No abstract

Tissue engineered heart valves (TEHVs) that can grow and remodel have the potential to serve as permanent replacements of the current non-viable prosthetic valves particularly for pediatric patients. A major challenge in designing functional TEHVs is to mimic both structural and anisotropic mechanical characteristics of the native valve leaflets. To establish a more biomimetic model of TEHV, we fabricated tri-layered scaffolds by combining electrospinning and microfabrication techniques. These constructs were fabricated by assembling microfabricated poly(glycerol sebacate) (PGS) and fibrous PGS/poly(-caprolactone) (PCL) electrospun sheets to develop elastic scaffolds with tunable anisotropic mechanical properties similar to the mechanical characteristics of the native heart valves. The engineered scaffolds supported valvular interstitial cells (VICs) and mesenchymal stem cells (MSCs) growth within the 3D structure and promoted the deposition of heart valve extracellular matrix (ECM). MSCs were also organized and aligned along the anisotropic axes of the engineered tri-layered scaffolds. In addition, the fabricated constructs opened and closed properly in an ex vivo model of porcine heart valve leaflet tissue replacement. The engineered tri-layered scaffolds have the potential for successful translation towards TEHV replacements.

This study is part of a FDA-sponsored project to evaluate the use and limitations of computational fluid dynamics (CFD) in assessing blood flow parameters related to medical device safety. In an interlaboratory study, fluid velocities and pressures were measured in a nozzle model to provide experimental validation for a companion round-robin CFD study. The simple benchmark nozzle model, which mimicked the flow fields in several medical devices, consisted of a gradual flow constriction, a narrow throat region, and a sudden expansion region where a fluid jet exited the center of the nozzle with recirculation zones near the model walls. Measurements of mean velocity and turbulent flow quantities were made in the benchmark device at three independent laboratories using particle image velocimetry (PIV). Flow measurements were performed over a range of nozzle throat Reynolds numbers (Re(throat)) from 500 to 6500, covering the laminar, transitional, and turbulent flow regimes. A standard operating procedure was developed for performing experiments under controlled temperature and flow conditions and for minimizing systematic errors during PIV image acquisition and processing. For laminar (Re(throat)=500) and turbulent flow conditions (Re(throat)≥3500), the velocities measured by the three laboratories were similar with an interlaboratory uncertainty of ∼10% at most of the locations. However, for the transitional flow case (Re(throat)=2000), the uncertainty in the size and the velocity of the jet at the nozzle exit increased to ∼60% and was very sensitive to the flow conditions. An error analysis showed that by minimizing the variability in the experimental parameters such as flow rate and fluid viscosity to less than 5% and by matching the inlet turbulence level between the laboratories, the uncertainties in the velocities of the transitional flow case could be reduced to ∼15%. The experimental procedure and flow results from this interlaboratory study (available at http://fdacfd.nci.nih.gov) will be useful in validating CFD simulations of the benchmark nozzle model and in performing PIV studies on other medical device models.

Computational fluid dynamics (CFD) is increasingly being used to develop blood-contacting medical devices. However, the lack of standardized methods for validating CFD simulations and blood damage predictions limits its use in the safety evaluation of devices. Through a U.S. Food and Drug Administration (FDA) initiative, two benchmark models of typical device flow geometries (nozzle and centrifugal blood pump) were tested in multiple laboratories to provide experimental velocities, pressures, and hemolysis data to support CFD validation. In addition, computational simulations were performed by more than 20 independent groups to assess current CFD techniques. The primary goal of this article is to summarize the FDA initiative and to report recent findings from the benchmark blood pump model study. Discrepancies between CFD predicted velocities and those measured using particle image velocimetry most often occurred in regions of flow separation (e.g., downstream of the nozzle throat, and in the pump exit diffuser). For the six pump test conditions, 57% of the CFD predictions of pressure head were within one standard deviation of the mean measured values. Notably, only 37% of all CFD submissions contained hemolysis predictions. This project aided in the development of an FDA Guidance Document on factors to consider when reporting computational studies in medical device regulatory submissions. There is an accompanying podcast available for this article. Please visit the journal's Web site (www.asaiojournal.com) to listen.

The fluid mechanics of artificial blood pumps has been studied since the early 1970s in an attempt to understand and mitigate hemolysis and thrombus formation by the device. Pulsatile pumps are characterized by inlet jets that set up a rotational "washing" pattern during filling. Strong regurgitant jets through the closed artificial heart valves have Reynolds stresses on the order of 10,000 dynes/cm 2 and are the most likely cause of red blood cell damage and platelet activation. Although the flow in the pump chamber appears benign, low wall shear stresses throughout the pump cycle can lead to thrombus formation at the wall of the smaller pumps (10-50 cc). The local fluid mechanics is critical. There is a need to rapidly measure or calculate the wall shear stress throughout the device so that the results may be easily incorporated into the design process. 65 Annu. Rev. Fluid Mech. 2006.38:65-86. Downloaded from www.annualreviews.org Access provided by University of California -San Diego on 02/04/15. For personal use only.

While cardiovascular device-induced thrombosis is associated with negative patient outcomes, the convoluted nature of the processes resulting in a thrombus makes the full thrombotic network too computationally expensive to simulate in the complex geometries and flow fields associated with devices. A macroscopic, continuum computational model is developed based on a simplified network, which includes terms for platelet activation (chemical and mechanical) and thrombus deposition and growth in regions of low wall shear stress (WSS). Laminar simulations are performed in a two-dimensional asymmetric sudden expansion geometry and compared with in vitro thrombus size data collected using whole bovine blood. Additionally, the predictive power of the model is tested in a flow cell containing a series of symmetric sudden expansions and contractions. Thrombi form in the low WSS area downstream of the asymmetric expansion and grow into the nearby recirculation region, and thrombus height and length largely remain within 95 % confidence intervals calculated from the in vitro data for 30 min of blood flow. After 30 min, predicted thrombus height and length are 0.94 and 4.32 (normalized by the 2.5 mm step height). Importantly, the model also correctly predicts locations of thrombus deposition observed in the in vitro flow cell of expansions and contractions. As the simulation results, which rely on a greatly reduced model of the thrombotic network, are still able to capture the macroscopic behavior of the full network, the model shows promise for timely predictions of device-induced thrombosis toward optimizing and expediting the device development process.

Tissue engineered heart valves (TEHV) could be useful in the repair of congenital or acquired valvular diseases due to their potential for growth and remodeling. The development of biomimetic scaffolds is a major challenge in heart valve tissue engineering. One of the most important structural characteristics of mature heart valve leaflets is their intrinsic anisotropy, which is derived from the microstructure of aligned collagen fibers in the extracellular matrix (ECM). In the present study, we used a directional electrospinning technique to fabricate fibrous poly-(glycerol sebacate):poly(caprolactone) (PGS:PCL) scaffolds containing aligned fibers, which resembled native heart valve leaflet ECM networks. In addition, the anisotropic mechanical characteristics of fabricated scaffolds were tuned by changing the ratio of PGS:PCL to mimic the native heart valve’s mechanical properties. Primary human valvular interstitial cells (VICs) attached and aligned along the anisotropic axes of all PGS:PCL scaffolds with various mechanical properties. The cells were also biochemically active in producing heart valve-associated collagen, vimentin, and smooth muscle actin as determined by gene expression. The fibrous PGS:PCL scaffolds seeded with human VICs mimicked the structure and mechanical properties of native valve leaflet tissues and would potentially be suitable for the replacement of heart valves in diverse patient populations.

Implantable blood recirculating devices have provided life saving solutions to patients with severe cardiovascular diseases. However, common problems of hemolysis and thromboembolism remain an impediment to these devices. In this article, we present a brief review of the work by several groups in the field that has led to the development of new methodologies that may facilitate achieving the daunting goal of optimizing the thrombogenic performance of blood recirculating devices. The aim is to describe work which pertains to the interaction between flow-induced stresses and the blood constituents, and that supports the hypothesis that thromboembolism in prosthetic blood recirculating devices is initiated and maintained primarily by the non-physiological flow patterns and stresses that activate and enhance the aggregation of blood platelets, increasing the risk of thromboembolism and cardioembolic stroke. Such work includes state-of-the-art numerical and experimental tools used to elucidate flow-induced mechanisms leading to thromboembolism in prosthetic devices. Following the review, the paper describes several efforts conducted by some of the groups active in the field, and points to several directions that should be pursued in the future in order to achieve the goal for blood recirculating prosthetic devices becoming more effective as destination therapy in the future.