率常数 (零级动力学 )和有机质含量成正比 ,运用 HYDRUS- 1D软件 ,分别就考虑和不考虑土壤有机氮的矿化速率的空间变异性这两种方案 ,对 2 0 0 0～ 2 0 0 1年冬小麦生长条件下农田尺度土壤氮素转化和硝态氮淋失规律进行了数值分析。两种方案的模拟结果表明 :考虑和不考虑土壤有机氮矿化速率的空间变异性对剖面 2 5 0 cm埋深处硝态氮淋失量的影响很小 ,其差异主要在于前者对土壤氮素的矿化量、固持及反硝化量、作物吸氮量的影响更大 ,其空间变异性高于不考虑矿化速率时的结果。剖面 2 5 0 cm埋深处平均的土壤水渗透量和累积硝态氮淋失量分别为 2 .2 5 mm、0 .0 0 984 m g/cm2 ,变异系数大于 1.4 6 ,属于强变异性。对模拟结果进行地统计学分析 ,结果表明 :剖面 2 5 0 cm埋深处的土壤水渗透量和硝态氮淋失量的半方差函数为纯块金形式 ,在空间上表现为相互独立。考虑有机氮矿化速率空间变异性时的土壤氮素净转化量、吸氮量均可用球状模型描述 ,其变程与土壤有机质含量的变程接近 ,约为 4 .7m;而不考虑有机氮矿化速率空间变异性时的土壤氮素净转化量用线性无基台值     

Modelling drug elution from stents: effects of reversible binding in the vascular wall and degradable polymeric matrix

Today the most popular approach for the prevention of the restenosis consists in the use of the drug eluting stents. The stent acts as a source of drug, from a coating or from a reservoir, which is transported into and through the artery wall. In this study, the behaviour of a model of a hydrophilic drug (heparin) released from a coronary stent into the arterial wall is investigated. The presence of the specific binding site action is modelled using a reversible chemical reaction that explains the prolonged presence of drug in the vascular tissue. An axi-symmetric model of a single stent strut is considered. First an advection-diffusion problem is solved using the finite element method. Then a simplified model with diffusion only in the arterial wall is compared with: (i) a model including the presence of reversible binding sites in the vascular wall and (ii) a model featuring a drug reservoir made of a degradable polymeric matrix. The results show that the inclusion of a reversible binding for the drug leads to delayed release curves and that the polymer erosion affects the drug release showing a quicker elution of the drug from the stent.     

A study on the effects of covered stents on tissue prolapse

Polyvinyl alcohol (PVA) cryogel covered stents may reduce complications from thrombosis and restenosis by decreasing tissue prolapse. Finite element analysis was employed to evaluate the effects of PVA cryogel layers of varying thickness on tissue prolapse and artery wall stress for two common stent geometries and two vessel diameters. Additionally, several PVA cryogel covered stents were fabricated and imaged with an environmental scanning electron microscope. Finite element results showed that covered stents reduced tissue prolapse up to 13% and artery wall stress up to 29% with the size of the reduction depending on the stent geometry, vessel diameter, and PVA cryogel layer thickness. Environmental scanning electron microscope images of expanded covered stents showed the PVA cryogel to completely cover the area between struts without gaps or tears. Overall, this work provides both computational and experimental evidence for the use of PVA cryogels in covered stents.     

The effects of different articulate curvature of artificial disc on loading distribution

Purpose: Deeper insights into the mechanical behavior of lumbar disc prostheses are required. Prior studies on the biomechanical performance of artificial discs were mostly performed with finite element analyses, but this has never been analyzed with altering articulate curvature. This study aimed to ascertain the influence of the geometry of a ball-and-socket disc prosthesis for the lumbar spine. Materials and Methods: Three-dimensional finite element model of human L4-L5 was reconstructed. Convex, concave, and elliptic artificial disc models were also established with Computer-Aided-Design software. Simulations included: (1) three articulate types of polyethylene (PE) insert were implanted inferiorly and (2) concave and convex PE inserts were implanted on the superior or inferior sides in flexion/extension, lateral bending, and axial rotation in the lumbar spine. Shear stresses and von Mises stresses on PE insert were assessed for their loading distributions. Results: High shear stresses of all articulate types occurred in flexion, and convex PE insert performed the maximum stress of 23.81 MPa. Under all conditions, stresses on concave PE inserts were distributed more evenly and lower than those on the convex type. Elliptic geometry enabled confining the rotation of the motion unit. The shear force on the convex PE insert on the inferior side could induce transverse crack because the shear stress exceeded yielding shear stress. Conclusions: The concave PE insert on the inferior side not only decreased loading concentration but had relatively low stress. Such a design may be applicable for artificial discs.