Umberto Morbiducci

Computational model of the fluid dynamics of a cannula inserted in a vessel: incidence of the presence of side holes in blood flow

Vascular access methods, performed by the insertion of cannulae into vessels, may disturb the physiological flow of blood, giving rise to non-physiological pressure variations and shear stresses. To date, the hydrodynamic behaviour of the cannulae has been evaluated comparing their pressure loss-flow rate relationships, as obtained from in vitro experiments using a monodimensional approach; this methodology neither furnish information about the local fluid dynamics nor the established flow field in specific clinical work conditions. Since the shear stress is a critical factor in the design of artificial circulatory devices, more knowledge should be necessary about the local values assumed by the haemodynamic parameters during cannulation. An alternative way to investigate the fluid dynamic as accurately as possible is given by numeric studies. A 3D model of cannula concentrically placed in a rigid wall vessel is presented, with the finite element methodology used to numerically simulate the steady-state flow field in two different venous cannulation case studies, with two cannulae having a central hole and two or four side holes, respectively, with the same boundary conditions. Lower velocity and shear stress peak values have been computed for the model with four side holes upstream of the central hole, in the region of the cannula where the inlet flows meet and towards cannulas outlet, due to the increased flow symmetry and inlet area with respect to the model with two side holes. Starting from the investigation of different cannula designs, numerically assessing the local fluid dynamics, indications can be drawn to support both the design phase and the device optimal clinical use, in order to limit risks of biomechanical origin. Thus the presence of four side holes implied, as a consequence of the greater inlet area and of the increased symmetry, a less disturbed blood flow, together with reduced shear stress values. Furthermore, results show that the numerical simulations furnished useful informations on the interaction between vessel and cannula, e.g. on the fluid dynamics establishing in the free luminal space left, in the vessel, by the inserted cannula.

ZebraBeat: a flexible platform for the analysis of the cardiac rate in zebrafish embryos

Heartbeat measurement is important in assesssing cardiac function because variations in heart rhythm can be the cause as well as an effect of hidden pathological heart conditions. Zebrafish (Danio rerio) has emerged as one of the most useful model organisms for cardiac research. Indeed, the zebrafish heart is easily accessible for optical analyses without conducting invasive procedures and shows anatomical similarity to the human heart. In this study, we present a non-invasive, simple, cost-effective process to quantify the heartbeat in embryonic zebrafish. To achieve reproducibility, high throughput and flexibility (i.e., adaptability to any existing confocal microscope system and with a user-friendly interface that can be easily used by researchers), we implemented this method within a software program. We show here that this platform, called ZebraBeat, can successfully detect heart rate variations in embryonic zebrafish at various developmental stages, and it can record cardiac rate fluctuations induced by factors such as temperature and genetic- and chemical-induced alterations. Applications of this methodology may include the screening of chemical libraries affecting heart rhythm and the identification of heart rhythm variations in mutants from large-scale forward genetic screens.

Innovative technologies for the assessment of cardiovascular medical devices: state-of-the-art techniques for artificial heart valve testing

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.

Role of the sinuses of Valsalva on the opening of the aortic valve

OBJECTIVEnThe present in vitro study was designed to ascertain whether the presence of sinuses of Valsalva in the aortic root were able to regulate the valve effective orifice area and modulate the gradient across the valve independently from root compliance.nnnMETHODSnFour different root configurations were prepared. Of the 4, 2 were silicon configurations with the same compliance, 1 with and 1 without sinuses of Valsalva, in which a 25-mm Solo stentless aortic valve was sutured inside. The other 2 configurations were obtained by substituting the upper part of the root with a straight Dacron graft or with a Valsalva graft in a remodeling fashion to reproduce the surgical situation. All roots were mounted in a pulse duplicator to measure the pressure decrease across the valve and effective orifice area at different cardiac outputs.nnnRESULTSnWith increasing cardiac output up to 7 L/min, an increase in the pressure decrease across the valve was evident in both configurations without sinuses of Valsalva (7.90 ± 1.7 and 11 mm Hg ± 0.1 mm Hg, respectively) but not in those with sinuses (2.87 ± 0.5 and 2.42 mm Hg ± 0.5 mm Hg). Similarly, with increasing cardiac output, the effective orifice area increased significantly only in the roots with sinuses (5.13 ± 0.5 and 5.47 ± 0.5 vs 3.06 ± 0.3 and 2.50 cm(2) ± 0.02 cm(2), respectively).nnnCONCLUSIONSnWhen the cardiac output is increased to greater than the resting physiologic values, the presence of sinuses of Valsalva, independently of root compliance, prevents an increase in the pressure decrease across the valve by way of an increase of the effective orifice area.

The Evolution of Computational Hemodynamics as a Clinical Tool in Decision Making, Patient Specific Treatment and Clinical Management

This journal issue concludes the two-part Special Issue on the application of computational hemodynamics in clinically relevant problems, in an effort to disseminate the current advances in the field and to stimulate discussion on future research directions. The Special Issue Call for Papers had an overwhelming response, reflecting the richness of techniques, methodologies and applications of computational hemodynamics to enhance the comprehension of a large variety of problems. In summary, it is well accepted that the hemodynamic environment plays a key role in the initiation and progression of blood vessel disease, in short and long term outcome of blood recirculating devices, and in the outcome of surgical strategies. Computational methods, by virtue of user controlled resolution, can provide quantitative, specific-to-subject information still not achievable with current imaging technologies, allowing the evaluation of normal and pathological functions, devices, and treatments. In this sense, computational hemodynamics has the capacity to enhance clinical diagnosis, prognosis and treatment. Specifically, it contributes to: (1) Enriching the knowledge of basic relationships between local hemodynamics and focal disease, testing quantitative hypotheses in controlled conditions; (2) Supporting decisions in the clinical practice, improving therapeutic treatments and surgical strategies; (3) Designing, optimizing and evaluating the performance of implants and devices. In this second Issue, we aim again in presenting the progress done by the research community to enhance and implement the potential features of computational hemodynamics, thus contributing to its translation into clinical practice, and to increase the awareness of the utility of hemodynamic modelling. The availability of advanced computational technology and efficiency of tools has allowed the assimilation of more clinical data from clinical imaging and other technologies into the computational framework and has upgraded computational hemodynamics modelling from image-based to patient-specific. It is expected that this ongoing effort will further be expanded in the near future to: (1) Include more cardiovascular applications, (2) Accelerate the rate of building large datasets, (3) Provide quantitative data useful for proof-of-concept and longitudinal studies on clinically relevant cohorts, and (4) Provide mechanistic explanations to clinical observations. We reiterate here the belief that the possibility to computationally explore a wide range of clinical solutions will enable clinicians gain insights, develop intuitions, and provide constructive feedback and guidance for the development of more representative models. The development of tools for patient-specific simulations will advance therapeutic planning, thanks to the possibility of investigating pre-operative conditions, to virtually explore postoperative scenarios and predict the outcome of therapeutic interventions. Our firm conviction is that this second part of the Special Issue provides a clear proof of evidence of the potential of computational hemodynamics in terms of its capability to provide mechanism-based insights for the study of the onset and progression of cardiovascular disease, patient-specific prediction Diego Gallo

A Versatile Bioreactor for Dynamic Suspension Cell Culture. Application to the Culture of Cancer Cell Spheroids.

A versatile bioreactor suitable for dynamic suspension cell culture under tunable shear stress conditions has been developed and preliminarily tested culturing cancer cell spheroids. By adopting simple technological solutions and avoiding rotating components, the bioreactor exploits the laminar hydrodynamics establishing within the culture chamber enabling dynamic cell suspension in an environment favourable to mass transport, under a wide range of tunable shear stress conditions. The design phase of the device has been supported by multiphysics modelling and has provided a comprehensive analysis of the operating principles of the bioreactor. Moreover, an explanatory example is herein presented with multiphysics simulations used to set the proper bioreactor operating conditions for preliminary in vitro biological tests on a human lung carcinoma cell line. The biological results demonstrate that the ultralow shear dynamic suspension provided by the device is beneficial for culturing cancer cell spheroids. In comparison to the static suspension control, dynamic cell suspension preserves morphological features, promotes intercellular connection, increases spheroid size (2.4-fold increase) and number of cycling cells (1.58-fold increase), and reduces double strand DNA damage (1.5-fold reduction). It is envisioned that the versatility of this bioreactor could allow investigation and expansion of different cell types in the future.

Uncertainty propagation of phase contrast-MRI derived inlet boundary conditions in computational hemodynamics models of thoracic aorta

Abstract This study investigates the impact that uncertainty in phase contrast-MRI derived inlet boundary conditions has on patient-specific computational hemodynamics models of the healthy human thoracic aorta. By means of Monte Carlo simulations, we provide advice on where, when and how, it is important to account for this source of uncertainty. The study shows that the uncertainty propagates not only to the intravascular flow, but also to the shear stress distribution at the vessel wall. More specifically, the results show an increase in the uncertainty of the predicted output variables, with respect to the input uncertainty, more marked for blood pressure and wall shear stress. The methodological approach proposed here can be easily extended to study uncertainty propagation in both healthy and pathological computational hemodynamic models.

Thermodynamic and kinetic stability of the Josephin Domain closed arrangement: evidences from replica exchange molecular dynamics

BackgroundMolecular phenomena driving pathological aggregation in neurodegenerative diseases are not completely understood yet. Peculiar is the case of Spinocerebellar Ataxia 3 (SCA3) where the conformational properties of the AT-3 N-terminal region, also called Josephin Domain (JD), play a key role in the first step of aggregation, having the JD an amyloidogenic propensity itself. For this reason, unraveling the intimate relationship between JD structural features and aggregation tendency may lead to a step forward in understanding the pathology and rationally design a cure. In this connection, computational modeling has demonstrated to be helpful in exploring the protein molecular dynamics and mechanism of action.ResultsConformational dynamics of the JD is here finely investigated by replica exchange molecular dynamics simulations able to sample the microsecond time scale and to provide both a thermodynamic and kinetic description of the protein conformational changes. Accessible structural conformations of the JD have been identified in: open, intermediate and closed like arrangement. Data indicated the closed JD arrangement as the most likely protein arrangement. The protein transition from closed toward intermediate/open states was characterized by a rate constant higher than 700xa0ns. This result also explains the inability of classical molecular dynamics to explore transitions from closed to open JD configuration on a time scale of hundreds of nanoseconds.ConclusionThis work provides the first kinetic estimation of the JD transition pathway from open-like to closed-like arrangement and vice-versa, indicating the closed-like arrangement as the most likely configuration for a JD in water environment. More widely, the importance of our results is also underscored considering that the ability to provide a kinetic description of the protein conformational changes is a scientific challenge for both experimental and theoretical approaches to date.ReviewersThis article was reviewed by Oliviero Carugo, Bojan Zagrovic.

Time dependent non-Newtonian numerical study of the flow field in a realistic model of aortic arch.

A three-dimensional time dependent numerical simulation was performed in a geometric model of aortic arch complete with a realistic aortic root and major branches originating from the arch, for a peak Reynolds number set at 2200 and Womersley number set at 20.4. The computational fluid dynamic analysis was aimed to provide spatial and temporal distribution of the shear stress all along the entire model together with the velocity patterns, related both to the non planar geometry of the aortic system here considered and to the pulsatility imposed on the numerical model to simulate physiologic conditions. A non-Newtonian evolving fluid was considered to account for the actual rheological nature of blood; a comparison on the incidence of wall shear stress, implementing a Newtonian fluid, was also made as reference. The spatial shear stress pattern, within the cardiac cycle, was shown to have higher values in correspondence to the inner wall of the aortic arch and the sites where the major vessels originated from the arch itself. The velocity patterns, on transversal sections of the aorta, resulted in highly skewed morphology. The resulting complex fluid dynamics, established in the aortic arch and in its branches, can be related to the possible endothelium response to mechanical stimuli, induced by wall shear stress, in the promotion of inflammatory events.

Multiresolution Analysis of Heart Rate Variability as Investigational Tool in Experimental Fetal Cardiac Surgery

Multiresolution analysis of heart rate variability derived from aortic blood pressure, acquired before and after (30 and 60xa0min) experimental fetal cardiac bypass performed on five ewes fetuses, was used to investigate the physiological response to an invasive clinical approach. Tachograms were implemented and analyzed by wavelet transform in order to verify the existence of a quantitative relationship between arterial blood gases and time series in the very-low (0.021 < f < 0.084xa0Hz) and low (0.084 < f < 0.337xa0Hz) frequency band. Multiresolution analysis showed an average decreasing trend from basal condition for all the fetuses investigated in the very-low frequency band, while an opposite trend was highlighted in the low frequency band: this resulting behavior could be related to the temporal evolution of blood gas data. Finally, a slight decrease of sympatho-vagal balance was monitored 30xa0min after the cardiac bypass was discontinued compared to basal condition. Multiresolution analysis could give more insights on fetal hypoxemia and could also represent a minimally invasive monitoring tool to limit the damage to the fetoplacental unit during experimental fetal cardiac surgery.