Zhongjun J. Wu

Design and hydrodynamic evaluation of a novel pulsatile bioreactor for biologically active heart valves

Biologically active heart valves (tissue engineered and recellularized tissue-derived heart valves) have the potential to offer enhanced function when compared to current replacement value therapies since they can possibly remodel, and grow to meet the needs of the patient, and not require chronic medication. However, this technology is still in its infancy and many fundamental questions remain as to how these valves will function in vivo. It has been shown that exposing biologically active tissue constructs to pulsatile pressures and flows during in vitro culture produces enhanced extracellular matrix protein expression and cellularity, although the ideal hydrodynamic conditioning regime is as yet unknown. Moreover, in vitro organ-level studies of living heart valves aimed at studying the remodeling processes require environments that can accurately reproduce in vivo hemodynamics under sterile conditions. To this end, we have developed a system to study the effects of subjecting biologically active heart valves to highly controlled pulsatile pressure and flow waveforms under sterile conditions. The device fits inside a standard incubator and utilizes a computer-controlled closed loop feedback system to provide a high degree of control. The mean pressure, mean flow rate, driving frequency, and shape of the pulsatile pressure waveform can be changed automatically in order to simulate both physiologic and nonphysiologic hemodynamic conditions. Extensive testing and evaluation demonstrated the devices ability to subject a biologically active heart valve to highly controlled pulsatile waveforms that can be modulated during the course of sterile incubation.

The use of computational fluid dynamics in the development of ventricular assist devices

Progress in the field of prosthetic cardiovascular devices has significantly contributed to the rapid advancements in cardiac therapy during the last four decades. The concept of mechanical circulatory assistance was established with the first successful clinical use of heart-lung machines for cardiopulmonary bypass. Since then a variety of devices have been developed to replace or assist diseased components of the cardiovascular system. Ventricular assist devices (VADs) are basically mechanical pumps designed to augment or replace the function of one or more chambers of the failing heart. Computational Fluid Dynamics (CFD) is an attractive tool in the development process of VADs, allowing numerous different designs to be characterized for their functional performance virtually, for a wide range of operating conditions, without the physical device being fabricated. However, VADs operate in a flow regime which is traditionally difficult to simulate; the transitional region at the boundary of laminar and turbulent flow. Hence different methods have been used and the best approach is debatable. In addition to these fundamental fluid dynamic issues, blood consists of biological cells. Device-induced biological complications are a serious consequence of VAD use. The complications include blood damage (haemolysis, blood cell activation), thrombosis and emboli. Patients are required to take anticoagulation medication constantly which may cause bleeding. Despite many efforts blood damage models have still not been implemented satisfactorily into numerical analysis of VADs, which severely undermines the full potential of CFD. This paper reviews the current state of the art CFD for analysis of blood pumps, including a practical critical review of the studies to date, which should help device designers choose the most appropriate methods; a summary of blood damage models and the difficulties in implementing them into CFD; and current gaps in knowledge and areas for future work.

A Quantitative Comparison of Mechanical Blood Damage Parameters in Rotary Ventricular Assist Devices: Shear Stress, Exposure Time and Hemolysis Index

Ventricular assist devices (VADs) have already helped many patients with heart failure but have the potential to assist more patients if current problems with blood damage (hemolysis, platelet activation, thrombosis and emboli, and destruction of the von Willebrand factor (vWf)) can be eliminated. A step towards this goal is better understanding of the relationships between shear stress, exposure time, and blood damage and, from there, the development of numerical models for the different types of blood damage to enable the design of improved VADs. In this study, computational fluid dynamics (CFD) was used to calculate the hemodynamics in three clinical VADs and two investigational VADs and the shear stress, residence time, and hemolysis were investigated. A new scalar transport model for hemolysis was developed. The results were compared with in vitro measurements of the pressure head in each VAD and the hemolysis index in two VADs. A comparative analysis of the blood damage related fluid dynamic parameters and hemolysis index was performed among the VADs. Compared to the centrifugal VADs, the axial VADs had: higher mean scalar shear stress (sss); a wider range of sss, with larger maxima and larger percentage volumes at both low and high sss; and longer residence times at very high sss. The hemolysis predictions were in agreement with the experiments and showed that the axial VADs had a higher hemolysis index. The increased hemolysis in axial VADs compared to centrifugal VADs is a direct result of their higher shear stresses and longer residence times. Since platelet activation and destruction of the vWf also require high shear stresses, the flow conditions inside axial VADs are likely to result in more of these types of blood damage compared with centrifugal VADs.

Ambulatory veno-venous extracorporeal membrane oxygenation: Innovation and pitfalls

OBJECTIVE End-stage lung disease and severe acute lung injury are complex entities that remain challenges to manage. Therapies include early institution of mechanical ventilation with positive end-expiratory pressure, permissive hypercapnia, pulmonary vasodilators, and complex fluid regimens. Veno-venous extracorporeal membrane oxygenation is an available treatment option for these patients but, in its conventional form, can be associated with significant complications. We present our early experience with an attempt to optimize extracorporeal membrane oxygenation, emphasizing reduced adjunctive mechanical ventilatory support and aggressive rehabilitation, with a goal of ambulation. This strategy has been enabled by the introduction of a dual-lumen draw and return cannula placed via the internal jugular vein. METHODS The first 10 patients (mean age of 45.3 years, 8 male) treated with this strategy between January 1, 2009, and October 1, 2009, were retrospectively reviewed. The ambulatory extracorporeal membrane oxygenation strategy was initiated with an aim of minimal mechanical ventilation and aggressive rehabilitation. The patients were intended to be weaned from all respiratory support or bridged to transplantation. RESULTS The mean duration of extracorporeal membrane oxygenation was 20 (9-59) days, with average mean blood flows of 3.5 (1.6-4.9) L/min, and levels of CO(2) removal and O(2) transfer of 228 (54-570) mL/min and 127 (36-529) mL/min, respectively. Six of 10 patients were weaned from respiratory support (N = 4) or underwent transplantation (N = 2) and survived to discharge from the hospital. The remaining 4 patients died of sepsis (N = 3) and withdrawal of care after renal failure (N = 1). Four of the 6 surviving patients were extubated and ambulatory while still on extracorporeal membrane oxygenation. During that time, 3 of the 4 patients exercised at the bedside, with the remaining patient able to undergo full cardiopulmonary rehabilitation, including treadmill walking. CONCLUSIONS Improvements in the durability of membrane blood oxygenators and pumps have prompted renewed consideration of extracorporeal membrane oxygenation in patients with severe lung disease. This report describes an attempt to augment extracorporeal membrane oxygenation with the goal of ambulation by minimizing mechanical ventilatory support and using aggressive in-and-out-of-bed rehabilitation.

Smooth muscle cell hypertrophy of renal cortex arteries with chronic continuous flow left ventricular assist

BACKGROUND Pathophysiology of long-term continuous flow left ventricular assist is not well described. With many of these devices becoming available, it is important to examine for possible pathologic effects. In this study we examined the relationship between diminished pulsatility and pathologic changes in renal cortical arteries. METHODS Twenty-nine calves were implanted with various continuous flow left ventricular assist systems in a left ventricle-descending thoracic aorta bypass configuration. Pulsatility was quantified by pulse pressure and pulsatility index. Pathologic changes of the renal cortex arteries were described and evaluated by medial thickness, medial/vascular cross-sectional area ratio, and smooth muscle cell count, to quantify hypertrophy or hyperplasia. Seven calves, which underwent a sham-implant, were used as controls. RESULTS Systolic arterial pressure, pulse pressure, and pulsatility index were significantly lower and diastolic pressure was significantly higher than before implant in pump-implanted animals. Twenty-three of 29 pumpimplanted calves (79.3%) had medial smooth muscle cell hypertrophy in renal cortex arteries, whereas none of sham-implanted calves had any abnormal lesions. When the pump-implanted calves were grouped according to the presence of smooth muscle cell hypertrophy, there was a clear trend toward lower pump flow rate in calves with lesions. Renal function was within the normal range in all calves. CONCLUSIONS There appears to be a relationship between smooth muscle cell hypertrophy in renal cortex arteries and continuous flow left ventricular assist. Furthermore, although the pathologic changes are likely multifactorial, these lesions appear to be related to lower pump assist rates.

Study of Flow‐Induced Hemolysis Using Novel Couette‐Type Blood‐Shearing Devices

To assist the development and application of blood-contacting medical devices, two novel flow-through Couette-type blood-shearing devices have been developed to study the quantitative relationship between blood damage indexes and flow-dependent parameters. One device is an axial flow-through Couette-type device supported by a pair of pin bearings adapted from the adult Jarvik 2000 blood pump. The other is a centrifugal flow-through Couette-type device supported with magnetic bearings adapted from the CentriMag blood pump. In both devices, a rotor spindle was used to replace the original impeller blades so that a small gap was created between the housing and the rotating spindle surface. Computational fluid dynamics simulations have shown that a uniform, high shear stress region can be generated inside the small gap while the shear stresses elsewhere are relatively low. The possibility of secondary blood damage caused by mechanical seals was eliminated due to the use of a magnetic rotor system. Blood flow through the gap was driven by an externally pressurized reservoir. By adjusting the rotational speed and blood flow rate, shear-induced hemolysis was quantified at a matrix of exposure time (0.039 to 1.48 s) and shear stress (50 to 320 Pa). All of the experiments were conducted at room temperature using heparinized ovine blood with a hematocrit value of 30%. The measured hemolysis levels were much lower than those published in the literature, and the overestimation of those earlier studies may be attributable to device-related secondary blood-damaging effects. A new set of coefficients for the power law model was derived from the regression of the experimental data.

Evaluation of Eulerian and Lagrangian models for hemolysis estimation

Hemolysis caused by flow-induced mechanical damage to red blood cells is still a problem in medical devices such as ventricular assist devices (VADs), artificial lungs, and mechanical heart valves. A number of different models have been proposed by different research groups for calculating the hemolysis, and of these, the power law–based models (HI(%)=Ct&agr;&tgr;&bgr;) have proved the most popular because of their ease of use and applicability to a wide range of devices. However, within this power law category of models there are a number of different implementations. The aim of this work was to evaluate different power law–based models by calculating hemolysis in a specifically designed shearing device and a clinical VAD, and comparing the estimated results with experimental measurements of the hemolysis in these two devices. Both the Eulerian scalar transport and all the Lagrangian models had fairly large percentage of errors compared with the experiments (minimum Eulerian 91% and minimum Lagrangian 57%) showing they could not accurately predict the magnitude of the hemolysis. However, the Eulerian approach had large correlation coefficients (>0.99) showing that this method can predict relative hemolysis, which would be useful in comparative analysis, for example, for ranking different devices or for design optimization studies.

Computational characterization of flow and hemolytic performance of the UltraMag blood pump for circulatory support

The Levitronix UltraMag blood pump is a next generation, magnetically suspended centrifugal pump and is designed to provide circulatory support for pediatric and adult patients. The aim of this study is to investigate the hemodynamic and hemolytic characteristics of this pump using the computational fluid dynamics (CFD) approach. The computational domain for CFD analysis was constructed from the three-dimensional geometry (3D) of the UltraMag blood pump and meshed into 3D tetrahedral/hybrid elements. The governing equations of fluid flow were computationally solved to obtain a blood flow through the blood pump. Further, hemolytic blood damage was calculated by solving a scalar transport equation where the scalar variable and the source term were obtained utilizing an empirical power-law correlation between the fluid dynamic variables and hemolysis. To obtain mesh independent flow solution, a comparative examination of vector fields, hydrodynamic performance, and hemolysis predictions were carried out. Different sizes of tetrahedral and tetrahedral/hexahedral mixed hybrid models were considered. The mesh independent solutions were obtained by a hybrid model. Laminar and SST κ-ω turbulence flow models were used for different operating conditions. In order to pinpoint the most significant hemolytic region, the flow field analysis was coupled to the hemolysis predictions. In summary, computational characterization of the device was satisfactorily carried out within the targeted operating conditions of the device, and it was observed that the UltraMag blood pump can be safely operated for its intended use to create a circulatory support for both pediatric and adult-sized patients.

Computational Fluid Dynamics Analysis of Thrombosis Potential in Left Ventricular Assist Device Drainage Cannulae

Cannulation is necessary when blood is removed from the body, for example in hemodialysis, cardiopulmonary bypass, blood oxygenators, and ventricular assist devices. Artificial blood contacting surfaces are prone to thrombosis, especially in the presence of stagnant or recirculating flow. In this work, computational fluid dynamics was used to investigate the blood flow fields in three clinically available cannulae (Medtronic DLP 12, 16, and 24 F), used as drainage for pediatric circulatory support and to calculate parameters that may be indicative of thrombosis potential. The results show that using the 24 F cannula below flow rates of about 0.75 L/min produces hemodynamic conditions, which may increase the risk of blood clotting within the cannula. No reasons are indicated for not using the 12 or 16 F cannulae with flow rates between 0.25 and 3.0 L/min.

Early in vivo experience with the pediatric Jarvik 2000 heart.

The need for smaller, more efficient ventricular assist devices that can be used in a more chronic setting have led to exploration of mechanical circulatory support in the pediatric population. The pediatric Jarvik 2000 heart (child size), under development, was implanted in six juvenile sheep and studied for both acute fit and chronic performance evaluation. Daily hemodynamic measurements of cardiac output and pump output at varying pump speeds were taken. In addition, plasma free hemoglobin, lactic acid dehydrogenase, and platelet activation from blood samples were determined at baseline, after implantation, and twice a week thereafter. The measured flow through the outflow graft at increasing speeds from 10,000 rpm to 14,000 rpm with an increment of 1,000 rpm were 1.47 ± 0.43, 1.89 ± 0.52, 2.36 ± 0.61, 2.80 ± 0.73, and 3.11 ± 0.86 (L/min). The baseline plasma free hemoglobin was 11.95 ± 4.76 (mg/dL), with subsequent mean values being <30 mg/dL at postimplantation and weekly postimplantation measurements. Both lactic acid dehydrogenase and platelet activation showed an acute increase within the first week after implantation with subsequent return to baseline by 2 weeks after surgery. Our initial animal in vivo experience with the pediatric Jarvik 2000 heart shows that a small axial flow pump can provide partial to nearly complete circulatory support with minimal adverse effects on blood components.