Ten-year NEDO BVAD development program: moving forward to the clinical arena.

Since 1995, the Baylor Group has been developing a totally implantable NEDO BVAD system. This 10-year program was completed in March 2005, and preparation for clinical trials is underway. This article summarizes the entire 10-year NEDO program and describes the strategy for clinical trials. The project aimed to achieve: (1) dual centrifugal pumps with the ability of full biventricular support, (2) a compact system implantable into small adults, (3) a totally implantable system with transcutaneous energy transmission system (TETS), (4) a durable system with a lifetime of over 5 years, and (5) a system free of thrombus and with minimal hemolysis. The final goals are to complete preclinical system evaluations and commence the clinical trials in the near future. In vitro studies have demonstrated a pump capacity of over 8.5 l/min and an Index of Hemolysis of <0.004 g/100 l. The pump-bearing life expectancy was over 5 years. To date, eight pumps endured in vivo studies of over 3 months without complications, including thromboembolic events. The in vitro endurance studies of eight pumps are longer than 1 year. There were no mechanical malfunctions or pump failure. A stepwise clinical trial is being planned: Step1, a wearable BVAD/VAD will be clinically studied; Step 2, the BVAD/VAD will be implanted intracorporeally without TETS; and, Step 3, a totally implantable system will be clinically evaluated. The NEDO BVAD system has completed preclinical testing. Clinical trial preparation is underway.

The pivot wash in two impeller modes for the Baylor/Miwatec centrifugal blood pump.

A centrifugal blood pump with a double pivot impeller and an eccentric inlet port is being developed as an implantable artificial heart by the Baylor College of Medicine and Miwatec Co. Ltd. Flow visualization measurements were conducted to compare the flow around the pivot for two impeller operational modes: the top and the bottom contact modes. In the top contact mode, one-way flow in the pivot gap due to the eccentric vortex was observed, and sufficient wall shear rate to prevent thrombus formation was attained around the bottom pivot for over 1,400 rpm. Computational fluid dynamic analyses confirmed that the causes of the eccentric vortex were the inlet eccentricity and the pressure imbalance in the volute.

Real-time studies of the pivot bearings in the NEDO Gyro PI-710 centrifugal blood pump.

The NEDO Gyro PI-710 centrifugal pump (Gyro PI-710 pump) incorporates a double pivot bearing system of which the male pivot and female bearings are fabricated from Al2O3 ceramic and ultrahigh molecular weight polyethylene. The top female bearing is a critical component because the impeller is levitated by hydraulic force and is maintained in the top contact position. A long-term in vitro examination of the pivot bearings was conducted using a biventricular assist model. In 7 animal experiments, the depth change of the top female bearing was examined. Animal experiments up to 90 days revealed that there was no noticeable depth increase in the top female bearing. According to the in vitro study, the life of the pivot bearings of the left and right pump was estimated to be approximately 3 and 7 years, respectively. Further improvement of this pivot bearing system is currently underway.

Development of a flexible inflow cannula with titanium inflow tip for the NEDO biventricular assist device.

A newly designed flexible inflow cannula has been developed for a biventricular assist device (BVAD). The inflow tip was designed for long-term ventricle drainage. Considering the anatomic differences between the right and left ventricles, a flexible inflow cannula, as a mass production model with a titanium tip, was developed and investigated in chronic BVAD animal experiments using the NEDO permanently implantable centrifugal blood pump. These flexible inflow cannulae consist of flexible plastic tubing with wire supported, titanium left and right tips. The right titanium inflow tip was designed with inner and outer stoppers to be inserted into the right ventricle wall and a beak shape to avoid sucking. The left tip was designed to be inserted into the left ventricle cavity. Five chronic BVAD bovine studies were performed to investigate the new beak shaped titanium tip. In these studies, the new beak shaped titanium tip and cannula prevented stenosis by a proliferation of pseudoneointimal, and supplied adequate blood flow to the pump without sucking. This newly designed inflow cannula with the beak shaped titanium tip was successfully implanted for 90 days.

Centrifugal blood pump with a hydraulically-levitated impeller for a permanently implantable biventricular assist device.

A permanently implantable biventricular assist device (BVAD) system has been developed with a centrifugal pump which is activated by a hydraulically-levitated impeller. The pump impeller floats hydraulically into the top contact position; this position prevents thrombus formation by creating a washout effect at the bottom bearing area, a common stagnant region. The pump was subjected to in vitro studies using a pulsatile mock circulation loop to confirm the impeller's top contact position and the swinging motion produced by the pulsation. Eleven in vivo BVAD studies confirmed that this swinging motion eliminated blood clot formation. Twenty-one pumps im-planted for up to three months did not reveal any thrombosis in the pumps or downstream organs. One exception was a right pump which was exposed to severe low flow due to the kinking of the outflow graft by the accidental pulling of the flow meter cable. Three ninety-day BVAD studies were achieved without thrombus formation.

Flow visualization in a centrifugal blood pump with an eccentric inlet port.

Flow visualization analysis was applied to the Baylor/Miwatec centrifugal artificial heart to evaluate its fluid dynamic characteristics regarding antithrombogenicity. An eccentric vortex was found both in the upper and the lower gaps of the impeller, which is supposed to be caused by the eccentric inlet port. Therefore, one-way flow toward the outlet is formed and washes the pivot. The combination of an eccentric vortex and a pivot bearing that is washed is unique to the Baylor/Miwatec pump. For the male pivots exposed to periodic wash, the minimum shear rate around the bottom pivot was estimated to be 650/s, which is higher than the threshold for thrombus formation shown by other studies. The wall shear rate at the impeller bottom surface was found to be larger in the top contact mode than in the bottom contact mode.

Development of silicone rubber hollow fiber membrane oxygenator for ECMO.

Silicone rubber hollow fiber membrane produces an ideal gas exchange for long-term ECMO due to nonporous characteristics. The extracapillary type silicone rubber ECMO oxygenator having an ultrathin hollow fiber membrane was developed for pediatric application. The test modules were compared to conventional silicone coil-type ECMO modules. In vitro experiments demonstrated a higher O2 and CO2 transfer rate, lower blood flow resistance, and less hemolysis than the conventional silicone coil-type modules. This oxygenator was combined with the Gyro C1E3 centrifugal pump, and three ex vivo experiments were conducted to simulate pediatric V-A ECMO condition. Four day and 6 day experiments were conducted in cases 1 and 2, respectively. Case 3 was a long-term experiment up to 2 weeks. No plasma leakage and stable gas performances were achieved. The plasma free hemoglobin was maintained within a normal range. This compact pump-oxygenator system in conjunction with the Gyro C1E3 centrifugal pump has potential for a hybrid total ECMO system.

Antithrombogenicity of the Gyro permanently implantable pump with the RPM dynamic suspension system for the impeller.

In 1995, a group at Baylor College of Medicine started to develop the NEDO biventricular assist device (BVAD) using two Gyro permanently implantable (PI) centrifugal pumps. This pump consists of a sealless pump housing and an impeller supported with a double pivot bearing. In May 2001, an RPM dynamic suspension system (RPM-DS) for the impeller was developed to improve durability and antithrombogenicity without a complex magnetic suspension system. From March 2000 to March 2002, eight BVAD bovine experimental studies were performed for more than 1 month. Two pumps were implanted in two cases without the RPM-DS (group A) and in six cases with the RPM-DS (group B). In group A, the survival period was 45 and 50 days. The primary reason for termination was an increase in the requiring power, which was related to deposition of white thrombus on the bottom bearing. In group B, the survival period was 37, 48, 51, 60, 80, and 90 days. The reasons for termination were not related to thrombus formation. No thrombus was observed in the pumps except for one right pump. In that experiment, the thrombus formation may have occurred when that pump had a low flow rate at a level of 1 L/min for 6 hr. These studies demonstrate the apparent antithrombogenic effect of RPM-DS. The NEDO BVAD is ready to move into a 3-month preclinical system evaluation.

In vivo evaluation of the NEDO biventricular assist device with an RPM dynamic impeller suspension system.

Since 1995, the Baylor College of Medicine group has been developing the NEDO Gyro permanent implantable (PI) pump. The Gyro PI pump has achieved outstanding results up to 284 days with no thrombus formation during the left ventricular assist device (LVAD) animal experiments. However, in biventricular assist device (BVAD) animal experiments, thrombus formation did occur. An in vitro experiment showed the reason for thrombus formation was caused by the missed magnetic balance between the impeller and the actuator. On the basis of this result, the revolutions per minute (RPM) impeller suspension system was developed. Six long-term animal studies were performed in bovine models. Survival periods were 90, 80, 60, 51, 48, and 37 days, respectively. No thrombus was observed in the pumps with the exception of one right pump. In that experiment, the thrombus formation may have occurred when the pump had a low flow because of outflow kinking. In this article, the antithrombogenic effect of this RPM impeller suspension system will be discussed.

Physiological adaptation to a nonpulsatile biventricular assist system.

Physiological adaptation of the recipient to a nonpulsatile biventricular assist system (NPBVAS) is not well understood. The aim of this study is to evaluate the physiological adaptation of experimental animals after NPBVAS implantation. Since May 2001, four long-term NPBVAS implant experiments in calves were performed. The blood gas and hemodynamic data were analyzed retrospectively. An additional prospective experiment was performed to confirm retrospective findings. All calves (n = 5) lived longer than 5 weeks without complication. In retrospective analysis, there was not a correlation between the O2 content and total blood flow in the pulmonary artery during the 1st postoperative week, but they began to correlate within the 2nd postoperative week. Then, there was a strong correlation after the 3rd postoperative week (r = 0.753). In the prospective experiment, O2 content related to total pulmonary flow after 2 weeks (r = 0.732) was the same as in the retrospective study. Most of the hemodynamic parameters studied became normalized after 14 days. In addition, easier controllability of the blood pumps was demonstrated after the 2nd postoperative week in all five experiments. Experimental results suggested that the native healthy heart accepted NPBVAS by reducing its cardiac output in 2 weeks. In addition, complicated control of the BPVAS was not necessary after 2 weeks of implantation. These results demonstrate the possibility of physiological adaptation to the NPBVAS being established within 2 postoperative weeks.

Flow visualization study to investigate the secondary flow behind the impeller in the Gyro centrifugal pump.

The Gyro permanently implantable pump consists of a sealless pump housing and an impeller supported with a double pivot bearing. The secondary vanes are attached to increase the secondary flow to avoid thrombus formation behind the impeller. Flow visualization studies using an oil film method were performed on three types of impellers: no secondary vanes, 0.5 mm height secondary vanes, and 1.0 mm height secondary vanes. Comparison studies of these impellers were performed on the surfaces of the impeller bottom and bottom housing. Regarding the surface of the impeller bottom, the impeller with no secondary vanes had the least stagnant areas around the shaft. On the other hand, the impeller having 1.0 mm height secondary vanes had the most distinguished flow lines on the bottom housing. Overall, the impeller secondary vanes with a height of 0.5 mm (current design) seemed to create the most effective secondary flow.

The balance of the impeller-driver magnet affects the antithrombogenicity in the Gyro permanently implantable pump.

The Gyro permanently implantable (PI) pump is activated magnetically when a double pivot bearing supported impeller is rotated at predetermined revolutions per minute (rpm). The male bearing shaft of the impeller is supported by the top and bottom female pivot bearing in a loosely mated fashion. The Gyro PI pump's impeller transfers to a floating condition when the rpm is increased. The design objective of the Gyro PI pump is to drive the impeller while maintaining a top contact position to prevent thrombus formation. As a left ventricular assist device (LVAD), the Gyro PI pumps achieved long-term survivals in calves without thrombus formation. However, thrombus formation occurred during a biventricular assist device (BVAD) implantation. Our hypothesis was that the impeller remaining in the bottom contact position during the BVAD experiment caused this thrombus formation. Therefore, a replica of the Gyro PI pump housing was fabricated from a transparent plastic to observe the floating conditions of the impeller. When simulating an LVAD animal experiment, the impeller was at a non-bottom contact position. However, when simulating the BVAD animal experiment, the impeller remained at the bottom contact position. This study shows that the magnet balance affects the antithrombogenicity in a Gyro PI pump.

Extracorporeal membrane oxygenator compatible with centrifugal blood pumps.

Coil-type silicone membrane oxygenators can only be used with roller blood pumps due to the resistance from the high blood flow. Therefore, during extracorporeal membrane oxygenation (ECMO) treatment, the combination of a roller pump and an oxygenator with a high blood flow resistance will induce severe hemolysis, which is a serious problem. A silicone rubber, hollow fiber membrane oxygenator that has a low blood flow resistance was developed and evaluated with centrifugal pumps. During in vitro tests, sufficient gas transfer was demonstrated with a blood flow less than 3 L/min. Blood flow resistance was 18 mm Hg at 1 L/min blood flow. This oxygenator module was combined with the Gyro C1E3 (Kyocera, Japan), and veno-arterial ECMO was established on a Dexter strain calf. An ex vivo experiment was performed for 3 days with stable gas performance and low blood flow resistance. The combination of this oxygenator and centrifugal pump may be advantageous to enhance biocompatibility and have less blood trauma characteristics.

Titania gel reduces thrombin generation.

Titanium alloy (Ti) commonly is used for long-term blood pumps as a conventional blood contacting material. Thrombus formation in the pump, however, is still a critical problem. Once thrombin is generated on the Ti surface, it activates platelets and the coagulation cascade, leading to thrombus formation. It would be expected that an inhibition of thrombin generation on a blood-contacting surface would prevent thrombus formation. In this study, the titania gel (Ti-gel) on the surface of Ti was formed with chemical modification. The surface structure and its effects on the coagulation cascade were evaluated. Scanning electron microscopic study revealed numerous cracks on the dried surface of Ti-gel, indicating a water-enriched layer. Blood coagulation on the Ti-gel was less than that on the Ti. Generated thrombin on the Ti-gel was less than that on the Ti in both the extrinsic and intrinsic pathways. There was no statistical difference of thrombin degradation. These results suggest that coagulation cascade on the Ti surface was inhibited by the Ti-gel formation. The Ti-gel may have better antithrombogenic characteristics for blood pumps because of its antiblood-coagulation effects.