Cardiovascular stent design and vessel stresses: a finite element analysis

Intravascular stents of various designs are currently in use to restore patency in atherosclerotic coronary arteries and it has been found that different stents have different in-stent restenosis rates. It has been hypothesized that the level of vascular injury caused to a vessel by a stent determines the level of restenosis. Computational studies may be used to investigate the mechanical behaviour of stents and to determine the biomechanical interaction between the stent and the artery in a stenting procedure. In this paper, we test the hypothesis that two different stent designs will provoke different levels of stress within an atherosclerotic artery and hence cause different levels of vascular injury. The stents analysed using the finite-element method were the S7 (Medtronic AVE) and the NIR (Boston Scientific) stent designs. An analysis of the arterial wall stresses in the stented arteries indicates that the modular S7 stent design causes lower stress to an atherosclerotic vessel with a localized stenotic lesion compared to the slotted tube NIR design. These results correlate with observed clinical restenosis rates, which have found higher restenosis rates in the NIR compared with the S7 stent design. Therefore, the testing methodology outlined here is proposed as a pre-clinical testing tool, which could be used to compare and contrast existing stent designs and to develop novel stent designs.     

Incorporating uncertainty in mechanical properties for finite element-based evaluation of bone mechanics

Finite element (FE) models of bone, developed from computed tomography (CT) scan data, are used to evaluate stresses and strains, load transfer and fixation of implants, and potential for fracture. The experimentally derived relationships used to transform CT scan data in Hounsfield unit to modulus and strength contain substantial scatter. The scatter in these relationships has potential to impact the results and conclusions of bone studies. The objectives of this study were to develop a computationally efficient probabilistic FE-based platform capable of incorporating uncertainty in bone property relationships, and to apply the model to a representative analysis; variability in stresses and fracture risk was predicted in five proximal femurs under stance loading conditions. Based on published variability in strength and modulus relationships derived in the proximal femur, the probabilistic analysis predicted the distributions of stress and risk. For the five femurs analyzed, the 1 and 99 percentile bounds varied by an average of 17.3 MPa for stress and by 0.28 for risk. In each femur, the predicted variability in risk was greater than 50% of the mean risk calculated, with obvious implications for clinical assessment. Results using the advanced mean value (AMV) method required only seven analysis trials (1h) and differed by less than 2% when compared to a 1000-trial Monte-Carlo simulation (400 h). The probabilistic modeling platform developed has broad applicability to bone studies and can be similarly implemented to investigate other loading conditions, structures, sources of uncertainty, or output measures of interest.     

Numerical investigations of the mechanical properties of a braided non-vascular stent design using finite element method

This paper discusses various issues relating to the mechanical properties of a braided non-vascular stent made of a Ni–Ti alloy. The design of the stent is a major factor which determines its reliability after implantation into a stenosed non-vascular cavity. This paper presents the effect of the main structural parameters on the mechanical properties of braided stents. A parametric analysis of a commercial stent model is developed using the commercial finite element code ANSYS. As a consequence of the analytical results that the pitch of wire has a greater effect than other structural parameters, a new design of a variable pitch stent is presented to improve mechanical properties of these braided stents. The effect of structural parameters on mechanical properties is compared for both stent models: constant and variable pitches. When the pitches of the left and right quarters of the stent are 50% larger and 100% larger than that of the central portion, respectively, the radial stiffness in the central portion increases by 10% and 38.8%, while the radial stiffness at the end portions decreases by 128% and 164.7%, the axial elongation by 25.6% and 56.6% and the bending deflection by 3.96% and 10.15%. It has been demonstrated by finite element analysis that the variable pitch stent can better meet the clinical requirements.     

Coronary stent implantation without balloon predilatation: a single-center experience

OBJECTIVE: Assessment of safety and efficacy of coronary stent deployment, without balloon predilatation. BACKGROUND: With newer high-performance balloon-premounted stents it has become more common to attempt coronary stent deployment without balloon pre- or postdilatation. METHODS: During 1998 524 coronary angioplasties were performed in the authors' institute, of which 279 resulted in coronary stenting. Of these 101 (36.2%) were stents without balloon predilatation (SWBP). PTCA was performed according to standard technique using mostly 7 F. guiding catheters, and 'rapid exchange' balloons and pre-mounted stents. RESULTS: Seventy-two patients had acute coronary syndromes (41 acute MI or post-MI angina, 28 unstable angina, 10 rescue PTCA after failed thrombolysis). Mean age was 56.4 3 11.1 years, 84.5% were males. Sixty per cent of the lesions were ACC-AHA type B2 or C. Target arteries were LAD 57.6%, LCX 21.2%, RCA 14.1% and SVG 7.1%. Procedure time was 18.2 3 17.3 minutes. Mean heparin dose was 3850 3 1570 units. Twenty-two patients received abciximab prior to stent deployment. Seven stents were not deployed without previous balloon dilatation and were retrieved safely via the guiding catheters and deployed after balloon dilatation. There was no stent embolization, ectopic suboptimal or partial stent deployment. Immediate angiographic success was obtained in 95 patients (94.1%). Minimal lumin diameter (MLD) increased from 0.27 3 0.15 to 3.23 3 2.1 mm. There were two in-hospital deaths (1.9%) due to cardiogenic shock. An intra-aortic balloon pump was required in eight patients. Two patients (1.9%) experienced subacute stent thrombosis. CONCLUSION: SWBP in selective groups of patients and lesions is feasible and safe. Larger randomized comparative trials are needed to assess the benefits and cost saving of this approach.     

A novel graded-stiffness footwear device for heel ulcer prevention and treatment: a finite element-based study

Biomechanics and Modeling in Mechanobiology - Diabetic heel ulceration is a serious, destructive, and costly complication of diabetes. In this study, a novel “graded-stiffness”...     

前导肽介导的蛋白折叠机制及其对脂肪酶影响的研究进展

大多数蛋白质的形成过程主要由合成前体蛋白和合成功能蛋白两个步骤组成.在这个过程中,前导肽能够辅助蛋白质折叠或抑制它的活性.前导肽作为脂肪酶结构中重要的一段多肽链,通常作为分子内分子伴侣来辅助脂肪酶的折叠,同时该序列上包括糖基化位点在内的一些特殊位点,对酶的活性、极端环境稳定性、甲醇耐受性和底物特异性等性质具有重要影响....     

A coarse-grained approach to protein design: learning from design to understand folding

Computational studies have given a great contribution in building our current understanding of the complex behavior of protein molecules; nevertheless, a complete characterization of their free energy landscape still represents a major challenge. Here, we introduce a new coarse-grained approach that allows for an extensive sampling of the conformational space of a large number of sequences. We explicitly discuss its application in protein design, and by studying four representative proteins, we show that the method generates sequences with a relatively smooth free energy surface directed towards the target structures.     

On the design and analysis of protein folding potentials

Pairwise interaction models to recognize native folds are designed and analyzed. Different sets of parameters are considered but the focus was on 20 x 20 contact matrices. Simultaneous solution of inequalities and minimization of the variance of the energy find matrices that recognize exactly the native folds of 572 sequences and structures from the protein data bank (PDB). The set includes many homologous pairs, which present a difficult recognition problem. Significant recognition ability is recovered with a small number of parameters (e.g., the H/P model). However, full recognition requires a complete set of amino acids. In addition to structures from the PDB, a folding program (MONSSTER) was used to generate decoy structures for 75 proteins. It is impossible to recognize all the native structures of the extended set by contact potentials. We therefore searched for a new functional form. An energy function U, which is based on a sum of general pairwise interactions limited to a resolution of 1 angstrom, is considered. This set was infeasible too. We therefore conjecture that it is not possible to find a folding potential, resolved to 1 angstrom, which is a sum of pair interactions.     

Simulated folding in polypeptides of diversified molecular tacticity: implications for protein folding and de novo design

Stereochemistry could be a powerful variable for conformational tune up of polypeptides for de novo design. It may be also useful probe of possible role of interamide energetics in selection and stabilization of conformation. The homopolypeptides Ac-Xxx30-NHMe, with Xxx = Ala, Val, and Leu, of diversified stereochemical structure are generated by simulated racemization with a modified GROMOS-96 force field. The polypeptides, and other systematic stereochemical variants, are folded by simulated annealing with another modified GROMOS-96 force field under the dielectric constant values 1, 4, and 10. The resultant 15,000 molecular folds of isotactic (poly-L-chiral), syndiotactic (alternating L,D-chiral), and heterotactic (random-L,D-chiral) stereochemical structure, belonging to three polypeptide series, achieved under three different folding conditions, are assessed statistically for structure-to-energy-to-conformation relationship. The results suggest that interamide electrostatics could be a major factor in secondary-structure selection in polypeptides while main-chain stereochemistry could dictate molecular packing and therefore the relative magnitude of hydrogen-bond and Lennard-Jones (LJ) contributions in conformational energy. A method for computational design of heterotactic molecular folds in polypeptide structure has been developed, and the first road map for a chiral tune up of polypeptide structure based on stereochemical engineering has been laid down. Broad implications for protein structure, folding, and de novo design are briefly discussed.     

Low-throughput model design of protein folding inhibitors

The stabilization energy of proteins in their native conformation is not distributed uniformly among all the amino acids, but is concentrated in few (short) fragments, fragments which play a key role in the folding process and in the stability of the protein. Peptides displaying the same sequence as these key fragments can compete with the formation of the most important native contacts, destabilizing the protein and thus inhibiting its biological activity. We present an essentially automatic method to individuate such peptidic inhibitors based on a low-throughput screening of the fragments which build the target protein. The efficiency and generality of the method is tested on proteins Src-SH3, G, CI2, and HIV-1-PR with the help of a simplified computational model. In each of the cases studied, we find few peptides displaying strong inhibitory properties, properties which are quite robust with respect to point mutations. The possibility of implementing the method through low-throughput experimental screening of the target protein is discussed.     

Modular enzyme design: regulation by mutually exclusive protein folding

A regulatory mechanism is introduced whereupon the catalytic activity of a given enzyme is controlled by ligand binding to a receptor domain of choice. A small enzyme (barnase) and a ligand-binding polypeptide (GCN4) are fused so that a simple topological constraint prevents them from existing simultaneously in their folded states. The two domains consequently engage in a thermodynamic tug-of-war in which the more stable domain forces the less stable domain to unfold. In the absence of ligand, the barnase domain is more stable and is therefore folded and active; the GCN4 domain is substantially unstructured. DNA binding induces folding of GCN4, forcibly unfolding and inactivating the barnase domain. Barnase-GCN4 is thus a "natively unfolded" protein that uses ligand binding to switch between partially folded forms. The key characteristics of each parent protein (catalytic efficiency of barnase, DNA binding affinity and sequence specificity of GCN4) are retained in the chimera. Barnase-GCN4 thus defines a modular approach for assembling enzymes with novel sensor capabilities from a variety of catalytic and ligand binding domains.     

The folding and design of repeat proteins: reaching a consensus

Although they are widely distributed across kingdoms and are involved in a myriad of essential processes, until recently, repeat proteins have received little attention in comparison to globular proteins. As the name indicates, repeat proteins contain strings of tandem repeats of a basic structural element. In this respect, their construction is quite different from that of globular proteins, in which sequentially distant elements coalesce to form the protein. The different families of repeat proteins use their diverse scaffolds to present highly specific binding surfaces through which protein-protein interactions are mediated. Recent studies seek to understand the stability, folding and design of this important class of proteins.     

Complete RNA inverse folding: computational design of functional hammerhead ribozymes

Nanotechnology and synthetic biology currently constitute one of the most innovative, interdisciplinary fields of research, poised to radically transform society in the 21st century. This paper concerns the synthetic design of ribonucleic acid molecules, using our recent algorithm, RNAiFold, which can determine all RNA sequences whose minimum free energy secondary structure is a user-specified target structure. Using RNAiFold, we design ten cis-cleaving hammerhead ribozymes, all of which are shown to be functional by a cleavage assay. We additionally use RNAiFold to design a functional cis-cleaving hammerhead as a modular unit of a synthetic larger RNA. Analysis of kinetics on this small set of hammerheads suggests that cleavage rate of computationally designed ribozymes may be correlated with positional entropy, ensemble defect, structural flexibility/rigidity and related measures. Artificial ribozymes have been designed in the past either manually or by SELEX (Systematic Evolution of Ligands by Exponential Enrichment); however, this appears to be the first purely computational design and experimental validation of novel functional ribozymes. RNAiFold is available at http://bioinformatics.bc.edu/clotelab/RNAiFold/.     

The evolution of an ideal stent design and its impact on the aortic endothelium during and after percutaneous replacement

Vascular support structures are important devices for treating valve stenosis. A large population of patients is treated for valvular disease and the preferred mode of treatment is percutaneous valve replacement. Stent devices are proving to be an improved technology in minimally invasive cardiac surgery. This new technology provides highly effective results at minimal cost and with a short duration of hospitalisation. Stents as a supporting structure for tissue valves have evolved over the years into remarkably useful and effective devices. During this process, a number of specific designs have come and gone, and a few have remained. Many design changes were successful, and many were not. This article describes the merits and demerits of various stent designs and details the specific reasons why a particular novel design is expected to be the most suitable implant during and after percutaneous aortic valve replacement.     

Stresses in peripheral arteries following stent placement: a finite element analysis

The success of stents to restore blood flow in atherosclerotic peripheral arteries is low relative to coronary arteries. It has been shown that joint flexion induces a mechanical environment that makes stent placement in these arteries highly incompatible, and damage and destruction of stents has been recorded. However, the effect of this environment on the stresses in the arteries is unknown. It is hypothesised that the stresses induced in arteries as a result of this mechanical environment could be sufficient to explain the relatively low success rates. To investigate this hypothesis, a finite element model of the stent-artery interaction was developed. Following stent expansion, bending was simulated by applying a displacement boundary condition to the artery. It is found that high stresses occur at the proximal/distal ends of the stent. As high stress and vascular injury are hypothesised to cause restenosis, the results presented here suggest that the mechanical environment of peripheral arteries could be the predominant cause of high restenosis rates.     

Our capricious vessels: The influence of stent design and vessel geometry on the mechanics of intracranial aneurysm stent deployment

There is a growing interest in virtual tools to assist clinicians in evaluating different procedures and devices for endovascular treatment. In the present study we use finite element analysis to investigate the influence of stent design and vessel geometry for stent assisted coiling of intracranial aneurysms. Nine virtual stenting procedures were performed: three nitinol stent designs ((i) an open cell stent resembling the Neuroform, (ii) a generic stiff and (iii) a more flexible closed cell design), were deployed in three patient-specific cerebral aneurysmatic vessels. We investigated the percentage of strut area covering the aneurysm neck, the straightening induced on the cerebrovasculature by the stent placement (quantified by the reduction in tortuosity), and stent apposition to the wall (quantified as the percentage of struts within 0.2mm of the vessel). The results suggest that the open cell design better covers the aneurysm neck (11.0±1.1%) compared to both the stiff (7.8±1.6%) and flexible (8.7±1.6%) closed cell stents, and induces less straightening of the vessel (-5.1±1.6% vs. -42.9±9.8% and -26.9±11.9% ). The open cell design has, however, less struts apposing well to the vessel wall (56.0±6.4%) compared to the flexible (73.4±4.6%) and stiff (70.4±5.1%) closed cell design. With the presented study, we hope to contribute to and improve aneurysm treatment, using a novel patient specific environment as a possible pre-operative tool to evaluate mechanical stent behavior in different vascular geometries.     

Protein design and folding: template trapping of self-assembled helical bundles.

An experimental system is described, permitting a detailed and systematic analysis of the factors governing self-assembly of amphipathic helices, e.g. to a four-helical bundle, a subject of major relevance for tertiary structure formation, protein folding and design. Following the Template Assembled Synthetic Proteins (TASP) approach, helices of different packing potential are competitively assembled in solution with a preformed two-helix TASP molecule, and after equilibration are covalently attached ('template trapping') via chemoselective thioether formation. The quantitative analysis of the individual TASP molecules by high performance liquid chromatography (HPLC) and electrospray mass spectrometry (ES-MS) allows the delineation of the role of complementary packing in helix bundle formation. The procedure established represents a general tool for the experimental verification of modern concepts in molecular recognition.     

Protein folding in the cell: reshaping the folding funnel

Models of protein folding have historically focused on a subset of 'well-behaved' proteins that can be successfully refolded from denaturants in vitro. Energy landscapes, including folding funnel 'cartoons', describe the largely uncomplicated folding of these isolated chains at infinite dilution. However, the frequent failure of many polypeptides to fold to their native state requires more comprehensive models of folding to accommodate the crucial role of interactions between partially folded intermediates. By incorporating additional deep minima, which reflect off-pathway interchain interactions, the folding funnel concept can be extended to describe the behavior of a more diverse set of proteins under more physiologically relevant conditions. In particular, the effects of ribosomes (translation), molecular chaperones and other aspects of the cellular environment on early chain conformations can be included to account for the folding behavior of polypeptide chains in cells.     

Realistic losses of rare species disproportionately impact higher trophic levels

Predicting the consequences of changes in biodiversity requires understanding both species' susceptibility to extirpation and their functional roles in ecosystems. However, few studies have evaluated the effects of realistic, non-random biodiversity losses, severely limiting the applicability of biodiversity research to conservation. Here, we removed sessile species from a rocky shore community in a way that deliberately mimicked natural patterns of species loss. We found that the rarest species in the system act from the bottom up to disproportionately impact the diversity and abundance of consumers. Realistic losses of rare species in a diverse assemblage of seaweeds and sessile invertebrates, collectively comprising <10% of sessile biomass, resulted in a 42-47% decline in consumer biomass. In contrast, removal of an equivalent biomass of dominant sessile species had no effect on consumers. Our results highlight the 'cornerstone' role that rare species can play in shaping the structure of the community they support.