Hwa Liang Leo

Flow in a Mechanical Bileaflet Heart Valve at Laminar and Near-Peak Systole Flow Rates: CFD Simulations and Experiments

Time-accurate, fully 3D numerical simulations and particle image velocity laboratory experiments are carried out for flow through a fully open bileaflet mechanical heart valve under steady (nonpulsatile) inflow conditions. Flows at two different Reynolds numbers, one in the laminar regime and the other turbulent (near-peak systole flow rate), are investigated. A direct numerical simulation is carried out for the laminar flow case while the turbulent flow is investigated with two different unsteady statistical turbulence modeling approaches, unsteady Reynolds-averaged Navier-Stokes (URANS) and detached-eddy simulation (DES) approach. For both the laminar and turbulent cases the computed mean velocity profiles are in good overall agreement with the measurements. For the turbulent simulations, however, the comparisons with the measurements demonstrate clearly the superiority of the DES approach and underscore its potential as a powerful modeling tool of cardiovascular flows at physiological conditions. The study reveals numerous previously unknown features of the flow.

Fluid Dynamic Assessment of Three Polymeric Heart Valves Using Particle Image Velocimetry

Polymeric heart valves have the potential to reduce thrombogenic complications associated with current mechanical valves and overcome fatigue-related problems experienced by bioprosthetic valves. In this paper we characterize the in vitro velocity and Reynolds Shear Stress (RSS) fields inside and downstream of three different prototype trileaflet polymeric heart valves. The fluid dynamic differences are then correlated with variations in valve design parameters. The three valves differ in leaflet thickness, ranging from 80 to 120 μm, and commisural design, either closed, opened, or semi-opened. The valves were subjected to aortic flow conditions and the velocity measured using three-dimensional stereo Particle Image Velocimetry. The peak forward flow phase in the three valves was characterized by a strong central orifice jet of approximately 2 m/s with a flat profile along the trailing edge of the leaflets. Leakage jets, with principle RSS magnitudes exceeding 4,500 dyn/cm2, were observed in all valves with larger leaflet thicknesses and also corresponded to larger leakage volumes. Additional leakage jets were observed at the commissural region of valves with the open and the semi-open commissural designs. The results of the present study indicate that commissural design and leaflet thickness influence valve fluid dynamics and thus the thrombogenic potential of trileaflet polymeric valves.

Laminar-flow immediate-overlay hepatocyte sandwich perfusion system for drug hepatotoxicity testing.

Drug hepatotoxicity testing requires in vitro hepatocyte culture to maintain the long-term and stable liver specific functions. We developed a drug testing platform based on laminar-flow immediate-overlay hepatocyte sandwich perfusion culture. The immediate-overlay sandwich (collagen-coated porous polymeric membrane as top overlay) protects the cells and integrity of the top collagen matrix from the impact of flow. A bioreactor was designed that allowed proper control of shear stress and mass transfer. The culture parameters such as the optimal perfusion initiation time and flow rate were systematically and mechanistically determined. The optimized system could re-establish hepatocyte polarity to support biliary excretion and to maintain other liver specific functions, such as the biotransformation enzyme activities, for two weeks that extended the usable in vitro hepatocyte-based drug testing window. When the perfusion cultured hepatocytes from days 7 or 14 were used for drug testing, the APAP-induced hepatotoxicity measurements were more sensitive and consistent over time than the static culture control, enabling further exploitations in large-scale drug testing applications.

A robust high-throughput sandwich cell-based drug screening platform

Hepatotoxicity evaluation of pharmaceutical lead compounds in early stages of drug development has drawn increasing attention. Sandwiched hepatocytes exhibiting stable functions in culture represent a standard model for hepatotoxicity testing of drugs. We have developed a robust and high-throughput hepatotoxicity testing platform based on the sandwiched hepatocytes for drug screening. The platform involves a galactosylated microfabricated membrane sandwich to support cellular function through uniform and efficient mass transfer while protecting cells from excessive shear. Perfusion bioreactor further enhances mass transfer and cellular functions over long period; and hepatocytes are readily transferred to 96-well plate for high-throughput robotic liquid handling. The bioreactor design and perfusion flow rate are optimized by computational fluid dynamics simulation and experimentally. The cultured hepatocytes preserved 3D cell morphology, urea production and cytochrome p450 activity of the mature hepatocytes for 14 days. When the perfusion-cultured sandwich is transferred to 96-well plate for drug testing, the hepatocytes exhibited improved drug sensitivity and low variability in hepatotoxicity responses amongst cells transferred from different dates of perfusion culture. The platform enables robust high-throughput screening of drug candidates.

Comparison of the hinge flow fields of two bileaflet mechanical heart valves under aortic and mitral conditions.

Background: Animal and clinical studies have shown that bileaflet mechanical heart valve designs are plagued by thromboembolic complications, with higher rates in the mitral than in the aortic position. This study evaluated the hinge flow dynamic of the 23 mm St. Jude Medical (SJM) Regent and the 23 mm CarboMedics (CM) valves under aortic conditions and compared these results with previous findings under mitral conditions. Method: Velocity and Reynolds shear stress fields were captured using two-component laser Doppler velocimetry. Results: Under aortic conditions, both the SJM and CM hinge flow fields exhibited a strong forward flow pattern during systole (maximum velocities of 2.31 and 1.75 m/s, respectively) and two main leakage jets during diastole (maximum velocities of 3.08 and 2.27 m/s, respectively). Conclusions: Aortic and mitral flow patterns within the two hinges were similar, but with a more dynamic flow during the forward flow phase under aortic conditions. Velocity magnitudes and shear stresses measured under mitral conditions were generally higher than those obtained in the aortic position, which may explain the higher rates of thromboembolism in the mitral implants when compared with the aortic implants.

A Comparison of Flow Field Structures of Two Tri-Leaflet Polymeric Heart Valves

Polymeric heart valves have the potential to reduce thrombogenic complications associated with current mechanical valves and overcome fatigue-related problems experienced by bioprosthetic valves. In this in vitro study, the velocity fields inside and downstream of two different prototype tri-lealfet polymeric heart valves were studied. Experiments were conducted on two 23 mm prototype polymeric valves, provided by AorTech Europe, having open or closed commissure designs and leaflet thickness of 120 and 80 μm, respectively. A two-dimensional LDV system was used to measure the velocity fields in the vicinity of the two valves under simulated physiological conditions. Both commissural design and leaflet thickness were found to affect the flow characteristics. In particular, very high levels of Reynolds shear stress of 13,000 dynes/cm2 were found in the leakage flow of the open commisure design. Maximum leakage velocities in the open and closed designs were 3.6 m/s and 0.5 m/s respectively; the peak forward flow velocities were 2.0 m/s and 2.6 m/s, respectively. In both valve designs, shear stress levels exceeding 4,000 dyne/cm2 were observed at the trailing edge of the leaflets and in the leakage and central orifice jets during peak systole. Additionally, regions of low velocity flow conducive to thrombus formation were observed in diastole. The flow structures measured in these experiments are consistent with the location of thrombus formation observed in preliminary animal experiments.

Numerical simulation of patient-specific left ventricular model with both mitral and aortic valves by FSI approach

Intraventricular flow is important in understanding left ventricular function; however, relevant numerical simulations are limited, especially when heart valve function is taken into account. In this study, intraventricular flow in a patient-specific left ventricle has been modelled in two-dimension (2D) with both mitral and aortic valves integrated. The arbitrary Lagrangian-Eulerian (ALE) approach was employed to handle the large mesh deformation induced by the beating ventricular wall and moving leaflets. Ventricular wall deformation was predefined based on MRI data, while leaflet dynamics were predicted numerically by fluid-structure interaction (FSI). Comparisons of simulation results with in vitro and in vivo measurements reported in the literature demonstrated that numerical method in combination with MRI was able to predict qualitatively the patient-specific intraventricular flow. To the best of our knowledge, we are the first to simulate patient-specific ventricular flow taking into account both mitral and aortic valves.

A thin-walled polydimethylsiloxane bioreactor for high-density hepatocyte sandwich culture

In vitro drug testing requires long‐term maintenance of hepatocyte liver specific functions. Hepatocytes cultured at a higher seeding density in a sandwich configuration exhibit an increased level of liver specific functions when compared to low density cultures due to the better cell to cell contacts that promote long term maintenance of polarity and liver specific functions. However, culturing hepatocytes at high seeding densities in a standard 24‐well plate poses problems in terms of the mass transport of nutrients and oxygen to the cells. In view of this drawback, we have developed a polydimethylsiloxane (PDMS) bioreactor that was able to maintain the long‐term liver specific functions of a hepatocyte sandwich culture at a high seeding density. The bioreactor was fabricated with PDMS, an oxygen permeable material, which allowed direct oxygenation and perfusion to take place simultaneously. The mass transport of oxygen and the level of shear stress acting on the cells were analyzed by computational fluid dynamics (CFD). The combination of both direct oxygenation and perfusion has a synergistic effect on the liver specific function of a high density hepatocyte sandwich culture over a period of 9 days. Biotechnol. Bioeng. 2013; 110: 1663–1673.

Microfabricated silicon nitride membranes for hepatocyte sandwich culture

We have developed a hepatocyte sandwich culture with improved mass transport properties based on ultra-thin microfabricated porous silicon nitride (Si(3)N(4)) membranes. The dimensions and uniformity of the membrane pores can be configurable, which confers more control over the mass transport. Instead of collagen gels used in conventional sandwich culture, we utilized galactose ligands immobilized on the Si(3)N(4) membranes to support hepatocyte attachment and function in the sandwich culture. Diffusion studies using FITC-dextrans confirmed that mass transport of the microfabricated Si(3)N(4) membrane based sandwich was significantly better than conventional collagen gel sandwich and can be configured by varying the porosity of the Si(3)N(4) membrane. Hepatocytes cultured in the microfabricated Si(3)N(4) membrane based sandwich culture exhibited earlier apical repolarization and biliary excretion, improved differentiated functions and enhanced drug sensitivity compared to hepatocytes cultured in a collagen gel sandwich. The Si(3)N(4) membrane based sandwich culture allows for a systematic optimization of the mass transport properties of hepatocyte culture by changing the pore size and inter-pore distance. This will enable more effective drug testing applications where optimal mass transport is required for hepatocyte function maintenance and drug accessibility.

Bileaflet Aortic Valve Prosthesis Pivot Geometry Influences Platelet Secretion and Anionic Phospholipid Exposure

AbstractThe clinical histories of the Medtronic Parallel (MP) and St. Jude Medical (SJM) Standard valves suggest pivot geometry influences the thrombogenic characteristics of bileaflet prostheses. This work studied the effects of various pivot geometries on markers of platelet damage in a controlled, in vitro apparatus. The Medtronic Parallel valve, two St. Jude Medical valves, and two demonstration prostheses were used to study the effects of bileaflet pivot design, gap width, and size on platelet secretion and anionic phospholipid expression during leakage flow. A centrifugal pump was used to drive blood through a circuit containing a bileaflet prosthesis. Samples were taken at set time intervals after the start of the pump. These samples were analyzed by cell counting, flow cytometry, and enzyme-linked immunosorbant assay. No significant differences were observed in platelet secretion or anionic phospholipid expression between experiments with the SJM 27 Standard regular leaker, the SJM 20 regular leaker, and the MP 27 valves. Significant differences in platelet secretion and anionic phospholipid expression were observed between a SJM 27 Standard regular leaker and a SJM 27 high leaker valve. These studies suggest that leakage gap width within bileaflet valve pivots has a significant effect on platelet damage initiated by leakage flow.