Toshihiko Kijima

Terumo implantable left ventricular assist system: results of long-term animal study.

The research group of Terumo Corporation, NTN Corporation, and the Setsunan University have been developing an implantable left ventricular assist system (T-ILVAS) featuring a centrifugal blood pump with a magnetically suspended impeller (MSCP). The present study describes results of chronic animal experiments using the MSCP. The MSCP has been tested ex vivo and in vivo in 6 sheep as a left heart bypass between the left ventricular apex and descending aorta. Ex vivo chronic sheep experiments using Model I demonstrated long-term durability, nonthrombogenicity, low hemolysis (<6 mg/dl), and excellent stability of the magnetic bearing with long-term survival for up to 864 days. Average pump flow rate was 4 L/min at a fixed rotational speed of 2000 rpm. Power spectral analyses of heart rate, aortic pressure, and blood temperature maintained normal 1/f fluctuation during the study. The retrieved pump was completely free from thrombus formation and there was no evidence of infarct in major organs. The implantable Model II was evaluated ex vivo in two sheep and intra-thoracically implanted in a sheep. These experiments were terminated at 70, 79, and 17 days due to blood leakage through the connector system within the housing. No thrombus formation was observed in any of the retrieved pumps. A modified Model II with a new connector system was subsequently intra-thoracically implanted in a sheep. The sheep survived for 482 days without any sign of thromboembolic complication or hemolysis at a fixed rotational speed of 1700 rpm and an average pump flow rate of 5 L/min. There was no intra-device thrombus formation or infarct in major organs. The Model III system, consisting of an implantable controller and a new MSCP with a reduced input power of 13 W, has been developed and implanted in a chronic sheep model. The MSCP was implanted in the left pleural space and the controller in the abdominal wall. The experiment is still in progress for more than 30 days without any significant complication to date. These animal studies strongly suggest the feasibility of the MSCP for use as long-term circulatory assist.

Recent progress in the development of Terumo implantable left ventricular assist system.

The research group of the Terumo Corporation, the NTN Corporation, and Setsunan University (T. Akamatsu) has been developing an implantable left ventricular assist system (ILVAS) featuring a centrifugal blood pump with a magnetically suspended impeller (MSCP). The impeller of the MSCP is suspended by a magnetic bearing, providing contact-free rotation of the impeller inside the pump housing. Thus the MSCP is expected to provide years of long-term durability. Ex vivo chronic sheep experiments using the extracorporeal model (Model I) demonstrated long-term durability, nonthrombogenicity, and a low hemolysis rate (plasma free Hb <6 mg/dl) for more than 2 years. The prototype implantable model (Model II; 196 ml, 400 g) was evaluated ex vivo in 2 sheep and intrathoracically implanted in a small sheep (45 kg). These experiments were terminated at 70, 79, and 17 days, respectively, because of blood leakage through the connector system within the housing of Model II. There was no thrombus formation on the retrieved pump surfaces. A new connector system was introduced to the Model II pump (modified Model II), and the pump was intrathoracically implanted in a sheep. Pump flow rate was maintained at 3-7 L/min at 1700-1800 rpm. The temperature elevation on the surfaces of the motor and the electromagnet inside the pump casing was kept less than 6 degrees C. The temperature of the tissue adjacent to the pump casing became normal 10 days postoperatively. The sheep survived for more than 5 months without any sign of mechanical failure or thromboembolic complication. In vitro real-time endurance tests of motor bearings made of stainless steel and silicone nitride have been conducted for more than 1 year without any sign of bearing wear. The next prototype system (Model III), with an implantable controller and a new MSCP with reduced input power, has been developed with a view toward a totally implantable LVAS.

EFFECTS OF SURFACE ROUGHNESS ON MECHANICAL HEMOLYSIS

Previous in vitro hemolysis test results showed that an inlet taper or a round corner in the leading edge of a stenotic connector played an important role in the reduction of hemolysis. However, computational fluid dynamics (CFD) analysis of these results indicated that the shear rate and hemolysis level were not always related to each other. Then, further research was performed, focusing on the effects of surface roughness on hemolysis. The results thus far can be summarized as threefold. First, the rate of hemolysis occurring at an abrupt change in the stenotic section was different if the longitudinal length of the stenosis was changed. The level of plasma-free hemoglobin after 6 h of circulation was decreased from 280 mg/dl to 70 mg/dl when the longitudinal length was shortened from 15 mm to 1 mm. Second, a comparison of hemolysis rates in identical stenotic connectors with differing surface roughness (Ra = 0.45 and 1.35 u.m) revealed that a smooth surface achieved as much as an 80% reduction in the rate of hemolysis. Third, the in vitro hemolysis results obtained were further defined through CFD analysis.

More Than 1 Year Continuous Operation of a Centrifugal Pump With a Magnetically Suspended Impeller

The authors have been developing a centrifugal pump with a magnetically suspended impeller (MSCP) designed for total artificial heart and long-term ventricular support. The MSCP consists of a magnetic bearing, an impeller and housing, and a driving motor. The impeller is suspended by a magnetic bearing, therefore providing contact free rotation of the impeller inside the pump. This study was designed to evaluate long-term durability and nonthrombogenicity of the MSCP in a chronic sheep model. The blood contacting surfaces of the pump and conduits were completely modified by a heparin immobilization technique (Hepaface). The MSCP was placed paracorporeally as a left heart bypass between left ventricle and descending aorta in three adult sheep. Coumadin was given orally to maintain prothrombin time at 15–20 sec. The coagulation and hematologic parameters, including plasma free hemoglobin, were periodically monitored throughout the experiment. Under daily movement in the cage, the pump could produce average flow rates of 3–6 L/min (50–100 ml/kg) at 1,700–2,000 rpm. Although the arterial pulse contour decreased, there was no physiologic deterioration. The axial impeller excursion monitored by a position sensor was <25 μ. Plasma free hemoglobin level remained at <5 mg/dl throughout the experiment. There was no increase in the motor current, which indicates no massive thrombus formation around the impeller. One experiment was terminated at 70 days due to Hall sensor dysfunction of the motor. The retrieved pump was entirely free from thrombus formation. There was no detectable thrombus formation inside the pump or the inflow and outflow conduits. Hematologic, renal, and hepatic parameters remained within the normal range throughout the experiment. The other two sheep have survived for more than 395 and 41 days without major complication. These studies demonstrated that the MSCP has significant potential for long-term use.

In vitro studies of immobilized heparin and sulfonated polyurethane using epifluorescent video microscopy.

In situ surface modification techniques to improve the blood compatibility of blood contacting surfaces of medical devices have been developed by the authors. The techniques include heparin immobilization and sulfonated polymer grafting onto a polyurethane (PU) surface by using either ozone oxidation or photo reaction. These modified PUs were evaluated using an epifluorescent video microscope combined with a parallel plate flow cell. The epifluorescent video microscope system measured the amount of platelet coverage on the PU surfaces using whole human blood containing mepacrine labeled platelets perfused at a wall shear rate of 100 sec-1 for 20 min. Platelet activation and complement activation were also measured. Both immobilized heparin and sulfonated PUs showed significantly lower levels of platelet adhesion than the control PU. The platelet activation levels of these modified PUs also correspond to the results of the platelet adhesion. As for complement activation, heparin the immobilized surface showed the least complement activation, while sulfonated PU and the control PU showed higher levels of complement activation. In situ surface modification techniques, which use either ozone oxidation or photo reaction, are useful in a variety of medical devices even of a complex design, such as membrane oxygenators or artificial hearts.

Can heparin immobilized surfaces maintain nonthrombogenic activity during in vivo long-term implantation?

The authors previously demonstrated that heparin immobilized surfaces showed excellent nonthrombogenic properties for extracorporeal membrane oxygenation experiments as long as 168 hr. The characteristics of the heparin immobilized surfaces include high heparin bioactivity and prevention of platelet adhesion and complement activation. However, it is not known whether the heparin immobilized surfaces would be effective for in vivo long-term implantation. Heparin bioactivity may be lost because of complete degradation or blocking of binding sites on heparin by adsorbed proteins. This study attempted to elucidate the in vivo long-term fate of heparin immobilized surfaces. The blood contacting surfaces of the ventricular assist device (VAD) made from polyurethane was modified with heparin immobilization and evaluated in a long-term sheep left VAD (LVAD) model for as long as 3 months. After removal of the VAD, heparin bioactivity was measured by Factor Xa assay. The blood contacting surfaces were analyzed with a scanning electron microscope, and the adsorbed proteins on the surfaces of the diaphragm were analyzed by SDS-PAGE and Western blotting. The thickness of adsorbed proteins on the surfaces also was measured by a confocal laser microscope. For the control ventricular assist devices, thrombus formation was observed within 1 month, whereas heparin immobilized VADs were able to operate thrombus free for periods as long as 3 months. The control surfaces demonstrated a thick adsorbed protein layer on thin surfaces, whereas heparin immobilized surfaces maintained thinner adsorbed proteins on thin surfaces. Anti Factor Xa activity of the heparinized surfaces disappeared after 15 days, but the surfaces remained nonthrombogenic even after heparin bioactivity was completely lost. The protein composition analyzed by SDS-PAGE showed an albumin dominant pattern on the heparinized surfaces. The band of 110 kD corresponding to C3b was detected only on the control surfaces, which possibly activated complement, and subsequently activated platelets and coagulation. Immunoblot showed degradation products of fibronectin and vitronectin on the control surfaces, which probably were promoted by surface generated protease, whereas the heparinized surfaces showed minimal degradation throughout the experimental periods. These results suggest that the heparin moiety has an ability to control adsorbed proteins, thereby inhibiting thrombus formation during in vivo long-term implantation.

Fluid Dynamic Investigation of Mechanical Blood Hemolysis

To obtain basic bio-fluid dynamic data that can be used to improve the design of blood pumps, we developed in vitro hemolysis testing methods and compared the hemolysis generated in various stenotic connectors. In parallel with the in vitro testing, we performed numerical analysis, using the finite element method (FEM); provides velocity profiles, pressure distribution, and shear rates. The results are summarized as follows: (1) Shear rate was not always a major cause of hemolysis. The rate of hemolysis at an abrupt change in the stenotic section, where the cross-sectional area was reduced by 75%, was four times greater than that of an inlet tapered (20°) connector. However, the calculated result showed a higher shear region at the end of the tapered section. (2) In vitro and FEM data indicated that the roughness of the inner surface would be a strong influencing factor in the reduction of hemolysis. A comparison of hemolysis in identical stenotic connectors with differing surface roughness (Ra = 0.45 and 1.35 µm) revealed that a smooth surface achieved up to 80% reduction of hemolysis.

Development of Terumo implantable left ventricular assist system (T-ILVAS) with a magnetically suspended centrifugal pump

The research group of Terumo, NTN, and the Setsunan University have been developing an implantable left ventricular assist system (T-ILVAS) featuring a centrifugal blood pump with a magnetically suspended impeller (MSCP). The present study describes recent progress in the development of the T-ILVAS, focusing on ex vivo and in vivo evaluations of the prototype MSCP. The MSCP is composed of four parts: a magnetic bearing, an impeller, a housing, and a DC burshless motor. The impeller is suspended by a magnetic bearing, thus providing contact-free rotation of the impeller inside the pump. The prototype MSCP was placed paracorporeally in three sheep and implanted intrathoracically in two sheep to evaluate its long-term durability and nonthrombogenicity. One sheep implanted ex vivo with the paracorporeal MSCP (Model I) survived for 864 days without any mechanical failure or thromboembolic complications, and with negligible hemolysis. The implantable Model II pump was evaluated ex vivo in two sheep and intrathoracically implanted in one sheep. These experiments were terminated 70, 79, and 17 days after implantation due to mechanical failure caused by blood leakage through the intrahousing connector of the Model II pump. However, there was no intradevice thrombus formation in any of the retrieved pumps. The dual connector system was then introduced to the Model II pump (the modified Model II), and the pump was intrathoracically implanted in a sheep. The sheep survived for more than 14 months without major complications, and the study is being continued. The preliminary chronic animal experiments demonstrated improved durability and nonthrombogenicity of the MSCP, with a low hemolysis rate for up to 864 days. Thus, the MSCP has significant potential for longterm application as an implantable circulatory assist system. Further developments toward a totally implantable system, including an implantable controller and a transcutaneous energy/information transfer system, are under way.

Development of Straight Path Centrifugal Pump

Centrifugal blood pumps have become very popular and their excellent efficacy has been demonstrated in open heart surgery and temporary circulatory support. However, recent new applications in percutaneous cardiopulmonary support and bridge to transplantation require improvements in these pumps. The long narrow percutaneous cannula requires a very high pumping speed, and brings about very high negative pressure at the pump inlet. Bridges demand durable pump materials which are blood-compatible for more than one month, the usual implant time.

Investigation of a Ventricular Assist Device for Serial Production

We have been investigating a pulsatile, pneumatic ventricular assist device (VAD) for extracorporeal assistance of the left and right heart. We believe that this VAD will be competitive in terms of cost, and better in performance when compared to existing cardiac assist devices, including centrifugal and intra-aortic balloon pumps. To make the VAD as cost-effective as possible, several aspects of its construction and design were investigated. The VADs were vacuum-formed in 20-ml and 40-ml sizes, both in Pellethane (Dow Chemical Japan, Tokyo, Japan) and an inexpensive food-grade polyurethane. Individual parts of the VADs were assembled using high-frequency welding and special glueing techniques. To reduce thrombus formation, the 20-ml VAD employed a novel active diaphragm-housing (D-H) junction, with immobilized-heparin blood contacting surfaces. The VADs have been tested both in vitro and in vivo in chronic animal experiments, the longest survival being with a sheep with a 20-ml VAD that operated thrombus-free for a period of 3 months. The 40-ml VAD, which yields 61/min in vitro, is currently under development. Using the vacuum-forming process, we were able to fabricate VADs to a reproducible quality and performance.