Hemodynamic analysis of a novel stent graft design with slit perforations in thoracic aortic aneurysm

Thoracic endovascular aortic repair (TEVAR) has been introduced as a less invasive approach to the treatment of thoracic aortic aneurysm (TAA). However, the effectiveness of TEVAR in the treatment of TAA is often limited due to the complex anatomy of aortic arch. Flow preservation at the three supra-aortic branches further increases the overall technical difficulty. This study proposes a novel stent graft design with slit perforations that can positively alter the hemodynamics at the aortic arch while maintaining blood flow to supra-aortic branches. We carried out a computational fluid dynamic (CFD) analysis to evaluate flow characteristics near stented aortic arch in simplified TAA models, followed by in-vitro experiments using particle image velocimetry (PIV) in a mock circulatory loop. The hemodynamics result was studied in terms of time-averaged wall shear stress (TAWSS), oscillating shear index (OSI), and endothelial cell action potential (ECAP). The results showed that the stent graft with slit perforations can reduce the disturbed flow region considerably. Furthermore, the effect of the slits on flow preservation to the supra-aortic branches was simulated and compared with experimental results. The effectiveness of the stent graft with slit perforations in preserving flow to the branches was demonstrated by both simulated and experimental results. Low TAWSS and elevated ECAP were observed in the aortic arch aneurysm after the placement of the stent graft with slits, implying the potential of thrombus formation in the aneurysm. On the other hand, the effects of the stent grafts with full-slit design and half-slit design on the shear stress did not differ significantly. The present analysis indicated that not only could the stent graft with slit perforations shield the aneurysm from rupture, but also it resulted in a favorable environment for thrombus that can contribute to the shrinkage of the aneurysm.     

Manufacture of small calibre quadruple lamina vascular bypass grafts using a novel automated extrusion-phase-inversion method and nanocomposite polymer

Long-term patency of expanded polytetrafluoroethylene (ePTFE) small calibre cardiovascular bypass prostheses (<6 mm) is poor because of thrombosis and intimal hyperplasia due to low compliance, stimulating the search for elastic alternatives. Wall porosity allows effective post-implantation graft healing, encouraging endothelialisation and a measured fibrovascular response. We have developed a novel poly (carbonate) urethane-based nanocomposite polymer incorporating polyhedral oligomeric silsesquioxane (POSS) nanocages (UCL-NANO?) which shows anti-thrombogenicity and biostability.We report an extrusion-phase-inversion technique for manufacturing uniform-walled porous conduits using UCL-NANO?. Image analysis-aided wall measurement showed that two uniform wall-thicknesses could be specified. Different coagulant conditions revealed the importance of low-temperature phase-inversion for graft integrity. Although minor reduction of pore-size variation resulted from the addition of ethanol or N,N-dimethylacetamide, high concentrations of ethanol as coagulant did not provide uniform porosity throughout the wall. Tensile testing showed the grafts to be elastic with strength being directly proportional to weight. The ultimate strengths achieved were above those expected from haemodynamic conditions, with anisotropy due to the manufacturing process. Elemental analysis by energy-dispersive X-ray analysis did not show a regional variation of POSS on the lumen or outer surface. In conclusion, the automated vertical extrusion–phase-inversion device can reproducibly fabricate uniform-walled small calibre conduits from UCL-NANO?. These elastic microporous grafts demonstrate favourable mechanical integrity for haemodynamic exposure and are currently undergoing in-vivo evaluation of durability and healing properties.     

A novel strategy for engineering vascularized grafts in vitro

Tissue engineering is an interdisciplinary field promising new therapeutic means for replacing lost or severely damaged tissues or organs. However, the fabrication of complex engineered tissues has been hampered due to the lack of vascularization to provide sufficient blood supply after implantation. In this article, we propose using rapid prototyping technology to prefabricate a scaffold with an inside hollowed vascular system including an arterial end, a venous end and capillary networks between them. The scaffold will be 'printed' layer by layer. When printing every layer, a 'low-melting point' material will be used to form a blood vessel network and a tissue-specific material will be used outside it. Hereafter the 'low-melting point' material will be evacuated by vaporization to ensure a hollowed vessel network. Then the inside hollowed capillary network can be endothelialized by using autologous endothelial cells in a cycling bioreactor while the outside material can be embedded with tissue-special cells. In the end, the new vascularized autologous grafts could be transferred to the defect site by using microsurgical techniques to connect the grafts with the host artery and vein. The strategy would facilitate construction of complex tissue engineering if the hypothesis proved to be practical.     

CD68 expression in aortocoronary saphenous vein bypass grafts

Atherosclerosis commonly affects the arteries harvested from patients 70 years of age or older. Saphenous vein grafts appear to maintain a higher patency rate after coronary artery bypass grafting in these subjects. The infiltration of macrophages is an early step in saphenous vein graft atherosclerosis; however, little is known regarding the underlying mechanisms of infiltration. The objective of the present report is to evaluate the presence of CD68-positive cells in the saphenous vein wall and correlate initial CD68-positive infiltration to specific clinical and biochemical parameters and the graft patency rate as estimated in patients undergoing coronary artery bypass grafting. A total of 309 patients were allocated into two groups: A1 patients, who were between 50 and 70 years of age, and A2 patients, who were 70 years or older at the time of vein harvesting. CD68 expression was evaluated by immunohistochemistry. There were no significant differences between A1 and A2 patients regarding macrophage expression within any of the analyzed vascular regions. Saphenous vein macrophages were never present in the tunica intima unless they were also expressed in the media or the adventitia. The patients with CD68-positive cells in the tunica intima had a significantly higher number of bypass stenoses when compared with the subjects who did not have CD68-positive cells in this layer. These findings suggest that the CD68-positive cells (those that have not yet developed into foam cells) present in the intima of saphenous vein grafts might serve as a very early marker of graft occlusion.     

Measurement of the flow in coronary artery bypass grafts

The aim of our study was to measure the flow in coronary artery bypass grafts and to compare the flow between two groups of patients. In group A the arterial revascularization was performed with both internal thoracic arteries using as a Y graft and in group B conventional revascularization using left internal thoracic artery (ITA) attached to the left anterior descending artery (LAD) and venous grafts to the other branches of the left coronary artery was performed. The flow in all grafts was measured at six time points during the operation. The cumulative flow at the end of the operation in the group A (arterial Y graft) was 51.8 +/- 24.5 ml/min and in group B (conventional technique) it was 96.8 +/- 41.1 ml/min (p < 0.05). The flow in left ITA to LAD was similar in both groups (27.3 +/- 15.9 ml/min and 26.3 +/- 16.1 ml/min in group A and B). The flow in right ITA (25.2 +/- 18.4 ml/min) was significantly lower than in venous grafts (72.5 +/- 45.5 ml/min). The calculated flow reserve was 2.2 in group A and 2.1 in group B. We found that the cumulative flow in arterial Y graft was lower in comparison with conventional revascularization. This is due to the lower flow in the right ITA branch of the Y graft compared to venous grafts. However based on clinical results, we can postulate that the flow in the Y graft is sufficient to meet the demand of the myocardium originally supplied by the left coronary artery.     

Bone ingrowth simulation for a concept glenoid component design

Glenoid component loosening is the major problem of total shoulder arthroplasty. It is possible that uncemented component may be able to achieve superior fixation relative to cemented component. One option for uncemented glenoid is to use porous tantalum backing. Bone ingrowth into the porous backing requires a degree of stability to be achieved directly post-operatively. This paper investigates the feasibility of bone ingrowth with respect to the influence of primary fixation, elastic properties of the backing and friction at the bone prosthesis interface. Finite element models of three glenoid components with different primary fixation configurations are created. Bone ingrowth into the porous backing is modelled based on the magnitude of the relative interface micromotions and mechanoregulation of the mesenchymal stem cells that migrated via the bonded part of the interface. Primary fixation had the most influence on bone ingrowth. The simulation showed that its major role was not to firmly interlock the prosthesis, but rather provide such a distribution of load, that would result in reduction of the peak interface micromotions. Should primary fixation be provided, friction has a secondary importance with respect to bone ingrowth while the influence of stiffness was counter intuitive: a less stiff backing material inhibits bone ingrowth by higher interface micromotions and stimulation of fibrous tissue formation within the backing.     

Vasoconstriction seen in coronary bypass grafts during handgrip in humans.

In animal studies, sympathetically mediated coronary vasoconstriction has been demonstrated during exercise. Human studies examining coronary artery dynamics during exercise are technically difficult to perform. Recently, noninvasive transthoracic Duplex ultrasound studies demonstrated that 1) patients with left internal mammary artery (LIMA) grafts to the left anterior descending artery can be imaged and 2) the LIMA blood flow patterns are similar to those seen in normal coronary arteries. Accordingly, subjects with LIMA to the left anterior descending artery were studied during handgrip protocols as blood flow velocity in the LIMA was determined. Beat-by-beat analysis of changes in diastolic coronary blood flow velocity (CBV) was performed in six male clinically stable volunteers (60 +/- 2 yr) during two handgrip protocols. Arterial blood pressure (BP) and heart rate (HR) were also measured, and an index of coronary vascular resistance (CVR) was calculated as diastolic BP/CBV. Fatiguing handgrip performed at [40% of maximal voluntary contraction (MVC)] followed by circulatory arrest did not evoke an increase in CVR (P = not significant). In protocol 2, short bouts of handgrip (15 s) led to increases in CVR (18 +/- 3% at 50% MVC and 20 +/- 8% at 70% MVC). BP was also increased during handgrip. Our results reveal that in conscious humans, coronary vasoconstriction occurs within 15 s of onset of static handgrip at intensities at or greater than 50% MVC. These responses are likely to be due to sympathetic vasoconstriction of the coronary circulation.     

MoiRNAiFold: a novel tool for complex in silico RNA design

Novel tools for in silico design of RNA constructs such as riboregulators are required in order to reduce time and cost to production for the development of diagnostic and therapeutic advances. Here, we present MoiRNAiFold, a versatile and user-friendly tool for de novo synthetic RNA design. MoiRNAiFold is based on Constraint Programming and it includes novel variable types, heuristics and restart strategies for Large Neighborhood Search. Moreover, this software can handle dozens of design constraints and quality measures and improves features for RNA regulation control of gene expression, such as Translation Efficiency calculation. We demonstrate that MoiRNAiFold outperforms any previous software in benchmarking structural RNA puzzles from EteRNA. Importantly, with regard to biologically relevant RNA designs, we focus on RNA riboregulators, demonstrating that the designed RNA sequences are functional both in vitro and in vivo. Overall, we have generated a powerful tool for de novo complex RNA design that we make freely available as a web server (https://moiraibiodesign.com/design/).     

A numerical simulation of steady flow fields in a bypass tube.

Steady flow in a complete by-pass tube was simulated numerically. The study was to consider a complete flow field, which included both the by-pass and the host tubes. The changes of the hemodynamics were investigated with three parameters: the inlet flow Reynolds number (Re), anastomotic angle (alpha) and the position of the occlusion in the host tube. The baseline flow field was set up with Re=200, alpha=45 degrees and the centered position of occlusion. The parametric study was then conducted on combination of Re=100, 200, 400, alpha=35 degrees, 45 degrees, 60 degrees, 75 degrees, 90 degrees and three occlusion positions: left, center and right. It was found that in the baseline case, large slow/recirculation flows could be seen in the host tube both upstream and downstream of the occlusion. The separation points were on the opposite walls to the junctions. Recirculation zones were also found near the toe and in the proximal outer wall of the by-pass tube. Their sizes were about one diameter of the tube or smaller. In some cases, pairing vortices could be seen in the host tube upstream of the occlusion. The shear rate distribution associated with the flow fields was presented. The flow pattern obtained was agreeable to those observed experimentally by other investigators. The difference of the flow fields between a complete bypass and simple anastomosis was discussed. The present numerical code provides a preliminary simulation/design tool for bypass graft flows.     

Geometric design improvements for femoral graft-artery junctions mitigating restenosis

The present study is based on the hypothesis that nonuniform hemodynamics, represented by large time-averaged wall shear stress gradients, trigger abnormal biological processes leading to rapid restenosis, i.e. excessive tissue overgrowth and renewed plaque formation, and hence early graft failure. It implies that this problem may be significantly mitigated by finding graft-artery bypass configurations for which the wall shear stress gradient is approximately zero and hence nearly uniform hemodynamics is achieved. These fluid flow and geometric design considerations are applied to four different end-to-side anastomoses for the distal end of a femoral artery bypass with an appropriate test input pulse and a typical 20–80 flow division. A validated finite-volume code has been used to compute the transient three-dimensional velocity vector fields, wall shear stress distributions and surface contours of the wall shear stress gradients. It is shown that large anastomotic flow areas, small continuously changing bifurcation angles, and smooth junction wall curvatures reduce local time-averaged wall shear stress gradients significantly and hence should mitigate restenosis.     

Development of a preclinical natural porcine knee simulation model for the tribological assessment of osteochondral grafts in vitro

In order to pre-clinically evaluate the performance and efficacy of novel osteochondral interventions, physiological and clinically relevant whole joint simulation models, capable of reproducing the complex loading and motions experienced in the natural knee environment are required. The aim of this study was to develop a method for the assessment of tribological performance of osteochondral grafts within an in vitro whole natural joint simulation model.The study assessed the effects of osteochondral allograft implantation (existing surgical intervention for the repair of osteochondral defects) on the wear, deformation and damage of the opposing articular surfaces. Tribological performance of osteochondral grafts was compared to the natural joint (negative control), an injury model (focal cartilage defects) and stainless steel pins (positive controls). A recently developed method using an optical profiler (Alicona Infinite Focus G5, Alicona Imaging GmbH, Austria) was used to quantify and characterise the wear, deformation and damage occurring on the opposing articular surfaces. Allografts inserted flush with the cartilage surface had the lowest levels of wear, deformation and damage following the 2 h test; increased levels of wear, deformation and damage were observed when allografts and stainless steel pins were inserted proud of the articular surface. The method developed will be applied in future studies to assess the tribological performance of novel early stage osteochondral interventions prior to in vivo studies, investigate variation in surgical precision and aid in the development of stratified interventions for the patient population.     

昆虫飞行模拟监控系统设计

本文根据昆虫飞行的特点,模拟昆虫飞行的实验装置,由飞行磨、单片机及微型计算机组成,编辑设计飞行监控软件,该程序分为三个模块：系统监控程序模块;时钟程序模块和信号处理程序模块。利用微机适时采集飞行数据,记录和分析监测结果,模拟昆虫的飞行速度和持续时间。     

Drosophila heparan sulfate, a novel design

Heparan sulfate (HS) proteoglycans play critical roles in a wide variety of biological processes such as growth factor signaling, cell adhesion, wound healing, and tumor metastasis. Functionally important interactions between HS and a variety of proteins depend on specific structural features within the HS chains. The fruit fly (Drosophila melanogaster) is frequently applied as a model organism to study HS function in development. Previous structural studies of Drosophila HS have been restricted to disaccharide composition, without regard to the arrangement of saccharide domains typically found in vertebrate HS. Here, we biochemically characterized Drosophila HS by selective depolymerization with nitrous acid. Analysis of the generated saccharide products revealed a novel HS design, involving a peripheral, extended, presumably single, N-sulfated domain linked to an N-acetylated sequence contiguous with the linkage to core protein. The N-sulfated domain may be envisaged as a heparin structure of unusually low O-sulfate content.     

A novel training-free method for real-time prediction of femoral strain

Surrogate methods for rapid calculation of femoral strain are limited by the scope of the training data. We compared a newly developed training-free method based on the superposition principle (Superposition Principle Method, SPM) and popular surrogate methods for calculating femoral strain during activity. Finite-element calculations of femoral strain, muscle, and joint forces for five different activity types were obtained previously. Multi-linear regression, multivariate adaptive regression splines, and Gaussian process were trained for 50, 100, 200, and 300 random samples generated using Latin Hypercube (LH) and Design of Experiment (DOE) sampling. The SPM method used weighted linear combinations of 173 activity-independent finite-element analyses accounting for each muscle and hip contact force. Across the surrogate methods, we found that 200 DOE samples consistently provided low error (RMSE < 100 µε), with model construction time ranging from 3.8 to 63.3 h and prediction time ranging from 6 to 1236 s per activity. The SPM method provided the lowest error (RMSE = 40 µε), the fastest model construction time (3.2 h) and the second fastest prediction time per activity (36 s) after Multi-linear Regression (6 s). The SPM method will enable large numerical studies of femoral strain and will narrow the gap between bone strain prediction and real-time clinical applications.     

Late results of aortocoronary bypass grafts in 100 patients with stable angina pectoris

From March 1969 to December 1972, 314 patients underwent elective aortocoronary saphenous vein bypass graft surgery at the Toronto General Hospital for the relief of stable disabling angina refractory to medical management. Inhospital mortality was 2.5%. Of these patients 100 agreed to return for follow-up hemodynamic and angiographic assessment at a mean interval of 19.7 months after operation. Seventy-four percent of patients were asymptomatic or had angina only with strenuous exertion at the time of follow-up. Seventy-five percent of the 142 grafts were patent, though a few had significant narrowings. Clinical improvement could be correlated with successful myocardial revascularization. Myocardial infarction was diagnosed by the presence of new Q waves after operation in 15% of patients. Many of these patients had patent grafts at follow-up and all were improved. Dyslipoproteinemia was not found to be a factor affecting late graft patency. Total left ventricular function was not shown to be improved by segmental revascularization. The trend toward improved survival in the intervening period for the total operated group is encouraging.     

Computational design,structure refinement and molecular dynamics simulation of novel engineered serratiopeptidase analogs

Communicated by Ramaswamy H. Sarma     

A novel technique for loading of paclitaxel-PLGA nanoparticles onto ePTFE vascular grafts

The major cause of hemodialysis vascular access dysfunction (HVAD) is the occurrence of stenosis followed by thrombosis at venous anastomosis sites due to the aggressive development of venous neointimal hyperplasia. Local delivery of antiproliferative drugs may be effective in inhibiting hyperplasia without causing systemic side effects. We have previously demonstrated that paclitaxel-coated expanded poly(tetrafluoroethylene) (ePTFE) grafts, by a dipping method, could prevent neointimal hyperplasia and stenosis of arteriovenous (AV) hemodialysis grafts, especially at the graft-venous anastomoses; however, large quntities of initial burst release have remained a problem. To achieve controlled drug release, paclitaxel (Ptx)-loaded poly(lactic-co-glycolic acid) (PLGA) nanoparticles (Ptx-PLGA-NPs) were prepared by the emulsion-solvent evaporation method and then transferred to the luminal surface and inner part of ePTFE vascular grafts through our micro tube pumping and spin penetration techniques. Scanning electron microscope (SEM) images of various stages of Ptx-PLGA-NPs unequivocally showed that micro tube pumping followed by spin penetration effectively transferred Ptx-PLGA-NPs to the inner part, as well as the luminal surface, of an ePTFE graft. In addition, the in vitro release profiles of paclitaxel demonstrated that this new system achieved controlled drug delivery with a reduced initial burst release. These results suggest that loading of Ptx-PLGA-NPs to the luminal surface and the inner part of an ePTFE graft is a promising strategy to ultimately inhibit the development of venous neointimal hyperplasia.