Tomoko Sugiyama

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.

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.

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.

Comparative blood compatibility of polyether vs polycarbonate urethanes by epifluorescent video microscopy.

The segmented polyether urethanes (PEUs) have been used in implantable medical devices due to excellent mechanical properties, acceptable blood compatibility, and good biostability. However, recent studies demonstrate that the polyether soft segment of PEU is susceptible to oxidative degradation in vivo due to scission of the polyether group. Recently, polycarbonate urethanes (PCUs) having no ether linkage in the soft segment have been developed, and show improved stability against oxidative degradation over PEUs. The current study evaluates blood compatibility of these PCUs in comparison with PEUs using epifluorescent video microscopy (EVM) combined with a parallel plate flow cell. The authors selected two PCUs, Corethane 80A (Corvita Corporation, Miami, FL) and PCU(1560), and two PEUs, Pellethene 2363–80AE (Dow Chemical Japan, Tokyo, Japan) and Tecoflex EG80A (Thermedics, Inc., Woburn, MA), all of which have similar hard segment compositions (MDI or HMDI:1,4-butanedio(BD)) and the same hardness of 80A. The EVM measured the amount of platelet coverage on the surfaces using human whole blood perfased at a wall shear rate of 100/sec for 20 min. Complement activation (C3a) also was measured. Both PEUs, especially Pellethane, showed significantly higher platelet adhesion than the PCUs (p < 0.05). There were no significant differences in platelet adhesion between the two PCUs. As for C3a measurements, Tecoflex showed higher complement activation than the others. Based on these results, it is recommended that PEUs should be replaced by ether free PCUs for use in implantable blood contacting devices such as artificial hearts and pacemaker lead insulators. ASAIO Journal 1997; 43:M500-M504.

Surface Modification Techniques for the Artificial Heart

We evaluated different surface modification techniques for polymeric materials used in the artificial heart. Proposed approaches to design nonthrombogenic polymer surfaces include (1) phase-separated micro-domain surfaces, (2) hydrophilic surfaces. (3) surfaces incorporating a bioactive molecule and (4) biomembrane-like surfaces. We have developed several in situ surface modification techniques to improve the blood compatibility of the blood-contacting surfaces of medical devices, including HEMA-styrene block copolymer (HEMA-st) coating, polyethylene glycol (PEG) grafting, human thrombomodulin (h-TM) and heparin (HEP) immobilization, and 2-methacryloyl oxyethyl phosphorylcholine (MPC) copolymer coating, each onto a segmented polyurethane (PU) surface. These surface-modified PUs were evaluated using an epifluorescent video microscope (EVM system) combined with a parallel plate flow cell for assessing in vitro platelet adhesion and activation and complement activation. All surfaces showed significantly lower platelet adhesion than nontreated PU, with the following ranking: HEMA-st ≧ MPC > h-TM = HEP ≧ PEG > PU. As for complement activation, h-TM and HEP showed the least C3a production, which we attributed to their inherent inhibitory effects on complement activation. HEP, PEG, or MPC copolymer treatments were applied in situ to the blood-contacting surfaces of artificial hearts made of PU, and evaluated ex vivo using 1-month implantation of the left ventricular assist devices in sheep. The preliminary results of ex vivo evaluations tend to confirm the in vitro results.

Biomedical Engineering. Relationship between Blood Compatibility and Nonthrombogenic Polymer Surfaces.

抗血栓性材料の設計概念として, 1) 多相系材料, 2) 高親水性材料, 3) 生理活性物質を利用した材料, 4) 生体膜類似表面を有する材料などが提唱されている.しかし, それらの設計概念による, 抗血栓性発現メカニズムの厳密な解答は得られていない.そのため, 血液一材料間相互作用の機序解明が望まれている.そこで我々は, それらの概念に基づく材料を, エピフルオレスセント・ビデオ・マイクロスコピー (EVM) システム, 拍動型左心室補助装置 (LVAD) モデルにより, 抗血栓性評価を行い, 材料との接触による血小板, 血漿タンパク, 補体などの血液成分の挙動の解析を行った.その結果, 材料との接触初期における血小板の粘着量がその後の血栓形成に反映し, 吸着タンパク層の組成, 厚さが表面の抗血栓性に影響を及ぼすことがわかった.補体活性と血小板粘着量との相関性はなかった.抗血栓性材料間での統一的な抗血栓性評価により, 血液-材料間相互作用の機序解明の指針が与えられた.

Nonthrombogenic Modification of Blood-Contacting Surfaces of Ventricular Assist Devices

We have developed a pneumatic ventricular assist device (VAD) for temporary right, left, or bi-ventricular assist. The blood pump consists of a soft housing, diaphragm, tricuspid outflow valve, and bi-flap inflow valve. All components, except for the bi-flap valve were made by the vacuum-forming technique from a polyurethane (Pellethane; Dow Chemical Japan, Tokyo, Japan). Our previous studies demonstrated that the pump showed excellent hemodynamic characteristics; however, the blood compatibility of the blood pump still remains as a major problem for longer-term application of more than 1 month. In this study, we applied a novel surface modification technique to improve the blood compatibility of the blood pump. The technique involved heparin immobilization, using ozone oxidation. The blood-contacting surfaces of the pump, including the valves, were first treated with ozone gas, followed by the surface grafting of poly(ethylene imine) (PEI), after which heparin was coupled to the PEI spacer. This technology has significant advantages in the application to artificial organs of a complex design. These surface modified blood pumps were evaluated in vitro, using an epifluorescent video microscope (EVM) in combination with a parallel plate flow chamber, and in vivo in a chronic sheep LVAD model. The preliminary results ( 3 months) are currently underway.