Wei Che Chiu

Device Thrombogenicity Emulation: A Novel Method for Optimizing Mechanical Circulatory Support Device Thromboresistance

Mechanical circulatory support (MCS) devices provide both short and long term hemodynamic support for advanced heart failure patients. Unfortunately these devices remain plagued by thromboembolic complications associated with chronic platelet activation – mandating complex, lifelong anticoagulation therapy. To address the unmet need for enhancing the thromboresistance of these devices to extend their long term use, we developed a universal predictive methodology entitled Device Thrombogenicity Emulation (DTE) that facilitates optimizing the thrombogenic performance of any MCS device – ideally to a level that may obviate the need for mandatory anticoagulation. DTE combines in silico numerical simulations with in vitro measurements by correlating device hemodynamics with platelet activity coagulation markers – before and after iterative design modifications aimed at achieving optimized thrombogenic performance. DTE proof-of-concept is demonstrated by comparing two rotary Left Ventricular Assist Devices (LVADs) (DeBakey vs HeartAssist 5, Micromed Houston, TX), the latter a version of the former following optimization of geometrical features implicated in device thrombogenicity. Cumulative stresses that may drive platelets beyond their activation threshold were calculated along multiple flow trajectories and collapsed into probability density functions (PDFs) representing the device ‘thrombogenic footprint’, indicating significantly reduced thrombogenicity for the optimized design. Platelet activity measurements performed in the actual pump prototypes operating under clinical conditions in circulation flow loops – before and after the optimization with the DTE methodology, show an order of magnitude lower platelet activity rate for the optimized device. The robust capability of this predictive technology – demonstrated here for attaining safe and cost-effective pre-clinical MCS thrombo-optimization – indicates its potential for reducing device thrombogenicity to a level that may significantly limit the extent of concomitant antithrombotic pharmacotherapy needed for safe clinical device use.

Thrombus Formation Patterns in the HeartMate II Ventricular Assist Device: Clinical Observations Can Be Predicted by Numerical Simulations

Postimplant device thrombosis remains a life-threatening complication and limitation of continuous-flow ventricular assist devices (VADs). Using advanced computational fluid dynamic (CFD) simulations, we successfully depicted various flow patterns, recirculation zones, and stagnant platelet trajectories which promote thrombus formation and observed that they matched actual thrombus formation patterns observed in Thoratec HeartMate II VADs explanted from patients with pump thrombosis. Previously, these small eddies could not be captured by either digital particle image velocimetry or CFD due to insufficient resolution. Our study successfully demonstrated the potential capability of advanced CFD to be adopted for device optimization, leading to enhanced safety and efficacy of VADs for long-term destination therapy.

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.

Ventricular Assist Device Implantation Configurations Impact Overall Mechanical Circulatory Support System Thrombogenic Potential.

Ventricular assist devices (VADs) became in recent years the standard of care therapy for advanced heart failure with hemodynamic compromise. With the steadily growing population of device recipients, various postimplant complications have been reported, mostly associated with the hypershear generated by VADs that enhance their thrombogenicity by activating platelets. Although VAD design optimization can significantly improve its thromboresistance, the implanted VAD need to be evaluated as part of a system. Several clinical studies indicated that variability in implantation configurations may contribute to the overall system thrombogenicity. Numerical simulations were conducted in the HeartAssist 5 (HA5) and HeartMate II (HMII) VADs in the following implantation configurations: 1) inflow cannula angles: 115° and 140° (HA5); 2) three VAD circumferential orientations: 0°, 30°, and 60° (HA5 and HMII); and 3) 60° and 90° outflow graft anastomotic angles with respect to the ascending aorta (HA5). The stress accumulation of the platelets was calculated along flow trajectories and collapsed into a probability density function, representing the “thrombogenic footprint” of each configuration—a proxy to its thrombogenic potential (TP). The 140° HA5 cannula generated lower TP independent of the circumferential orientation of the VAD. Sixty-degree orientation generated the lowest TP for the HA5 versus 0° for the HMII. An anastomotic angle of 60° resulted in lower TP for HA5. These results demonstrate that optimizing the implantation configuration reduces the overall system TP. Thromboresistance can be enhanced by combining VAD design optimization with the surgical implantation configurations for achieving better clinical outcomes of implanted VADs.

Thrombogenicity comparison of axial ventricular assist devices by dte methodology: Micromed heartassist 5 and thoratec heartmate II

Mechanical circulatory devices, such as ventricular assist devices (VADs), have become the life-saving alternative for the patients who suffered from severe heart failure (1). These devices were utilized as the bridge-transplant devices; however, due to the fast growing population of cardiovascular diseases and the eligible organ donations are very limited, these devices have been considered for the application of life-long implantation. The continuous-flow VADs offer better hemodynamic performance than the first generations pulsatile flow VADs, its compact design offers surgical advantage; however, due to the non-physiological blood flow past constricted geometrics where platelets are exposed to elevated wall shear stress (2), VADs are burdened with high incidence of thromboembolic events, mandating anticoagulation therapies for its recipients (3).© 2012 ASME

Comparative studies of axial ventricular assist devices (VAD) and the effect of outflow cannulation

Congestive heart failure has reached epidemic proportions in the United States with more than 5.7 million patients suffering from it annually (1). Due to the limited availability of donor hearts, patients in their late stage heart failure who may require cardiac transplantation are dying while waiting for a matched heart. Mechanical circulatory support devices (MCS), such as ventricular assist devices (VAD), are utilized as a bridge to transplantation, and recently as destination therapy for extending the life of these patients. Continuous-flow VAD offer a surgical advantage over older generation pulsatile-flow VAD due to their compact design; however, due to the high RPM these VADs are operated with and the non-physiological blood flow patterns they generates, VADs are burdened with high incidence of thromboembolic events, and antiplatelet/anticoagulation regimens are mandated for the device recipients.Copyright

In Vitro Evaluation of Shear-Induced Platelet Activation in the MicroMed DeBakey Ventricular Assist Device With Antiplatelet Therapy

Mechanical circulatory support (MCS) devices, which include ventricular assist devices (VADs), offer an attractive solution to approximately 35,000 end-stage heart failure patients eligible for transplants, of which only 2,000–2,300 are performed annually [1]. These devices are employed to augment the function of the ailing left and/or right ventricle and serve as bridge-to-transplant or destination therapy, but are often accompanied by thrombotic complications. Pathologic flow patterns are characteristic of VADs and increase susceptibility to shear-induced platelet activation, which leads to thrombus formation [2]. Patients implanted with such devices are routinely prescribed antiplatelets to tackle these complications. Despite this concurrent therapy, thromboembolic incident rates of 0.9–13% are reported for the widely-implanted Thoratec HeartMate II and MicroMed DeBakey VADs [3, 4]. This has spurred the development of design optimization techniques to lower or eliminate the incidence of thrombosis and reduce the dependence on pharmacotherapy management.Copyright

Design optimization of a novel polymeric prosthetic heart valve and a ventricular assist device via device thrombogenicity emulation

Thrombotic complications, such as hemorrhage or embolism, remain a major concern of blood contacting medical devices [1], including prosthetic heart valves (PHV) and mechanical circulatory support devices, e.g. ventricular assist devices (VAD) or the Total Artificial Heart (TAH) [2]. In most cases device recipients require life-long anticoagulation therapy, which increases the risk of hemorrhagic stroke and other bleeding disorders. In order to obviate the need for anticoagulants and reduce stroke risks, our group developed a unique optimization methodology, Device Thrombogenicity Emulation (DTE) [2–5]. With the DTE, the thrombogenic potential of a device is evaluated using extensive numerical modeling and calculating multiple platelet trajectories flowing through the device. The platelet stress-time waveforms are then emulated in our Hemodynamic Shearing Device (HSD) and their activation level is measured with our Platelet Activation State (PAS) assay. This provides a proxy validation of the simulation. We identify high shear stress producing regions within the device and modify its design to reduce or eliminate those potentially thrombogenic ‘hot-spots.’ Through an iterative process, we can optimize the device design prior to prototyping.© 2013 ASME

Design Optimization of Rotary Blood Pumps: Alternatives to Anticoagulation Therapy

Mechanical circulatory support (MCS) devices such as the ventricular assist devices (VADs) provide life saving short-term bridge-to-transplant solutions (1) to a large proportion of patients who suffer from chronic heart failure. Although hemodynamically efficient, such devices are burdened with high incidence of thromboembolic events due to non-physiological flow past constricted geometries where platelets (the principal cellular clotting elements in blood) are exposed to elevated shear stresses and exposure times (2) — requiring mandatory anticoagulation. We recently developed an optimization methodology — Device Thrombogenicity Emulator (DTE)(3) — that integrates device specific hemodynamic stresses (from numerical simulations) with experimental measurements of platelet activation. The DTE was successfully applied by our group to measure / optimize the thromboresistance of mechanical heart valves (MHV) (3, 4).Copyright