Jawaad Sheriff

Platelet Activation Due to Hemodynamic Shear Stresses: Damage Accumulation Model and Comparison to in vitro Measurements

The need to optimize the thrombogenic performance of blood recirculating cardiovascular devices, e.g., prosthetic heart valves (PHV) and ventricular assist devices (VAD), is accentuated by the fact that most of them require lifelong anticoagulation therapy that does not eliminate the risk of thromboembolic complications. The formation of thromboemboli in the flow field of these devices is potentiated by contact with foreign surfaces and regional flow phenomena that stimulate blood clotting, especially platelets. With the lack of appropriate methodology, device manufacturers do not specifically optimize for thrombogenic performance. Such optimization can be facilitated by formulating a robust numerical methodology with predictive capabilities of flow-induced platelet activation. In this study, a phenomenological model for platelet cumulative damage, identified by means of genetic algorithms (GAs), was correlated with in vitro experiments conducted in a Hemodynamic Shearing Device (HSD). Platelets were uniformly exposed to flow shear representing the lower end of the stress levels encountered in devices, and platelet activity state (PAS) was measured in response to six dynamic shear stress waveforms representing repeated passages through a device, and correlated to the predictions of the damage accumulation model. Experimental results demonstrated an increase in PAS with a decrease in “relaxation” time between pulses. The model predictions were in very good agreement with the experimental results.

Evaluation of Shear-Induced Platelet Activation Models Under Constant and Dynamic Shear Stress Loading Conditions Relevant to Devices

The advent of implantable blood-recirculating devices such as left ventricular assist devices and prosthetic heart valves provides a viable therapy for patients with end-stage heart failure and valvular disease. However, device-generated pathological flow patterns result in thromboembolic complications that require complex and lifelong anticoagulant therapy, which entails hemorrhagic risks and is not appropriate for certain patients. Optimizing the thrombogenic performance of such devices utilizing numerical simulations requires the development of predictive platelet activation models that account for variations in shear-loading rates characterizing blood flow through such devices. Platelets were exposed in vitro to both dynamic and constant shear stress conditions emulating those found in blood-recirculating devices in order to determine their shear-induced activation and sensitization response. Both these behaviors were found to be dependent on the shear loading rates, in addition to shear stress magnitude and exposure time. We then critically examined several current models and evaluated their predictive capabilities using these results. Shear loading rate terms were then included to account for dynamic aspects that are either ignored or partially considered by these models, and model parameters were optimized. Independent optimization for each of the two types of shear stress exposure conditions tested resulted in different sets of best-fit constants, indicating that universal optimization may not be possible. Inherent limitations of the current models require a paradigm shift from these integral-based discretized power law models to better address the dynamic conditions encountered in blood-recirculating devices.The advent of implantable blood-recirculating devices such as left ventricular assist devices and prosthetic heart valves provides a viable therapy for patients with end-stage heart failure and valvular disease. However, device-generated pathological flow patterns result in thromboembolic complications that require complex and lifelong anticoagulant therapy, which entails hemorrhagic risks and is not appropriate for certain patients. Optimizing the thrombogenic performance of such devices utilizing numerical simulations requires the development of predictive platelet activation models that account for variations in shear-loading rates characterizing blood flow through such devices. Platelets were exposed in vitro to both dynamic and constant shear stress conditions emulating those found in blood-recirculating devices in order to determine their shear-induced activation and sensitization response. Both these behaviors were found to be dependent on the shear loading rates, in addition to shear stress magnitude and exposure time. We then critically examined several current models and evaluated their predictive capabilities using these results. Shear loading rate terms were then included to account for dynamic aspects that are either ignored or partially considered by these models, and model parameters were optimized. Independent optimization for each of the two types of shear stress exposure conditions tested resulted in different sets of best-fit constants, indicating that universal optimization may not be possible. Inherent limitations of the current models require a paradigm shift from these integral-based discretized power law models to better address the dynamic conditions encountered in blood-recirculating devices.

Design Optimization of a Mechanical Heart Valve for Reducing Valve Thrombogenicity—A Case Study with ATS Valve

Patients implanted with mechanical heart valves (MHV) or with ventricular assist devices that use MHV require mandatory lifelong anticoagulation for secondary stroke prevention. We recently developed a novel Device Thrombogenicity Emulator (DTE) methodology that interfaces numerical and experimental approaches to optimize the thrombogenic performance of the device and reduce the bleeding risk associated with anticoagulation therapy. Device Thrombogenicity Emulator uses stress-loading waveforms in pertinent platelet flow trajectories that are extracted from highly resolved numerical simulations and emulates these flow conditions in a programmable hemodynamic shearing device (HSD) by which platelet activity is measured. We have previously compared two MHV, ATS and the St. Jude Medical, and demonstrated that owing to its nonrecessed hinge design, the ATS valve offers improved thrombogenic performance. In this study, we further optimize the ATS valve thrombogenic performance, by modifying various design features of the valve, intended to achieve reduced thrombogenicity: 1) optimizing the leaflet-housing gap clearance; 2) increasing the effective maximum opening angle of the valve; and 3) introducing a streamlined channel between the leaflet stops of the valve that increases the effective flow area. We have demonstrated that the DTE optimization methodology can be used as test bed for developing devices with significantly improved thombogenic performance.

Thrombogenic Potential of Innovia Polymer Valves versus Carpentier-Edwards Perimount Magna Aortic Bioprosthetic Valves

Trileaflet polymeric prosthetic aortic valves (AVs) produce hemodynamic characteristics akin to the natural AV and may be most suitable for applications such as transcatheter implantation and mechanical circulatory support (MCS) devices. Their success has not yet been realized due to problems of calcification, durability, and thrombosis. We address the latter by comparing the platelet activation rates (PARs) of an improved polymer valve design (Innovia LLC) made from poly(styrene-block-isobutylene-block-styrene) (SIBS) with the commercially available Carpentier-Edwards Perimount Magna Aortic Bioprosthetic Valve. We used our modified prothrombinase platelet activity state (PAS) assay and flow cytometry methods to measure platelet activation of a pair of 19 mm valves mounted inside a pulsatile Berlin left ventricular assist device (LVAD). The PAR of the polymer valve measured with the PAS assay was fivefold lower than that of the tissue valve (p = 0.005) and fourfold lower with flow cytometry measurements (p = 0.007). In vitro hydrodynamic tests showed clinically similar performance of the Innovia and Magna valves. These results demonstrate a significant improvement in thrombogenic performance of the polymer valve compared with our previous study of the former valve design and encourage further development of SIBS for use in heart valve prostheses.

A novel mathematical model of activation and sensitization of platelets subjected to dynamic stress histories.

Blood recirculating devices, such as ventricular assist devices and prosthetic heart valves, are burdened by thromboembolic complications requiring complex and lifelong anticoagulant therapy with its inherent hemorrhagic risks. Pathologic flow patterns occurring in such devices chronically activate platelets, and the optimization of their thrombogenic performance requires the development of flow-induced platelet activation models. However, existing models are based on empirical correlations using the well-established power law paradigm of constant levels of shear stress during certain exposure times as factors for mechanical platelet activation. These models are limited by their range of application and do not account for other relevant phenomena, such as loading rate dependence and platelet sensitization to high stress conditions, which characterize the dynamic flow conditions in devices. These limitations were addressed by developing a new class of phenomenological stress-induced platelet activation models that specifies the rate of platelet activation as a function of the entire stress history and results in a differential equation that can be directly integrated to calculate the cumulative levels of activation. The proposed model reverts to the power law under constant shear stress conditions and is able to describe experimental results in response to a diverse range of highly dynamic stress conditions found in blood recirculating devices. The model was tested in vitro under emulated device flow conditions and correlates well with experimental results. This new model provides a reliable and robust mathematical tool that can be incorporated into computational fluid dynamic studies in order to optimize design, with the goal of improving the thrombogenic performance of blood recirculating devices.

In Vitro Evaluation of a Novel Hemodynamically Optimized Trileaflet Polymeric Prosthetic Heart Valve

Calcific aortic valve disease is the most common and life threatening form of valvular heart disease, characterized by stenosis and regurgitation, which is currently treated at the symptomatic end-stages via open-heart surgical replacement of the diseased valve with, typically, either a xenograft tissue valve or a pyrolytic carbon mechanical heart valve. These options offer the clinician a choice between structural valve deterioration and chronic anticoagulant therapy, respectively, effectively replacing one disease with another. Polymeric prosthetic heart valves (PHV) offer the promise of reducing or eliminating these complications, and they may be better suited for the new transcatheter aortic valve replacement (TAVR) procedure, which currently utilizes tissue valves. New evidence indicates that the latter may incur damage during implantation. Polymer PHVs may also be incorporated into pulsatile circulatory support devices such as total artificial heart and ventricular assist devices that currently employ mechanical PHVs. Development of polymer PHVs, however, has been slow due to the lack of sufficiently durable and biocompatible polymers. We have designed a new trileaflet polymer PHV for surgical implantation employing a novel polymer-xSIBS-that offers superior bio-stability and durability. The design of this polymer PHV was optimized for reduced stresses, improved hemodynamic performance, and reduced thrombogenicity using our device thrombogenicity emulation (DTE) methodology, the results of which have been published separately. Here we present our new design, prototype fabrication methods, hydrodynamics performance testing, and platelet activation measurements performed in the optimized valve prototype and compare it to the performance of a gold standard tissue valve. The hydrodynamic performance of the two valves was comparable in all measures, with a certain advantage to our valve during regurgitation. There was no significant difference between the platelet activation rates of our polymer valve and the tissue valve, indicating that similar to the latter, its recipients may not require anticoagulation. This work proves the feasibility of our optimized polymer PHV design and brings polymeric valves closer to clinical viability.

Hemocompatibility of Poly(vinyl alcohol)–Gelatin Core–Shell Electrospun Nanofibers: A Scaffold for Modulating Platelet Deposition and Activation

In this study, we evaluate coaxial electrospun nanofibers with gelatin in the shell and poly(vinyl alcohol) (PVA) in the core as a potential vascular material by determining fiber surface roughness, as well as human platelet deposition and activation under varying conditions. PVA scaffolds had the highest surface roughness (Ra=65.5±6.8 nm) but the lowest platelet deposition (34.2±5.8 platelets) in comparison to gelatin nanofibers (Ra=36.8±3.0 nm and 168.9±29.8 platelets) and coaxial nanofibers (1 Gel:1 PVA coaxial, Ra=24.0±1.5 nm and 150.2±17.4 platelets. 3 Gel:1 PVA coaxial, Ra=37.1±2.8 nm and 167.8±15.4 platelets). Therefore, the chemical structure of the gelatin nanofibers dominated surface roughness in platelet deposition. Due to their increased stiffness, the coaxial nanofibers had the highest platelet activation rate, rate of thrombin formation, in comparison to gelatin and PVA fibers. Our studies indicate that mechanical stiffness is a dominating factor for platelet deposition and activation, followed by biochemical signals, and lastly surface roughness. Overall, these coaxial nanofibers are an appealing material for vascular applications by supporting cellular growth while minimizing platelet deposition and activation.

Microfluidic emulation of mechanical circulatory support device shear-mediated platelet activation.

Thrombosis of ventricular assist devices (VADs) compromises their performance, with associated risks of systemic embolization, stroke, pump stop and possible death. Anti-thrombotic (AT) drugs, utilized to limit thrombosis, are largely dosed empirically, with limited testing of their efficacy. Further, such testing, if performed, typically examines efficacy under static conditions, which is not reflective of actual shear-mediated flow. Here we adopted our previously developed Device Thrombogenicity Emulation methodology to design microfluidic platforms able to emulate representative shear stress profiles of mechanical circulatory support (MCS) devices. Our long-term goal is to utilize these systems for point-of-care (POC) personalized testing of AT efficacy under specific, individual shear profiles. First, we designed different types of microfluidic channels able to replicate sample shear stress patterns observed in MCS devices. Second, we explored the flexibility of microfluidic technology in generating dynamic shear stress profiles by modulating the geometrical features of the channels. Finally, we designed microfluidic channel systems able to emulate the shear stress profiles of two commercial VADs. From CFD analyses, the VAD-emulating microfluidic systems were able to replicate the main characteristics of the shear stress waveforms of the macroscale VADs (i.e., shear stress peaks and duration). Our results establish the basis for development of a lab-on-chip POC system able to perform device-specific and patient-specific platelet activation state assays.

Computational evaluation of the thrombogenic potential of a hollow-fiber oxygenator with integrated heat exchanger during extracorporeal circulation

The onset of thromboembolic phenomena in blood oxygenators, even in the presence of adequate anticoagulant strategies, is a relevant concern during extracorporeal circulation (ECC). For this reason, the evaluation of the thrombogenic potential associated with extracorporeal membrane oxygenators should play a critical role into the preclinical design process of these devices. This study extends the use of computational fluid dynamics simulations to guide the hemodynamic design optimization of oxygenators and evaluate their thrombogenic potential during ECC. The computational analysis accounted for both macro- (i.e., vortex formation) and micro-scale (i.e., flow-induced platelet activation) phenomena affecting the performances of a hollow-fiber membrane oxygenator with integrated heat exchanger. A multiscale Lagrangian approach was adopted to infer the trajectory and loading history experienced by platelet-like particles in the entire device and in a repetitive subunit of the fiber bundles. The loading history was incorporated into a damage accumulation model in order to estimate the platelet activation state (PAS) associated with repeated passes of the blood within the device. Our results highlighted the presence of blood stagnation areas in the inlet section that significantly increased the platelet activation levels in particles remaining trapped in this region. The order of magnitude of PAS in the device was the same as the one calculated for the components of the ECC tubing system, chosen as a term of comparison for their extensive diffusion. Interpolating the mean PAS values with respect to the number of passes, we obtained a straightforward prediction of the thrombogenic potential as a function of the duration of ECC.

Hemodynamic and thrombogenic analysis of a trileaflet polymeric valve using a fluid-structure interaction approach

Surgical valve replacement in patients with severe calcific aortic valve disease using either bioprosthetic or mechanical heart valves is still limited by structural valve deterioration for the former and thrombosis risk mandating anticoagulant therapy for the latter. Prosthetic polymeric heart valves have the potential to overcome the inherent material and design limitations of these valves, but their development is still ongoing. The aim of this study was to characterize the hemodynamics and thrombogenic potential of the Polynova polymeric trileaflet valve prototype using a fluid-structure interaction (FSI) approach. The FSI model replicated experimental conditions of the valve as tested in a left heart simulator. Hemodynamic parameters (transvalvular pressure gradient, flow rate, maximum velocity, and effective orifice area) were compared to assess the validity of the FSI model. The thrombogenic footprint of the polymeric valve was evaluated using a Lagrangian approach to calculate the stress accumulation (SA) values along multiple platelet trajectories and their statistical distribution. In the commissural regions, platelets were exposed to the highest SA values because of highest stress levels combined with local reverse flow patterns and vortices. Stress-loading waveforms from representative trajectories in regions of interest were emulated in our hemodynamic shearing device (HSD). Platelet activity was measured using our platelet activation state (PAS) assay and the results confirmed the higher thrombogenic potential of the commissural hotspots. In conclusion, the proposed method provides an in depth analysis of the hemodynamic and thrombogenic performance of the polymer valve prototype and identifies locations for further design optimization.