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Change in oxygen metabolic conditions accompanying the conversion of systemic flow from pulsatile to nonpulsatile (from P-mode to N-mode) was investigated in association with blood norepinephrine levels. Total left heart bypass was instituted through a left thoracotomy under general anesthesia in 10 adult goats. Pulsatile and nonpulsatile pumps were incorporated in the circuit in parallel, and the flow character was rapidly converted from the P-mode to the N-mode. Norepinephrine levels increased significantly after the conversion, from 222 +/- 54 pg/ml to 285 +/- 65 pg/ml. While oxygen delivery (DO2) was kept constant, the oxygen extraction ratio significantly decreased, from 21 +/- 3% to 16 +/- 3%, and venous oxygen saturation (SvO2) significantly increased, from 77 +/- 6% to 84 +/- 6% after depulsation. The serum lactate level was significantly higher in the N-mode than the P-mode (P-mode: 35 +/- 2 mg/dl, N-mode: 45 +/- 5 mg/dl). Strong positive and negative correlations of norepinephrine levels were observed with oxygen extraction ratio and SvO2, respectively, whereas norepinephrine levels did not correlated with DO2. Regression lines in these correlations unveiled higher oxygen uptake in the P-mode than the N-mode at the same norepinephrine level. These results indicate that, in the setting of an acute animal experiment, oxygen uptake is less efficient with the absence of pulsatility, and the higher norepinephrine concentration functioned to tune the oxygen metabolism in the initial stage of nonpulsatile systemic circulation.

It is generally considered that the natural lung metabolizes various vasoactive substances through the pulmonary circulation. However, the influences of bypassing or eliminating the pulmonary circulation have not been fully elucidated, especially for prolonged periods. In this study, we performed total cardiopulmonary bypass and exclusion of the pulmonary circulation for up to 336 hr in awake goats to clarify the importance of the metabolic function of the lung. In seven adult goats, biventricular bypass with a pulsatile ventricular assist system was first established. After 2 weeks, the biventricular bypass was converted to total cardiopulmonary bypass without anesthesia. Adequate gas exchange and perfusion support were achieved in all animals. However, the institution of total cardiopulmonary bypass led to marked decreases in the mean aortic pressure and systemic vascular resistance, and they remained low thereafter. The arterial levels of prostaglandin E2 and norepinephrine, which are inactivated naturally through the pulmonary circulation, increased remarkably. These results indicate that the natural lung plays an important role in controlling systemic circulation by metabolizing various vasoactive substances. Understanding the non respiratory function of the natural lung is of prime importance for advancement of lung and heart-lung support.

Liquid ventilation with perfluorocarbon (PFC) has been considered to offer advantages over gas ventilation to respiratory distress syndrome patients. We developed a volume-controlled liquid ventilator with pressure-limit mode; inspiration is performed mechanically with an actuator under the preset limit of the intratracheal pressure (Paw); expiration is performed by gravity assistance. Oxygenation and CO2 removal of PFC are done with a membrane oxygenator. An endotracheal tube with a Paw monitor line was placed in 5 rabbits weighing 2.7 +/- 0.6 kg, and liquid ventilation was conducted with the condition that the upper and lower limits of Paw were 20 and -20 mm Hg, respectively. The best arterial pH and gas tension were examined. The averaged arterial pH and gas tension were examined. The averaged arterial pH. Pao2, Paco2, and Sao2 were 7.45 mm Hg, 369 mm Hg, 46.2 mm Hg, and 100% at the best values, respectively. Ventilatory conditions at the best values were as follows: ventilation rates, tidal volume peak Paw, average Paw, and trough Paw were 5-15 (11 +/- 4) times/min, 13.3-17.3 (15.6 +/- 1.4) ml/kg, 5-18 (12 +/- 5) mm Hg, -7-4 (-1 +/- 4) mm Hg, and -20(-)-6 (-13 +/- 5) mm Hg, respectively. Pressure-limit control of the system worked well, but in the initial 3 animals, fluorothrax, that is the leakage of PFC into thoracic cavity, was recognized at the Paw from 20 to 25 mm Hg after the upper pressure limit was raised to 25 mm Hg to improve Paco2. The fluorothrax seemed to be caused by excess end-expiratory residual volume. An expiratory control mechanism appears to be imperative for further improvement of our liquid ventilator.

Influence of non pulsatile systemic circulation on oxygen metabolism was examined regarding tissue perfusion in 12 adult goats weighing from 46 to 55 kg. Under general anesthesia, a flow character, changeable total left heart bypass circuit consisting of pulsatile and non pulsatile pumps was installed through a left thoracotomy. Systemic flow was converted from pulsatile to non pulsatile in 7 of 12 animals, and in the reverse order in the other 5, by changing the driving pump. Esophageal mucosal blood flow was determined by a colored microsphere method that estimated tissue blood flow at the pre capillary level. Esophageal intramucosal pH was evaluated with a silicone balloon tonometer catheter surgically placed in the submucosal space. Hemodynamic and arterial blood gas parameters were unchanged at flow mode conversion. Although oxygen delivery was comparable between pulsatile and non pulsatile circulation, oxygen extraction ratio was lower and venous oxygen saturation was higher in non pulsatile than pulsatile circulation. Although statistically not significant, serum lactate level tended to be higher with non pulsatile circulation. No difference was observed in esophageal mucosal blood flow between pulsatile and non pulsatile circulation, whereas intramucosal pH, which strongly correlated with arterial pH regardless of the flow mode, was significantly lower under non pulsatile than pulsatile conditions. In conclusion, systemic oxygen uptake is less efficient in non pulsatile than pulsatile circulation in the setting of an acute experiment using animals, which may be accounted for by the disparity between the pre capillary blood flow and actual tissue oxygen metabolism.

Background: A novel control system for the EVAHEART left ventricular assist device (LVAD), known as the Native Heart Load Control System (NHLCS), can change the device’s rotational speed (RS) in synchrony with the heartbeat. The system enhanced coronary flow (CoF) with the counter-pulse mode in normal goats’ hearts, so we examined the change in CoF in goats with acute ischemic heart failure (HF). Methods and Results: We studied 14 goats (56.1±6.9kg) with acute ischemic HF induced by coronary microsphere embolization. We installed EVAHEART and ran the device in 4 modes [continuous support, circuit-clamp, counter-pulse (raise RS in diastole), and co-pulse (raise RS in systole)] with 50% or 100% bypass in each mode. In comparison with the circuit-clamp mode, CoF was 121.0±14.1% in the counter-pulse mode and 102.9±7.9% in the co-pulse mode, whereas it was 113.5±10.6% in the continuous mode, with 100% bypass (P

We investigated early clinical outcomes of a new extracorporeal life support (ECLS) system (Endumo 2000, Heiwa Bussan, Tokyo, Japan), which consists of a ROTAFLOW centrifugal pump, a BIOCUBE oxygenator with plasma-leakage-tight polymer fibers, and a biocompatible coating (T-NCVC coating), in pediatric patients

What the most causative factor affecting hemolysis is still controversial. To resolve this problem, we investigated the relationship between hemolysis and heat generation in six types of centrifugal blood pumps (Bio-Pump, Delphin, Capiox, Nikkiso, Isoflow, and Toyobo). The analyzed parameters were index of hemolysis in fresh goat blood, pumping performance, and heat generation in a thermally isolated mock circuit. These parameters were analyzed at a flow rate of 5 L/min by changing the pressure head (100 mm Hg and 500 mm Hg). At 500 mm Hg of pressure head, the Bio-Pump needed the highest rotation number and showed the highest hemolytic rate and heat generation. The index of hemolysis is well correlated to heat generation (r2 = 0.721). Heat may originate from the motor by conduction, hydraulic energy loss, and mechanical friction between the shaft and seal. We strongly suspect that hemolysis was caused by a factor such as mechanical friction which generates heat locally.

A novel cardiopulmonary support (CPS) system as a long-term total substitute for the natural heart and lung was designed and evaluated. The CPS system is composed of a ventricular assist device (VAD) and a newly developed compact artificial lung (AL). The pneumatic VAD was originally developed in the authors' institute and has proven durable and antithrombogenic in over 120 clinical uses. The AL, with 1.2 m2 membrane surface area and 140 ml priming volume, consists of a special gas exchange membrane where not only are micropores blind-ended to prevent serum leakage, but the blood contacting surface is treated with heparin binding to ease systemic anticoagulation. Chronic animal experiments of total CPS were carried out in three goats weighing from 28 to 36 kg. Venoarterial bypass was instituted with the CPS system in which all venous blood was drawn from both the right atrium and ventricle and returned to the aorta. No systemic anticoagulation was conducted except for heparin added fluid infusion from pressure lines. One animal survived for 2 weeks without any device related problems until electively euthanized. Blood flow rate ranged between 3.2 to 4.5 L/min, O2 transfer between 120 to 220 ml/min, and CO2 removal between 60 to 210 ml/min. No substantial changes were found in platelet count or other coagulation factors. These results indicate that the system has the ability to be used for long-term CPS, such as a bridge to lung or heart-lung transplantation.

From an engineering point of view, the suitable revolution number for high efficiency operation of an axial flow pump is known. A multistage axial flow pump is a useful tool for reducing revolution number with a high efficiency axial flow pump. A two stage (25) axial flow pump designed at a 5 L/min flow rate and a 100 mmHg pressure head was evaluated in three kinds of in vitro hemolysis tests. Each stage design point of the 2s pump was tested at a 5 L/min flow rate and a 50 mmHg pressure head. Specific speed and revolution number of the 2S pump were 1400 rpm, m3/min, m, and 15500 rpm, respectively. In the first test the 2S pump was compared with two single stage axial flow pumps (1S-A and 1S-B100) designed by the same method. The specific speed of the 1A was the same as that of the 2S pump, which was driven at 26000 rpm. The impeller of the 1S-B100 was the same as that of the 2S pump, which was driven at a 22000 rpm RN and a 1100 specific speed. The 2S pump was separated into two single stage axial flow pumps and the effect of series operation on hemolysis was evaluated in the second test. In the third test the 2S pump was compared with the 1S-B100 by using diluted goat blood samples with three different hematocrit values. The results showed that the hemolysis index of the 2S pump, regarded as a total hemolysis index of both stage axial flow pumps, was less than those of the single stage axial flow pumps at all hematocrit values.

In an attempt to decrease hemolysis caused by an axial-flow blood pump, we studied whether specific speed (Ns) at a design point (determined by flow in m3/min, pump head in m, and pump speeds in rpm), should be kept within the existing engineering standard range (1000 < Ns < 2500) or whether pump speed should be reduced to a minimum (Ns < 1000). Four pumps (A: 14,000 rpm, B: 18,000 rpm, C: 22,000 rpm, and D: 26,000 rpm), each with an impeller 11.8 mm in diameter, were designed to accommodate a flow rate of 5 L/min and a pressure head of 100 mmHg. At this design point, the Ns of each pump was calculated as A:758, B:974, C:1191, and D:1407. Pump performance was observed, and the total efficiency of each pump was calculated. The hemolysis index (HI) was calculated after simultaneous testing in duplicate of all four pumps using fresh goat blood (anticoagulated with citrate-dextrose solution) in a closed mock-loop circuit. Total efficiency of each pump was calculated as A:49%, B:50%, C:45%, and D:22%. In the first hemolytic test, HIs were measured as A:0.066, B:0.18, and C:0.13; a water seal failed in pump D. In the second test, HIs were B:0.077, C:0.0499, and D:0.12; a bearing failed in pump A. It is concluded that a lower level of hemolysis is associated with a pump speed in the minimum range at the design point, even though Ns is outside the standard range.

Aortic insufficiency (AI) is a serious complication for patients on long-term support with left ventricular assist devices (LVAD). Postoperative aortic valve opening is an important predictor of AI. A system is presently available that can promote native aortic flow by reducing rotational speed (RS) for defined intervals. However, this system can cause a reduction in pump flow and lead to insufficient support. We therefore developed a novel "delayed copulse mode" to prevent AI by providing both minimal support for early systole and maximal support shortly after aortic valve opening by changing the RS in synchronization with heartbeat. To evaluate whether our drive mode could open the aortic valve while maintaining a high total flow (sum of pump flow and native aortic flow), we installed a centrifugal LVAD (EVAHEART(®); Sun Medical) in seven goats each with normal hearts and acute LV dysfunction created by micro-embolization of the coronary artery. We intermittently switched the drive mode from continuous (constant RS) with 100 % bypass to delayed copulse mode with 90 % bypass. Total flow did not significantly change between the two modes. The aortic valve opened when the delayed copulse mode was activated. The delayed copulse mode allowed the aortic valve to open while maintaining a high total flow. This novel drive mode may considerably benefit patients with severe heart failure on long-term LVAD support by preventing AI.

Systemic inflammatory responses in patients receiving cardiac surgery with the use of the cardiopulmonary bypass (CPB) significantly contribute to CPB-associated morbidity and mortality. We hypothesized that insufflated hydrogen gas (H₂) would provide systemic anti-inflammatory and anti-apoptotic effects during CPB, therefore reducing proinflammatory cytokine levels. In this study, we examined the protective effect of H₂ on a rat CPB model. Rats were divided into three groups: the sham operation (SHAM) group, received sternotomy only; the CPB group, which was initiated and maintained for 60 min; and the CPB + H₂ group in which H₂ was given via an oxygenator during CPB for 60 min. We collected blood samples before, 20 min, and 60 min after the initiation of CPB. We measured the serum cytokine levels of (tumor necrosis factor-α, interleukin-6, and interleukin-10) and biochemical markers (lactate dehydrogenase, aspartate aminotransferase, and alanine aminotransferase). We also measured the wet-to-dry weight (W/D) ratio of the left lung 60 min after the initiation of CPB. In the CPB group, the cytokine and biochemical marker levels significantly increased 20 min after the CPB initiation and further increased 60 min after the CPB initiation as compared with the SHAM group. In the CPB + H₂ group, however, such increases were significantly suppressed at 60 min after the CPB initiation. Although the W/D ratio in the CPB group significantly increased as compared with that in the SHAM group, such an increase was also suppressed significantly in the CPB + H₂ group. We suggest that H₂ insufflation is a possible new potential therapy for counteracting CPB-induced systemic inflammation.

Using simple, safe, and economical in-body tissue engineering, autologous valved conduits (biovalves) with the sinus of Valsalva and without any artificial support materials were developed in animal recipients’ bodies. In this study, the feasibility of the biovalve as an aortic valve was evaluated in a goat model. Biovalves were prepared by 2-month embedding of the molds, assembled using two types of specially designed plastic rods, in the dorsal subcutaneous spaces of goats. One rod had three projections, resembling the protrusions of the sinus of Valsalva. Completely autologous connective tissue biovalves (type VI) with three leaflets in the inner side of the conduit with the sinus of Valsalva were obtained after removing the molds from both terminals of the harvested implants with complete encapsulation. The biovalve leaflets had appropriate strength and elastic characteristics similar to those of native aortic valves; thus, a robust conduit was formed. Tight valvular coaptation and a sufficient open orifice area were observed in vitro. Biovalves (n = 3) were implanted in the specially designed apico-aortic bypass for 2 months as a pilot study. Postoperative echocardiography showed smooth movement of the leaflets with little regurgitation under systemic circulation (2.6 ± 1.1 l/min). α-SMA–positive cells appeared significantly with rich angiogenesis in the conduit and expanded toward the leaflet tip. At the sinus portions, marked elastic fibers were formed. The luminal surface was covered with thin pseudointima without thrombus formation. Completely autologous biovalves with robust and elastic characteristics satisfied the higher requirements of the systemic circulation in goats for 2 months with the potential for valvular tissue regeneration.

Using simple, safe, and economical in-body tissue engineering, autologous valved conduits (BIOVALVEs) with the sinus of Valsalva and without any artificial support materials were developed in animal recipients’ bodies. In this study, the feasibility of theBIOVALVE as an aortic valve was evaluated in a goat model. BIOVALVEs were prepared by 2-month embedding of the molds, assembled using 2 types of specially designed plastic rods, in the dorsal subcutaneous spaces of goats. One rod had 3 projections, resembling the protrusions of the sinus of Valsalva. Completely autologous connective tissue BIOVALVEs with 3 leaflets in the inner side of the conduit with the sinus of Valsalva were obtained after removing the molds from both terminals of the harvested implants with complete encapsulation. The BIOVALVE leaflets had appropriate strength and elastic characteristics similar to those of native aortic valves; thus, a robust conduit was formed. Tight valvular coaptation and sufficient open orifice area were observed in vitro. BIOVALVEs (n=3) were implanted in the specially designed apico-aortic bypass for 2 months as a pilot study under the systemic circulation. Postoperative echocardiogram and angiogram showed smooth movement of the leaflets with little regurgitation (2.6 ±1.1 L/min). The α-SMA–positive cells migrated in the tissue of the conduit significantly with rich angiogenesis and expanded toward the leaflet tip. At the sinus portions, marked elastic fibers were formed. The luminal surface was covered with thin pseudointima without thrombus formation. Completely autologous BIOVALVEs with robust and elastic characteristics satisfied the higher requirements of systemic circulation in goats for 2 months with the potential for valvular tissue regeneration.

To clarify the influences of nonpulsatile blood flow on the physiologic function of the lung, we established nonpulsatile pulmonary circulation with a centrifugal pump in a chronic animal model (adult goats, n = 6). As the initial phase, a pulsatile right ventricular assist device was implanted to bypass the whole blood supply from both the right atrium and right ventricle to the pulmonary artery. After 2 weeks of pumping, the pulsatile pump was replaced with a centrifugal pump without anesthesia, and nonpulsatile pulmonary circulation was instituted. In this experimental model, no significant change was observed in either mean pulmonary arterial pressure or pulmonary vascular resistance index during the pulsatile pumping compared with that on the fourteenth day of nonpulsatile pumping. Blood gas data, extravascular lung water content, and serum level of angiotensin-converting enzyme were maintained within normal ranges. There was also no significant change in the ventral to dorsal blood perfusion ratio of the lower lobe of the right lung. These results indicate that pulmonary functions are not affected by nonpulsatile pulmonary circulation for a period of 14 days in this animal model.

Continuous-flow left ventricular assist devices (LVADs) have greatly improved the prognosis of patients with end-stage heart failure, even if continuous flow is different from physiological flow in that it has less pulsatility. A novel pump controller of continuous-flow LVADs has been developed, which can change its rotational speed (RS) in synchronization with the native cardiac cycle, and we speculated that pulsatile mode, which increases RS just in the systolic phase, can create more pulsatility than the current system with constant RS does. The purpose of the present study is to evaluate the effect of this pulsatile mode of continuous-flow LVADs on pulsatility in in vivo settings. Experiments were performed on eight adult goats (61.7 ± 7.5 kg). A centrifugal pump, EVAHEART (Sun Medical Technology Research Corporation, Nagano, Japan), was installed by the apex drainage and the descending aortic perfusion. A pacing lead for the detection of ventricular electrocardiogram was sutured on the anterior wall of the right ventricle. In the present study, we compared pulse pressure or other parameters in the following three conditions, including Circuit-Clamp (i.e., no pump support), Continuous mode (constant RS), and Pulsatile mode (increase RS in systole). Assist rate was calculated by dividing pump flow (PF) by the sum of PF and ascending aortic flow (AoF). In continuous and pulsatile modes, these assist rates were adjusted around 80-90%. The following three parameters were used to evaluate pulsatility, including pulse pressure, dp/dt of aortic pressure (AoP), and energy equivalent pulse pressure (EEP = (∫PF*AoP dt)/(∫PF dt), mm Hg). The percent difference between EEP and mean AoP is used as an indicator of pulsatility, and normally it is around 10% of mean AoP in physiological pulse. Both pulse pressure and mean dp/dt max were decreased in continuous mode compared with clamp condition, while those were regained by pulsatile mode nearly to clamp condition (pulse pressure, clamp/continuous/pulsatile, 25.0 ± 7.6/11.7 ± 6.4/22.6 ± 9.8 mm Hg, mean dp/dt max, 481.9 ± 207.6/75.6 ± 36.2/351.1 ± 137.8 mm Hg/s, respectively). In clamp condition, %EEP was 10% higher than mean AoP (P = 0.0078), while in continuous mode, %EEP was nearly equivalent to mean AoP (N.S.). In pulsatile mode, %EEP was 9% higher than mean AoP (P = 0.038). Our newly developed pulsatile mode of continuous-flow LVADs can produce pulsatility comparable to physiological pulsatile flow. Further investigation on the effect of this novel drive mode on organ perfusion is currently ongoing.

An electrohydraulic total artificial heart (EHTAH) has been developed and evaluated by long-term in vivo studies. The EHTAH is composed of blood pumps with an interatrial shunt (IAS), an energy converter, and electronics. The EHTAH with external electronics was implanted in four calves weighing from 81-90 kg. Two animals died on the 1st and 5th post operative days, the third animal survived for 32 days, and the fourth for 159 days. The IAS was free of thrombus at autopsy in all animals. The longest surviving animal increased in size from a pre operative weight of 81 kg to 134 kg on day 144. Cardiac output ranged from 9.3 to 10.5 L/min, whereas right and left atrial pressures increased with the calf's growth from 4-10 to 16-20 mmHg and from 8-14 to 18-22 mmHg, respectively. The animal favorably tolerated up to 3.4 km/hr of treadmill exercise, both hemodynamically and metabolically. The elevation of atrial pressures during treadmill exercise was significantly alleviated by employing an automatic control mode. It is concluded that the device has the potential to be a totally implantable system for permanent use.

To facilitate research and development (RD) and to expedite the review processes of medical devices, the Ministry of Health, Labor and Welfare (MHLW) and the Ministry of Economy, Trade and Industry (METI) founded a joint committee to establish guidance for newly emerging technology. From 2005 to 2007, two working groups held discussions on ventricular assist devices and total artificial hearts, including out-of-hospital programs, based on previous guidance documents and standards. Based on this discussion, the METI published the RD Guidelines for innovative artificial hearts in 2007, and in 2008 the MHLW published a Notification by Director regarding the evaluation criteria for emerging technology.

Driveline infection is a serious complication in long-term therapy using a ventricular assist device (VAD). However, measures taken against this complication have not been sufficient. In this study, we evaluated our newly developed infection-resistant skin-button system against driveline infection of an implantable VAD in a chronic animal study. The skin button is made of two flanges using tissue-compatible segmented polyurethane. The exposed upper layer is made of a nonporous sheet with relative flexibility similar in texture to the skin. In addition, this shape was designed to defuse excessive stress at the edge of the skin caused by the external force put on the driveline. The lower layer, which is implanted subcutaneously, is made of a porous material with a three-dimensional reticular structure. The combination of these two flanges with different features enables the driveline to fix to the skin without epithelial downgrowth and peridriveline pocket formation and can prevent bacterial infection over a prolonged period. Results of 90 days of animal tests, the button maintained secure adhesion to the skin and did not exfoliate without special daily treatments, such as dressing or disinfection, and there were no infections or inflammations at the exit site. This study demonstrates that our newly developed skin-button system can be useful for preventing infections at the driveline exit site.

The effect of rotary left ventricular assist devices (LVADs) on myocardial perfusion has yet to be clearly elucidated, and several studies have shown decreased coronary flow under rotary LVAD support. We have developed a novel pump controller that can change its rotational speed (RS) in synchronization with the native cardiac cycle. The aim of our study was to evaluate the effect of counterpulse mode, which increases the RS in diastole, during coronary perfusion. Experiments were performed on ten adult goats. The EVAHEART LVAD was installed by the left ventricular uptake and the descending aortic return. Ascending aortic flow, pump flow, and coronary flow of the left main trunk were monitored. Coronary flow was compared under four conditions: circuit-clamp, continuous mode (constant pump speed), counterpulse mode (increased pump speed in diastole), and copulse mode (increased pump speed in systole). There were no significant baseline changes between these groups. In counterpulse mode, coronary flow increased significantly compared with that in continuous mode. The waveform analysis clearly revealed that counterpulse mode mainly resulted in increased diastolic coronary flow. In conclusion, counterpulse mode of rotary LVADs can enhance myocardial perfusion. This novel drive mode can provide great benefits to the patients with end-stage heart failure, especially those with ischemic etiology.

Bridge to recovery has become a major goal after left-ventricular-assist-device (LVAD) implantation thanks to recent development in adjunctive therapies. Precise assessment of native heart function under minimum LVAD support is the key for successful LVAD explantation. However, weaning of centrifugal LVADs normally generates diastolic intracircuit backward flow. This retrograde flow may become excessive load for the native heart during off-pump test. The flow itself is an inevitable characteristic of centrifugal pumps. Therefore, evaluating this retrograde flow in vitro is of considerable significance, even if its amount is different from that in clinical settings. The purpose of this study was to assess diastolic backflow of continuous-flow centrifugal LVADs in a mock circulation model. A centrifugal LVAD (EVAHEART, Sun Medical Technology) was installed in a mock circulation model by the left ventricle uptake and the ascending aortic return. Pump flow was measured at the pump rotational speed of 1000, 1500, 2000, and 2500 rpm, and pulse rate of the virtual native heart was varied to 60, 90, and 120 beats/min. After data collection, pump flow was integrated, and forward and backward intracircuit flow were calculated. As a result, nonphysiological reverse flow of approximately 2.0 L/min exists at the rotational speed, providing 0 L/min mean pump flow. An ideal off-test trial condition should be realizing both ± 0 L/min pump flow and no intracircuit backward flow at the same time. We are developing a novel EVAHEART drive mode that can change its rotational speed in synchronization with cardiac cycle with the aim of controlling this retrograde flow with the new drive mode and creating an ideal off-test condition.

The authors suggested that a mammal immediately accommodates well to nonpulsatile flow in the systemic circulation. In the current study, nonpulsatile pulmonary blood flow using a centrifugal pump was established in chronic models to analyze its influence on the pulmonary circulation. A pulsatile right ventricular assist device (RVAD) was implanted to draw blood from both the right atrium and ventricle and send blood to the pulmonary artery in six goats. After 2 weeks, the pulsatile pump was quickly replaced with a centrifugal pump without anesthesia, and a 100% non-pulsatile pulmonary blood flow was obtained. Cardiac output was kept at 80-120 ml/kg/min during the experiments. No changes were observed in hemodynamic parameters, including pulmonary arterial pressure, pulmonary vascular resistance index, and blood gas data, after the immediate depulsation of the pulmonary blood flow. There was also no significant change in the ventral to dorsal tissue blood flow ratio of the lower lobe of the right lung, which was calculated by a colored microsphere method, between pulsatile and non-pulsatile pulmonary blood perfusion. These results suggest that pulmonary function, including blood flow distribution, is not affected by non-pulsatile pulmonary circulation for periods up to 14 days.

A series of star-shaped cationic polymers, termed star vectors (SVs), has been developed as effective nonviral gene delivery carriers. In this study, we separated SVs into several fractions having different molecular weights with very narrow molecular weight distributions in order to examine in detail the influence of the molecular weight of the SVs on the gene transfection efficiency. As a model compound for several types of SVs, 4-branched poly(N,N-dimethylaminopropyl acrylamide) having a molecular weight (M(n)) of approximately 35 kDa and polydispersity of 1.6 was prepared by iniferter-based radical polymerization. The SVs were separated using size-exclusion chromatography to obtain seven fractions having M(n) ranging from 27 kDa to 73 kDa with polydispersity ranging from 1.1 to 1.2. All the fractionated SVs have similar pH of 10.2-10.4 and were able to interact with and condense luciferase-encoding plasmid deoxyribonucleic acid (DNA) to yield SV/DNA polyplexes. A water-soluble tetrazolium-1 (WST) assay showed that all SVs had minimal cellular cytotoxicity under an N/P charge ratio of 10. The critical micellar concentration decreased with an increase in the M(n) of the fractionated SVs; however, the particle size of the polyplexes, exclusion activity of ethidium bromide, and zeta-potential of the polyplexes increased. An in vitro evaluation using COS-1 cells at an N/P ratio of 10 showed that transfection activity increased almost linearly with M(n). The highest transfection activity was obtained for SVs with the highest M(n) (73 kDa), which was over 7 times that for the SVs with the lowest M(n) (27 kDa), the nonfractionated original SV, or PEI standard. The transfection efficiency was more correlated with the amphiphilicity or hydrophobicity of the SVs and the surface potential and condensate density of the polyplexes than with the particle size.

Because currently available peritoneal dialysis catheters are not sufficiently biocompatible with the skin and subcutaneous tissue at the site of penetration, exit-site infection due to pericatheter pocket formation caused by epidermal downgrowth over a long period of time has increasingly become a problem. We developed a new, biocompatible, segmented polyurethane porous material and devised a novel skin-penetrating pad, the form and material of which we optimized for application in peritoneal dialysis catheters. For the extent of tissue ingrowth into this porous material to be examined, test materials with different pore diameters were inserted into hollow silicone tubes and implanted in the subcutaneous tissue of a goat. Four weeks later, the tubes were extracted, and, after the extent of granulation tissue ingrowth was measured, histopathological evaluation was made. Our novel skin-penetrating pad has three disklike layers of the segmented polyurethane material with different pore sizes, into the center of which a polyurethane catheter is inserted. These pads were implanted in the skin of a goat and clinically observed over a 2-year period, after which they were extracted and histopathologically analyzed. In accordance with actual clinical procedures, a commercial CAPD catheter equipped with our skin-penetrating pad was left indwelling in a goat for 4 months, and the performance of the pad was evaluated after repeated periodic infusion and drainage of the dialysate in and out of the abdominal cavity. There was no inflammation of the ingrown tissue in the pores of the segmented polyurethane material as well as the surrounding tissue, which indicated favorable tissue biocompatibility. The extent of tissue ingrowth was greater as the pore size of the material was larger, and the tissue tended to be mature, mainly consisting of collagenous fibers. The skin-penetrating pad using the porous material, of which tissue ingrowth was thus optimized, tightly adhered to the goat skin throughout the 2-year experimental period without any special wound care such as cleansing or disinfection. The performance of the skin-penetrating pad was similarly favorable when attached to a commercial continuous ambulatory peritoneal dialysis catheter. The newly developed segmented polyurethane porous material had excellent tissue biocompatibility and tissue ingrowth. The skin-penetrating pad devised by using this porous material did not cause epidermal downgrowth, suggesting that it may be effective for the prevention of exit-site infection.

Our group is currently developing a pneumatic ventricular assist device (PVAD). In general, the major causes of hemolysis in a pulsatile VAD are cavitation, and Reynolds shear stress (RSS) in the mechanical heart valve (MHV). In a previous study, we investigated MHV cavitation. To select the optimal bileaflet valve for our PVAD, in the current study, we investigated RSS and viscous shear stress (VSS) downstream of three different types of commercial bileaflet valves by means of 2D particle image velocimetry (PIV). To carry out flow visualization inside the blood pump and near the valve, we designed a model pump with the same configuration as that of our PVAD. Three types of bileaflet valves (i.e., the ATS valve, the St. Jude valve, and the Sorin Bicarbon valve) were mounted at the aortic position of the model pump, and flow was visualized according to the PIV method. The maximum flow velocity and RSS of the Sorin Bicarbon valve were lower than those of the other two bileaflet valves. The maximum VSS was only 1% of the maximum RSS. Thus, the effect of VSS on blood cell trauma was neglected. The Sorin Bicarbon valve exhibited relatively low levels of RSS, and was therefore considered to be the best valve for our PVAD among the three valves tested.

Our group is currently developing a pneumatic ventricular assist device (PVAD), and in previous studies, we reported the mechanical heart valve (MHV) cavitation intensity at the inlet valve in the PVAD only. In this study, we investigated the effect of the running conditions on the cavitation intensity both for the inlet and outlet valve in the PVAD using an acoustic signal. A 23-mm Medtronic Hall valve with an opening angle of 70 degrees was mounted in the inlet and outlet port of the PVAD after removing the sewing ring. A mini pressure sensor with high frequency was mounted 15 mm downstream from the inlet valve and downstream from the outlet valve. The pressure signal was band-pass filtered between 35 and 500 kHz using a digital filter. The band-pass filtered root mean squared (RMS) pressure was used as an index of the cavitation intensity. The RMS pressure of the inlet valve was higher than that of the outlet valve. Even if the outlet valve has a lower RMS pressure than the inlet valve, cavitation occurs. In case of a full-filling and full-ejection condition, the RMS pressure of the inlet valve was higher than that of the partial-filling and partial-ejection condition. This means that a partial-filling and partial-ejection condition is best to prevent the hemolysis caused by the cavitation phenomenon and the damage to the valve surface in our PVAD system.

An implantable, compact rotary blood pump has been newly developed using an axial flow turbo pump with hydrodynamic bearings. The rotating impeller, which is hydrodynamically levitated with the assistance of repulsive magnetic force, has no contact with the inner surface of the pump. To evaluate the hemodynamic performance and biocompatibility, the pump was installed into four calves for up to 90 days. The pump was installed in the left heart bypass fashion, and placed paracorporeally in the first two calves and in the thoracic cavity in the other two calves. All calves received anticoagulation and antiaggregation therapy during the study. Aortic pressure, heart rate and pump-operating parameters were continuously measured. Hematologic and biochemical tests to evaluate anemia, hepato-renal function and the extent of hemolysis were performed on schedule. Each calf was killed at the termination of the experiments, and pathological analysis for the biocompatibility of the pump system was performed, including the thrombi in the device, emboli in the systemic organs and signs of infection. The pump stably produced a flow of 5 l/min. Each calf was supported for 78, 50, 90 and 90 days, respectively, with no incidence of hemorrhage, organ failure or significant hemolysis. No thrombus formation or mechanical wearing was observed inside the pump. There was no evidence of heat injury around the pump. Device-related infections were observed, but the severity of infection was mild in the implant case compared to the paracorporeal case. The pump demonstrated acceptable hemodynamic performance and biocompatibility in the initial in vivo testing.

Our group has developed an electrohydraulic total artificial heart (EHTAH) with two diaphragm-type blood pumps. Cavitation in a mechanical heart valve (MHV) causes valve surface damage. The objective of this study was to investigate the possibility of estimating the MHV cavitation intensity using the slope of the driving pressure just before valve closure in this artificial heart. Twenty-five and twenty-three-millimeter Medtronic Hall valves were mounted at the inlet and outlet ports, respectively, of both pumps. The EHTAH was connected to the experimental endurance tester developed by our group, and tested under physiological pressure conditions. Cavitation pits could be seen on the inlet valve surface and on the outlet valve surface of the right and left blood pumps. The pits on the inlet valves were more severe than those on the outlet valves in both blood pumps, and the cavitation pits on the inlet valve of the left blood pump were more severe than those on the inlet valve of the right blood pump. The longer the pump running time, the more severe the cavitation pits on the valve surfaces. Cavitation pits were concentrated near the contact area with the valve stop. The major cause of these pits was the squeeze flow between the leaflet and valve stop.

A new method for long–term respiratory assistance using a right ventricular assist device (RVAD) system and a membrane oxygenator (MO) was designed and evaluated. An air–driven RVAD was implanted between the right atrium and the pulmonary artery in five goats and art MO was set on the outlet conduit of the RVAD 2 weeks postoperatively. Two types of MOs [the SciMed (Life Systems) silicone sheet MO and a prototype MO using a novel multilayered composite membrane] were used in this study. Respiratory support with this system under systemic heparinization could be conducted for 4–8 days without major problems accompanied with conventional extracorporeal membrane oxygenation (ECMO) such as surgical bleeding, destruction of the blood components, serum leakage, insufficient bypass flow, and fatal systemic thrombosis. This method opened the possibility for ECMO to be used as a bridge before lung or heart–lung transplantation.

The “washout effect” inside a blood pump may depend in part on the configuration of the blood pump, including its “port angle.” The port angle, which is primarily decided based on anatomical considerations, may also be important from the rheological viewpoint. In our department, a next-generation diaphragm-type blood pump is being developed. In this study, we examined the influence of the port angle on flow conditions inside our new blood pump. Acrylic resin mock pumps with three different port angles (0°, 30°, and 45°) were prepared for flow visualization. Mechanical monoleaflet valves were mounted on the inlet and outlet ports of the mock pumps. Flow conditions within the mock pumps were visualized by means of particle image velocimetry during a half stroke. As a result, a high flow velocity region was seen along the main circular flow from the inlet to the outlet port. This circular flow was almost uniform and parallel to the plane of the diaphragm-housing junction (DhJ) when viewed from the inlet and outlet sides. Moreover, the proportion of high flow velocity vectors in the plane in the vicinity of the DhJ decreased as the degree of the port angle increased. In conclusion, we found that the flow behavior in the plane in the vicinity of the DhJ changed with the port angle, and that a port angle of 0° may be suitable for our diaphragm-type blood pump in view of the washout effect.

Our group is currently developing a pneumatic ventricular assist device (PVAD). In this study, in order to select the optimal bileaflet valve for our PVAD, three kinds of bileaflet valve were installed and the flow was visualized downstream of the outlet valve using the particle image velocimetry (PIV) method. To carry out flow visualization inside the blood pump and near the valve, we designed a model pump that had the same configuration as our PVAD. The three bileaflet valves tested were a 21-mm ATS valve, a 21-mm St. Jude valve, and a 21-mm Sorin Bicarbon valve. The mechanical heart valves were mounted at the aortic position of the model pump and the flow was visualized by using the PIV method. The maximum flow velocity was measured at three distances (0, 10, and 30 mm) from the valve plane. The maximum flow velocity of the Sorin Bicarbon valve was less than that of the other two valves; however, it decreased slightly with increasing distance it the X-Y plane in all three valves. Although different bileaflet valves are very similar in design, the geometry of the leaflet is an important factor when selecting a mechanical heart valve for use in an artificial heart.

When patients are fitted with a totally implantable artificial heart (TAH), they need to be implanted with two additional devices: one for the transmission of energy and one for information. However, this is a cumbersome process that affects the quality of life of the recipient. Therefore, we investigated the use of electromagnetic coupling for the transmission of energy and information and the possibility of unifying two transcutaneous transformers for the simultaneous transmission of energy and information. While unifying the transformers, it is important to suppress the electromagnetic coupling between energy and information transmission. Therefore, we ensured that the electromagnetic fields generated from the transformer windings for the transmissions of information and energy intersected perpendicularly. If the fields are perpendicular, the electromagnetic coupling between the energy and information transmissions will be suppressed significantly. The characteristics of the simultaneous transmission of information and energy using the unified transcutaneous transformer, developed experimentally, were evaluated by changing the number of windings used for the transmission of information. The electromagnetic coupling between the energy and information transmissions was suppressed by determining the direction of the magnetic field. Moreover, the optimum number of transformer windings required for the simultaneous transmission of energy and information was determined. We concluded that the externally coupled transcutaneous transformer unified for the simultaneous transmission of energy and information performed with good transmission characteristics.

Transcutaneous energy transmission (TET) that uses electromagnetic induction between the external and internal coils of a transformer is the most promising method to supply driving energy to a totally implantable artificial heart without invasion. Induction-heating (IH) cookers generate magnetic flux, and if a cooker is operated near a transcutaneous transformer, the magnetic flux generated will link with the external and internal coils of the transcutaneous transformer. This will affect the performance of the TET and the artificial heart system. Hence, it is necessary to improve the magnetic field immunity of the TET system. During operation of the system, if the transcutaneous transformer is in close proximity to an IH cooker, the electric power generated by the cooker and coupled to the transformer can drive the artificial heart system. To prevent this coupling, the external coil was shielded with a conductive shield that had a slit in it. This reduces the coupling between the transformer and the magnetic field generated by the induction cooker. However, the temperature of the shield increased due to heating by eddy currents. The temperature of the shield can be reduced by separating the IH cooker and the shield.

To investigate the characteristics of cavitation intensity, we performed a synchronized analysis of the visual images of cavitation and the pressure signals using a pulsatile device. The pulsatile device employed was a pneumatic ventricular assist device (PVAD) that is currently being developed by our group. A 23-mm Medtronic Hall valve (M-H valve) and a 23-mm Sorin Bicarbon bileaflet valve (S-B valve) were mounted in the inlet port of the PVAD after the sewing ring had been removed. A function generator provided a square signal, which was used as the trigger signal, via Electrocardiogram R wave (ECG-R) mode, of the control — drive console for circulatory support. The square signal was also used, after a suitable delay, to synchronize operation of a pressure sensor and a high-speed video camera. The data were stored using a digital oscilloscope at a 1-MHz sampling rate, and then the pressure signal was band-pass filtered between 35 and 200 kHz using a digital filter. The valve-closing velocity, visual cavitation time, and root mean square (RMS) pressure of the M-H valve were greater than those of the S-B valve. Both the visual cavitation time and RMS pressure represent the cavitation intensity, and this is a very important factor when estimating mechanical heart valve cavitation intensity in an artificial heart.

Cardiopulmonary bypass (CPB) with hemodilution has been proposed as a useful method for many types of cardiovascular surgery. Although the harmful effects of severe hemodilution need to be prevented, blood transfusion should be avoided whenever possible. Therefore, we have been developing a new CPB technique using liposome-encapsulated hemoglobin (LEH). The purpose of this study was to evaluate the combined therapy of diluted CPB and LEH focusing on the influence of LEH on oxygen metabolism. Male kid goats (n = 8) were divided into two groups: the LEH and control groups. CPB was maintained at between 36 degrees and 37 degrees C. There was no significant difference in hemoglobin concentrations (6.3 +/- 1.5 g/dl in the LEH group and 6.2 +/- 1.3 g/dl in the control group) after initiation of CPB between the two groups. Thus, there was no distinction in oxygen deliveries between the two groups (11.0 +/- 2.0 ml/kg/min in the LEH group and 11.0 +/- 2.3 ml/kg/min in the control group). Oxygen consumption in the LEH group (2.5-2.7 ml/kg/min), however, had a tendency to be higher than that in the control group (2.4-2.5 ml/kg/min). In addition, the lactate/pyruvate ratio decreased earlier in the LEH group. These results suggest that the application of LEH in the pump-priming solution improves decreased aerobic oxygen metabolism during CPB without any serious adverse effects.

A series of guidelines for development and assessment of next-generation medical devices has been drafted under an interagency collaborative project by the Ministry of Health, Labor and Welfare and the Ministry of Economy, Trade and Industry. The working group for assessment guidelines of next-generation artificial hearts reviewed the trend in the prevalence of heart failure and examined the potential usefulness of such devices in Japan and in other countries as a fundamental part of the process of establishing appropriate guidelines. At present, more than 23 million people suffer from heart failure in developed countries, including Japan. Although Japan currently has the lowest mortality from heart failure among those countries, the number of patients is gradually increasing as our lifestyle becomes more Westernized; the associated medical expenses are rapidly growing. The number of heart transplantations, however, is limited due to the overwhelming shortage of donor hearts, not only in Japan but worldwide. Meanwhile, clinical studies and surveys have revealed that the major causes of death in patients undergoing long-term use of ventricular assist devices (VADs) were infection, thrombosis, and mechanical failure, all of which are typical of VADs. It is therefore of urgent and universal necessity to develop next-generation artificial hearts that have excellent durability to provide at least 2 years of event-free operation with a superior quality of life and that can be used for destination therapy to save patients with irreversible heart failure. It is also very important to ensure that an environment that facilitates the development, testing, and approval evaluation processes of next-generation artificial hearts be established as soon as possible.