A simple, economical, and effective portable paediatric mock circulatory system.

Ventricular assist devices (VADs) and total artificial hearts have been in development for the last 50 years. Since their inception, simulators of the circulation with different degrees of complexity have been produced to test these devices in vitro. Currently, a new path has been taken with the extensive efforts to develop paediatric VADs, which require totally different design constraints. This paper presents the manufacturing details of an economical simulator of the systemic paediatric circulation. This simulator allows the insertion of a paediatric VAD, includes a pumping ventricle, and is adjustable within the paediatric range. Rather than focusing on complexity and physiological simulation, this simulator is designed to be simple and practical for rapid device testing. The simulator was instrumented with medical sensors and data were acquired under different conditions with and without the new PediaFlowTM paediatric VAD. The VAD was run at different impeller speeds while simulator settings such as vascular resistance and stroke volume were varied. The hydraulic performance of the VAD under pulsatile conditions could be characterized and the magnetic suspension could be tested via manipulations such as cannula clamping. This compact mock loop has proven to be valuable throughout the PediaFlow development process and has the advantage that it is uncomplicated and can be manufactured cheaply. It can be produced by several research groups and the results of different VADs can then be compared easily.

Drag-reducing polymers diminish near-wall concentration of platelets in microchannel blood flow.

The accumulation of platelets near the blood vessel wall or artificial surface is an important factor in the cascade of events responsible for coagulation and/or thrombosis. In small blood vessels and flow channels this phenomenon has been attributed to the blood phase separation that creates a red blood cell (RBC)-poor layer near the wall. We hypothesized that blood soluble drag-reducing polymers (DRP), which were previously shown to lessen the near-wall RBC depletion layer in small channels, may consequently reduce the near-wall platelet excess. This study investigated the effects of DRP on the lateral distribution of platelet-sized fluorescent particles (diam. = 2 µm, 2.5 × 108/ml) in a glass square microchannel (width and depth = 100 µm). RBC suspensions in PBS were mixed with particles and driven through the microchannel at flow rates of 6-18 ml/h with and without added DRP (10 ppm of PEO, MW = 4500 kDa). Microscopic flow visualization revealed an elevated concentration of particles in the near-wall region for the control samples at all tested flow rates (between 2.4 ± 0.8 times at 6 ml/h and 3.3 ± 0.3 times at 18 ml/h). The addition of a minute concentration of DRP virtually eliminated the near-wall particle excess, effectively resulting in their even distribution across the channel, suggesting a potentially significant role of DRP in managing and mitigating thrombosis.

An extended convection diffusion model for red blood cell-enhanced transport of thrombocytes and leukocytes.

Transport phenomena of platelets and white blood cells (WBCs) are fundamental to the processes of vascular disease and thrombosis. Unfortunately, the dilute volume occupied by these cells is not amenable to fluid-continuum modeling, and yet the cell count is large enough that modeling each individual cell is impractical for most applications. The most feasible option is to treat them as dilute species governed by convection and diffusion; however, this is further complicated by the role of the red blood cell (RBC) phase on the transport of these cells. We therefore propose an extended convection-diffusion (ECD) model based on the diffusive balance of a fictitious field potential, Psi, that accounts for the gradients of both the dilute phase and the local hematocrit. The ECD model was applied to the flow of blood in a tube and between parallel plates in which a profile for the RBC concentration field was imposed and the resulting platelet concentration field predicted. Compared to prevailing enhanced-diffusion models that dispersed the platelet concentration field, the ECD model was able to simulate a near-wall platelet excess, as observed experimentally. The extension of the ECD model depends only on the ability to prescribe the hematocrit distribution, and therefore may be applied to a wide variety of geometries to investigate platelet-mediated vascular disease and device-related thrombosis.

Drag reducing polymers improve tissue perfusion via modification of the RBC traffic in microvessels.

This paper reports a novel, physiologically significant, microfluidic phenomenon generated by nanomolar concentrations of drag-reducing polymers (DRP) dissolved in flowing blood, which may explain previously demonstrated beneficial effects of DRP on tissue perfusion. In microfluidic systems used in this study, DRP additives were found to significantly modify traffic of red blood cells (RBC) into microchannel branches as well as reduce the near-wall cell-free layer, which normally is found in microvessels with a diameter smaller than 0.3 mm. The reduction in plasma layer size led to attenuation of the so-called "plasma skimming" effect at microchannel bifurcations, increasing the number of RBC entering branches. In vivo, these changes in RBC traffic may facilitate gas transport by increasing the near vessel wall concentration of RBC and capillary hematocrit. In addition, an increase in near-wall viscosity due to the redirection of RBC in this region may potentially decrease vascular resistance as a result of increased wall shear stress, which promotes endothelium mediated vasodilation. These microcirculatory phenomena can explain the previously reported beneficial effects of DRP on hemodynamics in vivo observed in many animal studies. We also report here our finding that DRP additives reduce flow separations at microchannel expansions, deflecting RBC closer to the wall and eliminating the plasma recirculation zone. Although the exact mechanism of the DRP effects on RBC traffic in microchannels is yet to be elucidated, these findings may further DRP progress toward clinical use.

Microhaemodynamics within the blade tip clearance of a centrifugal turbodynamic blood pump.

A persistent challenge facing the quantitative design of turbodynamic blood pumps is the great disparity of spatial scales between the primary and auxiliary flow paths. Fluid passages within journals and adjacent to the blade tips are often on the scale of several blood cells, confounding the application of macroscopic continuum models. Yet, precisely in these regions there exists the highest shear stress, which is most likely to cause cellular trauma. This disparity has motivated these microscopic studies to visualize the kinematics of the blood cells within the small clearances of a miniature turbodynamic blood pump. A transparent model of a miniature centrifugal pump having an adjustable tip clearance (50-200 microm) was prepared for direct optical visualization of the region between the impeller blade tip and the stationary housing. Synchronized images of the blood cells were obtained by a microscopic visualization system, consisting of an inverted microscope fitted with long-working-distance objective lens (40x), mercury lamp, and high-resolution charge-coupled device camera electronically triggered by the rotation of the impeller. Experiments with 7 microm fluorescent particles revealed the influence of the gap dimension on the trajectory across the blade thickness. The lateral component of velocity (perpendicular to the blade) was dramatically enhanced in the 50 microm gap compared with the 200 microm gap, thereby reducing the exposure time. Studies with diluted bovine blood (Ht = 0.5 per cent) showed that the concentration of cells traversing the gap is also reduced dramatically (30 per cent) as the blade tip clearance is reduced from 200 microm to 50 microm. These results motivate further investigation into the microfluidic phenomena responsible for cellular trauma within turbodynamic blood pumps.

Association between arterial stiffness and the deformability of red blood cells (RBCs).

The relationship between the flexibility of atherosclerotic vessels and RBC deformability has been investigated. A significant difference of RBC deformability was found among the arterial stiffness groups classified by oscillometric measurement of blood pressure. The deformability was determined by direct microscopic observation of RBCs subjected to shear stress of 0.3 to 40.0 Pa with a rotating rheoscope. The deformability of stiffen group - abnormal pulse wave pattern group or moderate cardiovascular risk group - was found to be much higher than that of normal groups in wide shear stress region (3.0, 10.0, 30.0, and 40.0 Pa). We postulate that the body adapts high shear stress in vivo by making RBCs more distensible, and therefore less likely to rupture under strain or microcirculatory alterations.

Collected nondimensional performance of rotary dynamic blood pumps.

"Nonpulsatile" or "continuous flow" blood pumps are a relatively new application of the rotary dynamic blood pumping principle. They fall outside the normal envelop of pumps, considering their small size, viscosity of the fluid pumped, need for particularly good internal flow patterns, and desire for high efficiency. This article establishes the state of the art in the field of blood pump performance. Trends in efficiency, shut off pressure coefficient, and nondimensional power behavior as a function of nondimensional flow are identified. Blood pumps show agreement with the published effects of low Reynolds numbers in conventional pumps.

Minimally invasive estimation of systemic vascular parameters.

A cardiovascular parameter estimator to identify the systemic vascular parameters was developed using an extended Kalman filter (EKF) algorithm. Measurements from a ventricular assist device (VAD) and arterial pressure were used in the estimator. The systemic vascular parameters are important indices of heart condition. However, obtaining these parameters usually requires invasive measurements, which are difficult to obtain under most clinical environments. Including a VAD model into the estimator and using the signals from a VAD to identify the cardiovascular parameters for VAD patients would minimize the need for indwelling sensors. This paper illustrates the use of a Novacor left ventricular assist system (LVAS) model with a cardiovascular model in the estimator to identify the systemic vascular parameters: characteristic resistance, blood inertance at the aorta, systemic compliance, and systemic resistance. Performance of the estimator was evaluated using data from a computer simulation and from a mock circulatory system experiment. Robustness of the estimator to the available measurements was also described. The estimation results showed that the estimates converged with reasonable accuracy in a limited time when the LVAS pump volume and arterial pressure were used as measurements. These parameter estimates can provide additional diagnostic information for patient and device monitoring and can be used for future VAD control development.

Computational fluid dynamics as a development tool for rotary blood pumps.

Computational fluid dynamics (CFD) is beginning to significantly impact the development of biomedical devices, in particular rotary cardiac assist devices. The University of Pittsburgh's McGowan Center for Artificial Organ Development has extensively used CFD as the primary tool to analyze and design a novel axial flow blood pump having a magnetically suspended rotor. The blood-contacting surfaces of the pump were developed using a design strategy based on CFD that involved closely coupling a Navier-Stokes solver to a parameterized geometry modeler and advanced mesh movement techniques. CFD-based blood damage models for shear-induced hemolysis as well as surrogate functions describing thrombosis potential were employed to help guide design improvements. This CFD-based design approach resulted in the timely development of a pump subjected to multiple geometric refinements without building expensive physical prototypes for each design iteration. A physical prototype of the final improved pump was fabricated and experimentally analyzed using particle imaging flow visualization. The CFD predicted results correlated well with the experimental data including pressure-flow (H-Q) performance and specific flow field features. It is estimated that the present CFD-based design approach shortened the overall design time frame from an order of years to months.

Pressure-volume relationship of a pulsatile blood pump for ventricular assist device development.

A mathematical model describing the pressure-volume relationship of the Novacor left ventricular assist system (LVAS) was developed. The model consists of lumped resistance, capacitance, and inductance elements with one time varying capacitor to estimate the cyclic pressure generation of the pump using pump volume measurement. The ejection and filling portions of the pump cycle were modeled with two separate functions. The corresponding model parameters were estimated by least squares fit to experimental data obtained in the laboratory. Pressure and volume waveforms obtained from the model were compared with data obtained from laboratory tests and from patients. It performed well in simulating pump operation throughout the entire cycle. This model can be used for the evaluation of LVAS performance, for on-line estimation of an LVAS patient's cardiovascular parameters, for pump controller development, and as a tool for engineer training.

Elastance-based control of a mock circulatory system.

A new control strategy for a mock circulatory system (MCS) has been developed to mimic the Starling response of the natural heart. The control scheme is based on Suga's elastance model, which is implemented using nested elastance and pressure feedback control systems. The elastance control loop calculates the desired chamber pressure using a time-varying elastance function and the ventricular chamber volume signal. The pressure control loop regulates the chamber pressure according to this reference signal. Simulations and tests on MCS hardware showed that the elastance-based controller responds to changes in preload, afterload, and contractility in a manner similar to the natural heart. Since the elastance function is an arbitrary function of time, the controller allows modification of ventricular chamber contractility, giving researchers a new tool to mimic various pathological conditions which can be used in the evaluation of cardiac devices such as ventricular assist devices.

HeartMate II left ventricular assist system: from concept to first clinical use.

The HeartMate II left ventricular assist device (LVAD) (ThermoCardiosystems, Inc, Woburn, MA) has evolved from 1991 when a partnership was struck between the McGowan Center of the University of Pittsburgh and Nimbus Company. Early iterations were conceptually based on axial-flow mini-pumps (Hemopump) and began with purge bearings. As the project developed, so did the understanding of new bearings, computational fluid design and flow visualization, and speed control algorithms. The acquisition of Nimbus by ThermoCardiosystems, Inc (TCI) sped developments of cannulas, controller, and power/monitor units. The system has been successfully tested in more than 40 calves since 1997 and the first human implant occurred in July 2000. Multicenter safety and feasibility trials are planned for Europe and soon thereafter a trial will be started in the United States to test 6-month survival in end-stage heart failure.

Relationship of blood pressure and pump flow in an implantable centrifugal blood pump during hypertension.

The purpose of this study was to evaluate the real time relationship between pump flow and pump differential pressure (D-P) during experimentally induced hypertension (HT). Two calves (80 and 68 kg) were implanted with the EVA-HEART centrifugal blood pump (SunMedical Technology Research Corp., Nagano, Japan) under general anesthesia. Blood pressure (BP) in diastole was increased to 100 mm Hg by norepinephrine to simulate HT. Pump flow, D-P, ECG, and BP were measured at pump speeds of 1,800, 2,100, and 2,300 rpm. All data were separated into systole and diastole, and pump flow during HT was compared with normotensive (NT) conditions at respective pump speeds. Diastolic BP was increased to 99.3+/-4.1 mm Hg from 66.5+/-4.4 mm Hg (p<0.01). D-P in systole was under 40 mm Hg (range of change was 10 to 40 mm Hg) even during HT. During NT, the average systolic pump flow volume was 60% of the total pump flow. However, during HT, the average systolic pump flow was 100% of total pump flow volume, although the pump flow volume in systole during HT decreased (33.1+/-5.7 vs. 25.9+/-4.0 ml/systole, p<0.01). In diastole, the average flow volume through the pump was 19.6+/-6.9 ml/diastole during NT and -2.2+/-11.1 ml/diastole during HT (p<0.01). The change in pump flow volume due to HT, in diastole, was greater than the change in pump flow in systole at each pump speed (p<0.001). This study suggests that the decrease of mean pump flow during HT is mainly due to the decrease of the diastolic pump flow and, to a much lesser degree, systolic pump flow.

Continuously maintaining positive flow avoids endocardial suction of a rotary blood pump with left ventricular bypass.

This study showed the usefulness of maintaining positive pump flow to avoid endocardial suction and as an assist bypass. Three calves were implanted with centrifugal pumps. Hemodynamics and pump parameters were measured at varying pump speeds (from 1,100 to 2,300 rpm). In each test pump, speed was adjusted to create 3 hemodynamic states: both positive and negative flow (PNF), positive and zero flow (PZF), and continuously positive flow (CPF). The pump flow volume was determined during systole (Vs) and diastole (Vd). Vs in PNF was 29.6 ml and was not significantly different from Vs in PZF (p > 0.15). Vd in PNF was significantly different from Vd in PZF (p < 0.05). All bypass rates of PNF were over 30% of pulmonary flow. All PZF bypass rates were between the PNF rate and the CPF rate. These data showed that PZF satisfied the minimum requirement of assist flow and was under 100% bypass. Thus, PZF may avoid endocardial suction.

Fluid dynamic characterization of operating conditions for continuous flow blood pumps.

As continuous flow pumps become more prominent as long-term ventricular assist devices, the wide range of conditions under which they must be operated has become evident. Designed to operate at a single, best-efficiency, operating point, continuous flow pumps are required to perform at off-design conditions quite frequently. The present study investigated the internal fluid dynamics within two representative rotary fluid pumps to characterize the quality of the flow field over a full range of operating conditions. A Nimbus/UoP axial flow blood pump and a small centrifugal pump were used as the study models. Full field visualization of flow features in the two pumps was conducted using a laser based fluorescent particle imaging technique. Experiments were performed under steady flow conditions. Flow patterns at inlet and outlet sections were visualized over a series of operating points. Flow features specific to each pump design were observed to exist under all operating conditions. At off-design conditions, an annular region of reverse flow was commonly observed within the inlet of the axial pump, while a small annulus of backflow in the inlet duct and a strong disturbed flow at the outlet tongue were observed for the centrifugal pump. These observations were correlated to a critical nondimensional flow coefficient. The creation of a "map" of flow behavior provides an additional, important criterion for determining favorable operating speed for rotary blood pumps. Many unfavorable flow features may be avoided by maintaining the flow coefficient above a characteristic critical coefficient for a particular pump, whereas the intrinsic deleterious flow features can only be minimized by design improvement. Broadening the operating range by raising the band between the critical flow coefficient and the designed flow coefficient, is also a worthy goal for design improvement.

Computational simulation of platelet deposition and activation: II. Results for Poiseuille flow over collagen.

We have previously described the development of a two-dimensional computational model of platelet deposition onto biomaterials from flowing blood (Sorensen et al., Ann. Biomed. Eng. 27:436-448, 1999). The model requires estimation of four parameters to fit it to experimental data: shear-dependent platelet diffusivity and three platelet-deposition-related reaction rate constants. These parameters are estimated for platelet deposition onto a collagen substrate for simple parallel-plate flow of whole blood in both the presence and absence of thrombin. One set of experimental results is used as a benchmark for model-fitting purposes. The "trained" model is then validated by applying it to additional test cases from the literature for parallel-plate Poiseuille flow over collagen at both higher and lower wall shear rates, and in the presence of various anticoagulants. The predicted values agree very well with the experimental results for the training cases, and good reproduction of deposition trends and magnitudes is obtained for the heparin, but not the citrate, validation cases. The model is formulated to be easily extended to synthetic biomaterials, as well as to more complex flows.

Computational simulation of platelet deposition and activation: I. Model development and properties.

To better understand the mechanisms leading to the formation and growth of mural thrombi on biomaterials, we have developed a two-dimensional computational model of platelet deposition and activation in flowing blood. The basic formulation is derived from prior work by others, with additional levels of complexity added where appropriate. It is comprised of a series of convection-diffusion-reaction equations which simulate platelet-surface and platelet-platelet adhesion, platelet activation by a weighted linear combination of agonist concentrations, agonist release and synthesis by activated platelets, platelet-phospholipid-dependent thrombin generation, and thrombin inhibition by heparin. The model requires estimation of four parameters to fit it to experimental data: shear-dependent platelet diffusivity and resting and activated platelet-surface and platelet-platelet reaction rate constants. The model is formulated to simulate a wide range of biomaterials and complex flows. In this article we present the basic model and its properties; in Part II (Sorensen et al., Ann. Biomed. Eng. 27:449-458, 1999) we apply the model to experimental results for platelet deposition onto collagen.

Rotary blood pump flow spontaneously increases during exercise under constant pump speed: results of a chronic study.

Many types of rotary blood pumps and pump control methods have recently been developed with the goal of clinical use. From experiments, we know that pump flow spontaneously increases during exercise without changing pump control parameters. The purpose of this study was to determine the hemodynamics associated with the long-term observation of calves implanted with centrifugal blood pumps (EVAHEART, Sun Medical Technology Research Corporation, Nagano, Japan). Two healthy female Jersey calves were implanted with devices in the left thoracic cavity. A total of 22 treadmill exercise tests were performed after the 50th postoperative day. During exercise, the following parameters were compared with conditions at rest: heart rate, blood pressure, central venous oxygen saturation (SvO2), pump speed, and pump flow. The pump flow in a cardiac cycle was analyzed by separating the systole and diastole. Compared to the base data, statistically significant differences were found in the following interrelated parameters: the heart rate (66.8 +/- 5.2 vs. 106 +/- 9.7 bpm), mean pump flow (4.8 +/- 0.2 vs. 7.0 +/- 0.3 L/min), and volume of pump flow in diastole (26.0 +/- 1.8 vs. 13.5 +/- 2.5 ml). During exercise, the volume of pump flow in systole was 3 times larger than that measured in diastole. Blood pressure, SvO2, and pump speed did not change significantly from rest to exercise. These results suggested that the mean pump flow depends on the systolic pump flow. Therefore, the increase in the mean pump flow during exercise under constant pump speed was caused by an increase in the heart rate.

Decrease in red blood cell deformability caused by hypothermia, hemodilution, and mechanical stress: factors related to cardiopulmonary bypass.

During extracorporeal circulation in cardiopulmonary bypass (CPB) surgery, blood is exposed to anomalous mechanical and environmental factors, such as high shear stress, turbulence, decreased oncotic pressure caused by dilution of plasma, and moderate and especially deep hypothermia widely applied during CPB in infants. These factors cause damage to the red blood cells (RBCs), which is manifest by immediate and delayed hemolysis and by changes in the mechanical properties of RBCs. These changes include, in particular, decrease in RBC deformability impeding the passage of RBCs through the microvessels and may contribute to the complications associated with CPB surgery. We investigated in vitro the independent and combined effects of hypothermia, plasma dilution, and mechanical stress on deformability of bovine RBCs. Our studies showed each of these factors to cause a significant decrease in the deformability of RBCs, especially acting synergistically. The impairment of RBC deformability caused by hypothermia was found to be more pronounced for RBCs suspended in phosphate buffered saline (PBS) than for RBCs suspended in plasma. The decrease in RBC deformability caused by mechanical stress was significantly exacerbated by dilution of plasma with PBS. In summary, results of our in vitro study strongly point to a possible detrimental consequence of conventional CPB arising from increased RBC rigidity, which may lead to impaired microcirculation and tissue oxygen supply.

A computational and experimental comparison of two outlet stators for the Nimbus LVAD. Left ventricular assist device.

Two designs of an outlet stator for the Nimbus axial flow left ventricular assist device (LVAD) are analyzed at nominal operating conditions. The original stator assembly (Design 1) has significant flow separation and reversal. A second stator assembly (Design 2) replaces the original tubular outer housing with a converging-diverging throat section with the intention of locally improving the fluid dynamics. Both stator designs are analyzed using computational fluid dynamics (CFD) analysis and experimental particle imaging flow visualization (PIFV). The computational and experimental methods indicate: 1) persistent regions of flow separation in Design 1 and improved fluid dynamics in Design 2; 2) blade-toblade velocity fields that are well organized at the blade tip yet chaotic at the blade hub for both designs; and 3) a moderate decrease in pressure recovery for Design 2 as compared with Design 1. The CFD analysis provides the necessary insight to identify a subtle, localized flow acceleration responsible for the decreased hydraulic efficiency of Design 2. In addition, the curiously low thrombogenicity of Design 1 is explained by the existence of a three-dimensional unsteady vortical flow structure that enhances boundary advection.