How Do Cord Compressions Affect the Umbilical Venous Flow Resistance? An In Vitro Investigation of the Biomechanical Mechanisms.

Umbilical vessels, that provide blood oxygenation and fetal nourishment in utero, are encased and protected against external forces by the umbilical cord. The biomechanics of this peculiar structure has not been deeply investigated so far. The purpose of this study is to investigate the hydraulic behaviour of human umbilical veins (UV) and its changes in presence of an external cord compression. Five umbilical cords were subjected to in vitro tests. UV was accurately cannulated and connected to a perfusion circuit, while the cord was subjected to an external compression. Pressure drops across UV were measured for various venous flow rates and various degrees of cord constriction. Compressive forces were measured, too. The UV hydraulic resistances measured in unloaded cords (0.029 ± 0.016 mmHg min cm-1 L-1) correspond to placenta-abdomen pressure drops well consistent with in utero measurements. As expected, at fixed flow rate, flow resistance augments when cord is compressed. Interestingly, resistance does not substantially change until a 30-50% cord thickness reduction, whereas slightly larger constriction cause a steep increase. Compressive forces becomes critical for values above 0.5-2 N, depending on the length of cord compression and on considered specimen. Moreover, at high cord constriction, hydraulic behaviour of UV is very peculiar. Namely, the slope of the pressure-flow relationship decreases at increasing flow rates and, in few cases, a surprising reduction of pressure drop was even observed. The biomechanical behaviour of the umbilical cord during compression is very complex, with high non-linearity of venous hydraulic behaviour.

Experimental setup to evaluate the performance of percutaneous pulmonary valved stent in different outflow tract morphologies.

Percutaneous pulmonary valve implantation is a potential treatment for right ventricular outflow tract (RVOT) dysfunction. However, RVOT implantation site varies among subjects and the success of the procedure depends on RVOT morphology selection. The aim of this study was to use in vitro testing to establish percutaneous valve competency in different previously defined RVOT morphologies. Five simplified RVOT geometries (stenotic, enlarged, straight, convergent, and divergent) were manufactured by silicone dipping. A mock bench was developed to test the percutaneous valve in the five different RVOTs. The bench consists of a volumetric pulsatile pump and of a hydraulic afterload. The pump is made of a piston driven by a low inertia programmable motor. The hydraulic afterload mimics the pulmonary input impedance and its design is based on a three element model of the pulmonary circulation. The mock bench can replicate different physiological and pathological hemodynamic conditions of the pulmonary circulation. The mock bench is here used to test the five RVOTs under physiological-like conditions: stroke volume range 40-70 mL, frequency range 60-80 bpm. The valved stent was implanted into the five different RVOT geometries. Pressures upstream and downstream of the valved stent were monitored. Flow rates were measured with and without the valved stent in the five mock RVOTs, and regurgitant fraction compared between the different valved stent RVOTs. The percutaneous valved stent drastically reduced regurgitant flow if compared with the RVOT without the valve. RVOT geometry did not significantly influence the flow rate curves. Mean regurgitant fractions varied from 5% in the stenotic RVOT to 7.3% in the straight RVOT, highlighting the influence of the RVOT geometry on valve competency. The mock bench presented in this study showed the ability to investigate the influence of RVOT geometry on the competence of valved stent used for percutaneous pulmonary valve treatment.

Engineered cartilage constructs subject to very low regimens of interstitial perfusion.

We have studied an in vitro engineered cartilage model, consisting of bovine articular chondrocytes seeded on micro-porous scaffolds and perfused with very low regimens of interstitial flow. Our previous findings suggested that synthesis of sulphated glycosaminoglycans (sGAG) was promoted in this model, if the level of shear generated on cells was maintained below 10 mPa (0.1 dyn/cm2). Constructs were stimulated with a median shear stress of 1.2 and 6.7 mPa using two independent culture chambers. Quantification of the applied stresses and of oxygen consumption rates was obtained from computational modelling. Experimentally, we set a time zero reference at 24 hours after cell seeding and total culture time at two weeks. The cell metabolic activity, measured by MTT, was significantly lower in all constructs at two weeks (-73% in static controls, -66% in the 1.2 mPa group and -60% in the 6.7 mPa group) vs. the time zero group, and significantly higher (+33%) in the 7 mPa group vs. static controls. The ratio between synthesis of collagen type II/type I, measured by Western Blot, was significantly higher in the 1.2 mPa constructs (+109% vs. the 6.7 mPa group, +120% vs. the time zero group and +286% vs. static controls). A trend of decreased alpha-actin expression was observed with increased ratio of type II to type I collagen, in all groups. These results reinforce the notion that, at early time points in culture, hydrodynamic shear below 10 mPa may promote formation of extra-cellular matrix specific to hyaline cartilage in chondrocyte-seeded constructs.

The effect of hydrodynamic shear on 3D engineered chondrocyte systems subject to direct perfusion.

Bioreactors allowing direct-perfusion of culture medium through tissue-engineered constructs may overcome diffusion limitations associated with static culturing, and may provide flow-mediated mechanical stimuli. The hydrodynamic stress imposed on cells within scaffolds is directly dependent on scaffold microstructure and on bioreactor configuration. Aim of this study is to investigate optimal shear stress ranges and to quantitatively predict the levels of hydrodynamic shear imposed to cells during the experiments. Bovine articular chondrocytes were seeded on polyestherurethane foams and cultured for 2 weeks in a direct perfusion bioreactor designed to impose 4 different values of shear level at a single flow rate (0.5 ml/min). Computational fluid dynamics (CFD) simulations were carried out on reconstructions of the scaffold obtained from micro-computed tomography images. Biochemistry analyses for DNA and sGAG were performed, along with electron microscopy. The hydrodynamic shear induced on cells within constructs, as estimated by CFD simulations, ranged from 4.6 to 56 mPa. This 12-fold increase in the level of applied shear stress determined a 1.7-fold increase in the mean content in DNA and a 2.9-fold increase in the mean content in sGAG. In contrast, the mean sGAG/DNA ratio showed a tendency to decrease for increasing shear levels. Our results suggest that the optimal condition to favour sGAG synthesis in engineered constructs, at least at the beginning of culture, is direct perfusion at the lowest level of hydrodynamic shear. In conclusion, the presented results represent a first attempt to quantitatively correlate the imposed hydrodynamic shear level and the invoked biosynthetic response in 3D engineered chondrocyte systems.

Multiscale modeling of the cardiovascular system: application to the study of pulmonary and coronary perfusions in the univentricular circulation.

The objective of this study is to compare the coronary and pulmonary blood flow dynamics resulting from two configurations of systemic-to-pulmonary artery shunts currently utilized during the Norwood procedure: the central (CS) and modified Blalock Taussig (MBTS) shunts. A lumped parameter model of the neonatal cardiovascular circulation and detailed 3-D models of the shunt based on the finite volume method were constructed. Shunt sizes of 3, 3.5 and 4 mm were considered. A multiscale approach was adopted to prescribe appropriate and realistic boundary conditions for the 3-D models of the Norwood circulation. Results showed that the average shunt flow rate is higher for the CS option than for the MBTS and that pulmonary flow increases with shunt size for both options. Cardiac output is higher for the CS option for all shunt sizes. Flow distribution between the left and the right pulmonary arteries is not completely balanced, although for the CS option the discrepancy is low (50-51% of the pulmonary flow to the right lung) while for the MBTS it is more pronounced with larger shunt sizes (51-54% to the left lung). The CS option favors perfusion to the right lung while the MBTS favors the left. In the CS option, a smaller percentage of aortic flow is distributed to the coronary circulation, while that percentage rises for the MBTS. These findings may have important implications for coronary blood flow and ventricular function.

Mathematical modeling of fluid dynamics in pulsatile cardiopulmonary bypass.

The design criteria of an extracorporeal circuit suitable for pulsatile flow are quite different and more entangled than for steady flow. The time and costs of the design process could be reduced if mutual influences between the pulsatile pump and other extracorporeal devices were considered without experimental trial-and-error activities. With this in mind, we have developed a new lumped-parameter mathematical model of the hydraulic behavior of the arterial side of an extracorporeal circuit under pulsatile flow conditions. Generally, components feature a resistant-inertant-compliant behavior and the most relevant nonlinearities are accounted for. Parameter values were derived either by experimental tests or by analytical analysis. The pulsatile pump is modeled as a pure pulsatile flow generator. Model predictions were compared with flow rate and pressure tracings measured during hydraulic tests on two different circuits at various flow rates and pulse frequencies. The normalized root mean square error did not exceed 24% and the model accurately describes the changes that occur in the basic features of the pressure and flow wave propagating from the pulsatile pump to the arterial cannula.