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The implantable left ventricular assist system (LVAS) using pulsatile pump technology has become an established therapeutic option for advanced heart failure patients. However, there have been technological limitations in some older designs, including a high incidence of infection and mechanical failures associated with moving parts, and the large size of both implantable pump and percutaneous cable. A smaller rotary blood pump emerged as a possible alternative to a large pulsatile pump to overcome some of these limitations. The technological advancement that defines the third-generation LVAS was the elimination of all mechanical contacts between the impeller and the drive mechanism. The DuraHeart TM LVAS is the world's first third-generation implantable LVAS to obtain market approval (CE-mark), which combines a centrifugal pump and active magnetic levitation. The initial clinical experience with the DuraHeart LVAS in Europe demonstrated that it provided significantly improved survival (85% at 6 months and 79% at 1 year), reduced adverse event rates and long-term device reliability (freedom from device replacement at 2 years: 96 ± 3%) over pulsatile LVAS.

The first clinical application of the first-generation pulsatile implantable left ventricular assist system (LVAS) was in the mid 1980 s as a bridge to transplantation and contributed to an advancement of this field from a clinical experiment to an established therapeutic option for treating advanced heart failure patients. However, there have been technological limitations that have surfaced as longer-term experience has been gained. These include a high incidence of thromboembolic complications, infection, mechanical failures associated with moving parts, and the large size of both implantable pump and percutaneous cable. In order to overcome the limitations of the first-generation pulsatile LVAS, a smaller rotary blood pump LVAS emerged as a possible alternative in the 1990 s and these new generation LVAS are in various stages of development and clinical application. This article reviews the history and current status of the implantable LVAS.

We have developed a pneumatically driven 20 cc soft ventricle for temporary right, left, or biventricular assist. The ventricle consists of a vacuum-formed soft housing, diaphragm, tricuspid outflow valve, and biflap inflow valve. All components including inflow and outflow valves were made with Pellethane. The advantages of this blood pump are as follows: it eliminates use of the quick connect system and therefore is less thrombogenic; the biflap inflow valve provides low inflow resistance; the soft ventricle is easy to implant; the polyurethane valves eliminate blood damage and thromboembolism and are low in cost compared with mechanical valves; and the vacuum-forming technique is reliable, fast, capable of mass production, and therefore inexpensive. We have already demonstrated in both in vitro and in vivo experiments that this ventricle has excellent hemodynamic performance with less blood damage and thrombogenesis. In this study, we evaluated the possible application of a well-defined and widely distributed intraaortic balloon pump (IABP) console to the 20 cc left ventricular assist device (LVAD) driver. The pump was tested in 6 mongrel dogs (6 to 10 kg) using an IABP console. The pump was connected between the left atrium and the ascending aorta, placed paracorporeally on the chest wall, and driven at a synchronous or fixed rate mode without using vacuum. The 20 cc ventricle could maintain the same output as the conl. rol output of the natural heart at filling pressures of 5 to 10 mm Hg during the entire observation time of S h. Thus, this 20 cc soft ventricle has the potential to be widely used for the treatment of severe heart failure in infants because of its excellent hemodynamic performance, simplicity, and low cost.

We have developed the Terumo Capiox centrifugal pump (CXP), which consists of a rotor having a unique straight-path design to reduce pump rotational speed without decreasing hydraulic efficiency. The CXP was tested in vitro for blood trauma with a specially designed test circuit using fresh bovine blood. The Biopump (BP) (Medtronic, Minneapolis, MN, U.S.A.) and the roller pump (RP) were used as controls. The CXP demonstrated the smallest elevation of free plasma hemoglobin compared with the BP and the RP. The CXP was then applied to cardiopulmonary bypass (CPB) in 10 patients (CXP group) who underwent elective coronary artery bypass grafting (CABG), and the results were compared with those for a comparable roller pump group (RP group). Free plasma hemoglobin level, platelet count, and serum beta-thromboglobulin (beta-TG) level were measured during CPB. There were no CXP-related complications nor hemodynamic abnormalities during CPB. The CXP group demonstrated less hemolysis and less platelet depletion than the RP group. Furthermore, the serum beta-TG level was significantly lower in the CXP group than in the RP group. The CXP showed excellent hemodynamic performance with less blood trauma both in vitro and in clinical application to open heart surgery. Thus, the CXP has significant potential to be safely applied to CPB for open heart surgery and circulatory support.

The DuraHeart is a centrifugal pump with a magnetically levitated impeller. We implant the DuraHeart blood pump, which is 72 mm in external diameter and 45 mm in height, in a preperitoneal pocket in the left upper abdomen. An apical cuff is sutured to the apical hole in the left ventricular apex with 12 mattress sutures of 3-0 Prolene pledgeted with Dacron felt. In the first six mattress sutures, the needle is exited from the apical hole after a full-thickness bite of myocardium, and in six additional mattress sutures, the needle is exited from the epicardial edge of the apical hole. Next, a double purse-string suture with 3-0 Prolene is placed on the Dacron pledgets around the apical hole. After the inflow conduit has been connected to the inlet port of the blood pump, the inflow conduit is secured to the apical cuff. The graft portion of the outflow conduit, which was connected to the blood pump beforehand, is sewn end-to-side to the ascending aorta with a 4-0 Prolene suture. Gentle suture connection of the apical cuff to the left ventricular apex and optimal alignment of the inflow conduit, which is bent by 60 degrees, are crucial in the surgical procedure. A detailed description of the implantation technique is presented to facilitate the use of this system.

Background The clinical application of the DuraHeart (Terumo Heart Inc, USA) has begun in Europe as a clinical trial of a third-generation implantable centrifugal blood pump. Four successful clinical implants are presented. Methods and Results Four male patients had end-stage left heart failure and received a DuraHeart VAD as a left ventricular assist device for bridge-to-transplantation. The pump showed good performance with flow rates of 4.9±0.5 L/min after gradual weaning of extracorporeal circulation. The pump flow was then maintained at 6.1±0.5, 5.5±0.3, 5.5±0.1, 5.7±0.1, 5.5, 6.4 and 6.5 L/min at the 1st, 4th, 8th, 12th, 16th, 20th and 24th postoperative week, respectively. No significant elevation of mean plasma-free hemoglobin was detected. The patients were discharged on the 18th, 42nd, 41st and 31st postoperative day, respectively, and all were successfully transplanted on the 202nd, 84th, 128th and 96th postoperative day, respectively. At the time of transplant surfaces of the removed pumps were free from thrombus formation, although intraventricular pannus growth was observed around the inflow cannulae in all patients. Conclusion The DuraHeart VAD showed stable and sufficient circulatory support for the bridge-to-transplant procedure in this cohort of 4 patients. (Circ J 2006; 70: 1421 - 1425)

The current status and future directions of mechanical circulatory support devices (MCSDs) in Japan are reviewed. Currently used clinical MCSDs, both domestic and imported systems and continuous flow devices that are coming into the clinical arena are emphasized. Clinical MCSDs include the extracorporeal pulsatile Toyobo and Zeon systems and the implantable Novacor and HeartMate I VE. A thorough review is presented of single-ventricle continuous flow MCSDs such as the Terumo DuraHeart and the SunMedical EVAHEART and the biventricular Miwatec/Baylor systems that are on the horizon. The future directions in management of end-stage cardiac patients with MCSDs are discussed, focusing on (1) device selection - pulsatile versus continuous flow devices; (2) single-ventricle support, biventricular support, or replacement; (3) bridge to transplantation, destination therapy, or bridge to recovery; and (4) government regulatory processes and the medical industry. We hope to promote the quality of life (QOL) of end-stage cardiac patients as well as the medical industry in Japan.

Objective: The Terumo implantable left ventricular assist system (T-ILVAS) consists of a titanium centrifugal pump with a unique magnetically suspended impeller producing continuous (non-pulsatile) flow up to 10 l/min. The interior surface is heparin-coated and there is no purge system. We implanted the device into six sheep to ascertain in-vivo haemodynamic function, mechanical reliability and biocompatibility. Methods: The T-ILVAS was implanted via left thoracotomy without cardiopulmonary bypass. The inflow cannula was placed in the left ventricular apex and a Dacron outflow graft anastomosed to the descending aorta. All animals recovered well. No anticoagulation (heparin or warfarin) was given after the surgery. Suspension position, motor current, impeller speed and pump flow were continuously monitored and stored by on-line computer. Serial blood samples were collected to determine haematological and biochemical indices of renal function, liver function and haemolysis. All animals were electively euthanized between 3 and 7 months postoperatively. The explanted pumps were examined for mechanical reliability and thrombus formation. Major organs were examined macroscopically and histologically for thromboembolism. Results: All animals appeared completely normal for up to 210 days. At speeds between 1500 and 2000 rev./min the device pumped up to 8 l/min capturing all mitral flow. There were no major complications (pump failure, thromboembolism, haemorrhage, or driveline infection). Indices of haemolysis, liver and renal function remained within normal limits. All pumps were mechanically sound and free from thrombus. One embolus was found in a sectioned kidney. Conclusion: The T-ILVAS successfully supported the systemic circulation without anticoagulation for up to 210 days. Mechanical reliability and biocompatibility were demonstrated. Organ function remained within normal limits during continuous non-pulsatile flow.

A compact and reliable mechanical ventricular assist device is expected for chronic use. A magnetically suspended centrifugal pump (MSCP) is a seal-less, bearingless pump that can be operated for a long time with-out fear of leak or thrombus formation around the shaft. This paper reports recent progress with the MSCP, including pulse-pressure generation: In three sheep with acute heart failure induced by injection of beta-blockers, left ventricular assist was instituted with an inflow cannula into the left atrium (LA) and left ventricle (LV), and the outflow cannula to the descending aorta. The timing of the pulsation was synchronized with the electrocardiogram. Cardiac performance was evaluated by a conductance catheter and a tipped manometer in the LV. As pump speed increased, the pump flow became almost continuous. After application of pulsation, the pulse pressure increased from 5 to 25 mmHg, irrespective of the inflow cannulation site and the timing of pulsation. With LA cannulation, LV pressure at copulsation was slightly higher than at counterpulsation. Chronic animal trial: The MSCP was implanted in three sheep. The inflow cannula was inserted into the LV. The native heart was kept intact. The inner surface was coated with heparin. Continuous hemodynamic monitoring as well as periodic blood sampling was performed. The duration of running of the pump was 60, 140, and 248 days. The causes of termination were infection and failure of magnetic suspension due to electrical short. No thrombus or embolic findings were observed in the whole body after sacrifice. Renal and hepatic functions were within normal range throughout the experiment. It is concluded that the MSCP can produce pulsation irrespective of the inflow cannulation site and timing of synchronization. It is a promising device for chronic ventricular support.

Diamond-like carbon (DLC) films have received much attention recently owing to their properties, which are similar to diamond: hardness, thermal conductivity, corrosion resistance against chemicals, abrasion resistance, good biocompatibility, and uniform flat surface. Furthermore, DLC films can be deposited easily on many substrates for wide area coat at room temperature. DLC films were developed for applications as biomedical materials in blood contacting-devices (e.g., rotary blood pump) and showed good biocompatibility for these applications. In this study, we investigated the surface roughness by Atomic Force Microscopy (AFM) and Hi-vision camera, SEM for surface imaging. The DLC films were produced by radio frequency glow discharge plasma decomposed of hydrocarbon gas at room temperature and low pressure (53 Pa) on several kinds of polycarbonate substrates. For the evaluation of the relation between deposition rate and platelet adhesion that we investigated in a previous study, DLC films were deposited at the same methane pressure for several deposition times, and film thickness was investigated. In addition, the deposition rate of DLC films on polymeric substrates is similar to the deposition rate of those deposited on Si substrates. There were no significant differences in substrates' surface roughness that were coated by DLC films in different deposition rates (16–40 nm). The surface energy and the contact angle of the DLC films were investigated. The chemical bond of DLC films also was evaluated. The evaluation of surface properties by many methods and measurements and the relationship between the platelet adhesion and film thickness is discussed. Finally, the presented DLC films appear to be promising candidates for biomedical applications and merit investigation.

There is currently an increasing interest in the use of DLC (diamond like carbon) films in biomedical applications. These investigations making use of DLC in the biomedical area indicate its attractive properties. In this study, we succeeded in depositing DLC on polymer substrates and found the best conditions and method for this application. We evaluated the blood compatibility of polycarbonate substrates coated by DLC (PC-DLC) under different conditions by using epifluorescent video microscopy (EVM) combined with a parallel plate flow chamber. Segmented polyurethane (SPU), which has been used to fabricate medical devices including an artificial heart, and proven to have acceptable blood compatibility, was compared with polycarbonate substrates coated with DLC film. The EVM system measured platelet adhesion on the surface of the DLC, by using whole human blood containing Mepacrine labeled platelets perfuse at a wall shear rate of 100 s(-1) at 1 min intervals for a period of 20 min. PC-DLC demonstrated that Tecoflex showed higher complement activation than PC-DLC. There were significant differences between the PC-DLC substrates. On the basis of these results, it is recommended for use as a coating material in implantable blood contacting devices such as artificial hearts, pacemakers, and other devices. This DLC seems to be a promising candidate for biomaterials applications and merits further investigation.

To measure blood hematocrit inside the magnetically suspended centrifugal pump, we have performed both forward and backward light scattering measurements using a specially designed optical cell. In the forward scattering measurement, an optical fiber was used to guide the near infrared light at 780 nm into a 250 microns gap region, and the light that forward scattered toward a detector fiber was measured using a phototransistor. The light intensity decreased exponentially with an increase in the hematocrit to around 20%. The forward scattering method suffered from sensitivity at the hematocrit levels around 25-45% due to the diffusion effect. By making the optical path length larger than several millimeters, the sensitivity of the forward scattering method in terms of hematocrit change can be improved. In the back scattering method, however, better sensitivity in terms of hematocrit change from 0-50% was obtained. By making the optical fiber separation distance less than 1 mm, the system will measure the first order back scattering from the shallow layer while, by making the fiber separation distance larger than several millimeters, the system will primarily measure the diffuse reflectance from the deeper layer. Both approaches will yield sensitive optical intensity change in terms of the physiological hematocrit range.

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

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.

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.

Australian-made spiial vortex blood pump with vacumm-formed diaphragm was used to establish thebest coating technique for blood contacting surface. The inner surface of the pump was coated by three different coating materials(TM5+DMFE-380+THFE-380+Cyclohexanon)in tum by using a Singapore-made three-dimentional rotational moulding workstation. After several trials, it wasconcluded that the most uniform layer could be achieved under the rotational speeds of Major Minoraxis at1. 00 1. 25rpm, respectively. Moreover, hemocompatibility test was conducted betweencoated and uncoated pumps under the mean flow rate of5L mina. It was indicated that lessthrombi were formed at the coated surface, then advantage of our present coating technique wasverified.

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.

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.

Case histories of 39 patients who underwent tricuspid valve replacement with the St. Jude Medical prosthesis between June 1979 and August 1992 were reviewed in March 1993. The average patient age at the time of the operation was 46 +/- 11 years (range from 17 to 68 years). Concomitant mitral and/or aortic valve replacements were performed in 30 patients. All patients were given warfarin to maintain thrombotest between 10% to 25%. This number was between 2.8 to 1.6 times the control value in the International Normalized Ratio of prothrombin time. Three operative deaths occurred (7.7%). Among six late deaths, two patients died suddenly of unknown causes, and the remaining patient deaths were not valve-related. The actuarial survival rate at 14 years was 54.7%. Valve thrombosis occurred in one patient and was successfully treated with intravenous urokinase. This was the only valve-related complication (0.67%/patient-year). No reoperations were necessary in the tricuspid position. In conclusion, the St. Jude Medical valve is our choice of prosthesis for tricuspid valve replacement in adult patients who can receive proper anticoagulation therapy.

To expand the usage of the centrifugal pump (CP) in open heart surgery, we performed two studies. In the first, we evaluated pulsatile flow in the CP. In vitro pump performance of the Terumo Capiox pump (TCP) and the Sarns Delphin pump (SDP) and increase of free hemoglobin (mg/dl) after driving 6 h were investigated using bovine blood. A roller pump (RP) was used as a comparison. Equally effective pulsatile flow was obtained in both CPs. Hemolysis was less severe in TCP (120 mg/ dl) than SDP (210 mg/dl) and RP (320 mg/dl). In the second study, we evaluated a simple flow control method. Flow rate was easily controlled with step–wise clamping of 3–pronged tubing (Triple–flow) without changing rotational speed, regardless of afterload. Fluctuation of flow was much less with this method than with the rotational speed change method. The use of pulsatile flow of TCP, with its minimum increase of hemolysis and the easier flow control method during the weaning process, may expand the usage of CP in open heart surgery.

A new intraventricular axial flow blood pump has been designed and developed as a totally implantable left ventricular assist device (LVAD). This pump consists of an impeller combined with a guide-vane, a tube housing, and a DC motor. The pump is introduced into the LV cavity through the LV apex, and the outlet cannula is passed antegrade across the aortic valve. Blood is withdrawn from the LV through the inlet ports at the pump base, and discharged to the ascending aorta. Our newly developed axial flow pump system has the following advantages: 1) it is a simple and compact system, 2) minimal blood stasis both in the device and the LV cavity, 3) minimal blood contacting surface of the pump, 4) easy accessibility with a less invasive surgical procedure, and 5) low cost. A pump flow > 5 L/min was obtained against 100 mmHg differential pressure in the mock circulatory system. The pump could produce a passive pulsatile flow effect with a beating heart more efficiently than other non-pulsatile pumps because of minimal pressure drop and inertia along the bypass tract. Anatomic fit studies using dissected hearts of dilated cardiomyopathy (DCM) cadavers showed that this pump could smoothly pass through the aortic valve without any interference with mitral valve function. Recently, a dynamic pressure groove bearing and a miniature lip seal have been developed. The dynamic pressure groove bearing has a simple structure and acts as a pressure resistant sealing mechanism.(ABSTRACT TRUNCATED AT 250 WORDS)

The authors have demonstrated that an amphiphilic block co-polymer composed of 2-hydroxyethyl methacrylate (HEMA) and styrene (HEMA-st) showed excellent blood compatibility in in vitro, ex vivo, and in vivo experiments. The poor elastomeric properties of HEMA-st, however, have been an obstacle to its wider application in medical devices. To improve the mechanical properties of HEMA-st, the authors have developed a new amphiphilic block co-polymer composed of HEMA and octylstyrene (HEMA-oct). The size and morphology of the microdomain structures of HEMA-oct observed by transmission electron microscopy were similar to those of HEMA-st. Kink resistance tests showed improved elastomeric properties of HEMA-oct over HEMA-st. The blood compatibility of HEMA-oct was evaluated using an in vitro flow cell system combined with an epifluorescent video microscope, in which real time platelet adhesion and activation in whole blood can be observed and quantified, and ex vivo rabbit A-A shunt experiments. HEMA-st and a polyurethane (Pellethane 2363-80AE) were used for comparison. In a flow cell system, both HEMA-st and HEMA-oct showed minimal platelet coverage on the surfaces and less platelet activation as measured by beta-thromboglobulin (beta-TG), whereas Pellethane showed a considerable amount of platelet coverage with high beta-TG production. A-A shunt occlusion times were 309 +/- 31.2 min for HEMA-st, 251 +/- 47.7 min for HEMA-oct, and 30 +/- 3.4 min for Pellethane.(ABSTRACT TRUNCATED AT 250 WORDS)

We have been developing an implantable left ventricular assist system (T-ILVAS) featuring a magnetically suspended centrifugal pump (MSCP) since 1995. In vitro and in vivo studies using a prototype MSCP composed of a polycarbonate housing and impeller (196 ml) have demonstrated long-term durability and excellent blood compatibility for up to 864 days, and excellent stability of the magnetic bearing of the MSCP. These preliminary results strongly suggested that the magnetic bearing of the MSCP is reliable and is a most feasible mechanism for a long-term circulatory assist device. We have recently devised a clinical version pump made of titanium (180 ml) with a new position sensor mechanism and a wearable controller with batteries. Cadaver fit study confirmed that the Type IV pump could be implanted in a small patient with a body surface area as small as 1.3. The in vitro performance tests of the Type IV pump demonstrated excellent hydrodynamic performances with an acceptable hemolysis rate. New position sensors for the titanium housing showed more uniform sensor outputs of a magnetic bearing than in the prototype polycarbonate pump. The Type IV pump then was evaluated in vivo in 6 sheep at the Oxford Heart Centre. Four sheep were electively sacrificed at 3 months and were allowed to survive for more than 6 months for long-term evaluation. In this particular series of experiments, no anticoagulant/antiplatelet regimen was utilized except for a bolus dose of heparin during surgery. There was a left ventricular mural thrombi around the inflow cannula in 1 sheep. Otherwise, there was no mechanical failure nor sign of thromboembolism throughout the study.

A new intraventricular axial flow blood pump has been designed and developed as an implantable left ventricular assist device (LVAD). The pump consists of a tube housing (10 cm in length and 14 mm in diameter), a three-vane impeller combined with a guide vane, and a DC motor. This pump is introduced into the LV cavity through the LV apex, and the outlet cannula is passed antegrade across the aortic valve. Blood is withdrawn from the LV through the inlet ports at the pump base, and discharged into the ascending aorta. A pump flow of > 8 L/min was obtained against 90 mmHg differential pressure in the mock circulatory system. In an acute dog model, this pump could produce a sufficient output of 200 ml/kg/min. In addition, the pump flow profile demonstrated a pulsatile pattern, although the rotation speed was fixed. This is mainly due to the changes in flow rate during a cardiac cycle--that is, during systole, the flow rate increases to the maximum, while the differential pressure between the LV and the aorta decreases to the minimum. Thus, this simple and compact axial flow blood pump can be a potential LVAD, with prompt accessibility and need for less invasive surgical procedures.

Objective: The DuraHeart (Terumo Heart, Inc., Ann Arbor, Michigan, USA) is the world’s first approved magnetically levitated centrifugal left ventricular assistsystem designedfor long-termcirculatory support.We reportthe clinicaloutcomes of 68patients implanted with theDuraHeart as a bridge to cardiac transplantation in Europe. Methods: Sixty-eight patients with advanced heart failure (six females), who were eligible for cardiac transplantation were implanted with the DuraHeart between January 2004 and July 2008. Median age was 58 (range: 29—74) years with 31% over 65 years. Thirty-three of these patients received the device as a part of the European multi-center clinical trial. Survival analyses were conducted for 68 patients and other safety and performance data were analyzed based on 33 trial patients. Results: Mean support duration was 242 243days(range:19—1148,median:161)withacumulativedurationof45years.Thirty-fivepatients(51%)remainongoing,18transplanted, 1 explanted, and 14 died during support with a median time to death of 62 days. The Kaplan—Meier survival rate during support was 81% at 6 months and 77% at 1 year. Of the 13 patients (21%) supported for >1 year, 4 supported for >2 years, 1 supported >3 years, 2 transplanted, 2 died, and 9 ongoing with a mean duration of 744 216 days (range: 537—1148, median: 651). Major adverse events included driveline/pocket infection, stroke, bleeding, and right heart failure. There was no incidence of pump mechanical failure, pump thrombosis, or hemolysis. Conclusions: The DuraHeart was able to provide safe and reliable long-term circulatory support with an improved survival and an acceptable adverse event rate in advanced heart failure patients who were eligible for transplantation. # 2008 European Association for Cardio-Thoracic Surgery. Published by Elsevier B.V. All rights reserved.

We have developed a magnetically suspended centrifugal pump (MSCP) for long-term ventricular support. This study reports results of chronic animal experiments using a new version of the MSCP. Three sheep weighing 50-70 kg were used in this study. A left heart assist system was established with cannulas into the descending aorta and the left ventricular apex. In two sheep the MSCP was positioned outside the body and in one sheep implanted on the chest wall. The pumping flow was estimated by the motor current and motor speed. The temperature of the pump and the muscle near the pump was recorded for 10 days after operation. The duration of continuous pumping was 60, 140, and 230 days+ (ongoing), respectively. The cause of termination was infection associated with thrombus formation in the first, and failure of magnetic suspension in the second sheep. No thrombus or embolus was observed after sacrifice of the second sheep. The third sheep has been going well despite skin necrosis around the pump pocket. The estimation of pumping flow was reliable even at 140 days. Temperature of the pump surface was 42 degrees C immediately after the operation and gradually reduced to 41 degrees C. The MSCP is a reliable pump for long-term circulatory assist.

The clinical application of the DuraHeart (Terumo Heart Inc, USA) has begun in Europe as a clinical trial of a third-generation implantable centrifugal blood pump. Four successful clinical implants are presented.Four male patients had end-stage left heart failure and received a DuraHeart VAD as a left ventricular assist device for bridge-to-transplantation. The pump showed good performance with flow rates of 4.9+/-0.5 L/min after gradual weaning of extracorporeal circulation. The pump flow was then maintained at 6.1+/-0.5, 5.5+/-0.3, 5.5+/-0.1, 5.7+/-0.1, 5.5, 6.4 and 6.5 L/min at the 1st, 4th, 8th, 12th, 16th, 20th and 24th postoperative week, respectively. No significant elevation of mean plasma-free hemoglobin was detected. The patients were discharged on the 18th, 42nd, 41st and 31st postoperative day, respectively, and all were successfully transplanted on the 202nd, 84th, 128th and 96th postoperative day, respectively. At the time of transplant surfaces of the removed pumps were free from thrombus formation, although intraventricular pannus growth was observed around the inflow cannulae in all patients.The DuraHeart VAD showed stable and sufficient circulatory support for the bridge-to-transplant procedure in this cohort of 4 patients.

The aim of this study is the grafting of photoreactive α-propylsulphate-poly(ethylene oxide) (PEO-SO 3 ), one end of which is capped with an azidophenyl group, on polyurethane (PU) surfaces via a photochemical technique. The anti-Factor Xa activity and the platelet adhesion characteristics of the modified PU surface were evaluated by a chromogenic assay method and by a flow-controlled chamber method, respectively. X-ray photoelectron spectroscopy analysis showed that PEO-SO 3 was covalently grafted on the PU surface. The grafted surface showed anti-Factor Xa activity in the presence of antithrombin III, and significantly reduced platelet adhesion characteristics as compared with those of the unmodified PU surface. These results suggest that the grafting of PEO-SO 3 improves the antithrombogenicity of PU surfaces.

Heart transplants have been decreasing globally due to the lack of available donor hearts. As a result, the increased use of artificial hearts is anticipated as an alternative therapy. Although biocompatibility issues, such as thrombus formation/thromboembolism and infection, are still the main cause of mortality associated with artificial hearts, more than 20 different types are now clinically available after a half-century of development and experimental trials. These devices range from extracorporeal pneumatic to implantable battery-powered artificial hearts. The early development of artificial hearts logically focused on volumetric pump designs incorporating functions similar to the natural heart. Today, development has shifted toward designs that are significantly different from the natural heart. These pumps utilize axial or centrifugal flow allowing for a much simpler design, which is smaller in size and has very few moving parts. With rapid advances in technology, this new generation of artificial heart pumps is beginning to emerge as an alternative to heart transplants.

Evolving blood pump technology has produced user-friendly continuous flow left ventricular assist devices, but uncertainty exists about the safety of chronic nonpulsatile circulation. We established consistently nonpulsatile blood flow in a sheep model using the Terumo magnetically suspended centrifugal pump. We then compared end-organ function between pulseless and control animals.Fifteen healthy sheep (65 to 85 kg) were allocated to either left ventricular assist device (n = 9) or control (n = 6) groups. We implanted the device through a left thoracotomy and determined the flow rate at which pulse pressure was absent. The flow rate was then adjusted to exceed that rate (4.2 +/- 1.5 L/min), and all variables of pump function were continuously monitored by computer. Blood tests were taken serially for hepatic and renal function and plasma renin levels. The sheep were sacrificed electively at 30 (n = 3), 90 (n = 4), 180 (n = 1), and 340 (n = 1) days. Detailed histologic examination was made of the brain, liver, kidney, myocardium, and major arteries.All animals remained in good condition until sacrifice. All measures of end-organ function remained within normal limits for both groups. There were no histologic differences between the organs of pulsatile and nonpulsatile animals. Although there was no significant difference in mean blood pressure, plasma renin levels were substantially elevated in pulseless animals (1.4 +/- 0.3 pg/mL versus 2.9 +/- 0.3 pg/mL; p0.05). We also identified thinning of the medial layer of the ascending aorta in nonpulsatile sheep (1.8 +/- 0.4 mm in left ventricular assist device animals versus 2.6 +/- 0.6 mm in control sheep; p0.05).Chronic nonpulsatile circulation was well tolerated, and we found neither functional nor histologic changes in major end organs. The renin-angiotensin system was upregulated, but this did not provide a significant rise in blood pressure. The changes in the aortic wall merit further investigation. As a result of these findings, we consider that nonpulsatile devices can be used safely for long-term circulatory support.

After the accumulation of clinical experience with the current generation of pulsatile implantable left ventricular assist systems (LVAS), these devices have demonstrated major limitations: high incidence of thromboembolic complications; large size; high infection rate; and limited long-term durability. To address the limitations of current-generation LVAS, second- and third-generation LVAS utilizing rotary blood pump technology are currently undergoing clinical trials and the final stage of product development. Among them, the rotary blood pump with a magnetically levitated impeller is one of the most promising pumps for long-term circulatory assist. The Terumo DuraHeart LVAS is one of the third-generation LVAS using a centrifugal pump with a magnetically levitated impeller. This article describes the characteristics of the DuraHeart LVAS and its development status.

Objectives: The magnetically suspended centrifugal pump has gained attentions as an implantable ventricular assist device for long-term use. We report recovery-oriented pump operation and results of a chronic animal experiment.Methods: In an acute experiment in 8 sheep having microspheres injected to induce heart failure, left ventricular assist was implemented by 2 inflow cannulas, 1 each in the left atrium and left ventricle. The pressure-volume loop of the left ventricle and myocardial oxygen consumption were measured varying the assist rate. The chronic animal experiment used 10 sheep whose native heart was kept intact. Continuous hemodynamic monitoring and periodic blood sampling were conducted.Results: In the acute study, myocardial oxygen consumption decreased proportionally with increasing assist rate in left atrial drainage, but was significantly less at a 100% assist rate in left ventricular drainage. External work in left ventricular drainage did not decrease until a 75% assist rate, suggesting that the left ventricle shape and size were maintained despite decreased myocardial oxygen consumption. In the chronic experiment, the pumping duration was 14 to 248 days. No thrombi or emboli in the pump or any major organ were found in sacrificed sheep after living more than 100 days. Hepatic and renal function were within an almost normal range throughout the experiment.Conclusion: Left ventricular blood drainage effectively reduces oxygen consumption, maintaining the shape of the left ventricle. The magnetically suspended centrifugal pump is suitable for recovery of a failing heart or semipermanent use.

This article describes a technique offering indirect measurements of pump pressure differential and flow with certain accuracy independent of changes in blood viscosity. This technique is based on noninvasive measurements of the motor current and rotation speed using the physical model equations of the centrifugal pump system. Blood viscosity included in the coefficients of the dynamic equations is first estimated, and then substitution of the estimated viscosity into the steady equations of the model provides pump flow and pressure differential. In vitro tests using a Capiox pump showed a sufficient linear correlation between actual values and their estimates for pressure differential and pump flow. An in vivo test using a 45 kg sheep showed that the proposed algorithm needs robustness for the convergence of estimates of viscosity. An overall evaluation, however, of the developed algorithm/model showed indications of success in terms of efficient computation and modeling.

An adult-sized pump has been developed based on our experience with the development of a pediatric-type ventricular assist pump using the vacuum-forming process. During the scale-up process, large oscillations of pressure and flow were observed, which resulted from the substitution of a trileaflet valve for a bileaflet valve in the inflow position. At the pump inlet, an in vitro study using a highspeed video camera indicated that the oscillation was induced by expansion of the flexible sinus of Valsalva during early systole. As the valve leaflets subsequently opened, a large pressure spike was induced and the oscillation commenced. This phenomenon could be reduced by using a thicker wall section for the sinus of Valsalva, or using a bileaflet valve in the inlet position.

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.

We have already demonstrated that an amphiphilic block copolymer composed of 2-hydroxyethyl methacrylate(HEMA) and styrene, HS, showed excellent blood compatibility. The present study was carried out to characterize the surface structure of HS under dry and wet conditions, and after 372 days implantation as a vascular graft, using transmission electron microscopy (TEM). The HS which contains 63 wt% of polyHEMA segment was synthesized by the coupling reaction between semitelechelic polyHEMA and telechelic polystyrene. Under dry condition, the top surface of HS film was almost completely covered with polystyrene segment. On the other hand, at the surface after hydration, the polystyrene microdomains wrapped with PHEMA segments stretched toward the water side, which indicated surface restructuring in response to environmental changes. Protein layer thickness on the graft surface after implantation measured by TEM indicated to be less than 200 A, and in the microdomain structure beneath the protein layer with an alternate arrangement of polystyrene and PHEMA segments, stretched domains could not be recognized. These differences in the surface structures might be attributable to differences of the ambient environment. Moreover, such surface dynamics might influence the blood compatibility of HS.

We have developed novel surface modification techniques to improve the blood compatibility of Polyurethane (PU). One was heparin immobilization using a polyethylene imine spacer and the other was a sulfonated polyallylamine grafting onto a PU surface. Both techniques utilized ozone-induced graft copolymerization, thereby having an advantage to be applied to medical devices even with a complex design. In vitro lood compatibility of modified PUs were eveluated using an epifluorescent video microscopy (EVM) combined with a parallel plate flow cell. Both modified PUs showed significantly less platelet coverage on the surfaces with less β-TG and C3a production compared to the control. These results suggest that both PU-PEI-HEP and PU-PAA-S03 surfaces are promising for the application to a variety of medical devices.

We evaluated the blood compatibility of six different segmented polyurethanes (PU), including five polyether-PUs and one polyurethane-urea (PUU), with poly (tetramethylene etherglycol) (PTMG) as the soft segment, using epifluorescent video microscopy (EVM) combined with a parallel plate flow chamber. An amphiphilic block copolymer composed of 2-hydroxyethyl methacrylate (HEMA) and styrene (St) (HEMA/St), which has already been proven to be an excellent nonthrombogenic polymer, was used as a control. The EVM system measured the platelet adhesion on the surfaces of the PUs, using whole human blood containing Mepacrine-labeled platelets perfused at a wall shear rate of 200 s−1 at 1-min intervals for a period of 20 min. Platelet activation (β-thromboglobulin; β-TG) and complement activation (C3 activation products; C3a) were also measured. PUU showed significantly higher levels of platelet adhesion than the other PUs. However, PU-PTMG (MW, 1500) showed the lowest platelet adhesion among the six PUs, comparable to that of HEMA/St. The β-TG levels of each polymer also corresponded to the platelet adhesion results. Furthermore, complement activation was inversely correlated with the results for platelet adhesion and activation potentials, except for HEMA/St, which showed the lowest platelet and complement activation levels. From their chemical compositions, we divided these PUs into three categories; (A) PUU, (B) PUs with a PTMG of lower MW and (C) PUs with a PTMG of higher MW. From our experimental results, we confirmed that, of these PUs, (C) showed the lowest levels of platelet adhesion and a higher activation level than (B), with (A) showing the highest platelet adhesion and complement activation level of the three categories. From these findings, it can be seen that the blood compatibility of the PUs was greatly influenced by the MW of the PTMG as the soft segment. We also found that the blood compatibility of the PUs varied according to whether urea binding was present.

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.

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.

Although percutaneous veno-arterial (VA) bypass is the most widely used assistance configuration, due to its ease of handling and low cost, its major disadvantages include the need for extensive anti-coagulation therapy and the early development of wet lung. To overcome these problems, we internally coated a Terumo percutaneous VA bypass system (EMERSAVE; Terumo, Tokyo, Japan) with heparin, and improved the durability of the oxygenator by heating around the gas outlet to prevent condensation. In an in vivo experiment, a sheep underwent left heart bypass (31/ min) with this system for 96 h, while activated coagulation time (ACT) was maintained at around 150 s. During bypass, the gas inlet pressure was maintained at the control level, and no significant deterioration in CO2 transfer was observed. Hematological measurements, of platelet count, the maximum aggregation ratio of platelets, antithrombin III (AT-III) level, and fibrinogen content, as well as measurement of pressure drop in the blood circuit, showed no significant changes. Macroscopically, only a slight amount of thrombus was detected, in the stagnation zone of the oxygenator, but there were no thrombi in the circuit or the centrifugal pump. Scanning electron microscope study revealed no significant platelet adhesion or deformity throughout the system. These improvements should lead to longer non-pulsatile VA bypass with fewer complications.

A novel heparin bonding method has been developed for in situ surface modification using ozone oxidation, and evaluated in vitro and in vivo during prolonged extracorporeal membrane oxygenation (ECMO) experiments. The ECMO system consisted of a Capiox hollow fiber membrane oxygenator (MO; Terumo Corp., Tokyo, Japan) with an integral heat exchanger, a Capiox centrifugal pump (CP), and an extracorporeal circuit. The blood contacting surfaces of the system were completely modified using the heparin bonding process, and evaluated in a chronic sheep model for extended period of time, ranging from 96 to 168 hr, under minimal systemic heparinization. The heparin bonded surface was able to maintain high levels of heparin bioactivity, and showed improved blood compatibility in in vitro epifluorescent video microscopy experiments by suppressing platelet adhesion/activation and complement activation. For the ECMO experiments, extracorporeal blood flow was maintained at 3 L/min and the activated clotting time was maintained at 150 sec. There was no significant change in the gas transfer capability or mean pressure drop across the MO over experimental times of up to 168 hr. Platelet count and other coagulation parameters remained stable within the physiologic range throughout the experiment. There were no detectable thrombi in the CP, tubing, or connectors in the test circuit. Local thrombus formation was noted in a stagnant area of the MO, although this did not interfere with its function or lead to any significant embolization. Based on these results, the heparin bonded ECMO system appears to be a safe and effective device for prolonged extracorporeal circulation under minimal systemic heparinization.

To improve the ease of driving a centrifugal pump that is afterload dependent, we have developed an automatic flow control system for the Terumo Capiox centrifugal pump system. This system consists of an autoflow cruise control system with a safety cutoff. The Capiox Pump Console 3000 was controlled by a personal computer through a serial communication line. In the usual manual mode, the motor speed knob works as a pump speed control, and in the autoflow mode, the same knob works as a blood flow rate control. After selecting and obtaining the desired flow rate, the mode was changed from manual to autoflow mode. In the autoflow mode, the computer compares the desired flow rate with the actual flow measured by an ultrasonic Doppler flow-meter and adjusts the motor rotational speed accordingly. During both in vivo and in vitro testing, this autoflow mode was able to return the changed flow that was disrupted by either clamping and declamping of the tubing or by the bolus injection of a vasomotor drug to the selected flow rate within 10 s without any significant fluctuation. In conclusion, the newly developed computer controlled autoflow system was able to produce a reliable and effective flow regulation for a centrifugal pump.

Although many synthetic vascular grafts have been developed and evaluated experimentally or clinically, none of them have met long-term patency when applied as a small diameter vascular substitute. We have recently developed a small caliber vascular graft (3 mm i.d.) using a nonthrombogenic polymer coating. The graft consists of three layered structures: Dacron for the outer layer, polyurethane in the middle layer, and a HEMA/ styrene block copolymer (HEMA-st) coating for the inner layer. HEMA-st is an amphiphilic block copolymer composed of 2-hydroxyethyl methacrylate and styrene which has demonstrated improved blood compatibility over existing biomedical polymers in both in vitro and ex vivo experiments. Ten grafts were evaluated in a dog bilateral carotid replacement model. The grafts were electively retrieved at 7, 14, 30, 92, and 372 days after implantation. All grafts were patent without detectable thrombi along the graft length including anastomotic sites. Scanning electron micrographs of retrieved graft lumen showed fairly clean surfaces covered with a homogenous protein-like layer without microthrombi or endothelial cell lining. The thickness of the surface protein layer measured by a transmission electron microscopy was what can be described as monolayer protein adsorption regardless of implantation periods of as much as 372 days. A stable monolayer adsorbed protein layer formed on HEMA-st surfaces demonstrated nonthrombogenic activities in vivo and secure long-term patency of small caliber vascular grafts with the absence of an endothelial cell lining.

Suitable evaluation systems are critical for ranking various biomaterials in order to develop a method to design and synthesize nonthrombogenic biomaterials. We have recently developed an in vitro test system to evaluate platelet/biomaterial interactions in whole blood. The system consists of a parallel plate flow cell and epifluorescent video microscopy (EVM). A glass coverslip coated with a polymer was incorporated into the flow cell, and blood was perfused using a syringe pump via a polymer–coated PVC tubing connected to the flow cell. Whole human blood was anticoagulated with heparin (2 U/ml), and the platelets were labeled with the fluorescent dye mepacrine (5 μM). This system permitted real–time and dynamic observations of platelet/biomaterial interactions in whole blood under a defined flow condition. In order to evaluate the feasibility of this system, two different segmented polyether–polyurethanes (SPEUs), PU–PTMG(650) and PU–PTMG(2000), were chosen as test polymers. Surface characteristics verified with electron spectroscopy for chemical analysis (ESCA) and contact angle measurements showed similar results in both SPEUs. Blood was perfused at a wall shear rate of 200 s–1 for 20 min. Excitation light was applied for 2 s at 1 min intervals. The real–time image was then analyzed at each time point for the percentage of surface area of platelet coverage. Plasma β–thromboglobulin (β–TG) levels were also measured before and after each run. PU–PTMG(650) showed a significantly higher number of adhered platelets than PU–PTMG(2000) at each time point. β–TG levels of PU–PTMG(650) were also higher than those of PU–PTMG(2000), which is comparable to the results of EVM. Thus, this EVM system has been proven to be an excellent and highly sensitive in vitro analytical method for evaluating platelet/biomaterial interactions.