A Computational Tool for the Microstructure Optimization of a Polymeric Heart Valve Prosthesis.

Styrene-based block copolymers are promising materials for the development of a polymeric heart valve prosthesis (PHV), and the mechanical properties of these polymers can be tuned via the manufacturing process, orienting the cylindrical domains to achieve material anisotropy. The aim of this work is the development of a computational tool for the optimization of the material microstructure in a new PHV intended for aortic valve replacement to enhance the mechanical performance of the device. An iterative procedure was implemented to orient the cylinders along the maximum principal stress direction of the leaflet. A numerical model of the leaflet was developed, and the polymer mechanical behavior was described by a hyperelastic anisotropic constitutive law. A custom routine was implemented to align the cylinders with the maximum principal stress direction in the leaflet for each iteration. The study was focused on valve closure, since during this phase the fibrous structure of the leaflets must bear the greatest load. The optimal microstructure obtained by our procedure is characterized by mainly circumferential orientation of the cylinders within the valve leaflet. An increase in the radial strain and a decrease in the circumferential strain due to the microstructure optimization were observed. Also, a decrease in the maximum value of the strain energy density was found in the case of optimized orientation; since the strain energy density is a widely used criterion to predict elastomer's lifetime, this result suggests a possible increase of the device durability if the polymer microstructure is optimized. The present method represents a valuable tool for the design of a new anisotropic PHV, allowing the investigation of different designs, materials, and loading conditions.

Structural changes of block copolymers with bi-modal orientation under fast cyclical stretching as observed by synchrotron SAXS.

Load-bearing tissues are composite materials that depend strongly on anisotropic fibre arrangement to maximise performance. One such tissue is the heart valve, with orthogonally arranged fibrosa and ventricularis layers. Their function is to maintain mechanical stress while being resilient. It is postulated that while one layer bears the applied stress, the orthogonal layer helps to regenerate the microstructure when the load is released. The present paper describes changes in the microstructure of a block copolymer with cylindrical morphology, having a bio-inspired microstructure of anisotropic orthogonally oriented layers, under uniaxial strain. To allow structural observations during fast deformation, equivalent to the real heart valve operation, we used a synchrotron X-ray source and recorded 2D SAXS patterns in only 1 ms per frame. The deformation behaviour of the composite microstructure has been reported for two arrangements of the cylinders in skin and core layers. The behaviour is very different to that observed either for uniaxially oriented or isotropic samples. Deformation is far from being affine. Cylinders aligned in the direction of stretch show fragmentation, but complete recovery of the spacing between cylinders on removal of the load. Those oriented perpendicular to the direction of stretch incline at an angle of approximately 25° to their original direction during load.

A global sensitivity analysis approach applied to a multiscale model of microvascular flow.

A global sensitivity analysis of a multiscale computational model of microvascular flow is presented. A total of 140 simulations have been completed and analyzed varying 6 input parameters and considering their effects on 7 output variables. Interestingly, the vascular network topology has been found as a determinant factor for both vasculature-related and interstitium-related quantities. Regarding the firsts, the vascular network topology has obtained a score of 5.5/6 and 6/6 for average and spatial distribution respectively (where 6 is the maximum and 1 is the minimum). On the other hand, considering interstitium-related quantities, the score is 4/6 and 5/6 for average and spatial distribution respectively. These results suggest that the network topology has a significant influence on the outcome of the computational analysis.

Model of arterial tree and peripheral control for the study of physiological and assisted circulation.

Peripheral vasomotion, interstitial liquid exchange, and cardiovascular system behaviour are investigated by means of a lumped parameter model of the systemic and peripheral circulation, from the aortic valve to the venules. This modelling work aims at combining arterial tree hemodynamics description, active peripheral flow regulation, and fluid exchange. The arterial compartment is constructed with 63 RCL segments and 30 peripheral districts including myogenic control on arterioles, metabolic control on venules, and Starling filtration through capillary membrane. The arterial behaviour is characterised as to the long term stability of pressure/flow waves in the different segments. Peripheral districts show autoregulatory capabilities against pressure changes over a wide range and also self-sustained oscillations mimicking vasomotor activity. A preliminary study was carried out as to the model response to changes induced by cardiopulmonary bypass (CPB). Among the induced alterations, the system responds mainly to hemodilution, which increased peripheral fluid loss and oedema beyond the compensatory capabilities of local regulation mechanisms. This resulted in an overall increase total arterial resistance. Local transport deficits were assessed for each district according to the different metabolic demand. This study shows the requirement of a suitable description of both arteries and peripheral mechanisms in order to describe cardiovascular response non-physiological conditions, as well as assisted circulation or other pathological conditions.

A new method to evaluate patient characteristic response to ultrafiltration during hemodialysis.

BACKGROUND: Several factors are involved in the pathogenesis of dialysis discomfort interfering with optimal fluid removal and reducing the efficacy of the treatment; the most important one is a decrease in blood volume caused by an imbalance between ultrafiltration (UF) and plasmarefilling (PR) rates. OBJECTIVES: This study is aimed at devising a method to tailor the dialysis therapy to each individual patient, by analyzing the relationship between PR and UF during the sessions in stable patients and widening the knowledge of fluid exchanges during the treatment. METHODS: Thirty stable patients undergoing maintenance hemodialysis were enrolled. Three dialysis sessions were monitored for each patient; systemic pressure, blood composition, blood volume % variation, weight loss and conductivity were recorded repeatedly. A Plasma Refilling Index (PRI), defined and calculated by means of parameters measured throughout the dialysis, was introduced as a novel instrument to study plasma refilling phenomena. Results. The PRI provides understanding of patient response (in terms of plasma refilling) to the set UF. In the monitored sessions, the PRI trend is found to be characteristic of each patient; a PRI course that is at variance with the characteristic trend is a signal of inadequate or unusual dialysis scheduling. Moreover, statistical analysis highlights two different PRI trends during the first hour and during the rest of the treatment, suggesting the presence of different treatment phases. CONCLUSION: The main advantage of the PRI index is that it is non-invasive peculiar to each patient and easy to compute in a dialysis routine based on online data recorded by the monitor. A deviation from the characteristic trend may be a warning for the clinician. The analysis of the PRI trend also suggests how to modulate UF as a function of interstitial to intravascular fluid removal balance during dialysis.

A mechanical model lung for hydraulic testing of total liquid ventilation circuits.

A new model lung (ML), designed to reproduce the tracheal pressure vs. fluid flow relationship in animals undergoing total liquid ventilation (TLV) trials, was developed to be used as a mock bench test for neonatal TLV circuits. The ML is based on a linear inertance-resistance-compliance (LRC) lumped-parameter model of the respiratory system with different resistance values for inspiration (R insp ) or expiration (R exp ). The resistant element was set up using polypropylene hollow fibres packed inside a tube. A passive one-way valve was used to control the resistance cross-section area provided for the liquid to generate different values for R insp or R exp , each adjustable by regulating the active length of the respective fibre pack. The compliant element consists of a cylindrical column reservoir, in which bars of different diameter were inserted to adjust compliance (C). The inertial phenomena occurring in the central airways during TLV were reproduced by specifically dimensioned conduits into which the endotracheal tube connecting the TLV circuit to the ML was inserted. A number of elements with different inertances (L) were used to simulate different sized airways. A linear pressure drop-to-flow rate relationship was obtained for flow rates up to 5 l/min. The measured C (0.8 to 1.3 mL cmH2O (-1) kg(-1)), R insp (90 to 850 cmH2O s l(-1)), and R exp (50 to 400 cmH2O s l(-1)) were in agreement with the literature concerning animals weighing from 1 to 12 kg. Moreover, features observed in data acquired during in vivo TLV sessions, such as pressure oscillations due to fluid inertia in the upper airways, were similarly obtained in vitro thanks to the inertial element in the ML.

The cardiac torsion as a sensitive index of heart pathology: A model study.

The torsional behaviour of the heart (i.e. the mutual rotation of the cardiac base and apex) was proved to be sensitive to alterations of some cardiovascular parameters, i.e. preload, afterload and contractility. Moreover, pathologies which affect the fibers architecture and cardiac geometry were proved to alter the cardiac torsion pattern. For these reasons, cardiac torsion represents a sensitive index of ventricular performance. The aim of this work is to provide further insight into physiological and pathological alterations of the cardiac torsion by means of computational analyses, combining a structural model of the two ventricles with simple lumped parameter models of both the systemic and the pulmonary circulations. Starting from diagnostic images, a 3D anatomy based geometry of the two ventricles was reconstructed. The myocytes orientation in the ventricles was assigned according to literature data and the myocardium was modelled as an anisotropic hyperelastic material. Both the active and the passive phases of the cardiac cycle were modelled, and different clinical conditions were simulated. The results in terms of alterations of the cardiac torsion in the presence of pathologies are in agreement with experimental literature data. The use of a computational approach allowed the investigation of the stresses and strains in the ventricular wall as well as of the global hemodynamic parameters in the presence of the considered pathologies. Furthermore, the model outcomes highlight how for specific pathological conditions, an altered torsional pattern of the ventricles can be present, encouraging the use of the ventricular torsion in the clinical practice.

Perfluorocarbons attenuate oxidative lung damage.

The aim of this study was to investigate the effect of tidal liquid ventilation (TLV) compared to conventional mechanical ventilation (CMV) on oxidative lung damage in the setting of acute respiratory distress syndrome (ARDS). After repeated lung lavages, 10 minipigs were treated with CMV or TLV for 4 hr before the animals were sacrificed. Samples for blood gas analysis and bronchial aspirate samples were withdrawn before the induction of lung injury, and at 10 min, 2 hr, and 4 hr after the beginning of ventilatory support. To assess lung oxidative damage, total hydroperoxide (TH) and advanced oxidation protein product (AOPP) concentrations were measured in bronchial aspirate samples. After 2 and 4 hr of ventilatory support, partial oxygen tension (PaO(2)) and base excess (BE) were significantly higher in the TLV group than in the CMV group, while PaCO(2) was slightly higher, but with no statistical significance. In the CMV group, the AOPP level was significantly higher at 4 hr than at baseline. TH and AOPP bronchial aspirate concentrations were higher in the CMV group than in the TLV group at 2 and 4 hr of ventilation. We conclude that animals treated with TLV showed lower oxidative lung damage compared to animals treated with CMV.

A numerical and experimental study of compliance and collapsibility of preterm lamb tracheae.

Knowledge of the mechanical behaviour of immature tracheae is crucial in order to understand the effects exerted on central airways by ventilatory treatments, particularly of Total Liquid Ventilation. In this study, a combined experimental and computational approach was adopted to investigate the compliance and particularly collapsibility of preterm lamb tracheae in the range of pressure likely applied during Total Liquid Ventilation (-30 to 30 cmH2O). Tracheal samples of preterm lambs (n = 5; gestational age 120-130 days) were tested by altering transmural pressure from -30 to 30 cmH2O. Inflation (Si) and collapsing (Sc) compliance values were calculated in the ranges 0 to 10 cmH2O and -10 to 0 cmH2O, respectively. During the tests, an asymmetric behaviour of the DeltaV/V0 vs. P curves at positive and negative pressure was observed, with mean Si = 0.013 cmH2O(-1) and Sc = 0.053 cmH2O(-1). A different deformed configuration of the sample regions was observed, depending on the posterior shape of cartilaginous ring. A three-dimensional finite-element structural model of a single tracheal ring, based on histology measurements of the tested samples was developed. The model was parameterised in order to represent rings belonging to three different tracheal regions (craniad, median, caudal) and numerical analyses replicating the collapse test conditions were performed to evaluate the ring collapsibility at pressures between 0 and -30 cmH2O. Simulation results were compared to experimental data to verify the model's reliability. The best model predictions occurred at pressures -30 to -10 cmH2O. In this range, a model composed of median rings best interpreted the experimental data, with a maximum error of 2.7%; a model composed of an equal combination of all rings yielded an error of 12.6%.

Intra-amniotic pressure is not affected by amniocentesis between 13 and 18 weeks of gestation.

Changes in amniotic fluid pressure before and after amniocentesis fell within the range of +/- 5 mmHg, except when uterine contractions were present. Intra-amniotic pressure is not affected by amniocentesis between 13 and 18 weeks of gestation. Amniotic fluid pressure was recorded in 82 pregnancies of patients undergoing genetic amniocentesis to determine whether sampling of amniotic fluid between 13 and 18 weeks changed intra-amniotic pressure. Pressures were recorded through a needle and saline filled catheter with a zero-level at the needle tip. Amniotic fluid pressure was unrelated to gestational age (P = 0.962) during the weeks we performed our measurements. Fluid samples of 12.6% of the total volume in a group of early genetic amniocentesis (n = 65) and of 7.5% of the total volume in a group of late genetic amniocentesis (n = 17) did not change significantly amniotic fluid pressure values. An increase in pressure of more than 5 mmHg only occurred in cases where uterine contractions were present. Other than these cases, all pressure change values fell within the range of +/- 5 mmHg. No difference in pregnancy outcome were present within the two groups. An argument for a standard method for stationing pressure is presented.

Liquid ventilation: a mathematical model of gas diffusion in the premature lung.

The liquid ventilation (LV) technique was previously demonstrated to be a valuable alternative to ordinary gas ventilation, particularly for newborn patients with severely distressed lungs. This work describes a mathematical model of gas transfer phenomena occurring within the lungs of a preterm newborn baby ventilated with liquid perfluorocarbon (PFC) RM-101. The model was conceived in order to perform computer simulations of LV treatments. Its input parameters are tidal volume, respiratory frequency, oxygen and carbon dioxide tension in inlet PFC; its output data are the partial pressures of respiratory gases in the alveolar environment. Such values may be evaluated at any instant from the beginning of the treatment, in order to judge whether the therapy is able to meet the necessary conditions to arterialize properly the patient's venous blood. The model also enables optimisation procedures to be defined and performed. Quantitative results and graphs are supplied, with reference to the simulation of LV applied to a preterm newborn of 28 gestational weeks. The main results point out that a relatively short duration of initial transients is attainable (200 to 240 s) and that blood arterialization is possible even with low oxygen tension in inlet PFC (29.7 kPa (223 mmHg)).

A model of neonatal tidal liquid ventilation mechanics.

Tidal liquid ventilation (TLV) with perfluorocarbons (PFC) has been proposed to treat surfactant-deficient lungs of preterm neonates, since it may prevent pulmonary instability by abating saccular surface tension. With a previous model describing gas exchange, we showed that ventilator settings are crucial for CO(2) scavenging during neonatal TLV. The present work is focused on some mechanical aspects of neonatal TLV that were hardly studied, i.e. the distribution of mechanical loads in the lungs, which is expected to differ substantially from gas ventilation. A new computational model is presented, describing pulmonary PFC hydrodynamics, where viscous losses, kinetic energy changes and lung compliance are accounted for. The model was implemented in a software package (LVMech) aimed at calculating pressures (and approximately estimate shear stresses) within the bronchial tree at different ventilator regimes. Simulations were run taking the previous model's outcomes into account. Results show that the pressure decrease due to high saccular compliance may compensate for the increased pressure drops due to PFC viscosity, and keep airway pressure low. Saccules are exposed to pressures remarkably different from those at the airway opening; during expiration negative pressures, which may cause airway collapse, are moderate and appear in the upper airways only. Delivering the fluid with a slightly smoothed square flow wave is convenient with respect to a sine wave. The use of LVMech allows to familiarize with LV treatment management taking the lungs' mechanical load into account, consistently with a proper respiratory support.

Umbilical flow distribution to the liver and the ductus venosus in human fetuses during gestation: an anatomy-based mathematical modeling.

The partitioning of umbilical vein blood flow between fetal liver and ductus venosus may be an indicator of the fetal well-being, because the goal of the ductus venosus is to supply oxygen and nutrients to heart and brain. Both distribution and blood flow rate of the umbilical vein are functions of the local vascular impedances that, in turn, depend on the anatomical features of the related vessels. In order to investigate the venous blood flows in human fetuses during a normal gestation, a simple lumped parameter mathematical model was developed on the basis of some information achievable by ultrasonographic techniques. Particularly, the diameter and length of umbilical vein and ductus venosus and the volume of the liver were used to derive the vascular impedances. Three different impedance models were adopted for the umbilical vein, the ductus venosus and the hepatic circulation. A linear model described viscous hydraulic dissipations through the umbilical vein, while a quadratic pressure-flow relationship was used for the ductus venosus due to the irregular local hemodynamics at its inlet. Finally, the equivalent impedance of the whole hepatic network was related to the hepatic volume assuming a tree-like, symmetric and self-similar fractal geometry. The hepatic vascular resistances predicted according to the fractal analysis were quite consistent with some experimental measurements in fetal lambs. In agreement with clinical observations, the model predicted blood flows through the ductus venosus and umbilical vein increasing (from about 25 to 75 ml/min and from about 45 to 370 ml/min, respectively) throughout the gestation (20-40 weeks), while the flow fraction shunted via the ductus venosus diminishes (from about 50 to 20%).

The use of liquid perfluorocarbons for neonatal lung ventilation.

Over the last years, physiological studies have proved that ventilation with a oxygenated liquid perfluorocarbon (PFC) provides effective gas exchange and acid base balance and improves lung function and recovery. Low surface tension and high respiratory gas solubility enable adequate oxygenation and carbon dioxide removal at low insufflation pressure. The elimination of air-liquid interfacial surface tension has recently suggested the adoption of total liquid PFC ventilation as an investigational therapy for severe respiratory distress in human infants. This work is aimed to determine the optimal volumes of PFC to be delivered, the frequency of the ventilatory cycle, the oxygen flow rate and the best circuit set up for neonatal application. The optimisation was obtained through the implementation of a simulation mathematical model of oxygen diffusion in a PFC-ventilated lung and of gas exchange between alveolar environment and pulmonary blood flow. The results show that total liquid ventilation is a valid alternative to traditional gas ventilation, particularly when immature neonates with insufficient or absent production of surfactant are concerned.

Haemodynamic alteration in patients undergoing chronic haemodialysis.

Fifteen elderly patients, 13 of them undergoing chronic haemodialysis, 1 acute and 1 coming from Continuous Ambulatory Peritoneal Dialysis (CAPD) either with no significant cardiovascular alteration or presenting various cardiovascular pathologies were studied to investigate the possibility of onset of hypotensive episodes during dialytic treatment depending on cardiac or vascular alteration in the patients. Monitoring of the arterial pressure on the contralateral arm and on the lower limbs by using the Takeda System, made it possible to compute the Windsor Index (WI). The figures obtained were correlated to the Ejection Fraction Index (EFI) to investigate the relation between WI alteration and haemodynamic variations in the patient. The results show that cardiothoracic recirculation is much more present in those patients with pathologies that affect EFI which worsens during dialysis due to the loss of fluid. Moreover the results obtained from the two patients with temporary access and no evident cardiovascular pathology show the constancy of the haemodynamic parameters throughout the dialytic treatment.

An approach to computer automation of the extracorporeal circulation.

In order to move towards extracorporeal circulation (ECC) automation, a virtual simulation of the process was designed. The ECC model is composed of a virtual patient linked to a virtual ECC circuit. A user interface panel allows to set control parameters for the simulation and to visualize results. It is possible to switch between manual and automatic control. Meaningful hemodynamic and hematochemical variables are continuously shown along with a score (from 0 to 10). The virtual model can play a crucial role in educating and training the personnel devoted to the managing of the heart-lung machine.

Pressure drop vs flow relationship in isolated preterm lamb tracheae.

Knowledge of immature tracheae mechanical behavior is fundamental in understanding the effects exerted on the upper airways by tidal liquid ventilation (TLV). Particularly, negative pressure can take place along the airways during expiration, which can cause airway collapse and flow limitation; therefore, representing a critical issue in preterm infant patients, whose airways are less stiff than adult ones. In this study, we investigated the expiratory pressure drop vs flow relationship of isolated preterm lamb tracheal samples to determine their hydraulic resistance, collapse pressure and collapse flow rate; a liquid flow through the samples was obtained by applying negative pressure at the outlet (cephalad) extremity of the tra-cheal sample, while keeping the inlet (caudal) extremity at atmospheric pressure. Histological analyzes were performed on the tracheal samples after each test session, in order to examine the morphological structure of the tracheal wall. Flow resistance tests demonstrated progressive lumen narrowing at increasing pressure drop (∆P=P in -P out ). The flow rate increased with ∆P un-til a plateau was reached, and then decreased, describing the onset of a collapse phenomenon; however, complete occlusion was not reached. The tracheal samples demonstrated a similar behavior to that of a Starling resistor during the collapse phase: when a critical ∆P was reached, collapse was observed starting at the outlet region, which was subjected to the greatest negative pressure, then propagating towards the caudal direction. (Journal of Applied Biomaterials & Biomechanics 2004; 2: 177-82).

The upper respiratory tract of dolphins.

The functional anatomy of the respiratory system of dolphins has been scarcely studied. Specifically, the capacity of the system to resist pressure changes during diving has not been fully understood. Here we shortly describe the upper respiratory tract of dolphins based on three common species, the bottlenose dolphin Tursiops truncatus, the Risso's dolphin Grampus griseus, and the striped dolphin Stenella coeruleoalba. We emphasize the keymorphological features that represent evolutionary adaptations to life in the water, and, furthermore, also present a model of the tracheo-bronchial tree based on mechanical characterization and subsequent computational simulation of its biomechanical behaviour. Comparisons with the goat allowed us to determine how different structures may respond to diving-related pressure.

Normalization of experimental results with respect to inlet conditions in membrane oxygenator testing.

This study looked at the problem of the excessive variability in oxygenator testing results, induced by variation of inlet parameters, particularly of inlet oxyhaemoglobin saturation. The investigation was carried out in the laboratory. An in vitro circuit was used to perfuse a small oxygenating cell. Blood flow rate (BFR) and film thickness (BFT) were varied to obtain different oxygenation conditions, while the inspired oxygen fraction (FiO2) and ventilation ratio were kept at constant values. With each test condition, inlet saturation was varied in the range 60-70% and a number of veno-arterial blood samples (at least 20) were withdrawn and analysed for numerical computing and statistical analysis. The generic law relating oxygenation increment to inlet saturation was found. This allowed a useful normalization procedure to be applied to oxygenator testing results and render them comparable, even if obtained at different inlet conditions.

Oxygen exchange mechanisms in the human placenta: mathematical modelling and simulation.

An exact knowledge of the human fetus's respiratory mechanisms is still lacking; in particular, the role of human placental anatomy in oxygen exchange has not yet been studied satisfactorily. In this paper, a mathematical model of placenta as O2 exchanger between maternal and fetal blood was developed; it led to the solution of equations based upon diffusion laws and the haemoglobin dissociation curve. Particular care was taken to represent the regimen of laminar motion or whirling into the capillaries. Theoretical results were compared, under physiological conditions, with clinical data relating to fetal oxygenated blood p O2 during the second half of gestation (20th-38th weeks), and a theoretical confirmation of the decreasing effectiveness of placental O2 exchange during gestation was found. The result was able to describe oxygen exchange during a period in which clinical data are scanty (23rd-30th weeks). The effects of some pathological events on O2 exchange were then simulated. Model parameters were changed to simulate the effects on oxygen exchange of some typical pathological variations of placental anatomical features: exchange surface thickness and capillary length. The curves obtained for different gestational ages can easily be correlated with echographic measures of placental volume and dimensions of placental capillaries. The results also show that the human placenta is more sensitive to pathologies when it is young than at term of gestation.