Development of the PSU Child Pump.

The Pennsylvania State University (PSU) Child Pump, a centrifugal continuous-flow ventricular assist device (cf-VAD), is being developed as a suitable long-term implantable device for pediatric heart failure patients between 10 and 35 kg, body surface area (BSA) of 0.5-1.2 m2, 1-11 years of age, and requiring a mean cardiac output of 1.0-3.5 L/min. In-vitro hydraulic and hemodynamic performances were evaluated on a custom mock circulatory loop with ovine blood. Normalized index of hemolysis (NIH) was evaluated under four conditions: 1) 8,300 rpm, 3.5 L/min, ΔP = 60 mm Hg, 2) 8,150 rpm, 5.1 L/min, ΔP = 20 mm Hg, 3) 8,400 rpm, 3.2 L/min, ΔP = 70 mm Hg, and 4) 9,850 rpm, 5.0 L/min, ΔP = 80 mm Hg, resulting in normalized index of hemolysis = 0.027 ± 0.013, 0.015 ± 0.006, 0.016 ± 0.008, and 0.026 ± 0.011 mg/dl, respectively. A mock fit study was conducted using a three-dimensional printed model of a 19 kg patient's thoracic cavity to compare the size of the PSU Child Pump to the HeartMate3 and the HVAD. Results indicate the PSU Child Pump will be a safer, appropriately sized device capable of providing the given patient cohort proper support while minimizing the risks of blood trauma as they wait for a transplant.

HeartWare Left Ventricular Assist Device Exercise Hemodynamics With Speed Adjustment Based on Left Ventricular Filling Pressures.

Functional capacity remains limited in heart failure patients with left ventricular assist devices (LVADs) due to fixed pump speed and inability to offload the left ventricle adequately. We hypothesized that manually adjusting LVAD speed during exercise based on pulmonary capillary wedge pressures would increase total cardiac output and maximal oxygen consumption. Two participants with a HeartWare LVAD underwent an invasive ramp study at rest followed by an invasive cardiopulmonary stress test exercising in two randomized phases: fixed speed and adjusted speed. In the latter phase, speed was adjusted every 1 minute during exercise at ±20 rpm/1 mm Hg change from baseline pulmonary capillary wedge pressure. There was no difference in maximal oxygen consumption between the two phases, with a modest increase in total cardiac output during speed adjustment. Filling pressures were initially controlled during speed adjustment until speed was capped at 4,000 rpm, at which point filling pressures increased. Blood pressure was variable. The pressure across the head of the pump (ΔP) was higher with speed adjustment. Contrary to our hypothesis, LVAD speed adjustment during exercise did not improve total cardiac output and functional capacity. This variable response may be attributed to the native cardiac reserve and baroreceptor response; however, additional studies are needed.

Examining Science and Technology/Engineering Educators' Views of Teaching Biomedical Concepts Through Physical Computing.

Programming and automation continue to evolve rapidly and advance the capabilities of science, technology, engineering, and mathematics (STEM) fields. However, physical computing (the integration of programming and interactive physical devices) integrated within biomedical contexts remains an area of limited focus in secondary STEM education programs. As this is an emerging area, many educators may not be well prepared to teach physical computing concepts within authentic biomedical contexts. This shortcoming provided the rationale for this study, to examine if professional development (PD) had a noticeable influence on high school science and technology and engineering (T&E) teachers' (1) perceptions of teaching biomedical and computational thinking (CT) concepts and (2) plans to integrate physical computing within the context of authentic biomedical engineering challenges. The findings revealed a significant difference in the amount of biomedical and CT concepts that teachers planned to implement as a result of the PD. Using a modified version of the Science Teaching Efficacy Belief Instrument (STEBI-A) Riggs and Enochs in Science Education, 74(6), 625-637 (1990), analyses revealed significant gains in teachers' self-efficacy toward teaching both biomedical and CT concepts from the PD. Further analyses revealed that teachers reported increases in their perceived knowledge of biomedical and CT concepts and a significant increase in their intent to collaborate with a science or T&E educator outside of their content area. This study provides implications for researchers and educators to integrate more biomedical and physical computing instruction at the secondary education level.

Kinetic and Dynamic Effects on Degradation of von Willebrand Factor.

The loss of high molecular weight multimers (HMWM) of von Willebrand factor (vWF) in aortic stenosis (AS) and continuous-flow left ventricular assist devices (cf-LVADs) is believed to be associated with high turbulent blood shear. The objective of this study is to understand the degradation mechanism of HMWM in terms of exposure time (kinetic) and flow regime (dynamics) within clinically relevant pathophysiologic conditions. A custom high-shear rotary device capable of creating fully controlled exposure times and flows was used. The system was set so that human platelet-poor plasma flowed through at 1.75 ml/sec, 0.76 ml/sec, or 0.38 ml/sec resulting in the exposure time ( texp ) of 22, 50, or 100 ms, respectively. The flow was characterized by the Reynolds number (Re). The device was run under laminar (Re = 1,500), transitional (Re = 3,000; Re = 3,500), and turbulent (Re = 4,500) conditions at a given texp followed by multimer analysis. No degradation was observed at laminar flow at all given texp . Degradation of HMWM at a given texp increases with the Re. Re ( p < 0.0001) and texp ( p = 0.0034) are significant factors in the degradation of HMWM. Interaction between Re and texp , however, is not always significant ( p = 0.73).

In Vivo Evaluation of a Physiologic Control System for Rotary Blood Pumps Based on the Left Ventricular Pressure-Volume Loop.

Current generation continuous flow assist devices to operate at a fixed speed, which limits preload response and exercise capacity in left ventricular assist device (LVAD) patients. A feedback control system was developed to automatically adjust pump speed based on direct measurements of ventricular loading using a custom cannula tip with an integrated pressure sensor and volume-sensing conductance electrodes. The input to the control system is the integral of the left ventricular (LV) pressure versus conductance loop (PGA) over each cardiac cycle. The feedback control system adjusts pump speed based on the difference between the measured PGA and the desired PGA. The control system and cannula tip were tested in acute ovine studies (n = 5) using the HeartMate II LVAD. The preload response of the control system was evaluated by partially occluding and releasing the inferior vena cava using a vessel loop snare. The cannula tip was integrated onto a custom centrifugal flow LVAD and tested in a 14-day bovine study. The control system adjusted pump support to maintain constant ventricular loading: pump speed increased (decreased) following an increase (decrease) in preload. This study demonstrated in vivo the Starling-like response of an automatic pump control system based on direct measurements of LV loading.

Experimental Hemodynamics Within the Penn State Fontan Circulatory Assist Device.

For children born with a single functional ventricle, the Fontan operation bypasses the right ventricle by forming a four-way total cavopulmonary connection and adapts the existing ventricle for the systemic circulation. However, upon reaching adulthood, many Fontan patients exhibit low cardiac output and elevated venous pressure, eventually requiring a heart transplantation. Despite efforts in developing a new device or using an existing device for failing Fontan support, there is still no Food and Drug Administration-approved device for subpulmonary support. Penn State University is developing a hydrodynamically levitated Fontan circulatory assist device (FCAD) for bridge-to-transplant or destination therapy. The hemodynamics within the FCAD, at both steady and patient averaged pulsatile conditions for three physiological pump operating conditions, were quantified using particle image velocimetry (PIV) to determine the velocity magnitudes and Reynolds normal and shear stresses within the device. Data were acquired at three planes (0 mm and ±25% of the radius) for the inferior and superior vena cavae inlets and the pulmonary artery outlet. The inlets had a blunt velocity profile that became skewed toward the collecting volute as fluid approached the rotor. At the outlet, regardless of the flow condition, a high-velocity jet exited the volute and moved downstream in a helical pattern. Turbulent stresses observed at the volute exit were influenced by the rotor's rotation. Regardless of inlet conditions, the pump demonstrated advantageous behavior for clinical use with a predictable flow field and a low risk of platelet adhesion and hemolysis based on calculated wall shear rates and turbulent stresses, respectively.

Miniaturized Fontan Circulation Assist Device: Chronic In Vivo Evaluation.

We have miniaturized and optimized our implantable rotary blood pump developed to provide long-term mechanical right heart support for patients who have failing Fontan circulation. The objective of this study was to evaluate the miniaturized Fontan circulation assist device (mini-FCAD) during 30-day sheep studies (n = 5). A complete right heart bypass was performed and all return flow was supported by the pump. Postoperatively, unfractionated heparin was given to maintain thromboelastography R times of 2× normal. The first two studies were terminated on day 0 and day 4 due to complications. In the final three studies, the animals remained healthy and were electively terminated at 30 ± 2 days. Pump flow was between 5 and 7 lpm, left atrial pressure remained normal, and inlet pressures were between 3 and 18 mm Hg with no incidents of suction. There was no evidence of hemolysis, end organ or pulmonary dysfunction, thromboembolic events, nor thermal damage to the surrounding tissue. Explanted devices from two studies were free of thrombi and in the third study there were unattached thrombi on the SVC inlet of the rotor. The mini-FCAD was successfully tested in vivo as a right heart replacement device demonstrating adequate circulatory support and normal physiologic pulmonary and venous pressures.

Dynamics of Blood Flows in Aortic Stenosis: Mild, Moderate, and Severe.

Supraphysiologic high shear stresses created in calcific aortic stenosis (AS) are known to cause hemostatic abnormalities, however, the relationship between the complex blood flows over the severity of AS and hemostatic abnormalities still remains unclear. This study systematically characterized the blood flow in mild, moderate, and severe AS. A series of large eddy simulations (LES) validated by particle image velocimetry were performed on physiologically representative AS models with a peak physiologic flow condition of 18 liter per minute. Time-accurate velocity fields, transvalvular pressure gradient, and laminar viscous-and turbulent (or Reynolds) shear stresses (RSSmax) were evaluated for each degree of severity. The peak velocities of mild, moderate, and severe AS were on the order of 2.0, 4.0, and 8.0 m/s, respectively. Jet velocity in severe AS was highly skewed with extremely high velocity (as high as 8 m/s) and mainly traveled through the posterior aortic wall up to the aortic arch while still carrying a relatively high velocity, that is, >4 m/s. The mean laminar viscous wall shear stresses (WSS) for mild, moderate, and severe AS were on the order of 40, 100, and 180 Pa, respectively. The RSSmax were on the order of 260, 490, and 2,500 Pa for mild, moderate, and severe AS, respectively. This study may provide a link between altered flows in AS and hemostatic abnormalities such as acquired von Willebrand syndrome and hemolysis, thus, help diagnosing and timing of the treatment.

Stress and Exposure Time on von Willebrand Factor Degradation.

Despite the prevailing use of the continuous flow left ventricular assist devices (cf-LVAD), acquired von Willebrand syndrome (AvWS) associated with cf-LVAD still remains a major complication. As AvWS is known to be dependent on shear stress (τ) and exposure time (texp ), this study examined the degradation of high molecular weight multimers (HMWM) of von Willebrand factor (vWF) in terms of τ and texp . Two custom apparatus, i.e., capillary-tubing-type degrader (CTD) and Taylor-Couette-type degrader (TCD) were developed for short-term (0.033 sec ≤ texp  ≤ 1.05 s) and long-term (10 s ≤ texp  ≤ 10 min) shear exposures of vWF, respectively. Flow conditions indexed by Reynolds number (Re) for CTD were 14 ≤ Re ≤ 288 with corresponding laminar stress level of 52 ≤  τ CTD  ≤ 1042 dyne/cm2 . Flow conditions for TCD were 100 ≤ Re ≤ 2500 with corresponding rotor speed of 180 ≤ o  ≤ 4000 RPM and laminar stress level of 50 ≤  τ TCD  ≤ 1114 dyne/cm2 . Due to transitional and turbulent flows in TCD at Re > 1117, total stress (i.e., τ total  = laminar + turbulent) was also calculated using a computational fluid dynamics (CFD) solver, Converge CFD (Converge Science Inc., Madison, WI, USA). Inhibition of ADAMTS13 with different concentration of EDTA (5 mM and 10 mM) was also performed to investigate the mechanism of cleavage in terms of mechanical and enzymatic aspects. Degradation of HMWM with CTD was negligible at all given testing conditions. Although no degradation of HMWM was observed with TCD at Re < 1117 ( τ total  = 1012 dyne/cm2 ), increase in degradation of HMWM was observed beyond Re of 1117 for all given exposure times. At Re ~ 2500 ( τ total  = 3070 dyne/cm2 ) with texp  = 60 s, a severe degradation of HMWM (90.7 ± 3.8%, abnormal) was observed, and almost complete degradation of HMWM (96.1 ± 1.9%, abnormal) was observed with texp  = 600 s. The inhibition studies with 5 mM EDTA at Re ~ 2500 showed that loss of HMWM was negligible (<10%, normal) for all given exposure times except for texp  = 10 min (39.5 ± 22.3%, borderline-abnormal). With 10 mM EDTA, no degradation of HMWM was observed (11.1 ± 4.4%, normal) even for texp  = 10 min. This study investigated the effect of shear stress and exposure time on the HMWM of vWF in laminar and turbulent flows. The inhibition study by EDTA confirms that degradation of HMWM is initiated by shear-induced unfolding followed by enzymatic cleavage at given conditions. Determination of magnitude of each mechanism needs further investigation. It is also important to note that the degradation of vWF is highly dependent on turbulence regardless of the time exposed within our testing conditions.

Cannula Tip With Integrated Volume Sensor for Rotary Blood Pump Control: Early-Stage Development.

The lack of direct measurement of left ventricular unloading is a significant impediment to the development of an automatic speed control system for continuous-flow left ventricular assist devices (cf-LVADs). We have developed an inlet cannula tip for cf-LVADs with integrated electrodes for volume sensing based on conductance. Four platinum-iridium ring electrodes were installed into grooves on a cannula body constructed from polyetheretherketone (PEEK). A sinusoidal current excitation waveform (250 µA pk-pk, 50 kHz) was applied across one pair of electrodes, and the conductance-dependent voltage was sensed across the second pair of electrodes. The conductance catheter was tested in an acute ovine model (n = 3) in conjunction with the HeartMate II rotary blood pump to provide circulatory support and unload the ventricle. Echocardiography was used to measure ventricular size during pump support for verification for the conductance measurements. The conductance measurements correlated linearly with the echocardiography dimension measurements more than the full range of pump support from minimum support to suction. This cannula tip will enable the development of automatic control systems to optimize pump support based on a real-time measurement of ventricular size.

Chronic In Vivo Test of a Right Heart Replacement Blood Pump for Failed Fontan Circulation.

An implantable rotary blood pump was developed to provide long-term mechanical right heart support for patients who have failing Fontan circulation. The objective of this study was to evaluate the pump in vivo in a 30 day sheep study. Pump speed was set at 3,900 rpm for the duration of the study, and pump power was between 4.3 and 4.6 W. The pump inlet pressures for the superior vena cava (SVC) and inferior vena cava (IVC) were 14 ± 15 and 11 ± 15 mm Hg, respectively, over the duration of the study. Hematocrit remained stable at 30% ± 4%. Partial thromboplastin time (PTT) steadily increased from 30 s preoperatively to a high of 59 s on postoperative day 20, while prothrombin time (PT) remained at 20 ± 2 s for the duration of the study. The implantation and postoperative recovery were successful, and the animal demonstrated normal physiologic pulmonary and venous pressures and cardiac output. On pump inspection, the IVC and SVC inlets were completely clear of any deposits, but there were small thrombi (approximately 0.5 mm diameter) between each of the three rotor blades and along 20% of the parting line of the two volute halves. A complete right heart bypass was performed, postoperative recovery was successful, and the pump demonstrated adequate circulatory support and normal physiologic pulmonary and venous pressures. This study was the first successful test of a right heart replacement device in a chronic animal study.

Continuous flow left ventricular pump support and its effect on regional left ventricular wall stress: finite element analysis study.

Left ventricular assist device (LVAD) support unloads left ventricular (LV) pressure and volume and decreases wall stress. This study investigated the effect of systematic LVAD unloading on the 3-dimensional myocardial wall stress by employing finite element models containing layered fiber structure, active contractility, and passive stiffness. The HeartMate II(®) (Thoratec, Inc., Pleasanton, CA) was used for LV unloading. The model geometries and hemodynamic conditions for baseline (BL) and LVAD support (LVsupport) were acquired from the Penn State mock circulatory cardiac simulator. Myocardial wall stress of BL was compared with that of LVsupport at 8,000, 9,000, 10,000 RPM, providing mean pump flow (Q(mean)) of 2.6, 3.2, and 3.7 l/min, respectively. LVAD support was more effective at unloading during diastole as compared to systole. Approximately 40, 50, and 60% of end-diastolic wall stress reduction were achieved at Q(mean) of 2.6, 3.2, and 3.7 l/min, respectively, as compared to only a 10% reduction of end-systolic wall stress at Q(mean) of 3.7 l/min. In addition, there was a stress concentration during systole at the apex due to the cannulation and reduced boundary motion. This modeling study can be used to further understand optimal unloading, pump control, patient management, and cannula design.

Ventricular contractility and compliance measured during axial flow blood pump support: in vitro study.

End-systolic elastance and end-diastolic compliance have been used to quantify systolic and diastolic function of the left ventricle (LV). In this study, the effective end-systolic elastance, (EES )eff , end-systolic volume intercept, (V0 )eff , and end-diastolic compliance of the LV were assessed at various levels of left ventricular assist device (LVAD) support. We tested the hypothesis that (EES )eff and (V0 )eff vary as a function of LVAD speed, while compliance does not change. The Penn State in vitro cardiac simulator was used in two heart conditions (control and heart failure [HF]) with the HeartMate II axial flow LVAD. The LVAD speed was linearly increased from 6000 to 11 000 rpm, with 500-rpm increments. The end-systolic and end-diastolic pressure-volume relationships were estimated at each LVAD speed. Acute LVAD support itself showed pseudo-improvement of ventricular contractility. The (EES )eff and (V0 )eff in HF were found to be dependent on the LVAD speed. The effective compliance for both control and HF was independent of the LVAD speed. Therefore, when examining the time-course cardiac recovery induced by the LVAD support, LV performance should be measured immediately before and after LVAD support while keeping LVAD speed consistent to avoid potential overestimation of long-term cardiac recovery.

Changes in the functional status measures of heart failure patients with mechanical assist devices.

Continuous-flow left ventricular assist devices (cfLVADs) have been proven safe and effective for bridge-to-transplant and destination therapy (DT) in patients with advanced heart failure. However, the fixed pump speed of these devices may lack response to activity and oxygen demand, thereby limiting exercise tolerance. The objective of this observational study was to describe exercise capacity as measured by peak oxygen consumption (peak VO2) that may be expected during support with a cfLVAD. Peak VO2 was measured in patients (mean age: 58.3 ± 11.7 years; 66.7% ischemic and 33.3% DT) before cfLVAD support (11.2 ± 3.0 ml/kg/min, n = 25), between 3 and 6 months (12.7 ± 3.5 ml/kg/min, n = 31), at 1 year (10.7 ± 2.6 ml/kg/min, n = 16), and longer than 1 year (11.2 ± 1.7 ml/kg/min, n = 10). There was no statistical improvement in peak VO2 at any time point after implantation. In addition, ventilatory efficiency remained poor after LVAD implantation at all time points. Although studies have shown an increase in survival and patient's quality of life, exercise capacity as measured by cardiopulmonary exercise testing remains low during cfLVAD support.

Chronic in vivo testing of the Penn State infant ventricular assist device.

The Penn State Infant Ventricular Assist Device (VAD) is a 12-14 ml stroke volume pneumatically actuated pump, with custom Björk-Shiley monostrut valves, developed under the National Heart, Lung, and Blood Institute Pediatric Circulatory Support program. In this report, we describe the seven most recent chronic animal studies of the Infant VAD in the juvenile ovine model, with a mean body weight of 23.5 ± 4.1 kg. The goal of 4-6 weeks survival was achieved in five of seven studies, with support duration ranging from 5 to 41 days; mean 26.1 days. Anticoagulation was accomplished using unfractionated heparin, and study animals were divided into two protocol groups: the first based on a target activated partial thromboplastin time of 1.5-2 times normal, and a second group using a target thromboelastography R-time of two times normal. The second group required significantly less heparin, which was verified by barely detectable heparin activity (anti-Xa). In both groups, there was no evidence of thromboembolism except in one animal with a chronic infection and fever. Device thrombi were minimal and were further reduced by introduction of the custom valve. These results are consistent with results of adult VAD testing in animals and are encouraging given the extremely low levels of anticoagulation in the second group.

An implantable Fabry-Pérot pressure sensor fabricated on left ventricular assist device for heart failure.

Continuous flow left ventricular assist devices (LVADs) are commonly used as bridge-to-transplantation or destination therapy for heart failure patients. However, non-optimal pumping speeds can reduce the efficacy of circulatory support or cause dangerous ventricular arrhythmias. Optimal flow control for continuous flow LVADs has not been defined and calls for an implantable pressure sensor integrated with the LVAD for real-time feedback control of pump speed based on ventricular pressure. A MEMS pressure sensor prototype is designed, fabricated and seamlessly integrated with LVAD to enable real-time control, optimize its performance and reduce its risks. The pressure sensing mechanism is based on Fabry-Pérot interferometer principle. A biocompatible parylene diaphragm with a silicon mirror at the center is fabricated directly on the inlet shell of the LVAD to sense pressure changes. The sensitivity, range and response time of the pressure sensor are measured and validated to meet the requirements of LVAD pressure sensing.

Effective ventricular unloading by left ventricular assist device varies with stage of heart failure: cardiac simulator study.

Although the use of left ventricular assist devices (LVADs) as a bridge-to-recovery (BTR) has shown promise, clinical success has been limited due to the lack of understanding the timing of implantation, acute/chronic device setting, and explantation. This study investigated the effective ventricular unloading at different heart conditions by using a mock circulatory system (MCS) to provide a tool for pump parameter adjustments. We tested the hypothesis that effective unloading by LVAD at a given speed varies with the stage of heart failure. By using a MCS, systematic depression of cardiac performance was obtained. Five different stages of heart failure from control were achieved by adjusting the pneumatic systolic/diastolic pressure, filling pressure, and systemic resistance. The Heart Mate II® (Thoratec Corp., Pleasanton, CA) was used for volumetric and pressure unloading at different heart conditions over a given LVAD speed. The effective unloading at a given LVAD speed was greater in more depressed heart condition. The rate of unloading over LVAD speed was also greater in more depressed heart condition. In conclusion, to get continuous and optimal cardiac recovery, timely increase in LVAD speed over a period of support is needed while avoiding the akinesis of aortic valve.

Rotary blood pump control using integrated inlet pressure sensor.

Due to improved reliability and reduced risk of thromboembolic events, continuous flow left ventricular assist devices are being used more commonly as a long term treatment for end-stage heart failure. As more and more patients with these devices are leaving the hospital, a reliable control system is needed that can adjust pump support in response to changes in physiologic demand. An inlet pressure sensor has been developed that can be integrated with existing assist devices. A control system has been designed to adjust pump speed based on peak-to-peak changes in inlet pressure. The inlet pressure sensor and control system have been tested with the HeartMate II axial flow blood pump using a mock circulatory loop and an active left ventricle model. The closed loop control system increased total systemic flow and reduced ventricular load following a change in preload as compared to fixed speed control. The increase in systemic flow occurred under all operating conditions, and maximum unloading occurred in the case of reduced ventricular contractility.

Development of an inlet pressure sensor for control in a left ventricular assist device.

A Tesla type continuous flow left ventricular assist device (VAD) has been designed by Penn State and Advanced Bionics, Inc. (ABI). When a continuous flow device is used, care must be taken to limit low pressures in the ventricle, which can produce an obstruction to the inlet cannula or trigger arrhythmias. Design of an inexpensive, semiconductor strain gauge inlet pressure sensor to detect suction has been completed. The research and design analysis included finite element modeling of the sensing region. Sensitivity, step-response, temperature dependence, and hysteresis tests have been performed on prototype units. All sensors were able to withstand the maximum expected strain of 82 microm/in at 500 mm Hg internal pressure. Average sensitivity was 0.52 +/- 0.24 microV/mm Hg with 0.5 V excitation (n = 5 units). Step-response time for a 0- to 90-mm Hg step change averaged 22 msec. Hysteresis was measured by applying and holding 75 mm Hg internal pressure for 4 hours, followed by a zero pressure measurement, and ranged from -15 to 4.1 mm Hg (n = 3 units). Offset drift varied between 180 and -140 mm Hg over a 4-week period (n = 2 units). Span temperature sensitivity ranged from 18 to -21 muV/ degrees C (n = 5 units). Gain temperature sensitivity ranged from -7.4 to 4.9 muV/ degrees C (n = 5 units). With the inherent drift, it is currently not possible to use the transducer to measure actual pressures, but it can easily be used to measure pressure changes throughout the cardiac cycle. This signal can then be used in the control system to avoid ventricular suction events.