Haematocrit heterogeneity in blood flows past microfluidic models of oxygenating fibre bundles.

Blood oxygenators act as an extracorporeal artificial lung during certain types of cardiac surgery and intensive care therapies. Inside these devices, blood is forced to flow across an oxygenating bundle, encountering interstitial gaps comparable to those typical of the microvasculature. Despite the well-known effects of such length scales on haemorheology and red blood cell (RBC) behavior, these are generally overlooked in oxygenator modeling and design; it is persistently assumed that RBCs are homogeneously distributed throughout the oxygenating bundle, independently of their microstructure arrangement or main flow directions. The goal of this study is to provide preliminary experimental evidence of heterogeneous RBC distributions inside oxygenating fibre bundles. To this end, a number of microchannels were manufactured inspired by actual oxygenating devices, considering simplified versions of their microstructure. These comprise staggered arrays of micro pillars, which were perfused with RBC suspensions, with feed haematocrit (Ht) and velocities relevant for clinical use. The microchannels were imaged using a microscope and high-speed camera to accurately capture cell distribution. The imaged blood flows revealed the non-uniform nature of RBC distributions in the arrays, characterized by local Ht gradients particularly around the O2 sources inside the bundle. These heterogeneous distributions should be accounted for during oxygenator design, as RBC concentration plays a key role in O2 transport and, ultimately, overall device performance.

Tuning of a deformable image registration procedure for skin component mechanical properties assessment.

Several studies report the mechanical properties of skin tissues but their values largely depend on the measurement method. Therefore, we investigated the feasibility of recognizing the cellular constituents mechanical properties of pigmented skin by Confocal Laser Scanner Microscopy (CLSM). With this purpose, an healthy volunteer was examined in three areas nearby a pigmented skin lesion in two configurations: deforming and non deforming the nevus. The tissue displacement of the nevus was then assessed by means of deformable registration of the images in these two configurations. There are several registration strategy able to overcome this task, among them, we proposed two methods with different deformation models: a Free Form Deformation (FFD) model based on b-spline and a second one based on Demons Registration Algorithm (DRA). These two strategies need the definition of several parameters in order to obtain optimal registration performances. Thus, we tuned these parameters by means of simulated data and evaluated their registration abilities on the real in vivo CLSM acquisitions in the two configurations. The results showed that the registration using DRA had a better performance in comparison to the FFD one, in particular in two out of the three areas the DRA performance was significantly better than the FFD one. The registration procedure highlighted deformation differences among the chosen areas.

How could robotic training and botolinum toxin be combined in chronic post stroke upper limb spasticity? A pilot study.

BACKGROUND: Spasticity has a role of primary importance in functional motor recovery of upper limb after a stroke. The widespread intervention is the botulinum toxin neurolysis, however robotic training could have a role as useful addition to this conventional therapy. AIM: The aim of this study was to verify how the combination of a short robotic training and chemical neurolysis reduces spasticity and improves function in chronic post-stroke patients. DESIGN: Prospective single blind randomized controlled clinical trial. SETTING: Post-stroke outpatients. POPULATION: Fifteen chronic post-stroke outpatients with severe upper limb spastic paresis. METHODS: Two experimental groups underwent ten sessions of robotic training, alone (Group A) or with Botulinum toxin neurolysis (Group B). Evaluation of motor function with Fugl Meyer Upper Limb Assessment Scale (FMA) and Box & Block Test (B&B), disability with Functional Indipendence Measure (FIM), spasticity with Modified Ashworth Scale (MAS), and the Quality of Life (Euro-Qol) and muscular recruitment pattern with dynamic surface electromyography were carried out before and after the interventions. RESULTS: Both groups showed improvement in FMA (Group A 8.25 and Group B 5.29). Higher improvement in B&B was detected in the group A (2.62 versus 0,14 in Group B). MAS was improved more in the Group B (-0,86 versus -0,14 in Group A). In both groups, sEMG showed a reduction of co-contractions and an increase of agonist muscles recruitment during the reaching movement and the robotic exercises. CONCLUSION: The demonstrated improvement in motor function and in muscular activation pattern suggests how a short robotic training could be effective in chronic post-stroke spasticity of upper limb and in less severe spasticity the only robotic treatment could be effective. CLINICAL REHABILITATION IMPACT: With the limits of small sample, the results showed some equivalence between these two approaches with respect to motor recovery and spasticity reduction suggesting that the cost effectiveness of each treatment may have an important role in this choice.

Deployment of self-expandable stents in aneurysmatic cerebral vessels: comparison of different computational approaches for interventional planning.

In the last few years, there has been a growing focus on faster computational methods to support clinicians in planning stenting procedures. This study investigates the possibility of introducing computational approximations in modelling stent deployment in aneurysmatic cerebral vessels to achieve simulations compatible with the constraints of real clinical workflows. The release of a self-expandable stent in a simplified aneurysmatic vessel was modelled in four different initial positions. Six progressively simplified modelling approaches (based on Finite Element method and Fast Virtual Stenting--FVS) have been used. Comparing accuracy of the results, the final configuration of the stent is more affected by neglecting mechanical properties of materials (FVS) than by adopting 1D instead of 3D stent models. Nevertheless, the differences showed are acceptable compared to those achieved by considering different stent initial positions. Regarding computational costs, simulations involving 1D stent features are the only ones feasible in clinical context.

Failure of silicone gel breast implants: is the mechanical weakening due to shell swelling a significant cause of prostheses rupture?

Silicone gel-filled breast implants nowadays are commonly used in breast surgery. Despite the improvements carried out during the years in the device design and manufacturing technologies, the long-term reliability of such prostheses is still doubted and the phenomena involved in the prostheses failure not yet clearly defined. This study investigates rupture causes by analysing the mechanical properties of failed and intact implants in the recent generation of silicon gel breast implants. The main scope is to assess whether mechanical weakness of the shells should be considered as a major cause of breast implant rupture or, on the contrary, the prosthesis shell damage is likely due to other random factors. Some tests were performed on the shells of a wide number of explanted prostheses, to evaluate the mechanical properties as a function of prostheses status at explantation (intact/ruptured) and variable degree of swelling. A weakening of the shell mechanical properties, so as a significant difference in the ultimate strength and stiffness of intact versus ruptured prostheses, was found. This attenuation of the properties may be justified as a consequence of the shell swelling phenomenon during implantation and has to be considered as a significant mechanism for silicone gel breast implant failure.

Virtual surgeries in patients with congenital heart disease: a multi-scale modelling test case.

The objective of this work is to perform a virtual planning of surgical repairs in patients with congenital heart diseases--to test the predictive capability of a closed-loop multi-scale model. As a first step, we reproduced the pre-operative state of a specific patient with a univentricular circulation and a bidirectional cavopulmonary anastomosis (BCPA), starting from the patient's clinical data. Namely, by adopting a closed-loop multi-scale approach, the boundary conditions at the inlet and outlet sections of the three-dimensional model were automatically calculated by a lumped parameter network. Successively, we simulated three alternative surgical designs of the total cavopulmonary connection (TCPC). In particular, a T-junction of the venae cavae to the pulmonary arteries (T-TCPC), a design with an offset between the venae cavae (O-TCPC) and a Y-graft design (Y-TCPC) were compared. A multi-scale closed-loop model consisting of a lumped parameter network representing the whole circulation and a patient-specific three-dimensional finite volume model of the BCPA with detailed pulmonary anatomy was built. The three TCPC alternatives were investigated in terms of energetics and haemodynamics. Effects of exercise were also investigated. Results showed that the pre-operative caval flows should not be used as boundary conditions in post-operative simulations owing to changes in the flow waveforms post-operatively. The multi-scale approach is a possible solution to overcome this incongruence. Power losses of the Y-TCPC were lower than all other TCPC models both at rest and under exercise conditions and it distributed the inferior vena cava flow evenly to both lungs. Further work is needed to correlate results from these simulations with clinical outcomes.

Uterine artery blood flow volume in pregnant women with an abnormal pulsatility index of the uterine arteries delivering normal or intrauterine growth restricted newborns.

The aim of this study was to assess and compare uterine artery (UtA) blood flow volume in pregnant patients with an abnormal uterine Doppler pulsatility index (PI) who delivered fetuses with an appropriate weight for gestational age (AGA) or with intrauterine growth restricted (IUGR). We prospectively recruited singleton pregnancies with abnormal uterine arteries P.I. between 18 and 38 weeks of gestation regardless of estimated fetal weight (EFW). Vessel diameter and blood flow velocity were measured along the UtA upstream to the vessel bifurcation in both the right and left UtAs. Uterine blood flow volumes measured in these pregnancies were compared to historical Control-pregnancies. Forty-three patients delivered at term a normal weight newborn (AGA-pregnancies). Thirty patients delivered growth restricted newborns at 32 weeks (i.r. 29-36w) with a median weight of 1160 gr (i.r. 1000-2065 gr) (IUGR-pregnancies). At mid-gestation (18 + 0 - 25 + 6 weeks + days of gestation) a significantly lower uterine blood flow volume per unit weight was observed between the two study groups and compared to controls: 142 ml/min/kg in IUGR-pregnancies, 217 ml/min/kg in AGA-pregnancies and 538 ml/min/kg in Control-pregnancies. These striking differences in blood flow volume were already present at mid-gestation, at a time when EFW was still normal. In late gestation (27 + 0 - 37 + 6 weeks + days of gestation), pregnancies with an abnormal uterine P.I. showed persistently low UtA flow (<50% of controls) even when corrected for fetal weight: 81 ml/min/kg in IUGR-pregnancies, 105 ml/min/kg in AGA-pregnancies, and 193 ml/min/kg in Control-pregnancies; p < 0.0001. Our findings are consistent with other recent studies regarding the association between reduced uterine blood flow volume and fetal growth restriction. However, the study brings new insight into the finding of abnormal uterine P.I. in normally grown fetuses typically dismissed as "falsely abnormal" or "false positive" findings. Our study suggests that blood flow volume measurement may serve as a new tool to assess this group of patients and possibly those with ischemic placental diseases that may provide some basis for therapeutic interventions.

Blood flow volume of uterine arteries in human pregnancies determined using 3D and bi-dimensional imaging, angio-Doppler, and fluid-dynamic modeling.

The primary aim of this pilot study was to study uterine artery (UtA) blood flow volume in uneventful human pregnancies delivered at term, at mid and late gestation by means of 3D and bi-dimensional ultrasound imaging with angio-Doppler combined with fluid-dynamic modeling. Secondary aims were to correlate flow volume to placental site and to UtA Pulsatility Index (PI). Women with singleton, low-risk pregnancies were examined at mid and late gestation. The structure and course of the uterine artery (UtA) was studied in each patient by means of 3D-angio-Doppler and included vessel diameter D, blood flow velocity and PI (measured along the UtA). Fetal weight estimation and placental insertion site were assessed by ultrasound. A robust fluid-dynamic modeling was applied to calculate absolute flow and flow per unit fetal weight. Mean UtA diameter and blood flow velocity increased significantly (p < 0.0001) from mid-gestation to late gestation from 2.6 mm and 67.5 cm/s, to 3.0 mm and 85.3 cm/s, respectively, yielding an increasing absolute flow troughout gestation. h coefficient, derived by fluid-dynamic modeling to calculate mean velocity, increased significantly from 0.52 at mid-gestation to 0.57 at late gestation. UtA blood flow volume ml/min/kg-fetal weight was significantly higher at mid-gestation than at late gestation (535 ml/min/kg vs 193 ml/min/kg; p < 0.0001). In cases with strictly lateral placentas the ipsilateral UtA accommodates at mid and late gestation 63% and 67% of the total UtA flow. In central placentas UtA flow was evenly distributed between the two vessels. An inverse correlation was observed between PI and blood flow volume ml/min/kg (Pearson's coefficient r = -0.54). Our work confirms the technological and methodological limitations in the measurement of uterine artery blood flow. However, Doppler measurements supported by three-dimensional angio imaging of the uterine vessel, high resolution imaging and diameter measurement, and a robust mathematical model of local circulation adds a genuine new area of investigation into human uterine circulation during pregnancy.

Computational models to predict stenosis growth in carotid arteries: which is the role of boundary conditions?

This work addresses the problem of prescribing proper boundary conditions at the artificial boundaries that separate the vascular district from the remaining part of the circulatory system. A multiscale (MS) approach is used where the Navier-Stokes equations for the district of interest are coupled to a non-linear system of ordinary differential equations which describe the circulatory system. This technique is applied to three 3D models of a carotid bifurcation with increasing stenosis resembling three phases of a plaque growth. The results of the MS simulations are compared to those obtained by two stand-alone models. The MS shows a great flexibility in numerically predicting the haemodynamic changes due to the presence of a stenosis. Nonetheless, the results are not significantly different from a stand-alone approach where flows derived by the MS without stenosis are imposed. This is a consequence of the dominant role played by the outside districts with respect to the stenosis resistance.

Modeling and mechanobiology of cerebral aneurysms.

The purpose of this work is to review the computational models of the adaptive behavior of the cerebral vascular wall aimed at simulating aneurysm formation and enlargement. Cerebral aneurysms are localized abnormal enlargements of the intracranial arterial vessels. The origin of this pathology is still unclear: however, aneurysm formation is thought to be the result of interplay between biomechanical properties of the vessel wall and their possible changes, such as adaptive response to mechanical stimuli. Recently, different computational approaches were suggested in the literature aiming to describe the mechanobiology of the cerebral vascular wall. Most of the computational adaptive models showed a common approach for the geometrically non-linear kinematic description of the phenomenon, whilst the constitutive laws defining the rates of growth variables may differ considerably according to the specific phenomenon considered. These studies allowed the reproduction of some peculiar aspects of aneurysm mechanobiology; however, continued interdisciplinary research is mandatory for a better understanding of the mechanisms involved in the evolution of cerebral aneurysms.

An axisymmetric computational model of skin expansion and growth.

Skin expansion is the principal technique used in plastic surgery to repair large cutaneous defects, typically after tumour removal, burn care, craniofacial surgery and post-mastectomy breast reconstruction. It allows a gain of new tissue by means of gradual expansion of a prosthesis, surgically implanted beneath the patient's skin. Nevertheless, wide clinical use is not supported by a deep quantitative knowledge of the phenomena occurring during the expansion. A finite element model of the skin expansion was developed to evaluate the stresses and the strains of the skin due to the expander inflation and validated by proper in vitro experiments; furthermore, a growth model based on the mechanical stimulus was implemented to estimate the skin area gain. The developed computational approach, composed of the skin expansion model interaction and the growth law, proved its validity to investigate skin expansion phenomena: its use suggests a new predictive tool to optimize clinical procedures and the expander devices' design.

Spatial velocity profile changes along the cord in normal human fetuses: can these affect Doppler measurements of venous umbilical blood flow?

OBJECTIVE: Several studies have assumed a parabolic velocity profile through the umbilical vein (UV) to derive the mean spatial velocity that is indispensable for flow rate calculations. However, the structure and arrangement of the umbilical cord suggest that velocity profiles may vary. The aim of this study was to evaluate UV spatial flow velocity profiles at different sites along the umbilical cord. METHODS: Ten singleton pregnancies with a gestational age between 26 and 34 weeks were included in the study. Ultrasound equipment with an inbuilt function for analysis of the spatial velocity profile along a line located in a fixed plane was used to obtain UV velocity profiles. Velocity profiles were obtained at the placental insertion and in a free intra-amniotic loop of the cord. Two-dimensional (2D) velocity distribution coefficients were evaluated as ratios between mean and maximum velocities along the investigated lines. RESULTS: 2D velocity distribution coefficients at the placental insertion (0.85 +/- 0.03) were significantly higher (P < 0.00001) than those obtained from a free loop of cord (0.76 +/- 0.03). Values indicated that velocity profiles are approximately flat at the placental insertion and become more parabolic moving downstream. Moreover, profiles become skewed in association with cord curvature and show peculiar biphasic shapes immediately downstream from the placenta. CONCLUSIONS: Flow velocity profiles in the UV are not perfectly parabolic and modify along the cord. These characteristics may affect the evaluation of UV blood flow rate.

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%).

Multiscale modelling as a tool to prescribe realistic boundary conditions for the study of surgical procedures.

This work was motivated by the problems of analysing detailed 3D models of vascular districts with complex anatomy. It suggests an approach to prescribing realistic boundary conditions to use in order to obtain information on local as well as global haemodynamics. A method was developed which simultaneously solves Navier-Stokes equations for local information and a non-linear system of ordinary differential equations for global information. This is based on the principle that an anatomically detailed 3D model of a cardiovascular district can be achieved by using the finite element method. In turn the finite element method requires a specific boundary condition set. The approach outlined in this work is to include the system of ordinary differential equations in the boundary condition set. Such a multiscale approach was first applied to two controls: (i) a 3D model of a straight tube in a simple hydraulic network and (ii) a 3D model of a straight coronary vessel in a lumped-parameter model of the cardiovascular system. The results obtained are very close to the solutions available for the pipe geometry. This paper also presents preliminary results from the application of the methodology to a particular haemodynamic problem: namely the fluid dynamics of a systemic-to-pulmonary shunt in paediatric cardiac surgery.

Doppler investigation in intrauterine growth restriction--from qualitative indices to flow measurements: a review of the experience of a collaborative group.

In 1997 we started a collaboration among three groups, combining our experience with Doppler examination of the human fetus, blood flow studies on fetal lamb, and mathematical modeling of human circulation. In preliminary investigations on fetal lambs, the same Doppler method designed for the human fetus was used to measure venous blood flow in the umbilical veins of seven fetal lambs. Doppler measurements and diffusion technique groups for umbilical venous flow were 210.8+/-18.8 and 205.7+/-38.5 ml/min/kg, respectively (p = 0.881). In human pregnancy the interobserver variabilities for the vein diameter, mean velocity, and absolute umbilical venous blood were 2.9%, 7.9%, and 12.7%, respectively. A cross-sectional study allowed us to establish normal reference values. Venous blood flow/kg of estimated fetal weight showed a nonsignificant linear reduction with gestational age, from 128.7 ml/min/kg at 20 weeks to 104.2 ml/min/kg at 38 weeks. In a series of 37 growth-restricted fetuses, the UV flow per kilogram was significantly lower in the more severe growth-restricted fetuses (abdominal circumference below the second percentile and abnormal umbilical arterial p.i.) than in normal comparable fetuses (p < 0.001). In a series of 140 normal fetuses, we calculated that the absolute blood flow rate in the ductus venosus (DV) increases significantly with advancing gestational age from 20 to 38 weeks of gestation (from 23.2+/-9.6 ml/min to 43.5+/-21.5 ml/min). This means that the percentage of umbilical blood flow shunted through the DV decreases significantly during gestation (from 50% at midgestation to 20% at 38 weeks). In a series of 45 growthrestricted fetuses, delivered because of nonreactive fetal heart rate (group 2) and for other reasons but still with a normal heart rate pattern (group 1), we measured the ductal inlet diameter. In these fetuses, the diameters at the ductal isthmus, normalized for the dimension of the abdominal circumference (inlet diameter/abdominal circumference), were significantly larger (group 1 = 6.8+/-2.3; group 29.4+/-2.8 ) than in the control group (6.1+/-0.3). This means that in this subset of fetuses the amount of blood shunted can be increased as a compensatory mechanism.

In vitro steady-flow analysis of systemic-to-pulmonary shunt haemodynamics.

A modified Blalock-Taussig shunt is a connection created between the systemic and pulmonary arterial circulations to improve pulmonary perfusion in children with congenital heart diseases. Survival of these patients is critically dependent on blood flow distribution between the pulmonary and systemic circulations which in turn depends upon the flow resistance of the shunt. Previously, we investigated the pressure-flow relationship in rigid shunts with a computational approach. to estimate the pulmonary blood flow rate on the basis of the in vivo measured pressure drop. The present study aims at evaluating, in vitro how the anastomotic distensibility and restrictions due to suture presence affect the shunt pressure-flow relationship. Two actual Gore-Tex shunts (3 and 4 mm diameters) were sutured to compliant conduits by a surgeon and tested at different steady flow rates (0.25-11 min(-1)) and pulmonary pressures (3-34 mmHg). Corresponding computational models were also created to investigate the role of the anastomotic restrictions due to sutures. In vitro experiments showed that pulmonary artery pressure affects the pressure-flow relationship of the anastomoses. particularly at the distal site. However, this occurrence scarcely influences the total shunt pressure drop. Comparisons between in vitro and computational models without anastomotic restrictions show that the latter underestimates the in vitro pressure drops at any flow rate. The addition of the anastomotic restrictions (31 and 47% of the original area of 3 and 4 mm shunts, respectively) to the computational models reduces the gap, especially at high shunt flow rate and high pulmonary pressure.

Modeling of the Norwood circulation: effects of shunt size, vascular resistances, and heart rate.

Hypoplastic left heart syndrome is the most common lethal cardiac malformation of the newborn. Its treatment, apart from heart transplantation, is the Norwood operation. The initial procedure for this staged repair consists of reconstructing a circulation where a single outlet from the heart provides systemic perfusion and an interpositioning shunt contributes blood flow to the lungs. To better understand this unique physiology, a computational model of the Norwood circulation was constructed on the basis of compartmental analysis. Influences of shunt diameter, systemic and pulmonary vascular resistance, and heart rate on the cardiovascular dynamics and oxygenation were studied. Simulations showed that 1) larger shunts diverted an increased proportion of cardiac output to the lungs, away from systemic perfusion, resulting in poorer O2 delivery, 2) systemic vascular resistance exerted more effect on hemodynamics than pulmonary vascular resistance, 3) systemic arterial oxygenation was minimally influenced by heart rate changes, 4) there was a better correlation between venous O2 saturation and O2 delivery than between arterial O2 saturation and O2 delivery, and 5) a pulmonary-to-systemic blood flow ratio of 1 resulted in optimal O2 delivery in all physiological states and shunt sizes.

Biomechanical properties of the human umbilical cord.

The umbilical cord is a complex and fascinating structure that connects the fetus to the placenta and encases the umbilical vessels. The response of its tissues to mechanical loading due to fetal movements and uterine contractions is not well understood. The aim of this study is the evaluation of the mechanical properties of the main components of the human umbilical cord. Fresh umbilical cord specimens were collected from neonates born at term of the gestation and submitted to compliance tests. Furthermore, uniaxial tensile and stress-relaxation tests were performed on samples of umbilical vein and Wharton's jelly. Both materials exhibited nonlinear stress-strain response with increasing strain, increasing the elastic modulus (E(high) about 10-20 times E(low)) and significant viscoelastic behavior. In addition, anisotropy of the vein was observed. Although the circumferential properties of the vein (mean E(high) about 2.4 MPa) were similar to those after birth, the longitudinal stiffness of both materials was higher (mean E(high) over 10 MPa) and comparable to that of the ligaments. These findings suggest a mechanism of protection acting against excessive elongations of the cord, which could cause undue restriction of the umbilical vessel area and interference with the fetal blood circulation.