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ABSTRACT: This paper reports a new low-cost passive microfluidic mixer design, based on a replication of identical mixing units composed of microchannels with variable curvature (clothoid) geometry. The micromixer presents a compact and modular architecture that can be easily fabricated using a simple and reliable fabrication process. The particular clothoid-based geometry enhances the mixing by inducing transversal secondary flows and recirculation effects. The role of the relevant fluid mechanics mechanisms promoting the mixing in this geometry were analysed using computational fluid dynamics (CFD) for Reynolds numbers ranging from 1 to 110. A measure of mixing potency was quantitatively evaluated by calculating mixing efficiency, while a measure of particle dispersion was assessed through the lacunarity index. The results show that the secondary flow arrangement and recirculation effects are able to provide a mixing efficiency equal to 80 % at Reynolds number above 70. In addition, the analysis of particles distribution promotes the lacunarity as powerful tool to quantify the dispersion of fluid particles and, in turn, the overall mixing. On fabricated micromixer prototypes the microscopic-Laser-Induced-Fluorescence (μLIF) technique was applied to characterize mixing. The experimental results confirmed the mixing potency of the microdevice.
Biomedical Microdevices 06/2012; 14(5):849-62. · 3.03 Impact Factor
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ABSTRACT: Microtubules (MTs) are fundamental structural elements in the cytoskeleton of eukaryotic cells. Their unique mechanical properties
depend on the properties of the tubulin dimer, its interactions with surrounding dimers and the geometric organization within
the MT. While the geometry has already been well described in experimental works, the mechanical characteristics of the dimer
as well as of the individual monomers have up to date not been described. These may therefore provide new, additional insight
to the microtubule tensile properties. In this paper we construct a mesoscale model of MT with a bottom-up approach. First,
we evaluate the elastic constants of each of the two monomers together with the interaction force between them by means of
molecular dynamics (MD) simulations carried out in an explicit water environment. Using the MD results, we model a 1μm long
MT as a cylinder constituted by interacting elastic elements and examine its properties via finite element method (FEM). The
obtained results show an elastic constant value for α-tubulin of 11N/m, while for the β-tubulin the elastic constant was
measured to be 15.6N/m. Concerning interactions between neighbouring monomers, the elastic constants along the protofilament
(45N/m for the intra-dimer interface and 18N/m for the inter-dimer interface) are more rigid than elastic constants calculated
for lateral interfaces (11 and 15N/m). The mesoscale model provides mechanical properties of the whole MT, thus allowing
the comparison with data obtained by other previous experimental and theoretical studies. We report here a Young modulus of
1.66GPa for the MT under axial tension. In perspective our approach provides a simple tool for the analysis of MT mechanical
behaviour under different conditions.
Journal of Materials Science 04/2012; 42(21):8864-8872. · 2.02 Impact Factor
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ABSTRACT: In this article, we present a computational multiscale model for the characterization of subcellular proteins. The model is encoded inside a simulation tool that builds coarse-grained (CG) force fields from atomistic simulations. Equilibrium molecular dynamics simulations on an all-atom model of the actin filament are performed. Then, using the statistical distribution of the distances between pairs of selected groups of atoms at the output of the MD simulations, the force field is parameterized using the Boltzmann inversion approach. This CG force field is further used to characterize the dynamics of the protein via Brownian dynamics simulations. This combination of methods into a single computational tool flow enables the simulation of actin filaments with length up to 400 nm, extending the time and length scales compared to state-of-the-art approaches. Moreover, the proposed multiscale modeling approach allows to investigate the relationship between atomistic structure and changes on the overall dynamics and mechanics of the filament and can be easily (i) extended to the characterization of other subcellular structures and (ii) used to investigate the cellular effects of molecular alterations due to pathological conditions.
Proteins Structure Function and Bioinformatics 02/2012; 80(6):1598-609. · 3.39 Impact Factor
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ABSTRACT: Here we present a study on the impact of assumptions on image-based hemodynamic simulations of healthy carotid bifurcations. In particular, we evaluate to which extent assumptions on blood rheology influence bulk flow features, driven by the fact that few studies have provided adequate insights into the influence of assumptions to confidently model the 4D hemodynamics within the bifurcation. The final goal is to complement, integrate and extend with a quantitative characterization of the bulk flow the description currently adopted to classify altered hemodynamics, which is based on wall shear stress (WSS). Hemodynamic simulations of two image-based carotid bifurcation geometries were carried out assuming a reference Newtonian viscosity, two non-Newtonian rheology models and Newtonian viscosities based on characteristic shear rates. WSS-based and Lagrangian-based metrics for helical flow quantification and for vorticity dynamics quantification were calculated. Our findings suggest that the assumption of Newtonian rheology: (1) could be reasonable for bulk flow metrics (differences from non-Newtonian behavior are lower than 10%); (2) influences at different levels the WSS-based indicators, depending on the bifurcation model, even if in our study it is lower than the major source of uncertainty as recognized by the literature (i.e., uncertainty on geometry reconstruction).
Journal of biomechanics 09/2011; 44(13):2427-38. · 2.66 Impact Factor
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ABSTRACT: The actin microfilament (F-actin) is a structural and functional component of the cell cytoskeleton. Notwithstanding the primary role it plays for the mechanics of the cell, the mechanical behaviour of F-actin is still not totally explored. In particular, the relationship between the mechanics of F-actin and its molecular architecture is not completely understood. In this study, the mechanical properties of F-actin were related to the molecular topology of its building monomers (G-actin) by employing a computational multi-level approach. F-actins with lengths up to 500 nm were modelled and characterized, using a combination of equilibrium molecular dynamics (MD) simulations and normal mode analysis (NMA). MD simulations were performed to analyze the molecular rearrangements of G-actin in physiological conditions; NMA was applied to compute the macroscopic properties of F-actin from its vibrational modes of motion. Results from this multi-level approach showed that bending stiffness, bending modulus and persistence length are independent from the length of F-actin. On the contrary, the orientations and motions of selected groups of residues of G-actin play a primary role in determining the filament flexibility. In conclusion, this study (i) demonstrated that a combined computational approach of MD and NMA allows to investigate the biomechanics of F-actin taking into account the molecular topology of the filament (i.e., the molecular conformations of G-actin) and (ii) that this can be done using only crystallographic G-actin, without the need of introducing experimental parameters nor of reducing the number of residues.
Journal of biomechanics 02/2011; 44(4):630-6. · 2.66 Impact Factor
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ABSTRACT: Elevation in non-esterified fatty acids (NEFA) has been shown to modulate insulin secretion and it is considered as a risk factor for the development of type 2 diabetes. Here we present a method that complements a mathematical model of NEFA kinetics with genetic algorithms for model identification. The complemented strategy allowed to assess parameters of NEFA kinetics and to get insight into their relationship with insulin during oral glucose tolerance tests in women with former gestational diabetes: (i) providing a reliable estimation of the model parameters, (ii) assuring the usability of the model, and (iii) promoting and facilitating its application in a clinical context.
Computers in biology and medicine 02/2011; 41(3):146-53. · 1.27 Impact Factor
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ABSTRACT: Microtubules are supramolecular structures that make up the cytoskeleton and strongly affect the mechanical properties of the cell. Within the cytoskeleton filaments, the microtubule (MT) exhibits by far the highest bending stiffness. Bending stiffness depends on the mechanical properties and intermolecular interactions of the tubulin dimers (the MT building blocks). Computational molecular modeling has the potential for obtaining quantitative insights into this area. However, to our knowledge, standard molecular modeling techniques, such as molecular dynamics (MD) and normal mode analysis (NMA), are not yet able to simulate large molecular structures like the MTs; in fact, their possibilities are normally limited to much smaller protein complexes. In this work, we developed a multiscale approach by merging the modeling contribution from MD and NMA. In particular, MD simulations were used to refine the molecular conformation and arrangement of the tubulin dimers inside the MT lattice. Subsequently, NMA was used to investigate the vibrational properties of MTs modeled as an elastic network. The coarse-grain model here developed can describe systems of hundreds of interacting tubulin monomers (corresponding to up to 1,000,000 atoms). In particular, we were able to simulate coarse-grain models of entire MTs, with lengths up to 350 nm. A quantitative mechanical investigation was performed; from the bending and stretching modes, we estimated MT macroscopic properties such as bending stiffness, Young modulus, and persistence length, thus allowing a direct comparison with experimental data.
Biophysical Journal 10/2010; 99(7):2190-9. · 3.65 Impact Factor
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ABSTRACT: Computational fluid dynamics (CFD) models have become very effective tools for predicting the flow field within the carotid bifurcation, and for understanding the relationship between local hemodynamics, and the initiation and progression of vascular wall pathologies. As prescribing proper boundary conditions can affect the solutions of the equations governing blood flow, in this study, we investigated the influence to assumptions regarding the outflow boundary conditions in an image-based CFD model of human carotid bifurcation. Four simulations were conducted with identical geometry, inlet flow rate, and fluid parameters. In the first case, a physiological time-varying flow rate partition at branches along the cardiac cycle was obtained by coupling the 3D model of the carotid bifurcation at outlets with a lumped-parameter model of the downstream vascular network. Results from the coupled model were compared with those obtained by imposing three fixed flow rate divisions (50/50, 60/40, and 70/30) between the two branches of the isolated 3D model of the carotid bifurcation. Three hemodynamic wall parameters were considered as indicators of vascular wall dysfunction. Our findings underscore that the overall effect of the assumptions done in order to simulate blood flow within the carotid bifurcation is mainly in the hot-spot modulation of the hemodynamic descriptors of atherosusceptible areas, rather than in their distribution. In particular, the more physiological, time-varying flow rate division deriving from the coupled simulation has the effect of damping wall shear stress (WSS) oscillations (differences among the coupled and the three fixed flow partition models are up to 37.3% for the oscillating shear index). In conclusion, we recommend to adopt more realistic constraints, for example, by coupling models at different scales, as in this study, when the objective is the outcome prediction of alternate therapeutic interventions for individual patients, or to test hypotheses related to the role of local fluid dynamics and other biomechanical factors in vascular diseases.
Journal of Biomechanical Engineering 09/2010; 132(9):091005. · 1.90 Impact Factor
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ABSTRACT: The basic unit in microtubules is alphabeta-tubulin, a heterodimer consisting of an alpha- and a beta-tubulin monomer. The mechanical characteristics of the dimer as well as of the individual monomers may be used to obtain new insight into the microtubule tensile properties. In the present work, we evaluate the elastic constants of each monomer and the interaction force between them by means of molecular dynamics simulations. Molecular models of alpha-, beta-, and alphabeta-tubulins were developed starting from the 1TUB.pdb structure from the RCSB database. Simulations were carried out in a solvated environment by using explicit water molecules. In order to measure the monomers' elastic constants, simulations were performed by mimicking experiments carried out with atomic force microscopy. A different approach was used to determine the interaction force between the alpha- and beta-monomers by using 16 different monomer configurations based on different intermonomer distances. The obtained results show an elastic constant value for alpha-tubulin of 3.8-3.9 Nm, while for the beta-tubulin, the elastic constant was measured to be 3.3-3.6 Nm. The maximum interaction force between the monomers was estimated to be 11.9 nN. A mechanical model of the tubulin dimer was then constructed and, using the results from MD simulations, Young's modulus was estimated to be 0.6 GPa. A fine agreement with Young's modulus values from literature (0.1-2.5 GPa) is found, thus validating this approach for obtaining molecular scale mechanical characteristics. In perspective, these outcomes will allow exchanging atomic level description with key mechanical features enabling microtubule characterization by continuum mechanics approach.
Journal of Biomechanical Engineering 09/2008; 130(4):041008. · 1.90 Impact Factor
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ABSTRACT: Alpha-actinin is a cytoskeleton-binding protein involved in the assembly and regulation of the actin filaments. In this work molecular dynamics method was applied to investigate the mechanical behaviour of the human skeletal muscle alpha-actinin. Five configurations were unfolded at an elongation speed of 0.1 nm/ps in order to investigate the conformational changes occurring during the extension process. Moreover, a sensitivity analysis at different velocities was performed for one of the R2-R3 spectrin-like repeat configuration extracted in order to evaluate the effect of the pulling speed on the mechanical behaviour of the molecule. Two different behaviours were recognized with respect to the pulling speed. In particular, at speed higher than 0.025 nm/ps a continuous rearrangement without evident force peaks was obtained, on the contrary at lower speed evident peaks in the range 500-750 pN were detected. R3 repeat resulted more stable than R2 during mechanical unfolding, due to the lower hydrophobic surface available to the solvent. The characterization of the R2-R3 units can be useful for the development of cytoskeleton network models based on stiffness values obtained by analyses performed at the molecular level.
Biomechanics and Modeling in Mechanobiology 12/2007; 6(6):399-407. · 3.19 Impact Factor
