Current mechanical circulatory support demonstrates excellent in vitro hemocompatibility when operated at the design point, although clinical requirements demand devices be used "off design," which may introduce higher stresses or residence times of blood. We evaluated the in vitro hemocompatibility of the BiVACOR total artificial heart (TAH) when operated at the boundaries of clinical need. Cattle blood was circulated in an in vitro blood loop at 3.0 L/min (low flow [LF]) or 12.0 L/min (high flow [HF]) in a pulsatile manner (+900 rev/min at 1 Hz) for 6 h using the TAH, for comparisons with a clinical comparator device operated in continuous flow. In LF, the normalized index of hemolysis (NIH) was 0.003 ± 0.002 g/100 L for the TAH, which was higher than the comparator (0.001 ± 0.001 g/100 L). In HF conditions, NIH was not different between devices: the TAH generated 0.004 ± 0.002 g/100 L and the comparator 0.002 ± 0.003 g/100 L. BiVACOR's TAH generated similar hemocompatibility to a clinically approved comparator, despite the TAH generating a clinically meaningful pulse pressure. Given that the TAH requires blood to transit the pump approximately twice as frequently as the comparator, these findings are promising for future applications.

INTRODUCTION:Peripheral veno-arterial extracorporeal membrane oxygenation (VA ECMO) creates a retrograde flow along the aorta competing with the left ventricle (LV) in the so-called 'mixing zone' (MZ). Detecting it is essential to understand which of the LV or the ECMO flow perfuses the upper body - particularly the brain and the coronary arteries - in case of differential hypoxemia (DH). METHODS:We described a mock circulation loop (MCL) that enabled experimental research on DH. We recreated the three clinical situations relevant to clinicians: where the brain is either totally perfused by the ECMO or the LV or both. In a second step, we used this model to investigate two scenarios to diagnose DH: (i) pulse pressure and (ii) thermodilution via injection of cold saline in the ECMO circuit. RESULTS:The presented MCL was able to reproduce the three relevant mixing zones within the aortic arch, thus allowing to study DH. Pulse pressure was unable to detect location of the MZ. However, the thermodilution method was able to detect whether the brain was totally perfused by the ECMO or not. CONCLUSION:We validated an in-vitro differential hypoxemia model of cardiogenic shock supported by VA ECMO. This MCL could be used as an alternative to animal studies for research scenarios.

Continuous monitoring of left ventricular stroke work (LVSW) may improve the medical management of patients with rotary left ventricular assist devices (LVAD). However, implantable pressure–volume sensors are limited by measurement drift and hemocompatibility. Instead, estimator algorithms derived from rotary LVAD signals may be a suitable alternative. An LVSW estimator algorithm was developed and evaluated in a range of in vitro and ex vivo cardiovascular conditions during full assist (closed aortic valve [AoV]) and partial assist (opening AoV) mode. For full assist, the LVSW estimator algorithm was based on LVAD flow, speed, and pump pressure head, whereas for partial assist, the LVSW estimator combined the full assist algorithm with an estimate of AoV flow. During full assist, the LVSW estimator demonstrated a good fit in vitro and ex vivo (R 2 : 0.97 and 0.86, respectively) with errors of ± 0.07 J. However, LVSW estimator performance was reduced during partial assist, with in vitro : R 2 : 0.88 and an error of ± 0.16 J and ex vivo : R 2 : 0.48 with errors of ± 0.11 J. Further investigations are required to improve the LVSW estimate with partial assist; however, this study demonstrated promising results for a continuous estimate of LVSW for rotary LVADs.

OBJECTIVE:Pulsatile-flow veno-arterial extracorporeal membrane oxygenation (V-A ECMO) has shown encouraging results for microcirculation resuscitation and left ventricle unloading in patients with refractory cardiogenic shock. We aimed to comprehensively assess different V-A ECMO parameters and their contribution to hemodynamic energy production and transfer through the device circuit.METHODS:We used the i-cor® ECMO circuit, which composed of Deltastream DP3 diagonal pump and i-cor® console (Xenios AG), the Hilite 7000 membrane oxygenator (Xenios AG), venous and arterial tubing and a 1 L soft venous pseudo-patient reservoir. Four different arterial cannulae (Biomedicus 15 and 17 Fr, Maquet 15 and 17 Fr) were used. For each cannula, 192 different pulsatile modes were investigated by adjusting flow rate, systole/diastole ratio, pulsatile amplitudes and frequency, yielding 784 unique conditions. A dSpace data acquisition system was used to collect flow and pressure data.RESULTS:Increasing flow rates and pulsatile amplitudes were associated with significantly higher hemodynamic energy production (both p < 0.001), while no significant associations were seen while adjusting systole-to-diastole ratio (p = 0.73) or pulsing frequency (p = 0.99). Arterial cannula represents the highest resistance to hemodynamic energy transfer with 32%-59% of total hemodynamic energy generated being lost within, depending on pulsatile flow settings used.CONCLUSIONS:Herein, we presented the first study to compare hemodynamic energy production with all pulsatile ECLS pump settings and their combinations and widely used yet previously unexamined four different arterial ECMO cannula. Only increased flow rate and amplitude increase hemodynamic energy production as single factors, whilst other factors are relevant when combined.

PurposeThe BiVACOR Total Artificial Heart (TAH) is designed as a short and long-term implantable replacement option for the failing human heart. The device combines rotary blood pump and magnetic levitation technology to produce a single, contact-free, spinning disc that reliably pumps blood to the systemic and pulmonary circulations. Rapid and cyclic changes in pump speed induces pulsatile outflow, while large blood gaps reduces stress on the blood. The development of the BiVACOR system over the last 10 years has produced multiple device iterations which have been implanted in more than 30 chronic animal studies for up to 3-month durations and operated on the benchtop for more than 4 years (ongoing). The final clinical grade version of the device was manufactured, and preclinical data evaluated in preparation for first-in-human clinical studies.MethodsDurability was assessed by continuously operating eight clinical grade BiVACOR devices in pulsatile outflow mode while submerged in saline. Hemolysis was evaluated by circulating bovine blood for 6hrs. In-vivo performance was demonstrated by implanting the BiVACOR device into five calves (82 - 108 kg), following a full cardiectomy, and then monitoring physiological function for 30 days, before elective termination.ResultsAll eight clinical grade BiVACOR devices are approaching one year durability (ongoing) without any device failures. Low levels of hemolysis (4 ± 2 mg/100L) were measured with pulsatile outflow at 12LPM. Five calves were successfully supported for 30 days by the BiVACOR device, while demonstrating normal hemodynamics, end organ function and hemocompatibility. No significant thrombi in the device or major organs were observed upon explant, despite minimal anticoagulation.ConclusionChronic in-vivo and benchtop in-vitro studies demonstrated promising durability, hemocompatibility, and physiological interaction of the BiVACOR TAH. These results underpin the progression of the BiVACOR Total Artificial Heart to first in human studies. The BiVACOR Total Artificial Heart (TAH) is designed as a short and long-term implantable replacement option for the failing human heart. The device combines rotary blood pump and magnetic levitation technology to produce a single, contact-free, spinning disc that reliably pumps blood to the systemic and pulmonary circulations. Rapid and cyclic changes in pump speed induces pulsatile outflow, while large blood gaps reduces stress on the blood. The development of the BiVACOR system over the last 10 years has produced multiple device iterations which have been implanted in more than 30 chronic animal studies for up to 3-month durations and operated on the benchtop for more than 4 years (ongoing). The final clinical grade version of the device was manufactured, and preclinical data evaluated in preparation for first-in-human clinical studies. Durability was assessed by continuously operating eight clinical grade BiVACOR devices in pulsatile outflow mode while submerged in saline. Hemolysis was evaluated by circulating bovine blood for 6hrs. In-vivo performance was demonstrated by implanting the BiVACOR device into five calves (82 - 108 kg), following a full cardiectomy, and then monitoring physiological function for 30 days, before elective termination. All eight clinical grade BiVACOR devices are approaching one year durability (ongoing) without any device failures. Low levels of hemolysis (4 ± 2 mg/100L) were measured with pulsatile outflow at 12LPM. Five calves were successfully supported for 30 days by the BiVACOR device, while demonstrating normal hemodynamics, end organ function and hemocompatibility. No significant thrombi in the device or major organs were observed upon explant, despite minimal anticoagulation. Chronic in-vivo and benchtop in-vitro studies demonstrated promising durability, hemocompatibility, and physiological interaction of the BiVACOR TAH. These results underpin the progression of the BiVACOR Total Artificial Heart to first in human studies.

Purpose: The BiVACOR Total Artificial Heart (TAH) combines magnetic levitation and rotary blood pump technology to create a small, durable and physiologically compatible device capable of replacing the failing heart. Pulsatile outflow is achieved via cyclic changes in pump speed, while large clearance gaps and flow paths improve hemocompatibility. The TAH is designed for implantation in women and some children, yet powerful enough to support adult males undergoing exercise. In preparation for first-in-human trials, in-vivo studies were undertaken using clinical-grade devices. Methods: The BiVACOR TAH was implanted into five calves (82 – 108 kg) for 30 days before elective termination. Hemodynamics, left-right balance, hemocompatibility, and end organ function were monitored throughout the study, while evidence of significant thromboembolism was evaluated at study termination via necropsy. Results: All five calves regained all physiological function (eating, drinking, defecating, standing, and regular treadmill exercise). The TAH demonstrated reliable operation, provided suitable hemodynamics (MAP 111 ± 6 mmHg, CVP 12 ± 5 mmHg, est.QL 12 ± 1 l/min) with pulsatile outflow (up to 40 mmHg @ 60BPM) and acceptable left/right balance (est.LAP-CVP 7.6 ± 3 mmHg). Normal end organ function was maintained (CREA 1 ± 0.44 mg/dL) with excellent hemocompatibility (pfHb 4.34 ± 0.74 mg/dL, LDH 1110 ± 182 U/L), while showing no evidence of significant device related thrombi or end organ dysfunction at necropsy. Summary: The BiVACOR TAH demonstrated promising chronic physiological performance, hemocompatibility, and physiological interaction. These results underpin progression of the BiVACOR TAH to first-in-human studies. The work was supported by NIH NHLBI under award number R44HL137454.

Rotary blood pumps (RBPs) are clinically utilised to support patients suffering from later stage heart failure and although the development of these devices has led to vast improvements, they still lack a physiological pulse. To overcome the drawbacks of the absence of pulsatility in RBPs, physiological control systems have been developed which introduce pulsatility by rapid speed modulation. Much of the research introducing pulsatility in patients supported by a HeartWare HVAD has focussed on haemodynamic output with no investigations on the limitations of the pump's electrical characteristics. Accordingly, the aim of the present study was to investigate the effect of rapid speed modulation on the accuracy of the flow estimator and power consumption as well as analysis of the shape of the flow and pressure waveforms when speed modulation was performed with quantised sine and square waves. The accuracy of the flow estimator was shown to be dependent on flow rate and independent of fluid viscosity, base speed or pulse amplitude. The average power consumption was shown not to differ greatly when pulsatility was introduced increasing by 0.72 +/- 0.31 W per 1000 RPM of peak-to-peak speed modulation. However, the instantaneous power draw was shown to increase by up to three times, particularly at low base speeds. Speed modulation using a quantised sine wave qualitatively demonstrated reductions in overshoot from the target speed when compared to speed modulation using a square wave. Information contained in this article will assist researchers in the development of physiological control systems employing rapid speed modulation techniques.

Design methods for large industrial pumps are well developed, but they cannot be relied upon when designing specialised miniature pumps, due to scaling issues. Therefore, the design and development phase of small pumps demand numerous experimental tests to ensure a viable prototype. Of initial interest is hydraulic design in the form of pump performance and efficiency curves. This project aimed to produce an automated test rig capable of generating both the performance (P-Q - pressure vs. flow rate) and efficiency curves that are reliable and repeatable. The apparatus is largely customizable and suitable for a range of smaller pump sizes. The pump impeller and volute were 3D printed, allowing for design flexibility and rapid prototyping and testing. The test loop was automated which allowed the flow rate to be incremented from 0 L/min to the maximum flow rate. At each step the pressure, flow rate, voltage and current were recorded to generate the P - Q and efficiency curves. Repeatability results showed low variations of +/- 3 mmHg (400 Pa) in pressure and +/- 2% in hydraulic efficiency. The given setup can be used to compare and evaluate the hydraulic performance of various pump designs. (C) 2020 The Author(s). Published by Elsevier Ltd.

Controlled and repeatable in vitro evaluation of cardiovascular devices using a mock circulation loop (MCL) is essential prior to in vivo or clinical trials. MCLs often consist of only a systemic circulation with no autoregulatory responses and limited validation. This study aimed to develop, and validate against human data, an advanced MCL with systemic, pulmonary, cerebral, and coronary circulations with autoregulatory responses. The biventricular MCL was constructed with pneumatically controlled hydraulic circulations with Starling responsive ventricles and autoregulatory cerebral and coronary circulations. Hemodynamic repeatability was assessed and complemented by validation using impedance cardiography data from 50 healthy humans. The MCL successfully simulated patient scenarios including rest, exercise, and left heart failure with and without cardiovascular device support. End-systolic pressure-volume relationships for respective healthy and heart failure conditions had slopes of 1.27 and 0.54 mm Hg mL(-1) (left ventricle), and 0.18 and 0.10 mm Hg mL(-1) (right ventricle), aligning with the literature. Coronary and cerebral autoregulation showed a strong correlation (R-2: .99) between theoretical and experimentally derived circuit flow. MCL repeatability was demonstrated with correlation coefficients being statistically significant (P < .05) for all simulated conditions while MCL hemodynamics aligned well with human data. This advanced MCL is a valuable tool for inexpensive and controlled evaluation of cardiovascular devices.

This study investigated the accuracy of the HeartWare HVAD flow estimator for left ventricular assist device (LVAD) support and biventricular assist device (BiVAD) support for modes of reduced speed (BiVAD-RS) and banded outflow (BiVAD-B). The HVAD flow estimator was evaluated in a mock circulatory loop under changes in systemic and pulmonary vascular resistance, heart rate, central venous pressure, and simulated hematocrit (correlated to viscosity). A difference was found between mean estimated and mean measured flow for LVAD (0.1 ± 0.3 L/min), BiVAD-RS (-0.1 ± 0.2 L/min), and BiVAD-B (0 ± 0.2 L/min). Analysis of the flow waveform pulsatility showed good correlation for LVAD (r2 = 0.98) with a modest spread in error (0.7 ± 0.1 L/min), while BiVAD-RS and BiVAD-B showed similar spread in error (0.7 ± 0.3 and 0.7 ± 0.2 L/min, respectively), with much lower correlation (r2 = 0.85 and r2 = 0.60, respectively). This study demonstrated that the mean flow error of the HVAD flow estimator is similar when the device is used in LVAD, BiVAD-RS, or BiVAD-B configuration. However, the instantaneous flow waveform should be interpreted with caution, particularly in the cases of BiVAD support.

Due to improved durability and survival rates, rotary blood pumps (RBPs) are the preferred left ventricular assist device when compared to volume displacement pumps. However, when operated at constant speed, RBPs lack a volume balancing mechanism which may result in left ventricular suction and suboptimal ventricular unloading. Starling-like controllers have previously been developed to balance circulatory volumes; however, they do not consider ventricular workload as a feedback and may have limited sensitivity to adjust RBP workload when ventricular function deteriorates or improves. To address this, we aimed to develop a Starling-like total work controller (SL-TWC) that matched the energy output of a healthy heart by adjusting RBP hydraulic work based on measured left ventricular stroke work and ventricular preload. In a mock circulatory loop, the SL-TWC was evaluated using a HeartWare HVAD in a range of simulated patient conditions. These conditions included changes in systemic hypertension and hypotension, pulmonary hypertension, blood circulatory volume, exercise, and improvement and deterioration of ventricular function by increasing and decreasing ventricular contractility. The SL-TWC was compared to constant speed control where RBP speed was set to restore cardiac output to 5.0 L/min at rest. Left ventricular suction occurred with constant speed control during pulmonary hypertension but was prevented with the SL-TWC. During simulated exercise, the SL-TWC demonstrated reduced LVSW (0.51 J) and greater RBP flow (9.2 L/min) compared to constant speed control (LVSW: 0.74 J and RBP flow: 6.4 L/min). In instances of increased ventricular contractility, the SL-TWC reduced RBP hydraulic work while maintaining cardiac output similar to the rest condition. In comparison, constant speed overworked and increased cardiac output. The SL-TWC balanced circulatory volumes by mimicking the Starling mechanism, while also considering changes in ventricular workload. Compared to constant speed control, the SL-TWC may reduce complications associated with volume imbalances, adapt to changes in ventricular function and improve patient quality of life.

Right ventricular failure is a common postoperative complication following left ventricular assist device (LVAD) implantation. Left ventricular assist devices are adapted for right ventricular assist device (RVAD) support by reducing the right pump speed or restricting the diameter of the outflow graft by "banding." We sought to conduct in vitro hemocompatibility testing in a pulmonary flow condition for current modification of an LVAD for RVAD support, with a specific aim to provide benchmark values for future RVAD development. Two HeartWare HVADs coupled to custom-built blood circulation loops, as RVADs, were tested using human blood (n = 6). The RVADs were either used in reduced speed (1,920 ± 50 RPM) or banding conditions (3,050 ± 50 revolutions per minute (RPM)) to mimic healthy pulmonary circulation hemodynamics. Blood from the loop was sampled at 0, 15, 60, 150, and 300 min to investigate the level of hemolysis, red blood cell (RBC) deformability, and the activation and aggregation of platelets. The amount of hemolysis and RBC deformability were significantly increased with banding compared with reduced speed (p < 0.05). No significant differences were found between the two conditions for platelet activation and platelet aggregation. In conclusion, we have evaluated the hemocompatibility of the HVAD when used for RVAD support in the clinically used modes of reduced speed and outflow graft banding under a pulmonary flow conditions that are commonly used in the biventricular failure population. We anticipate the benchmark values in the current study will facilitate future RVAD development. Over the last few decades, left ventricular assist devices (LVADs) have become a standard treatment option for end-stage systolic heart failure, either as a bridge-to-transplant or destination therapy in individuals considered ineligible for transplantation.1 One of the most serious complication following LVAD implantation is right ventricular failure (RVF), which occurs in up to 40% of patients.2 Severe RVF necessitating short-term or long-term right ventricular assist devices (RVADs) support occurs in 6–11% of LVAD recipients with the usage of RVADs continuously increasing.3 However, the technology is lagging behind in the development of RVADs.4 This frustrating reality is reflected by the fact that there are currently no clinically approved RVADs existing with these specifications in the market.4,5 Due to the lack of a clinically available long-term implantable rotary RVAD, some clinicians have implanted a second rotary LVAD as an RVAD off-label to mechanically support the failed right ventricle. Left ventricular assist devices are designed to perform under the load of the high-resistance systemic circulation, and as such require modification to meet the lower-resistance pulmonary circulation.6 The current modifications used by clinicians to adapt rotary LVADs for RVAD support typically include reducing the RVAD speed or banding the RVAD outflow graft. Reduced speed7–9 and banding10–14 have successfully supported patients in previous trials, though high rates of major adverse events were reported; these include multisystem organ failure, respiratory failure, pump thrombosis, infection, stroke, and gastrointestinal bleeding.2,11,15–18 There is an urgent need for the development of long-term RVADs that are specifically designed for the unique characteristic of pulmonary circulation. When developing a ventricular assist device (VAD), hemocompatibility is one of the most critical elements for assessment. Therefore, it is important to assess overall blood damage of a new device against a baseline control device which serves as a benchmark in the early stage of the development process. This should help VAD developers to recognize the potential need for design iterations without delay. To provide in vitro benchmark data for adult and pediatric LVAD development, we previously tested the CentriMag blood pump (St. Jude Medical Inc., St. Paul, MN) for standard adult flow conditions,19 the EXCOR VAD (Berlin Heart Inc., The Woodland, TX), and HeartMate II (St. Jude Medical Inc.) for pediatric flow conditions.20 In these studies, pump flow rate and differential pressure across the pumps in standard flow conditions were (Q = 5 ± 0.25 L/min; ΔP = 100 ± 3 mm Hg) and pediatric flow conditions were (Q = 2.5 ± 0.25 L/min; ΔP = 68 ± 5 mm Hg). However, limited in vitro hemocompatibility evaluation studies have been reported in pulmonary flow conditions so far. This study aimed to evaluate the hemocompatibility of an LVAD used for RVAD support in the clinically used modes of reduced speed and outflow graft banding under a pulmonary flow conditions (Q = 5 ± 0.25 L/min; ΔP = 17 ± 3 mm Hg). Hemocompatibility was evaluated by measuring the effects of each condition on hemolysis, blood counts, red blood cell (RBC) deformability, platelet activation, and aggregation. The purpose of the current study was to provide benchmark values for future RVAD development. Materials and Methods Preparation of Test Blood Our aim was to design the experiment with as much clinical relevance as possible; therefore, fresh human blood was chosen for this reason since the shear stress-induced blood damage in animal blood and human blood were demonstrated to be different.21,22 This study was conducted with approval from the Human Research Ethics Committees of The Prince Charles Hospital, Chermside, Australia (HREC/16/QPCH/75: Characterization of the interaction between blood and a LVAD used for right ventricular support). All volunteers gave informed written consent and were informed about the aims of the study in accordance with the Declaration of Helsinki. Fresh whole blood was obtained from human donors (~450 ml, n = 6) by standard venipuncture. Blood was anticoagulated in citrate phosphate dextrose adenine-1 blood collection bags (T2118, Fresenius Kabi AG, Bad Homburg, Germany). Blood was recalcified with 1 mM calcium chloride (CaCl2) to replicate physiologic calcium levels (~1.2 mM in whole blood). Thus, 0.7 U/ml heparin diluted in 1 mM CaCl2 was injected into the blood bag for 15 min before the blood was infused into the blood circulation loop. The mean hematocrit value of circulating blood in both loops were 38.5 ± 0.6% to align with reported hematocrit of 38 ± 7.0% of congestive heart failure patients.23 Right Ventricular Assist Device Blood Circulation Loops The outflow of each RVAD, for banding and reduced speed circuits, were connected to outflow grafts (Vascutek, Gelweave, Terumo, MI) of 10 cm length incorporated in the blood circulatory loops (BCLs). The reduced speed circuit consisted of a straight 10 mm diameter graft while the banded circuit consisted of a 10 mm diameter graft banded to 5 mm with a 3D-printed (Objet24, Stratasys, Eden Prairie, MN) restrictor placed around the outflow graft. In order to replicate the geometry of a typical RVAD banded outflow graft, a senior cardiac surgeon, who had completed several banded RVAD implantations using surgical staples, was consulted. The internal and external dimensions of the banded graft were used to design (SolidWorks 2015, Dassault Systèmes, Vélizy-Villacoublay, France) a repeatable, 3D-printed banded outflow graft restrictor which was used for all banding BCLs. Blood from each participant was distributed into two BCLs (BCL volume of 185 ± 5 ml) (Figure 1), each with a HVAD (HeartWare, Framingham, MA) inline, to facilitate direct comparison of the two RVAD operating conditions (i.e., reduced speed or banding) and to mitigate interindividual variance in blood cell fragility. Two explanted HVADs were utilized throughout the current study and assigned randomly to one of the two RVAD operating conditions. Each BCL (total length 1,200 mm) comprised tubing (∅ 9.5 mm, Carmeda, Medtronic, MN) connected to two reservoirs (R-38, Medtronic, MN) via 9.525 × 9.525 mm connectors (Intersept, Medtronic, Minneapolis, MN), and a HVAD. The BCLs were then filled with an isotonic, buffered intravenous crystalloid solution (Plasmalyte-148, Baxter, Deerfield, IL) and loops were immersed in a temperature-controlled water bath with an immersion recirculation heater (MGW, Lauda, Munich, Germany) set at 37 ± 1°C. The crystalloid solution was circulated by the action of the pump for 20 min to ensure all surfaces were wetted and then was drained. Subsequently, blood was infused into the two BCLs and purged of any air bubbles, to prevent blood-air interaction. Each blood loop was maintained at 37 ± 1°C and circulated for 5 hours; thus, all measurements were completed within 6 hours of blood donation.Figure 1.: Schematic representation of (A) reduced speed and (B) outflow graft banding blood circulation loops. G, outflow graft without banding; B, outflow graft with banding using a printed restrictor; Pin, RVAD inlet pressure; Pout1, RVAD outlet pressure before outflow graft; Pout2, RVAD outlet pressure after outflow graft; SP, sampling port; R, reservoir; Res, resistor; Q, flow meter. RVAD, right ventricular assist device.After each blood-RVAD experiment, two HVADs were rinsed with saline and soaked in 0.6% Medizyme (Whiteley Medical Pty Ltd, NSW, Australia) solution for 24 hour to dissolve all possible blood residue. They were rinsed with deionized water and then rotating at different speeds (1,800, 2,400, 2,800 RPM) in deionized water for 20 min to ensure all residue was thoroughly washout before dried with filtered air. HeartWare HVADs Two explanted HVADs were utilized randomly in two BCLs under two modifications used in clinical RVAD therapy to establish pulmonary hemodynamics by either reducing RVAD speed to 1,920 RPM or banding the outflow graft of a pump running at 3,050 RPM. To account for blood volume reduction within the BCLs due to blood sampling, plates either side of the reservoirs were compressed using a Hoffman clamp to maintain the circuit pressure. A Hoffman clamp was used to adjust circuit resistance and attain pulmonary hemodynamic parameters observed in the human adult including cardiac output (5.0 ± 0.25 L/min), and mean pulmonary artery pressure (17 ± 3 mm Hg). The Hoffman clamp was applied over flexible 300 mm metal plates to create a gradual restriction rather than a step resistance. Pulmonary hemodynamic parameters for reduced speed and banding flow regimes of the HVAD were adjusted as shown in Table 1. An ultrasonic flow meter (ME9PXL1153; Transonic Systems Inc., NY) was used to monitor RVAD flow, while inlet and outlet pressures were monitored with silicone strain-gauge pressure transducers (PX181B- 015C5V; Omega Engineering, Stamford, CT). All hemodynamic parameters were captured using a Labjack U3- HV USB data acquisition device (U3-HV; LabJack Corporation, CO) and visualized using LabVIEW software (LabVIEW 2015; National Instruments Corporation, TX).Table 1.: Pulmonary Hemodynamic Parameters for Reduced Speed (n = 6) and Banding (n = 6) Flow Regimes of the HeartWare HVADBlood Sampling A total of five samples were evaluated per loop for each participant. Blood samples were collected from the sampling port downstream of the RVAD outflow in the BCL at time points: 0, 15, 60, 150, and 300 min. The BCL volume of 185 ± 5 ml only allowed for up to five samples to be taken, thus experiment durations of 300 min were chose, which differs from the recommended experiment duration in American society for testing and materials (ASTM) F 1841–97.24 Before collection of each blood sample, a small volume of blood (~0.5 ml) was drawn from the sampling port and discarded to ensure the line was free of stagnant blood. Immediately afterwards, 8 ml of blood was collected into a sterile 10 ml syringe with 2 ml transferred into a collecting tube containing ethylenediaminetetraacetic acid (BD Vacutainer; ethylenediaminetetraacetic acid (EDTA); 1.8 mg/ml), 2 ml transferred into a collecting tube containing hirudin (Roche Diagnostics GmbH, Mannheim, Germany; 15 μg/ml), and 4 ml transferred into a collecting tube containing citrate (BD Vacutainer; 109 mol/m3). These aliquots were then used for the different blood analyses described below. Following withdrawal of blood from the BCL that caused a volume loss, the resistances across the reservoirs were adjusted to maintain pressure and flow at baseline values. Hemolysis Assay The Harboe assay was used for determining hemolysis.25 The methods were explained in detail previously.26 The plasma free hemoglobin (pfHb) and normalized index of hemolysis (NIH) were calculated as described by Equations 1 and 2, respectively. V is the circuit volume, Q is the flow rate, Ht is the hematocrit, and T is the sampling time. Cell Counts A 20 µl EDTA blood sample was collected at 0, 15, 60, 150, and 300 min to measure hematocrit, total numbers of platelets, and RBCs using a hematology analyzer (COULTER Ac·T diff, Beckman Coulter, Brea, CA). Measurement of Red Blood Cell Deformability Blood from an EDTA vacutainer was used for the assessment of RBC deformability via ektacytometry (Rheoscan-D200, Sewon Meditech. Inc., Seoul, Korea). The methods were explained in detail previously.26 Platelet Activation Assay Platelet activation was determined for EDTA blood samples collected at T = 0, 60, and 300 min with platelet activation surface markers, CD62P (also known as P-selectin, a granule glycoprotein that relocates to the platelet surface upon activation) and CD42b (also known as glycoprotein Ib alpha binds to von Willebrand factor and initial platelet adhesion upon activation) using BD FACS Canto Flow Cytometry Cell Analyzer. The methods were explained in detail previously.21 Measurement of Platelet Aggregation Platelet aggregation was determined for hirudin blood samples collected at T = 0, 60, and 300 min, using the Multiplate analyzer (Roche Diagnostics; Basel, Switzerland) within 15 min of collection from the sample port. The methods were explained in detail previously.26 Data Analysis Statistical analysis was done using Statistica (TIBCO Software Inc, Palo Alto, CA) statistical software package (version 13.2). Normality of distribution was assessed by inspecting histogram and pp-plot in addition to using a Shapiro-Wilk test. Two-way analysis of variance (ANOVA) with repeated measures was used to compare differences between reduced speed and banding over time for all investigated parameters expect for NIH. When simple main effects and/or interaction between time and condition was significant, a Tukey's post hoc test was performed for multiple comparisons. For NIH, the assumption of homogeneity of variances was not met and therefore, a Kruskall-Wallis test was used to compare reduced speed or banding over time. Measurements between the two experimental groups were compared with a Mann-Whitney U test for each particular time point. A p value ≤0.05 was considered statistically significant. All data are expressed as mean ± SD. Results Hemolysis Hemolysis was evident in blood samples collected under banding and reduced speed conditions. A steady increase in pfHb was evident at each time interval, with a statistically significant difference between 60 min (p = 0.0004), 150 min (p = 0.0002), and 300 min (p = 0.0002) compared with baseline for banding condition (Figure 2A). In the reduced speed condition, hemolysis levels were also significantly increased at 300 min compared with baseline (p = 0.0003). Significant differences between both conditions were also evident after 150 min (p = 0.0002) and 300 min (p = 0.0002) with greater hemolysis under banding condition. The mean NIH values of the banding and reduced speed conditions were 0.0151 ± 0.00381 and 0.0033 ± 0.00026 g/100 L, respectively (Figure 2B).Figure 2.: Comparison of changes in pfHb between reduced speed and banding. (A) Hemolysis evaluation and (B) calculated NIH. NIH, index of hemolysis; pfHb, plasma free hemoglobin. *indicates significant differences (p<0.05) compared to baseline T = 0 min. #indicates significant differences (p<0.05) between Reduced speed and Banding at a particular time point.Cell Counts The concentration of circulating RBCs and platelets collected from the BCL was monitored throughout the testing timeline. Results indicated no significant changes in RBCs (Figure 3A) or platelets (Figure 3B) between all time points, tested under the banding and reduced speed conditions.Figure 3.: (A) total number of red blood cell, RBC and (B) total number of platelet measured by automatic hematology analyzer for 0, 15, 60, 150 and 300 min in reduced speed and banding conditions. Results expressed as mean ± standard deviation.Red Blood Cell Deformability The normalized RBC deformability (i.e., SS1/2: EImax) following exposure to the HVAD during reduced speed and banding conditions is presented in Figure 4. When compared with baseline values (T = 0 min), the banding condition resulted in significantly increased RBC deformability after 60, 150, and 300 min (p < 0.001) of circulation. In contrast, RBC deformability was significantly increased only after 300 min of circulation in the reduced speed condition (p <0.001).Figure 4.: RBC deformability measured as the ratio of SS1/2:EImax (the ratio of shear stress required for half of maximum elongation index: the maximum theoretical elongation index at infinite shear stress) for reduced speed and banding conditions. RBC, red blood cell. *indicated significant differences (p<0.05) compared to baseline T = 0 min.Platelet Activation Platelet activation was monitored using flow cytometry with two different antibodies specific for platelet cell surface antigens CD62P and CD42b (Figure 5). For banding and reduced speed conditions, CD62P showed significant increases in platelet activation at T = 60 min and T = 300 min, when compared with T = 0 min (p < 0.001). Whereas CD42P showed a significant increase in platelet activation only at T = 300 min compared with baseline. Results indicate that no significant differences in platelet activation were detected between the banded condition and the reduced speed condition.Figure 5.: The percentage of platelet activation (%) detected by (A) CD62P and (B) CD42b antibodies at discrete time points (0, 60, 300 min) in reduced speed and banding conditions. *indicated significant differences (p<0.05) compared to baseline T = 0 min.Platelet Aggregation A significant decrease in platelet aggregation was detected over time for adenosine diphosphate and TRAP-6 stimulated platelets (p < 0.05) for both reduced speed and banding conditions (Figure 6). However, no significant difference was found between the reduced speed and banded conditions.Figure 6.: (A) ADP and (B) TRAP-6-induced platelet aggregation—AUC measured at discrete time points (0, 60, 300 min) in reduced speed and banding conditions. ADP, Adenosine diphosphate; AUC, area under the aggregation curve; TRAP-6, thrombin receptor activating peptide-6. *indicated significant differences (p<0.05) compared to baseline T = 0 min.Discussion Options for long-term or permanent mechanical circulatory support for chronic right ventricular device support still does not exist.4 To meet the lower pulmonary vascular resistance, clinicians have steered towards operating the HVAD for RVAD support either at reduced speeds of less than 2,200 RPM7,8 or by artificially increasing the resistance at the outflow graft by using a restriction band.10–12 HeartWare is currently working on regulatory approval for modifications to the HVAD for use in RVAD support.27 We felt, therefore, it would be prudent to test using an HVAD as RVAD in banded outflow and reduced speed conditions that is commonly used in biventricular support in this study to serve as benchmark data for future RVAD development. The current study demonstrated that banding the outflow graft resulted in significantly higher levels of hemolysis when compared with reduced speed. We previously reported that the overall hemolysis result under normal range condition (HVAD pump speed = 3,282 RPM; Q = 5 L/min; ΔP = 90 mm Hg) used as LVAD is similar to our current reduce speed condition (HVAD pump speed = 1,920 RPM; Q = 5 L/min; ΔP = 19 mm Hg). Therefore, the change of rotational pump speed does not cause hemolysis.26The increased hemolysis associated with banding was expected given the additional resistance incurred at the site of the restriction. Notably, the average NIH value of the banding condition was higher than the recommended acceptable value of 0.01 g/100 L, whereas the average NIH value of reduced speed was found to be below this threshold.28 A functional property of the RBC, cellular deformability, was paradoxically increased following circulation in the loops. Specifically, RBC deformability increased after 60 min, which was sustained for the remainder of the study during the banding condition. The reduced speed condition resulted in a much longer elapsed period before detection of increased RBC deformability (300 min). While increased RBC deformability typically indicates "improved" cell function, the present findings agree with accumulating evidence that supraphysiological shear exposure disproportionately affects older and more rigid cells within the blood, thus resulting in a "filtering" effect, whereby only the younger and more deformable cells remain.29,30 When viewed holistically, in conjunction with the concurrent increase of pfHb, this increase in RBC deformability actually indicates a paradoxical sign of blood damage.31 In our previous study, the same antibodies were used to detect platelet activation in different shear-controlled environments.21 The results revealed similar trends that CD42b detected higher levels of platelet activation than CD62P in the same shear condition. In the reduced speed condition, between 60 and 300 min, an increase in platelet activation was detected by CD62P followed by a decrease. This is expected considering CD62P is an end-stage activation marker, where activation and translocation to the membrane surface is followed by receptor shedding.32 This is consistent with the results obtained, where a combination of flow cytometry and platelet function results indicated an increase in platelet activation and a simultaneous decrease in platelet aggregation, throughout 300 min of in vitro testing. These results may suggest that platelet activation, concomitant receptor shedding, and platelet aggregation may induce a paradoxical effect on platelet function. More activated platelets may increase the risk of thrombosis while the reduction in platelet receptors and aggregation capacity may increase the propensity for bleeding.33 While the reduced speed condition exhibited lower rates of hemolysis and higher RBC membrane integrity when compared with the banded condition, other considerations may be required when determining the optimal RVAD operating condition. Wu et al.34 demonstrated that banding improved pulmonary valve washout compared with reduced speed in a range of systemic and pulmonary vascular resistances, which may be beneficial in preventing fusion, insufficiency, and/or thrombosis. Timms et al.,35 however, reported outflow graft banding required up to five times as much power consumption in comparison to reduced speed, which may be important in maintaining battery life as a long-term therapy. Moreover, operating HVADs at reduced speeds have been shown to induce erroneous estimated-flow waveforms,7 which may impede the use of these devices in reduced speed conditions. A limitation of the current study was that the BCL volume only allowed for up to five samples to be taken and without static control blood; thus, experiment durations were shortened to 300 min instead of 360 min recommended by ASTM F 1841–97.24 The BCL volume could not be increased as the total blood volume drawn from each donor was ~450 ml and required to be divided into two BCLs in order to mitigate interindividual variances. In addition, mixing two donor sources of blood is not recommended by the ASTM standards because the mixture may potentially induce added hemolysis or a change in red blood resistance against trauma.36 Another limitation was the HVADs used in this study were explanted devices from patients. Therefore, HVADs were randomized between the two conditions to eliminate any risk of the individual pump contributing to the results. In addition, the 3D-printed restrictor may create uneven wrinkles before, at, and after the restriction area of outflow graft that may affect the hemocompatibility results of banding condition. Nevertheless, this in vitro work provides a fast and simple way to evaluate and compare the hemocompatibility between the two conditions of modified LVAD for RVAD for the current treatment of RVF. We have conducted hemocompatibility testing both on using an HVAD as RVAD in banded outflow and reduced speed conditions that is commonly used in biventricular support. In the present in vitro model using human blood, the reduced speed condition demonstrated a lower hemolysis profile compared with the banding condition under a pulmonary flow conditions intended to simulate the right heart support. The results in the current study will serve as benchmarks for future RVAD development.

The high cost of ventricular assist devices results in poor cost-effectiveness when used as a short-term bridging solution, thus a low-cost alternative is desirable. The present study aimed to develop an intraventricular balloon pump (IVBP) for short-term circulatory support, and to evaluate the effect of balloon actuation timing on the degree of cardiac support provided to a simulated in vitro severe heart failure (SHF) patient. A silicone IVBP was designed to avoid contact with internal left ventricular (LV) features (ie, papillary muscles, chordae, aortic, and mitral valves) based on LV computed tomography data of 10 SHF patients with dilated cardiomyopathy. The hemodynamic effects of varying balloon inflation and deflation timing parameters (inflation duty [D] and end-inflation point [σ]) were evaluated in a purpose-built systemic mock circulatory loop. Three IVBP actuation timing categories were defined: co-, transitional, and counterpulsation. Compared to the SHF baseline, co-pulsation increased aortic flow from 3.5 to 5.2 L/min, mean arterial pressure from 72.1 to 94.8 mmHg and ejection fraction from 14.4% to 21.5%, while mean left atrial pressure decreased from 14.6 to 10 mmHg. Transitional and counterpulsation resulted in a double ventricular pulse and extended the duration of increased ventricular pressure, potentially impeding diastolic filling and coronary perfusion. This in vitro study showed the IVBP could restore the hemodynamic balance of a simulated SHF patient with dilated cardiomyopathy to healthy levels.

Left ventricular assist devices (LVADs) have been developed to support end-stage heart failure patients. First-generation LVADs are volume displacement pumps, which function by mimicking the native heart and can be implanted intra-, extra-, or paracorporeally. These devices operate by periodically allowing blood to fill a pumping chamber followed by an ejection of blood from that chamber via pneumatic or electric actuation. Initial development of volume displacement pumps for post-cardiotomy support was undertaken in the 1960s. In 1978, the first patient was bridged to heart transplantation using a LVAD. Subsequently, commercial LVADs became available in the late 1980s and early 1990s. In 2001, the "Randomized Evaluation of Mechanical Assistance for the Treatment of Congestive Heart Failure (REMATCH) trial" established the efficacy of first-generation LVADs, finding that LVADs improved patient survival and quality of life compared to optimal medical management. Although commercially approved volume displacement pumps have demonstrated improved outcomes in comparison to medical therapy and deliver pulsatile flow, their durability, reliability, and reduced survival rates, in contrast to rotary blood pumps, have limited their use. Future considerations of volume displacement pumps have included flow optimization, valve design, and designing a cost-effective device.

Earlier left ventricular assist devices (LVADs) were volume displacement pumps (VDPs) that delivered pulsatile flow. However, due to improved survival rates of rotary blood pumps (RBPs), they are now the preferred device. Originally, RBPs operated at a constant speed and therefore delivered flow continuously with an absent or diminished pulse. Although RBPs were an improvement to the previous VDPs, the delivery of continuous flow has led to secondary complications, such as vascular and aortic valve dysfunction and gastrointestinal bleeding. Therefore, research has been made toward pulsatile RBPs by rapidly modulating pump speed. However, deriving pulsatile flow with RBPs has not been without controversy. Issues of debate have included the quantification of an adequate pulse and the influence of blood trauma and power consumption when generating a pulse with a RBP. Meanwhile, the pulsatility controversy has also expanded to total artificial heart and extracorporeal membrane oxygenator (ECMO) support. Nevertheless, commercial developments have been made toward combining the benefits of improved durability and survival rates of RBPs with a pulsing mechanism for mechanical circulatory support.

Bridge to recovery with left ventricular assist device (LVAD) support has been more prominent with volume displacement pumps (VDPs) than with rotary blood pumps (RBPs), which may be due to VDPs providing greater ventricular unloading and coronary artery flow. To compare ventricular unloading and coronary flow of VDPs and RBPs in a repeatable environment, a physiologic coronary circulation was added to a pre-existing mock circulatory loop. In this study, a physiologic coronary circulation, mimicking a healthy or diseased auto-regulatory response was implemented in a mock circulatory loop. Using the mock circulation loop, a VDP with original (Björk-Shiley) and then replacement (jellyfish) valves was operated in clinically recommended modes and compared to full and partial assist RBP operating at constant speed and rapid speed modulated modes. The Björk-Shiley VDP resulted in increased pressure-volume area, which resulted in greater coronary artery flow when compared to the improved jellyfish valves. Full assist RBP support reduced left ventricular stroke work, pressure-volume area and coronary flow compared to partial assist, whilst the effect of speed modulation modes was not as significant. Of all LVAD operating modes, the counter-pulsed VDP with jellyfish valves demonstrated the greatest reduction in pressure-volume area and improved coronary flow. This study provides a basis for further investigation into RBP speed modulation profiles to match the improved haemodynamic performance of VDPs.

Rotary left ventricular assist devices (LVADs) are commonly operated at a constant speed, attenuating blood flow pulsatility. Speed modulation of rotary LVADs has been demonstrated to improve vascular pulsatility and pump washout. The effect of LVAD speed modulation on intraventricular flow dynamics is not well understood, which may have an influence on thromboembolic events. This study aimed to numerically evaluate intraventricular flow characteristics with a speed modulated LVAD. A severely dilated anatomical left ventricle was supported by a HeartWare HVAD in a three-dimensional multiscale computational fluid dynamics model. Three LVAD operating scenarios were evaluated: constant speed and sinusoidal co- and counter-pulsation. In all operating scenarios, the mean pump speed was set to restore the cardiac output to 5.0 L/min. Co- and counter-pulsation was speed modulated with an amplitude of 750 rpm. The risk of thrombosis was evaluated based on blood residence time, ventricular washout, kinetic energy densities, and a pulsatility index map. Blood residence time for co-pulsation was on average 1.8 and 3.7% lower than constant speed and counter-pulsation mode, respectively. After introducing fresh blood to displace preexisting blood for 10 cardiac cycles, co-pulsation had 1.5% less old blood in comparison to counter-pulsation. Apical energy densities were 84 and 27% higher for co-pulsation in comparison to counter-pulsation and constant speed mode, respectively. Co-pulsation had an increased pulsatility index around the left ventricular outflow tract and mid-ventricle. Improved flow dynamics with co-pulsation was caused by increased E-wave velocities which minimized blood stasis. In the studied scenario and from the perspective of intraventricular flow dynamics, co-pulsation of rotary LVADs could minimize the risk of intraventricular thrombosis.

Right ventricular failure is a common complication associated with rotary left ventricular assist device (LVAD) support. Currently, there is no clinically approved long-term rotary right ventricular assist device (RVAD). Instead, clinicians have implanted a second rotary LVAD as RVAD in biventricular support. To prevent pulmonary hypertension, the RVAD must be operated by either reducing pump speed or banding the outflow graft. These modes differ in hydraulic performance, which may affect the pulmonary valve opening (PVO) and subsequently cause fusion, valvular insufficiency, and thrombus formation. This study aimed to compare PVO with the RVAD operated at reduced speed or with a banded outflow graft. Baseline conditions of systemic normal, hypo, and hypertension with severe biventricular failure were simulated in a mock circulation loop. Biventricular support was provided with two rotary VentrAssist LVADs with cardiac output restored to 5 L/min in banded outflow and reduced speed conditions, and systemic and pulmonary vascular resistances (PVR) were manipulated to determine the range of conditions that allowed PVO without causing left ventricular suction. Finally, RVAD sine wave speed modulation (±550 rpm) strategies (co- and counter-pulsation) were implemented to observe the effect on PVO. For each condition, outflow banding had higher PVR (97 ± 20 dyne/s/cm5 higher) for when the pulmonary valve closed compared to reduced speed. In addition, counter-pulsation demonstrated greater PVO than co-pulsation and constant speed. For the purpose of reducing the risks of pulmonary valve insufficiency, fusion, and thrombotic event, this study recommends a RVAD with a steeper H-Q gradient by banding and further exploration of RVAD speed modulation.

Mitral valve regurgitation (MVR) is common in patients receiving left ventricular assist device (LVAD) support, however the haemodynamic effect of MVR is not entirely clear. This study evaluated the haemodynamic effect of MVR with LVAD support and the influence of inflow cannulation site and LVAD speed modulation. Left atrial (LAC) and ventricular (LVC) cannulation was evaluated in a mock circulation loop with no, mild, moderate and severe MVR with constant speed and speed modulation (±600 RPM) modes. The use of an LVAD relieved pulmonary congestion during severe MVR, by reducing left atrial pressure from 20.5 to 10.8 (LAC) and 11.5 (LVC) mmHg. However, LAC resulted in decreased left ventricular stroke work (−0.08 J), ejection fraction (−7.9%) and higher MVR volume (+12.7 mL) and pump speed (+100 RPM) compared to LVC. This suggests that LVC, in addition to reducing MVR severity, also improves ventricular washout over LAC. LVAD speed modulation in synchrony with ventricular systole reduced MVR volume and increased ejection fraction with LAC and LVC, thus demonstrating the potential benefits of this mode, despite a reduction in cardiac output.