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We present a computational fluid dynamics (CFD)-based model aimed at the identification of optimized culture conditions promoting efficient cardiogenesis of hydrogel-bead-encapsulated embryonic stem cells (ESCs) within a rotating bioreactor. The numerical approach, integrating diffusion, convection, and multiphase fluid dynamics calculations, allowed to evaluate (i) the microgravity motion of the floating beads, (ii) the O(2) delivery to the cells, also (iii) taking into account the cellular O(2) consumption, as a function of different rotation speeds of the breeding chamber. According to our results, a 25 rpm rotation (i) enhances an adequate mixing of the cell carriers, avoiding sedimentation and excessive packing, also maintaining a quite homogeneous distribution of the suspended beads and (ii) imparts a proper cellular O(2) supply, providing cells close to a normoxia condition. The bioreactor working conditions derived from the numerical analysis allowed the attainment of in vitro long-term cell viability maintenance, supporting efficient large-scale generation of ESC-derived cardiomyocytes (ESC-DCs) through a chemical-based conditioning bioprocess. In conclusion, we demonstrated the feasibility of using CFD-based tools, as a reliable and cost-effective strategy to assist the design of a 3D cardiogenic bioprocess.

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.

It has been demonstrated that computational fluid dynamics (CFD) have the potential to enhance the comprehension of the role played by hemodynamic factors involved in atherosclerosis. Recently, phase-contrast magnetic resonance imaging (PC-MRI) has emerged as an effective tool for providing accurate vascular geometries for CFD simulations and quantitative data on blood flow rates, which can be used to specify realistic boundary conditions (BCs). However, the application of acquired flow waveforms at boundaries is not straightforward, mainly (i) due to possible occurrences of phase shifts and attenuations of outflow with respect to inflow rate and (ii) due to the instantaneous mass conservation constraint, which is required in hemodynamic simulations with rigid wall models, but is not guaranteed in in vivo measurements. As an alternative, new boundary conditions schemes have been developed in an effort to consider the interaction between the computational domain and the upstream/downstream vasculature by coupling through-scale hemodynamic models [1]. However, the identification of the parameters of these simplified vascular models on a subject-specific base involves both pressure and flow rates measurements [2]. In this context, it is clear that the direct application of individual PC-MRI measured flow rates waveforms as BCs in patient-specific simulations should be preferred [3]. In order to overcome the limitations mentioned above, measured flow rates should be combined with stress-free conditions or fixed mass flow ratio (derived from the same set of PC-MRI data) between inlet and multiple outlet sections. However, prescribing different BCs at boundaries can affect the solutions of the equations governing blood flow [1]. For this reason, different strategies in combining outlet BCs could lead to different simulated hemodynamics. This work analyzes the influence of different possible strategies of applying PC-MRI measured flow rates on an image-based hemodynamic model of a healthy human aortic arch with supra-aortic vessels. A total of six flow simulations was carried out applying six different schemes for treating BCs at outlets. Three common wall shear stress (WSS)-based indicators of abnormal flow were considered and the sensitivity of these indicators to the outlet treatment strategy was evaluated.Copyright © 2011 by ASME

It is widely accepted that the local hemodynamics in the arterial system affects the atherogenic process. In particular the hemodynamic environment at the carotid artery bifurcation has been widely studied due to its predilection for atherosclerosis. Much effort has been spent in the past on image-based CFD carotid bifurcation models to assess the sensitivity to several assumptions of wall shear stress (WSS)-based parameters as indicators of abnormal flow. This luminal-surface-oriented approach was historically driven by histological observations on samples of the vessel wall. The consequence for this was that the reduction of the complexity of 4D flow fields focused mainly on WSS. However, few studies have provided adequate insights into the influence of these assumptions in order to confidently model the 4D hemodynamics within the bifurcation. Only recently the interest in the role played by the bulk flow in the development of the arterial disease has grown dramatically. This is the consequence of the emerging awareness that arterial hemodynamics, being an intricate process that involves interaction, reconnection and continuous re-organization of structures, could play a primary role in the regulation of mass transfer, and of its athero-protective/susceptible effect. Earlier works [1] pointed out the existence of a relationship between helical/vortical flow patterns and transport processes that could affect blood-vessel wall interaction, and might cause alterations in the residence time of atherogenic particles involved in the initiation of inflammatory response. Recently we introduced robust quantitative descriptors of bulk flow that can “reduce” the inherent complexity associated with 4D flow fields in arteries [1]. Here we present a study on the impact of assumptions on blood rheology and outflow boundary conditions (BCs) on bulk flow features within healthy carotid bifurcations, by using 4D flow descriptors. The final goal is to provide adequate insights not only to complement and to integrate, but also to extend with a quantitative characterization of the bulk flow the description currently adopted to classify altered hemodynamics.Copyright © 2011 by ASME

Actin dynamics, which is at the basis of many fundamental cellular processes as cell migration [1], is governed by the self-assembly and disassembly of actin monomers (G-actin) that, in turn, are determined by the kinetics of ATP hydrolysis and by the local concentrations of Mg2+ and Ca2+ [2]. During cell migration, interactions of the actin filaments (F-actin) with different nucleotide-cation complexes induce local topological rearrangements, because the filament building G-actins undergo conformational shifts between multiple equilibrium states separated by low-energy barriers. For example, the structural rearrangements of the DNase-I binding loop (residues 38–52) in subdomain 2 are driven by ATP hydrolysis and the changes in the conformation of subdomain 4 are induced by the presence of a tightly-bound Mg2+ or Ca2+ ion (Figure 1a). These conformational shifts alter the cross-linking between monomers, varying the contact surfaces among adjacent inter- and intrasubdomains of G-actin, and reflect on the overall properties of F-actin.Copyright © 2011 by ASME

The purpose of this study is to investigate how the imposition of personalized, non-invasively measured blood flow rates as boundary conditions (BCs) influences image-based computational hemodynamic studies in the human aorta. We extracted from 4D phase-contrast MRI acquisitions of a healthy human (1) the geometry of the thoracic aorta with supra-aortic arteries and (2) flow rate waveforms at all boundaries. Flow simulations were carried out, and the implications that the imposition of different BC schemes based on the measured flow rates have on wall shear stress (WSS)-based indicators of abnormal flow were analyzed. Our results show that both the flow rate repartition among the multiple outlets of the aorta and the distribution and magnitude of the WSS-based indicators are strongly influenced by the adopted BC strategy. Keeping as reference hemodynamic model the one where the applied BC scheme allowed to obtain a satisfactory agreement between the computed and the measured flow rate waveforms, differences in WSS-based indicators up to 49% were observed when the other BC strategies were applied. In conclusion, we demonstrate that in subject-specific computational hemodynamics models of the human aorta the imposition of BC settings based on non-invasively measured flow rate waveforms influences indicators of abnormal flow to a large extent. Hence, a BCs set-up assuring realistic, subject-specific instantaneous flow rate distribution must be applied when BCs such as flow rates are prescribed.

Here, we consider the issue of generating a suitable controlled environment for the evaluation of phase contrast (PC) MRI measurements. The computational framework, tailored to build synthetic datasets, is based on a two-step approach, i.e., define and implement (1) an accurate CFD model and (2) an image generator able to mime the overall outcomes of a PC MRI acquisition starting from datasets retrieved by the computational model. About 20 different datasets were built by changing relevant image parameters (pixel size, slice thickness, time frames per cardiac cycle). Focusing our attention on the thoracic aorta, synthetic images were processed in order to: (1) verify to which extent the fluid dynamics into the aortic arch is influenced by the image parameters; (2) establish the effect of spatial and temporal interpolation. Our study demonstrates that the integral scale of the aortic bulk flow could be described satisfactorily even when using images which are nowadays acquirable with MRI scanners. However, attention must be paid to near-wall velocities that can be affected by large inaccuracy. In detail, in bulk flow regions error values are well bounded (below 5% for most of the analyzed resolutions), while errors greater than 100% are systematically present at the vessel’s wall. Moreover, also the data interpolation process can be responsible for large inaccuracies in new data generation, due to the inherent complexity of the flow field in some connected regions.

We aimed to analyze the shape of the glucose, insulin, and C-peptide curves during a 3-h oral glucose tolerance test (OGTT). Another aim was defining an index of shape taking into account the whole OGTT pattern. Five-hundred ninety-two OGTT curves were analyzed, mainly from women with former gestational diabetes, with glycemic concentrations characterized by normal glucose tolerance ( n = 411), impaired glucose metabolism ( n = 134), and Type 2 diabetes ( n = 47). Glucose curves were classified according to their shape (monophasic, biphasic, triphasic, and 4/5-phases), and the metabolic condition of the subjects, divided according to the glucose shape stratification, was analyzed. Indices of shape based on the discrete second-order derivative of the curve patterns were also defined. We found that the majority of the glucose curves were monophasic ( n = 262). Complex shapes were less frequent but not rare ( n = 37 for the 4/5-phases shape, i.e., three peaks). There was a tendency toward the amelioration of the metabolic condition for increasing complexity of the shape, as indicated by lower glucose concentrations, improved insulin sensitivity and β-cell function. The shape index computed on C-peptide, WHOSHCP (WHole-Ogtt-SHape-index–C-peptide), showed a progressive increase [monophasic: 0.93 ± 0.04 (dimensionless); 4/5-phases: 1.35 ± 0.14], and it showed properties typical of β-cell function indices. We also found that the type of glucose shape is often associated to similar insulin and C-peptide shape. In conclusion, OGTT curves can be characterized by high variability, and complex OGTT shape is associated with better glucose tolerance. WHOSHCP (WHole-Ogtt-SHape-index) may be a powerful index of β-cell function much simpler than model-based indices.

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).

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.

Gestational diabetes mellitus (GDM) makes women at risk of type 2 diabetes during their life. In order to predict this later abnormal glucose intolerance, several antepartum and postpartum predictors have been identified. In this study we conjecture that future evolution is predictable from morphology of the oral glucose tolerance test (OGTT) curves at baseline. To test our hypothesis, as a first step we evaluated the association between the curve morphologies of normal and diabetic patient condition at baseline. In particular, we analysed glucose and insulin curves of a group of women with a history of GDM. A Self-organizing map (SOM) was proposed to evaluate shape differences among control, normal, impaired glucose tolerance and diabetic curves shape. We compared our results with the currently applied clinical classification. We found that morphology contains information about the current status of the patient, because the SOM analysis clearly allows to discriminate subjects belonging to healthy or diabetic group. Moreover, SOMs highlighted additional information that could be used for prognostic purposes.

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.

Although flow-driven mechanisms associated with vascular physiopathology also deal with four-dimensional phenomena such as species transport, the majority of the research on the subject focuses primarily on wall shear stress as indicator of disturbed flow. Indeed, the role that bulk flow plays in vascular physiopathology has not been thoroughly investigated, partly because of a lack of descriptors that would be able to reduce the intricacy of arterial hemodynamics. Here, an approach is proposed to investigate, in silico, the bulk flow within the carotid bifurcation. For this purpose, we coupled a three-dimensional model of carotid bifurcation with a lumped model of the downstream vasculature. For the sake of comparison, we also imposed three different fixed flow rate repartitions between the internal and external carotid arteries on the three-dimensional model. The bulk flow was characterized by applying a descriptor of helical motion, the helical flow index (HFI) to the model; the HFI has recently been shown to provide an accurate representation of complex flows. Moreover, a new metric is presented to investigate the vorticity dynamics within the bifurcation. Our results highlight the effectiveness of these metrics in the following contexts: (i) identifying and ranking emerging hemodynamic features and (ii) quantifying the influence of the outflow boundary conditions on the composition of the translational and rotational components of the fluid motion. The metrics applied herein allow for a more comprehensive analysis, which may lead to the development of an instrument to relate the bulk flow to vascular pathophysiological events that involve not only fluid-related forces, but also transport phenomena within blood.

Cell mechanics depends on the mechanical properties of actin microfilaments (MFs), microtubules (MTs) and intermediate filaments (IFs), that build the cytoskeleton. Actin microfilaments are the most abundant components and play significant roles in various cellular processes [1]. Among them, the mechanical properties of MFs are essential for the functions of the cytoskeleton and are directly related to their molecular architecture.Copyright © 2010 by ASME

Vascular endothelial cells functions are modulated by shear stress at vessel wall. The presence of “abnormal” blood flow patterns can give rise to local variations from physiological wall shear stress (WSS) time histories. These variations might be risk factors that increase a vessel’s atherosusceptibility.Copyright © 2010 by ASME

The hemodynamics within the aorta of five healthy humans were investigated to gain insight into the complex helical flow patterns that arise from the existence of asymmetries in the aortic region. The adopted approach is aimed at (1) overcoming the relative paucity of quantitative data regarding helical blood flow dynamics in the human aorta and (2) identifying common characteristics in physiological aortic flow topology, in terms of its helical content. Four-dimensional phase-contrast magnetic resonance imaging (4D PC MRI) was combined with algorithms for the calculation of advanced fluid dynamics in this study. These algorithms allowed us to obtain a 4D representation of intra-aortic flow fields and to quantify the aortic helical flow. For our purposes, helicity was used as a measure of the alignment of the velocity and the vorticity. There were two key findings of our study: (1) intra-individual analysis revealed a statistically significant difference in the helical content at different phases of systole and (2) group analysis suggested that aortic helical blood flow dynamics is an emerging behavior that is common to normal individuals. Our results also suggest that helical flow might be caused by natural optimization of fluid transport processes in the cardiovascular system, aimed at obtaining efficient perfusion. The approach here applied to assess in vivo helical blood flow could be the starting point to elucidate the role played by helicity in the generation and decay of rotating flows in the thoracic aorta.

In recent years, interest is growing on compact measures for assessing the role of local hemodynamics in the pathogenesis of atherosclerosis and atherogenesis. CFD and its power in evaluating and predicting the effect of some hemodynamic variables in vascular disease is becoming a key factor in clinical research. Recently, Lee and Steinman [1] assessed the importance of blood rheology assumptions to ascertain the effect of constitutive relation for blood on local wall shear stress (WSS) and on the correlated vascular pathology. We present a preliminary in silico investigation on the sensitivity of helical flow measure with respect to the blood constitutive adopted model. Our main objective was to verify if, through the carotid bifurcation model, the rheological properties of blood significantly influence the bulk flow topology, whose evolution and stability are strictly linked to helicity. In fact helicity — an invariant in fluid dynamics — has been demonstrated to describe and reveal the global organization in a fluid flow. For this purpose several blood models (Newtonian and non-Newtonian) were implemented. A specific Lagrangian-based “bulk” flow descriptor, the Helical Flow Index (HFI) [2], was calculated in order to get a “measure” of the helical structure in the blood flow. Therefore, its sensitivity to blood rheology and hematocrit (Ht) was assessed and compared with the sensitivity of WSS based on other fluid dynamics descriptors (Time Averaged WSS, TAWSS, and Oscillating Shear Index, OSI).Copyright © 2009 by ASME

A comprehensive computational study modelling the operation of a rotating hollow-fiber bioreactor for artificial liver (BAL) was performed to explore the interactions between the oxygenated culture medium and the cultured hepatocytes. Computational fluid dynamics investigations were carried out using two-dimensional (2D) and 3D time-dependent numerical simulations, integrating calculations of diffusion, convection, and multiphase fluid dynamics. The analysis was aimed at determining the rotational speed value of the chamber to ensure homogenous distribution of the floating microcarrier-attached aggregated cells (microCAACs) and avoid their sedimentation and excessive packing, analyzing oxygen (O(2)) delivery and cellular O(2) consumption as an index of cellular metabolic activity, and analyzing the fluid-induced mechanical stress experienced by cells. According to our results, homogeneous distribution of cells is reached at a rotational speed of 30 rpm; spreading of cellular concentration at around the initial value of 12% was limited (median = 11.97%, 5th percentile = 10.94%, 95th percentile = 13.2%), resulting in uniform suspension of microCAACs, which did not appear to be excessively packed. Mixing within the rotating fluid caused a maximum fluid-induced stress value of 0.05 Pa, which was neither endangering for liver-specific functions of cultured cells, nor causing disruption of the floating aggregates. Moreover, an inlet medium flow rate of 200 mL/m with a partial pressure of oxygen (pO(2)) value of 160 mmHg was found to guarantee an adequate O(2) supply for the hepatocytes (2.7 x 10(8) hepatocytes are simulated); under such conditions, the minimum pO(2) value (23 mmHg) is above the critical threshold value, causing the onset of cellular hypoxia (10 mmHg). We proved that numerical simulation of transport phenomena is a valuable tool for the computer-aided design of BALs, helping overcome the unsolved issues in optimizing the cell-environment conditioning procedure in rotating BALs.

The initiation and progression of vessel wall pathologies have been linked to disturbances of blood flow and altered wall shear stress. The development of computational techniques in fluid dynamics, together with the increasing performances of hardware and software allow to routinely solve problems on a virtual environment, helping to understand the role of biomechanics factors in the healthy and diseased cardiovascular system and to reveal the interplay of biology and local fluid dynamics nearly intractable in the past, opening to detailed investigation of parameters affecting disease progression. One of the major difficulties encountered when wishing to model accurately the cardiovascular system is that the flow dynamics of the blood in a specific vascular district is strictly related to the global systemic dynamics. The multiscale modelling approach for the description of blood flow into vessels consists in coupling a detailed model of the district of interest in the framework of a synthetic description of the surrounding areas of the vascular net [1]. In the present work, we aim at evaluating the effect of boundary conditions on wall shear stress (WSS) related vessel wall indexes and on bulk flow topology inside a carotid bifurcation. To do it, we coupled an image-based 3D model of carotid bifurcation (local computational domain), with a lumped parameters (0D) model (global domain) which allows for physiological mimicking of the haemodynamics at the boundaries of the 3D carotid bifurcation model here investigated. Two WSS based blood-vessel wall interaction descriptors, the Time Averaged WSS (TAWSS), and the Oscillating Shear Index (OSI) were considered. A specific Lagrangian-based “bulk” blood flow descriptor, the Helical Flow Index (HFI) [2], was calculated in order to get a “measure” of the helical structure in the blood flow. In a first analysis the effects of the coupled 0D models on the 3D model are evaluated. The results obtained from the multiscale simulation are compared with the results of simulations performed using the same 3D model, but imposing a flow rate at internal carotid (ICA) outlet section equal to the maximum (60%) and the minimum (50%) flow division obtained out from ICA in the multiscale model simulation (the presence of the coupled 0D model gives variable internal/external flow division ratio during the cardiac cycle), and a stress free condition on the external carotid (ECA).Copyright © 2009 by ASME

Altered haemodynamics are implicated in the blood cells damage that leads to thromboembolic complications in presence of prosthetic cardiovascular devices, with platelet activation being the underlying mechanism for cardioemboli formation in blood flow past mechanical heart valves (MHVs). Platelet activation can be initiated and maintained by flow patterns arising from blood flowing through the MHV, and can lead to an enhancement in the aggregation of platelets, increasing the risk for thromboemboli formation. Hellums and colleagues compiled numerous experimental results to depict a locus of incipient shear related platelet activation on a shear stress – exposure time plane, commonly used as a standard for platelet activation threshold [1]. However, platelet activation and aggregation is significantly greater under pulsatile or dynamic condition relative to exposure to constant shear stress [2]. Previous studies do not allow to determine the relationship existing between the measured effect — the activation of a platelet, and the cause — the time-varying mechanical loading, and the time of exposure to it as might be expected in vivo when blood flows through the valve. The optimization of the thrombogenic performance of MHVs could be facilitated by formulating a robust numerical methodology with predictive capabilities of flow-induced platelet activation. To achieve this objective, it is essential (i) to quantify the link between realistic valve induced haemodynamics and platelet activation, and (ii) to integrate theoretical, numerical, and experimental approaches that allow for the estimation of the thrombogenic risk associated with a specific geometry and/or working conditions of the implantable device. In this work, a comprehensive analysis of the Lagrangian systolic dynamics of platelet trajectories and their shear histories in the flow through a bileaflet MHV is presented. This study uses information extracted from the numerical simulations performed to resolve the flow field through a realistic model of MHV by means of an experimentally validated fluid-structure interaction approach [3]. The potency of the device to mechanically induce activation/damage of platelets is evaluated using a Lagrangian-based blood damage cumulative model recently identified using in vitro platelet activity measurements [4,5].Copyright © 2009 by ASME

Gaseous embolism is still a concern in cardiopulmonary bypass, and the use of arterial line filters (ALFs) is widespread because of their recognized role in increasing safety. Currently, the methods used for the optimization/evaluation of ALF designs are based on a trial-and-error approach. In this work, we propose a method to objectively assess the air-handling capabilities of ALFs, using computational fluid dynamics (CFD) simulations to track the trajectory of large numbers of bubbles traversing the device under examination. We applied the CFD method to ALF prototypes, whose design featured the classical purge/screen configuration, to establish the relative roles of the bubble-trap and bubble-barrier deairing effects. Simulations were run at the maximum rated blood flows. Clusters of hundred bubbles in the micro- to macroembolic size range (10-1,000 microm diameter) were tracked. The results quantified the relative amount of bubbles whose fate is either to reach the purge line or to be intercepted by the filter screen. For microbubbles, the analysis detailed how the screen barrier is exploited, mapping the percent distribution of the intercepted bubbles along the screen surface. We conclude that the method proposed increases knowledge and awareness in designing an optimal exploitation of the filtration mechanisms involved in ALFs.

Thromboembolism and the attendant risk of cardioembolic stroke remains an impediment to the development of prosthetic cardiovascular devices. In particular, altered haemodynamics are implicated in the acute blood cell damage that leads to thromboembolic complications, with platelet activation being the underlying mechanism for cardioemboli formation in blood flow past mechanical heart valves (MHVs) and other blood re-circulating devices. In this work, a new modeling paradigm for evaluating the cardioembolic risk of MHVs is described. In silico fluid-structure interaction (FSI) approach is used for providing a realistic representation of the flow through a bileaflet MHV model, and a Lagrangian analysis is adopted for characterizing the mechanism of mechanically induced activation of platelets by means of a mathematical model for platelet activation state prediction. Additionally, the relationship between the thromboembolic potency of the device and the local flow dynamics is quantified by giving a measure of the role played by the local streamwise and spanwise vorticity components. Our methodology indicates that (i) mechanically induced activation of platelets when passing through the valve is dependent on the phase of the cardiac cycle, where the platelet rate of activation is lower at early systole than late systole; (ii) local spanwise vorticity has greater influence on the activation of platelets (Ror=0.94) than streamwise vorticity (Ror=0.78). In conclusion, an integrated Lagrangian description of key flow characteristics could provide a more complete and quantitative picture of blood flow through MHVs and its potential to activate platelets: the proposed "comprehensive scale" approach could represent an efficient and novel assessment tool for MHV performance and may possibly lead to improved valve designs.

BACKGROUND The time from carotid to femoral pulse wave propagation (pulse transit time (PTT)) is required to estimate the carotid-femoral pulse wave velocity (PWV), a reliable index for evaluating large artery stiffness. METHODS In this work, we propose a novel, noncontact laser-based technique, named optical vibrocardiography (VCG), for evaluating PTT from synchronous recordings of the motion of the skin on the neck and the groin. These measurements, which have been demonstrated to be related to the radial displacement of the underlying blood vessels, were performed on 14 healthy subjects. As validation, applanation tonometry was performed to determine PTT between the carotid and the femoral artery. RESULTS PTT evaluated by VCG was not different from applanation tonometry (74.86 +/- 8.63 ms vs. 75.85 +/- 8.61 ms, P = 0.377). CONCLUSIONS Our preliminary results demonstrate that laser-based noncontact measurement in young healthy volunteers is feasible, and yields PTTs that are equivalent to those measured using arterial applanation tonometry. Its clinical application can overcome limitations inherent to a contact method like arterial tonometry.

In this paper we report experimental data obtained using a novel, non contact and unified approach for the monitoring of some important vital parameters: Heart Rate, Heart Rate Variability, Respiration Rate, Filling Time, Pulse Transit Time. The measurement approach - named optical vibrocardiography (VCG) - has been recently described by some of the authors for what concerns the assessment of a single parameter or measurement and technical aspects. Here, we discuss the experimental setup realized to operate optical VCG in order to measure the previously cited vital parameters. We present two novel configurations for the assessment of the respiration rate and the pulse transit time. The quantities measured by optical VCG have been compared with the ones measured with golden standard instrumentations; the comparison reference instruments has shown differences with no statistical and clinical significance. Optical VCG therefore can be considered a valid, fully non-contact measurement method for the assessment of vital signs, with the additional advantage that such parameters can be assessed using one single instrument instead of a set of dedicated devices.

The mechanics of blood flow in arteries plays a key role in the health of individuals. In this framework, the role played by the presence of helical flow in the human aorta is still not clear in its relation to physiology and pathology. We report here a method for quantifying helical flow in vivo employing time-resolved cine phase contrast magnetic resonance imaging to obtain the complete spatio-temporal description of the three-dimensional pulsatile blood flow patterns in aorta. The method is applied to data of one healthy volunteer. Particle traces were calculated from velocity data: to them we applied a Lagrangian-based method for helical flow quantification, the Helical Flow Index, which has been developed and evaluated in silico in order to reveal global organization of blood flow. Our results: (i) put in evidence that the systolic hemodynamics in aorta is characterized by an evolving helical flow (we quantified a 24% difference in terms of the content of helicity in the streaming blood, between mid and early systole); (ii) indicate that in the first part of the systole helicity is ascrivable mainly to the asymmetry of blood flow in the left ventricle, joined with the laterality of the aorta. In conclusion, this study shows that the quantification of helical blood flow in vivo is feasible, and it might allow detection of anomalies in the expected physiological development of helical flow in aorta and accordingly, could be used in a diagnostic/prognostic index for clinical practice The mechanics of blood flow in arteries plays a key role in the health of individuals. In this framework, the role played by the presence of helical flow in the human aorta is still not clear in its relation to physiology and pathology. We report here a method for quantifying helical flow in vivo employing time-resolved cine phase contrast magnetic resonance imaging to obtain the complete spatio-temporal description of the three-dimensional pulsatile blood flow patterns in aorta. The method is applied to data of one healthy volunteer. Particle traces were calculated from velocity data: to them we applied a Lagrangian-based method for helical flow quantification, the Helical Flow Index, which has been developed and evaluated in silico in order to reveal global organization of blood flow. Our results: (i) put in evidence that the systolic hemodynamics in aorta is characterized by an evolving helical flow (we quantified a 24% difference in terms of the content of helicity in the streaming blood, between mid and early systole); (ii) indicate that in the first part of the systole helicity is ascrivable mainly to the asymmetry of blood flow in the left ventricle, joined with the laterality of the aorta. In conclusion, this study shows that the quantification of helical blood flow in vivo is feasible, and it might allow detection of anomalies in the expected physiological development of helical flow in aorta and accordingly, could be used in a diagnostic/prognostic index for clinical practice.

Through several decades many different models of prosthetic artificial heart valves (PHV) have been designed and optimized in order to enhance hemodynamic properties. These properties are not only material dependent but the major influence results from the mechanical assembly of the particular PHV. For the experimental assessment of the flow through such PHVs particle image velocimetry (PIV) is already an accepted method [1] due to its noninvasive optical approach and accuracy. Here, we present various modifications of PIV in order to explain, compare and realize which method is the most suitable for the quantification of such flows. The choice of the experimental procedure for testing the PHVs is strongly dependent on the optical access of the designed in-vitro testing loops simulating the human heart and vascular system. The hardware demand and its configuration for, e.g., stereoscopic PIV is much more complex than standard 2D PIV, therefore the conditions and design of the testing loop have to be realized to allow the desired flow measurement. The flow in heart valves as an unsteady periodically generated flow, can be obtained by averaged phaselocked or measurements with high temporal. The properties, advantages and drawbacks of specific PIV techniques to visualize the flow behind a PHV will be discussed.

The mechanics of blood flow in arteries represents a central issue of the biological research [Liepsch, 1986]. The asymmetry of the blood flow in the left ventricle, assumed to facilitate the ejection of blood in the primary circulation, joined with the righthanded twist of the great arteries, produce a flow field characterized by complicated helical motions in the aortic arch [Kilner, 1993]. The role played by the presence of helical flow in the human aorta has not been fully clarified, and several aspects are still not clear in their relation to physiology. The challenge in this field is represented by the search for a quantitative description from the in vivo available information. We report here the first attempt of quantifying helical flow in vivo employing time-resolved CINE PC MRI to obtain complete spatio-temporal coverage of the 3D pulsatile blood flow patterns in aorta. To do this, we applied a quantitative method [Grigioni, 2005; Morbiducci., 2007], which has been found useful to reveal global organization of the flow.

The main purpose of this study is to reproduce in silico the dynamics of a bileaflet mechanical heart valve (MHV; St Jude Hemodynamic Plus, 27 mm characteristic size) by means of a fully implicit fluid–structure interaction (FSI) method, and experimentally validate the results using an ultrafast cinematographic technique. The computational model was constructed to realistically reproduce the boundary condition (72 beats per minute (bpm), cardiac output 4.5 l/min) and the geometry of the experimental setup, including the valve housing and the hinge configuration. The simulation was carried out coupling a commercial computational fluid dynamics (CFD) package based on finite-volume method with user-defined code for solving the structural domain, and exploiting the parallel performance of the whole numerical setup. Outputs are leaflets excursion from opening to closure and the fluid dynamics through the valve. Results put in evidence a favorable comparison between the computed and the experimental data: the model captures the main features of the leaflet motion during the systole. The use of parallel computing drastically limited the computational costs, showing a linear scaling on 16 processors (despite the massive use of user-defined subroutines to manage the FSI process). The favorable agreement obtained between in vitro and in silico results of the leaflet displacements confirms the consistency of the numerical method used, and candidates the application of FSI models to become a major tool to optimize the MHV design and eventually provides useful information to surgeons.

The implantation of cardiovascular devices such as prosthetic heart valves, even though very common in the clinical domain, is still not free from complications. Thromboembolic events and hemolysis are the major clinical problems that can occur, upon implantation. In this paper, we analyze the role of the particular fluid dynamics associated to such devices, in relation to the clinical outcome. A major issue, still debated, is the way to correlate the experimental findings with blood damage. The availability of advanced techniques such as LDA or PIV is necessary to evaluate the hemodynamical performance of a given implantable device at the local level and to draw reliable conclusions about potentially adverse clinical effects.

In order to investigate the reliability of the so called mean velocity/vessel area formula adopted in clinical practice for the estimation of the flow rate using an intravascular Doppler guide wire instrumentation, a multiscale computational model was used to give detailed predictions on flow profiles within Y-shaped coronary artery bypass graft (CABG) models. At this purpose three CABG models were built from clinical patient's data and used to evaluate and compare, in each model, the computed flow rate and the flow rate estimated according to the assumption of parabolic velocity profile. A consistent difference between the exact and the estimated value of the flow rate was found in every branch of all the graft models. In this study we showed that this discrepancy in the flow rate estimation is coherent to the theory of Womersley regarding spatial velocity profiles in unsteady flow conditions. In particular this work put in evidence that the error in flow rate estimation can be reduced by using the estimation formula recently proposed by Ponzini et al. [Ponzini R, Vergara C, Redaelli A, Veneziani A. Reliable CFD-based estimation of flow rate in haemodynamics measures. Ultrasound Med Biol 2006;32(10):1545-55], accounting for the unsteady nature of blood, applicable in the clinical practice without resorting to further measurements.

The need to optimize the thrombogenic performance of blood recirculating cardiovascular devices, e.g., prosthetic heart valves (PHV) and ventricular assist devices (VAD), is accentuated by the fact that most of them require lifelong anticoagulation therapy that does not eliminate the risk of thromboembolic complications. The formation of thromboemboli in the flow field of these devices is potentiated by contact with foreign surfaces and regional flow phenomena that stimulate blood clotting, especially platelets. With the lack of appropriate methodology, device manufacturers do not specifically optimize for thrombogenic performance. Such optimization can be facilitated by formulating a robust numerical methodology with predictive capabilities of flow-induced platelet activation. In this study, a phenomenological model for platelet cumulative damage, identified by means of genetic algorithms (GAs), was correlated with in vitro experiments conducted in a Hemodynamic Shearing Device (HSD). Platelets were uniformly exposed to flow shear representing the lower end of the stress levels encountered in devices, and platelet activity state (PAS) was measured in response to six dynamic shear stress waveforms representing repeated passages through a device, and correlated to the predictions of the damage accumulation model. Experimental results demonstrated an increase in PAS with a decrease in "relaxation" time between pulses. The model predictions were in very good agreement with the experimental results.

Objective Automatic devices have been recently introduced to make the anastomosis procedure quick and efficient when creating a coronary bypass on the beating heart. However, the implantation of these devices could modify the graft configuration, consistently affecting the hemodynamics usually found in the traditional anastomosis. As local fluid dynamics could play a significant role in the onset of vessel wall pathologies, in this article a computational approach was designed to investigate flow patterns in the presence of the Ventrica magnetic vascular positioner (Ventrica MVP®) device. Methods A model of standard hand-sewn anastomosis and of automated magnetic anastomosis were constructed, and the finite volume method was used to simulate in silico realistic graft hemodynamics. Synthetic analytical descriptors - i.e., time-averaged wall shear stress (TAWSS), oscillating shear index (OSI) and helical flow index (HFI) - were calculated and compared for quantitative assessment of the anastomosis geometry hemodynamic performance. Results In this case study, the same most critical region was identified for the 2 models as the one with the lowest TAWSS and the highest OSI (TAWSS=0.229, OSI=0.255 for the hand-sewn anastomosis; TAWSS=0.297, OSI=0.171 for the Ventrica MVP®). However, the shape of the Ventrica MVP® does not induce more critical wall shear stresses, oscillating flow and damped helicity in the graft fluid dynamics, as compared with conventional anastomosis. Conclusions We found that the use of the Ventrica MVP® for the case study under investigation was not associated with more critical fluid dynamics than with conventional hand-sewn anastomosis. Thereby, the device could facilitate beating heart and minimally invasive coronary artery bypass grafting without increasing local hemodynamic-related risks of failure. (Int J Artif Organs 2007; 30: 628–39)

Three mechanical heart valves (two bileaflet prostheses and a tilting one) were investigated in a basic hardware setup in order to evaluate with a hydrophone their opening and closing action in time and in amplitude of each beat. The recorded signal was then segmented into the series of cycles xi(t) having a temporal duration equal to the working period imposed on the valve. Two return maps were defined, in order to evaluate the degree of dispersion of the resulting scatter plot: (i) the amplitude map xi(t) versus xi+1(t); (ii) the delay map for the closure of the valve within each beat versus the successive ones. To evaluate the results obtained, two indices were proposed based on both the degree of dispersion and the deviation of the regression line of the resulting scatter plot with respect to the bisector of the map plane. The tilting disc valve showed a lower degree of dispersion, both in the amplitude signal and in the closure time delays, with respect to the other two bileaflet heart valves. The methodology proposed here could be regarded as an alternative non-invasive tool to investigate the dynamic behaviour of prosthetic heart valves, especially in the case of their suspected failure.

Platelets are the pre-eminent cell involved in hemostasis and thrombosis. In recent years it has been demonstrated that flow-induced platelet activation is a major cause for the relatively high incidence of thromboembolic complications in mechanical heart valves (MHVs) [1,2].The platelet activation state (PAS) assay has proved to be a reliable technique for the experimental measurement of procoagulant activity [3]. A Predictive numerical model for platelets damage accumulation could provide critical information for thrombogenicity optimization of implantable prosthetic devices. This would lead to improving the safety and efficacy of implantable devices. Reliable models able to predict this phenomenon are still lacking. The aim of this work is an attempt to bridge this gap. A model for describing the activation of formed elements in blood requires establishing a correlation between mechanical loading, exposure time and the phenomenological response of these elements to it. A physically consistent phenomenological model is used [4] and genetic algorithms (GAs) [5], have been successfully applied to the tuning of the model parameters by correlating its predictions to PAS measurements conducted in a Hemodynamic Shearing Device (HSD) by exposing platelets to prescribed shear stress loading waveforms.Copyright © 2007 by ASME

Laser Doppler vibrometry has been recently applied for non-contact monitoring of the cardiac activity, both in terms of cardiac rate and heart rate variability, measuring the velocity of the skin surface of the chest wall and the neck (optical Vibrocardiography, VCG). To go further insight in the analysis of VCG recordings, in this study authors have compared heart sounds by digital Phonocardiography (PCG) with the motion of the skin on the chest wall by optical VCG, the final aim being the identification of some events of cardiac mechanics in the VCG signals. PCG and VCG traces were synchronously recorded on 10 healthy subjects, along with ECG. To reach this goal, multiresolution analysis together with Hilbert transforms for envelope calculation on PCG and VCG have been applied, temporal and morphological features were extracted from the signals. Data collection and signal processing allowed us to identify some events of cardiac mechanics, correlating the heart sounds relative to the closure of the mitral valve, and the following closure of the aortic and pulmonary valve with characteristic deflections identifiable on VCG traces.

Minimal model analysis of glucose and insulin data from an IVGTT (intravenous glucose tolerance test) is widely used to estimate insulin sensitivity; however, the use of the model often requires intervention by a trained operator and some problems can occur in the estimation of model parameters. In the present study, a new method for minimal model analysis, termed GAMMOD, was developed based on genetic algorithms for the estimation of model parameters. Such an algorithm does not require the fixing of initial values for the parameters (that may lead to unreliable estimates). Our method also implements an automated weighting scheme not requiring manual intervention of the operator, thus improving the usability of the model. We studied a group of 170 women with a history of previous gestational diabetes. Results obtained by GAMMOD were compared with those obtained by MINMOD (a traditional gradient-based algorithm for minimal model analysis). Insulin sensitivity by GAMMOD was (3.86+/-0.19) compared with (4.33+/-0.20) x 10(-4) micro-units.ml(-1) x min(-1) by MINMOD; glucose effectiveness was 0.0236+/-0.0005 compared with 0.0229+/-0.0005 min(-1) respectively. The difference in the estimation by the two methods was within the precision expected for such metabolic parameters and is probably of no clinical relevance. Moreover, both the coefficient of variation of the estimated parameters and the error of fit were generally lower in GAMMOD, despite the fact that it does not require manual intervention. In conclusion, the GAMMOD approach for parameter estimation in the minimal model provides a reliable estimation of the model parameters and improves the usability of the model, thus facilitating its further use and application in a clinical context.

In this paper we present a novel, non-invasive measurement system for optical monitoring of the cardiac rate. This measurement method, called vibrocardiography (VCG), is based on the use of a laser Doppler vibrometer for the measurement of the velocity of displacement of the skin in correspondence of the chest wall. We report the typical VCG signals measured on 4 healthy subject and in particular, we investigated the effect on the signal of the measurement position respect to the chest wall as well as the effect of the surface characteristics on the measured signal.

We present an optical non-contact method for heart beat monitoring, based on the measurement of chest wall movements induced by the pumping action of the heart, which is eligible as a surrogate of electrocardiogram (ECG) in assessing both cardiac rate and heart rate variability (HRV). The method is based on the optical recording of the movements of the chest wall by means of laser Doppler interferometry. To this aim, the ECG signal and the velocity of vibration of the chest wall, named optical vibrocardiography (VCG), were simultaneously recorded on 10 subjects. The time series built from the sequences of consecutive R waves (on ECG) and vibrocardiographic (VV) intervals were compared in terms of heart rate (HR). To evaluate the ability of VCG signals as quantitative marker of the autonomic activity, HRV descriptors were also calculated on both ECG and VCG time series. HR and HRV indices obtained from the proposed method agreed with the rate derived from ECG recordings (mean percent difference

Prosthetic heart valves (PHVs) are engineered devices used for replacing diseased natural cardiac valves. This article presents several investigational techniques for the evaluation of the performance of these clinical devices, whose implantation is not completely free of drawbacks. The state-of-the-art in the technological approach for PHV testing is addressed. As the fluid dynamics of PHVs are particularly complex, the main focus will be on experimental velocimetric techniques and computational analysis. A methodology for the analysis of the valve’s signature, in terms of its characteristic sound in the opening and closing phases, is also presented. The aforementioned techniques are necessary to guarantee an operational life of the implanted device as free as possible from clinical complications. It can be realistically expected that this characterization will help designers in improving PHV performance.

The measurement of a cardiac valve's area is a common procedure, usually performed with noninvasive, Doppler-based techniques. Such measurements are not, however, without problems: a potential source of errors is the value of a valve's discharge coefficient. In-vitro pressure and flow measurements relative to the bileaflet valve of four brands were performed. A total of 12 valve samples was studied to cover the entire range of valve sizing. The data were used in the Gorlin formula for valve area measurements, and the dependence of the discharge coefficient on the internal diameter of the valve and the flow rate was accurately determined. The reported results can be used in a great number of follow-up clinical assessments to improve the accuracy of valvular orifice measurements.

Monitoring heart beat and in venereal cardiac activity is a typical task requested in a clinical environment to analyze a great variety of patient’s conditions. Obtaining this information without contact with the patient’s skin represents a future tool in a large number of fields also outside the clinics. Generally this task cannot be accomplished when the patient’s condition determines impairment of their health so that having skin contact or any other surface contact has to be avoided, or when the type of functional situation (people with or within confined environment) does not permit the use of any kind of sensors or electrodes within the examination environment. We propose a new technique using laser vibrometry capable of obtaining non-contact monitoring of the heart rate (HR) and retrieving physiological quantities characterizing cardiac activity measuring the motion’s properties of the external surface of the human chest on several cardiovascular sites or on the carotideo site. ECG and vibratory signals from the chest wall and carotid were simultaneously recorded. To do this, a measurement bench was realized based on a laser Doppler vibrometer. Recorded signals were collected afterwards to measure the consecutive RR and vibrocardiographic (VV) intervals. Sequences of both RR and corresponding VV intervals were obtained; based on these, tachograms were built. Poincare maps, displaying the relationship between a point and its consecutive in a time series, were obtained. In order to stress the limits of the vibratory signals in representing HR variability (HRV) as the ECG, the power spectral densities of the tachograms were performed. A comparison of the obtained results highlights the coincidence for ECG and the chest wall vibratory investigated information content, confirming the proposed method as an alternative to the typical ECG method when non contact HR activity monitoring must be provided.

Traditional methods to evaluate the ventricular mechanics need intraventricular pressure and volume recordings for multiple variably loaded beats. To do this, a complex and invasive procedure must be applied, that may decrease the clinical use. To overcome this limitation, a method to estimate the ventricular mechanics beat-by-beat is presented, modeling the ventricular pressure-volume relationship with a time-varying elastance function. The ability of the genetic algorithms (GAs) as identification technique is exploited. Applying GAs on surrogated data simulating variably loading conditions, the parameters of the time-varying elastance function, considered a measure of the contractility of the myocardial fibers are identified. These single-beat estimates are highly correlated with the end systolic pressure-volume relationship slope obtained by conventional multiple-beat analysis. The main advantage in using GAs for single beat analysis may lie, in the perspective of an use for in vivo investigations, both in their stochastic nature, and in the guaranteed better performance with respect to other search techniques on problems involving noisy signals. Future studies will approach the reduction in GAs computational costs, for a real time in vivo application.