Fluid Dynamic Study of the Penn State Pediatric Total Artificial Heart.

Penn State University is developing a pediatric total artificial heart (TAH) as a bridge-to-transplant device that supports infants and small children with single ventricle anomalies or biventricular heart failure to address high waitlist mortality rates for pediatric patients with severe congenital heart disease (CHD). Two issues with mechanical circulatory support devices are thrombus formation and thromboembolic events. This in vitro study characterizes flow within Penn State's pediatric total artificial heart under physiological operating conditions. Particle image velocimetry (PIV) is used to quantify flow within the pump and to calculate wall shear rates (WSRs) along the internal pump surface to identify potential thrombogenic regions. Results show that the diastolic inflow jets produce sufficient wall shear rates to reduce thrombus deposition potential along the inlet side of the left and right pumps. The inlet jet transitions to rotational flow, which promotes wall washing along the apex of the pumps, prevents flow stasis, and aligns flow with the outlet valve prior to systolic ejection. However, inconsistent high wall shear rates near the pump apex cause increased thrombogenic potential. Strong systolic outflow jets produce high wall shear rates near the outlet valve to reduce thrombus deposition risk. The right pump, which has a modified outlet port angle to improve anatomical fit, produces lower wall shear rates and higher thrombus susceptibility potential (TSP) compared to the left pump. In summary, this study provides a fluid dynamic understanding of a new pediatric total artificial heart and indicates thrombus susceptibility is primarily confined to the apex, consistent with similar pulsatile heart pumps.

The Accelerated Transcatheter Heart Valve Testing Environment: Loading, Motion, and Fluid Dynamics.

Transcatheter aortic valve replacements (TAVRs) are an increasingly common treatment for aortic valve disease due to their minimally invasive delivery. As TAVR designs require thinner leaflets to facilitate catheter-based delivery, they experience greater leaflet operational stresses and potentially greater durability issues than conventional surgical valves. Yet, our understanding of TAVR durability remains largely unexplored. Currently, preclinical TAVR durability is evaluated within an ISO:5840 compliant accelerated wear tester (AWT) up to a required 200 × 106 cycles, corresponding to approximately five years in vivo. While AWTs use high cycle frequencies (10-20 Hz) to achieve realistic timeframes, the resulting valve loading behaviors and fluid dynamics are not representative of the in vivo environment and thus may not accurately predict failure mechanisms. Despite the importance of fatigue and failure predictions for replacement heart valves, surprisingly, little quantitative information exists on the dynamic AWT environment. To better understand this environment, we examined frequency and diastolic period effects for the first time using high-speed enface imaging and particle image velocimetry to quantify valve motion and flow, respectively, using a Durapulse™ AWT at frequencies of 10, 15, and 20 Hz. Regardless of operating condition, no waveform achieved a physiologically relevant transvalvular loading pressure, despite having an ISO compliant geometric orifice area (GOA) and waveform. General fluid mechanics were consistent with in vivo but the AWT geometry developed secondary flow structures, which could impact mechanical loading. Therefore, the nonphysiologic loading and variability induced by changes in operating condition must be carefully regulated to ensure physiologically relevant fatigue.

Experimental Hemodynamics Within the Penn State Fontan Circulatory Assist Device.

For children born with a single functional ventricle, the Fontan operation bypasses the right ventricle by forming a four-way total cavopulmonary connection and adapts the existing ventricle for the systemic circulation. However, upon reaching adulthood, many Fontan patients exhibit low cardiac output and elevated venous pressure, eventually requiring a heart transplantation. Despite efforts in developing a new device or using an existing device for failing Fontan support, there is still no Food and Drug Administration-approved device for subpulmonary support. Penn State University is developing a hydrodynamically levitated Fontan circulatory assist device (FCAD) for bridge-to-transplant or destination therapy. The hemodynamics within the FCAD, at both steady and patient averaged pulsatile conditions for three physiological pump operating conditions, were quantified using particle image velocimetry (PIV) to determine the velocity magnitudes and Reynolds normal and shear stresses within the device. Data were acquired at three planes (0 mm and ±25% of the radius) for the inferior and superior vena cavae inlets and the pulmonary artery outlet. The inlets had a blunt velocity profile that became skewed toward the collecting volute as fluid approached the rotor. At the outlet, regardless of the flow condition, a high-velocity jet exited the volute and moved downstream in a helical pattern. Turbulent stresses observed at the volute exit were influenced by the rotor's rotation. Regardless of inlet conditions, the pump demonstrated advantageous behavior for clinical use with a predictable flow field and a low risk of platelet adhesion and hemolysis based on calculated wall shear rates and turbulent stresses, respectively.

Results of the Interlaboratory Computational Fluid Dynamics Study of the FDA Benchmark Blood Pump.

Computational fluid dynamics (CFD) is widely used to simulate blood-contacting medical devices. To be relied upon to inform high-risk decision making, however, model credibility should be demonstrated through validation. To provide robust data sets for validation, researchers at the FDA and collaborators developed two benchmark medical device flow models: a nozzle and a centrifugal blood pump. Experimental measurements of the flow fields and hemolysis were acquired using each model. Concurrently, separate open interlaboratory CFD studies were performed in which participants from around the world, who were blinded to the measurements, submitted CFD predictions of each benchmark model. In this study, we report the results of the interlaboratory CFD study of the FDA benchmark blood pump. We analyze the results of 24 CFD submissions using a wide range of different flow solvers, methods, and modeling parameters. To assess the accuracy of the CFD predictions, we compare the results with experimental measurements of three quantities of interest (pressure head, velocity field, and hemolysis) at different pump operating conditions. We also investigate the influence of different CFD methods and modeling choices used by the participants. Our analyses reveal that, while a number of CFD submissions accurately predicted the pump performance for individual cases, no single participant was able to accurately predict all quantities of interest across all conditions. Several participants accurately predicted the pressure head at all conditions and the velocity field in all but one or two cases. Only one of the eight participants who submitted hemolysis results accurately predicted absolute plasma free hemoglobin levels at a majority of the conditions, though most participants were successful at predicting relative hemolysis levels between conditions. Overall, this study highlights the need to validate CFD modeling of rotary blood pumps across the entire range of operating conditions and for all quantities of interest, as some operating conditions and regions (e.g., the pump diffuser) are more challenging to accurately predict than others. All quantities of interest should be validated because, as shown here, it is possible to accurately predict hemolysis despite having relatively inaccurate predictions of the flow field.

Effect of Hematocrit and Elevated Beat Rate on the 12cc Penn State Pediatric Ventricular Assist Device.

Congenital heart disease affects approximately 40,000 infants annually in the United States with 25% requiring invasive treatment. Due to limited number of donor hearts and treatment options available for children, pediatric ventricular assist devices (PVADs) are used as a bridge to transplant. The 12cc pneumatic Penn State PVAD is optimized to prevent platelet adhesion and thrombus formation at patient nominal conditions; however, children demonstrate variable blood hematocrit and elevated heart rates. Therefore, with pediatric patients exhibiting greater variability, particle image velocimetry is used to evaluate the PVAD with three non-Newtonian hematocrit blood analogs (20%, 40%, and 60%) and at two beat rates (75 and 120 bpm) to understand the device's performance. The flow fields demonstrate a strong inlet jet that transitions to a solid body rotation during diastole. During systole, the rotation dissipates and reorganizes into an outlet jet. This flow field is consistent across all hematocrits and beat rates but at a higher velocity magnitude during 120 bpm. There are also minor differences in flow field timing and surface washing due to hematocrit. Therefore, despite patient differences in hematocrit or required pumping output, thorough surface washing can be achieved in the PVAD by altering operating conditions, thus reducing platelet adhesion potential.

Computational Modeling of the Penn State Fontan Circulation Assist Device.

To address the increasing number of failing Fontan patients, Penn State University and the Penn State Hershey Medical Center are developing a centrifugal blood pump for long-term mechanical support. Computational fluid dynamics (CFD) modeling of the Penn State Fontan Circulatory Assist Device (FCAD) was performed to understand hemodynamics within the pump and its potential for hemolysis and thrombosis. CFD velocity and pressure results were first validated against experimental data and found to be within the standard deviations of the velocities and within 5% of the pressures. Further simulations performed with a human blood model found that most of the fluid domain was subjected to low shear stress (<50 Pa), with areas of highest stress around the rotor blade tips that increased with pump flow rate and rotor speed (138-178 Pa). However, the stresses compared well to previous CFD studies of commercial blood pumps and remained mostly below common thresholds of hemolysis and platelet activation. Additionally, few regions of low shear rate were observed within the FCAD, signifying minimal potential for platelet adhesion. These results further emphasize the FCAD's potential that has been observed previously in experimental and animal studies.

Transcatheter Heart Valve Downstream Fluid Dynamics in an Accelerated Evaluation Environment.

Transcatheter aortic valve replacements (TAVRs) provide minimally invasive delivery of bioprosthetic heart valves (BHVs) for the treatment of aortic valve disease. While surgical BHVs show efficacy for 8-10 years, long-term TAVR durability remains unknown. Pre-clinical testing evaluates BHV durability in an ISO:5840 compliant accelerated wear tester (AWT), yet, the design and development of AWTs and their accuracy in predicting in vivo performance, is unclear. As a result of limited knowledge on AWT environment and BHV loading, durability assessment of candidate valves remains fundamentally empirical. For the first time, high-speed particle image velocimetry quantified an ISO:5840 compliant downstream AWT velocity field, Reynolds stresses, and turbulence intensity. TAVR enface imaging quantified the orifice area and estimated the flow rate. When valve area and flow rate were at their maximum during peak systole (1.49 cm2 and 16.05 L/min, respectively), central jet velocity, Reynolds normal and shear stress, and turbulence intensity grew to 0.50 m/s, 265.1 Pa, 124.6 Pa, and 37.3%, respectively. During diastole, unique AWT recirculation produced retrograde flow and the directional changes created eddies. These novel AWT findings demonstrated a substantially reduced valve fully loaded period and pressure not matching in vivo or in vitro studies, despite the comparable fluid environment and TAVR motion.

Dynamics of Blood Flows in Aortic Stenosis: Mild, Moderate, and Severe.

Supraphysiologic high shear stresses created in calcific aortic stenosis (AS) are known to cause hemostatic abnormalities, however, the relationship between the complex blood flows over the severity of AS and hemostatic abnormalities still remains unclear. This study systematically characterized the blood flow in mild, moderate, and severe AS. A series of large eddy simulations (LES) validated by particle image velocimetry were performed on physiologically representative AS models with a peak physiologic flow condition of 18 liter per minute. Time-accurate velocity fields, transvalvular pressure gradient, and laminar viscous-and turbulent (or Reynolds) shear stresses (RSSmax) were evaluated for each degree of severity. The peak velocities of mild, moderate, and severe AS were on the order of 2.0, 4.0, and 8.0 m/s, respectively. Jet velocity in severe AS was highly skewed with extremely high velocity (as high as 8 m/s) and mainly traveled through the posterior aortic wall up to the aortic arch while still carrying a relatively high velocity, that is, >4 m/s. The mean laminar viscous wall shear stresses (WSS) for mild, moderate, and severe AS were on the order of 40, 100, and 180 Pa, respectively. The RSSmax were on the order of 260, 490, and 2,500 Pa for mild, moderate, and severe AS, respectively. This study may provide a link between altered flows in AS and hemostatic abnormalities such as acquired von Willebrand syndrome and hemolysis, thus, help diagnosing and timing of the treatment.

Substrate Stiffness Affects Human Keratinocyte Colony Formation.

Restoration of epidermal organization and function in response to a variety of pathophysiological insults is critically dependent on coordinated keratinocyte migration, proliferation, and stratification during the process of wound healing. These processes are mediated by the reconfiguration of both cell-cell (desmosomes, adherens junctions) and cell-matrix (focal adhesions, hemidesmosomes) junctions and the cytoskeletal filament networks that they serve to interconnect. In this study, we investigated the role of substrate elasticity (stiffness) on keratinocyte colony formation in vitro during the process of nascent epithelial sheet formation as triggered by the calcium switch model of keratinocyte culture. Keratinocytes cultured on pepsin digested type I collagen coated soft (nominal E = 1.2 kPa) polyacrylamide gels embedded with fluorescent microspheres exhibited (i) smaller spread contact areas, (ii) increased migration velocities, and (iii) increased rates of colony formation with more cells per colony than did keratinocytes cultured on stiff (nominal E = 24 kPa) polyacrylamide gels. As assessed by tracking of embedded microsphere displacements, keratinocytes cultured on soft substrates generated large local substrate deformations that appeared to recruit adjacent keratinocytes into joining an evolving colony. Together with the observed differences in keratinocyte kinematics and substrate deformations, we developed two ad hoc analyses, termed distance rank (DR) and radius of cooperativity (RC), that help to objectively ascribe what we perceive as increasingly cooperative behavior of keratinocytes cultured on soft versus stiff gels during the process of colony formation. We hypothesize that the differences in keratinocyte colony formation observed in our experiments could be due to cell-cell mechanical signaling generated via local substrate deformations that appear to be correlated with the increased expression of ß4 integrin within keratinocytes positioned along the periphery of an evolving cell colony.